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TITULO: Comparación de la eficacia hipolipemiante/aumentadora de 7 estatinas en pacientes con dislipidemia, enfermedades cardiovasculares o diabetes mellitus: revisión sistemática y metanálisis en red de 50 ensayos controlados aleatorios
TIPO DE ESTUDIO: METANALISIS ALTO SESGO
AÑO:2020
AUTOR:Xiaodan Zhang
RESULTADOS: Como resultado, se usaron para los análisis siete tratamientos de monoterapia con estatinas en 50 estudios (51956 participantes). Las estatinas incluían simvastatina (SIM), fluvastatina (FLU), atorvastatina (ATO), rosuvastatina (ROS), lovastatina (LOV), pravastatina (PRA) y pitavastatina (PIT). En términos de reducción de LDL-C, la rosuvastatina ocupó el primer lugar con un valor de superficie bajo clasificación acumulada (SUCRA) del 93,1%. La eficacia comparativa del tratamiento para la reducción de LDL-C fue ROS>ATO>PIT>SIM>PRA>FLU>LOV>PLA. Todos los demás resultados de clasificación y NMA se informaron en diagramas y tablas de clasificación de SUCRA.
https://pubmed.ncbi.nlm.nih.gov/32411300/

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Affiliations

¹ Department of Pharmacy, Base for Clinical Trial, Peking University First Hospital, Beijing 100034, China.

² Department of Pharmacy, China Pharmaceutical University, Nanjing 210000, China.

³ Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.

Free PMC article

Free PMC article

Affiliations

¹ Department of Pharmacy, Base for Clinical Trial, Peking University First Hospital, Beijing 100034, China.

² Department of Pharmacy, China Pharmaceutical University, Nanjing 210000, China.

³ Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.

Abstract

Objective: The drug efficacy may differ among different statins, and evidence from head-to-head comparisons is sparse and inconsistent. The study is aimed at comparing the lipid-lowering/increasing effects of 7 different statins in patients with dyslipidemia, cardiovascular diseases, or diabetes mellitus by conducting systematic review and network meta-analyses (NMA) of the lipid changes after certain statins' use.

Methods: In this study, we searched four electronic databases for randomized controlled trials (RCTs) published through February 25, 2020, comparing the lipid-lowering efficacy of no less than two of the included statins (or statin vs. placebo). Three reviewers independently extracted data in duplicate. Firstly, mixed treatment overall comparison analyses, in the form of frequentist NMAs, were conducted using STATA 15.0 software. Then, subgroup analyses were conducted according to different baseline diseases. At last, sensitivity analyses were conducted according to age and follow-up duration. The trial was registered with PROSPERO (number CRD42018108799).

Results: As a result, seven statin monotherapy treatments in 50 studies (51956 participants) were used for the analyses. The statins included simvastatin (SIM), fluvastatin (FLU), atorvastatin (ATO), rosuvastatin (ROS), lovastatin (LOV), pravastatin (PRA), and pitavastatin (PIT). In terms of LDL-C lowering, rosuvastatin ranked 1 st with a surface under cumulated ranking (SUCRA) value of 93.1%. The comparative treatment efficacy for LDL-C lowering was ROS>ATO>PIT>SIM>PRA>FLU>LOV>PLA. All of the other ranking and NMA results were reported in SUCRA plots and league tables.

Conclusions: According to the NMAs, it can be concluded that rosuvastatin ranked 1 st in LDL-C, ApoB-lowering efficacy and ApoA1-increasing efficacy. Lovastatin ranked 1 st in TC- and TG-lowering efficacy, and fluvastatin ranked 1 st in HDL-C-increasing efficacy. The results should be interpreted with caution due to some limitations in our review. However, they can provide references and evidence-based foundation for drug selection in both statin monotherapies and statin combination therapies.

Conflict of interest statement

The authors declare no conflict of interest.

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References

Kones R., Rumana U. Current treatment of dyslipidemia: a new paradigm for statin drug use and the need for additional therapies. Drugs. 2015;75(11):1187-1199. doi: 10.1007/s40265-015-0428-4. - DOI - PubMed

Vavlukis M., Vavlukis A. Adding ezetimibe to statin therapy: latest evidence and clinical implications. Drugs in Context. 2018;7 doi: 10.7573/dic.212534. - DOI - PMC - PubMed

Grundy S. M., Stone N. J., Bailey A. L., et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018;139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000625. - DOI - PMC - PubMed

Maxwell W. D., Ramsey L. B., Johnson S. G., et al. Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2017;37(9):1172-1190. doi: 10.1002/phar.1981. - DOI - PubMed

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national center for biotechnology information

# data[].attributes.attachment_link.title
Comparative Lipid-Lowering/Increasing Efficacy of 7 Statins in Patients with Dyslipidemia, Cardiovascular Diseases, or Diabetes Mellitus: Systematic Review and Network Meta-Analyses of 50 Randomized Controlled Trials - PubMed

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According to the NMAs, it can be concluded that rosuvastatin ranked 1 st in LDL-C, ApoB-lowering efficacy and ApoA1-increasing efficacy. Lovastatin ranked 1 st in TC- and TG-lowering efficacy, and fluvastatin ranked 1 st in HDL-C-increasing efficacy. The results should ...

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Título: Association of statin use and clinical outcomes in heart failure patients: a systematic review and meta-analysis/ Asociación del uso de estatinas y resultados clínicos en pacientes con insuficiencia cardíaca: una revisión sistemática y un meta-análisis

Autor, año: Dabrowa, A; 2019
Tipo de estudio: Revisión sistemática y meta-análisis.

Resultados:  En comparación con el uso sin estatinas, el uso de estatinas se asoció con un menor riesgo de mortalidad por todas las causas (HR 0,77, intervalo de confianza del 95% [IC], 0,72–0,83, P < 0,0001, I2 = 63%), mortalidad CV (HR 0,82, IC del 95%: 0,76– La mortalidad por todas las causas se redujo en el tratamiento con estatinas en IC con FE < 40% y ≥ 40% (HR: 0,77, 95% Cl: 0,68–0,86, P < 0,00001 y HR 0,75, IC 95%: 0,69–0,82, P < 0,00001, respectivamente). De manera similar, la mortalidad CV (HR 0,86, IC 95%: 0,79–0,93,P = 0,0003, y HR 0,83, IC 95%: 0,77–0,90, P < 0,00001, respectivamente), y las hospitalizaciones CV (FC 0,80 IC del 95%: 0,64–0,99, P = 0,04).

Conclusiones: Las estatinas pueden tener un efecto beneficioso en los resultados CV, independientemente de la etiología de la IC y el nivel de FEVI.

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Agata Bielecka-Dabrowa orcid.org/0000-0001-6666-3999 1,2 na1,

Ibadete Bytyçi 3,4 na1,

Stephan Von Haehling 5,

Stefan Anker 6,

Jacek Jozwiak 7,

Jacek Rysz 8,

Adrian V. Hernandez 9,10,

Gani Bajraktari 3,4,

Dimitri P. Mikhalidis 11 &

Maciej Banach 1,2

Lipids in Health and Disease 18, Article number: 188 (2019) Cite this article

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A Correction to this article was published on 20 September 2020

Abstract

Background

The role of statins in patients with heart failure (HF) of different levels of left ventricular ejection fraction (LVEF) remains unclear especially in the light of the absence of prospective data from randomized controlled trials (RCTs) in non-ischemic HF, and taking into account potential statins' prosarcopenic effects. We assessed the association of statin use with clinical outcomes in patients with HF.

Methods

We searched PubMed, EMBASE, Scopus, Google Scholar and Cochrane Central until August 2018 for RCTs and prospective cohorts comparing clinical outcomes with statin vs non-statin use in patients with HF at different LVEF levels. We followed the guidelines of the 2009 PRISMA statement for reporting and applied independent extraction by multiple observers. Meta-analyses of hazard ratios (HRs) of effects of statins on clinical outcomes used generic inverse variance method and random model effects. Clinical outcomes were all-cause mortality, cardiovascular (CV) mortality and CV hospitalization.

Results

Finally we included 17 studies (n = 88,100; 2 RCTs and 15 cohorts) comparing statin vs non-statin users (mean follow-up 36 months). Compared with non-statin use, statin use was associated with lower risk of all-cause mortality (HR 0.77, 95% confidence interval [CI], 0.72-0.83, P < 0.0001, I ² = 63%), CV mortality (HR 0.82, 95% CI: 0.76-0.88, P < 0.0001, I ² = 63%), and CV hospitalization (HR 0.78, 95% CI: 0.69-0.89, P = 0.0003, I ² = 36%). All-cause mortality was reduced on statin therapy in HF with both EF < 40% and ≥ 40% (HR: 0.77, 95% Cl: 0.68-0.86, P < 0.00001, and HR 0.75, 95% CI: 0.69-0.82, P < 0.00001, respectively). Similarly, CV mortality (HR 0.86, 95% CI: 0.79-0.93, P = 0.0003, and HR 0.83, 95% CI: 0.77-0.90, P < 0.00001, respectively), and CV hospitalizations (HR 0.80 95% CI: 0.64-0.99, P = 0.04 and HR 0.76 95% CI: 0.61-0.93, P  = 0.009, respectively) were reduced in these EF subgroups. Significant effects on all clinical outcomes were also found in cohort studies' analyses; the effect was also larger and significant for lipophilic than hydrophilic statins.

Conclusions

In conclusion, statins may have a beneficial effect on CV outcomes irrespective of HF etiology and LVEF level. Lipophilic statins seem to be much more favorable for patients with heart failure.

Background

The management of heart failure (HF) remains a significant challenge. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol have no recommendation regarding statin therapy in patients with New York Heart Association class II-IV HF [ 1]. Moreover, the recent European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of HF do not support the initiation of statin therapy in most patients with chronic HF and reduced left ventricular (LV) ejection fraction (HFrEF). However, in HF patients who already are under the treatment with statin therapy because of underlying coronary artery disease (CAD) and/or hyperlipidemia, continuation of this therapy should be considered [ 2].

The issue of whether or not to use statins in patients with HF remains controversial. More than half of patients with HF have LV mid-range EF (HFmrEF) and preserved LVEF (HFpEF) and mortality and morbidity of patients with these types of HF are also high [ 3, 4]. The pathophysiology of HFpEF is poorly understood, and the presence of a systemic pro-inflammatory state was also proposed [ 3, 4].

Statins (3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors), apart from their lipid-lowering properties and mevalonate inhibition, exert their actions through multiple additional mechanisms [ 5]. These pleiotropic effects of statins may potentially influence the course of HF. Therefore, the aim of this meta-analysis was to assess the effect of statins on clinical outcomes in patients with HF.

Methods

We followed the guidelines of the 2009 PRISMA statement [ 6] for reporting. Due to the study design (meta-analysis), neither Institutional Review Board (IRB) approval nor patient informed consent was needed.

Search strategy

We searched PubMed, EMBASE, Scopus, Google Scholar, the Cochrane Central Registry of Controlled Trials and ClinicalTrial.gov until August 2018, using the following keywords: 'heart failure' OR 'HF' OR 'left ventricular dysfunction' OR 'heart failure with preserved ejection fraction' OR 'HFpEF' 'heart failure with reduced ejection fraction' OR 'HFrEF' OR 'heart failure with mid-range ejection fraction' OR 'HFmrEF' AND 'statin' OR 'statins' OR 'lipid-lowering therapy' OR 'dyslipidemia therapy' OR 'simvastatin' OR 'atorvastatin' OR 'rosuvastatin' OR 'pitavastatin' OR 'pravastatin' OR 'lovastatin' AND 'all-cause mortality', 'cardiovascular mortality', 'hospitalizations' AND 'lipid' OR 'lipids' OR 'cholesterol' OR 'lipoprotein' OR 'lipoproteins'. The details on the search strategy can be found in the Additional file 1. Additional searches for potential trials included the references of review articles, and abstracts at ESC, AHA, ACC, European Society of Atherosclerosis (EAS) and National Lipid Association (NLA) meetings. The literature search was limited to articles published in English and to studies in humans.

Study selection

We included randomized controlled trials (RCTs) and prospective cohort studies with HF patients with LVEF < 40% and ≥ 40%, i.e. involving all types of patients as per the 2016 ESC HF guidelines classification: preserved, mid-range and reduced ejection fraction (HFpEF, HFmrEF and HFrEF) [ 7]. Because most of studies were performed before 2016, we divided them into HFrEF studies (patients with LV EF < 40%) and both HFpEF and HFmrEF studies (patients with EF ≥40%). Other inclusion criteria were: follow-up ≥12 months, CV events as the primary or secondary outcomes, a control arm, ≥50 participants, and patients of 18 years or older.

Exclusion criteria were: (1) retrospective studies (2), follow-up < 12 months, and (3) ongoing trials. Two reviewers (AB-D and IB) independently evaluated each article separately. No filters were applied. The remaining articles were obtained in full-text and assessed again by the same two researchers. Disagreements were resolved by discussion with a third party (MB).

Outcome variables

Primary clinical outcomes were: all-cause mortality, cardiovascular (CV) mortality and CV hospitalization. We used study definitions for all outcomes. We evaluated the longest available follow-up according to per protocol definitions.

Data extraction

We independently extracted: 1) first author's name, 2) year of publication, 3) name of study, 4) country where the study was performed, 5) number of centers, 6) study design, 7) number of participants per arm 8) HF and statin, 9) mean follow-up, 10) age and sex of study participants, 10) baseline level of triglycerides (TGs) and total cholesterol (TC), 11) diabetes mellitus (DM) and arterial hypertension (HTN), and, 12) data regarding CV events. Discrepancies in extractions were resolved by discussion with a third author (MB).

Risk of bias assessment

Assessment of risk of bias RCTs was evaluated by the same investigators for each study and was performed independently using the Cochrane risk of bias tool [ 8]. Evaluated items were: random sequence generation (selection bias), allocation sequence concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other potential sources of bias. The risk of bias in each study was judged to be "low", "high" or "unclear".

For the assessment of risk of bias in cohort studies we used the Newcastle-Ottawa Scale (NOS). Three domains were evaluated with the following items: a. Selection: 1) representativeness of the exposed cohort, 2) selection of the non-exposed cohort, 3) ascertainment of exposure and 4) demonstration that outcome of interest was not present at start of study; b. Comparability of exposed and non-exposed; and c. Exposure: 1) assessment of outcome, 2) was follow-up long enough for outcomes to occur?, and 3) adequacy of follow-up of cohorts. The risk of bias in each study was judged to be "good", "fair" or "poor" [ 9].

Statistical analysis

A two-tailed p < 0.05 was considered significant [ 10]. Study baseline characteristics were reported as median and range. Mean and standard deviation (SD) values were estimated using the method described by Hozoetet et al. [ 11]. Meta-analyses were performed with random effects models as we expected heterogeneity of effects among studies. The generic inverse variance method was used to combine log hazard ratios (log HR) and standard errors of the log HR (SElogHR). The log HRs were adjusted for a common set of confounders across studies, such as age and gender. Heterogeneity between studies was assessed using the Cochrane Q test and I ²statistic. As a guide, I ² < 25% indicated low, 25-50% moderate and > 50% high heterogeneity [ 12]. Publication bias was assessed using visual inspections of funnel plots and Egger's test. Subgroup analyses by EF level (< 40% vs ≥ 40%) and type of statin (lipophilic vs hydrophilic) were performed. Sensitivity analyses in cohort studies only were also done. Meta-analyses were conducted using RevMan 5.1 (The Cochrane Collaboration, Copenhagen, Denmark).

Results

Search results and trial flow

Of 578 articles initially identified, 281 studies were screened as potentially relevant. After excluding 222 studies, 59 full text articles were assessed. Among the remaining 59 trials checked for eligibility, 42 studies were excluded. After careful assessment, 17 articles met the inclusion criteria [ 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]: two RCTs (n = 9585) and 15 cohort studies ( n = 78,515) (Fig. 1).

Characteristics of included studies

Seventeen studies with a total of 88,100 patients, 42,400 treated with statins and 45,700 without statins, with a mean follow-up 36 months were finally included in the meta-analysis (Table 1). The mean age of patients was 67 ± 7.2 years, 68% male, 33% had diabetes, 71% had arterial hypertension and 54% were smokers (Table 2). Studies of Sola (2005) [ 14], Go (2006) [ 17], Roik (2008) [ 21], and Hong (2005) [ 16] evaluated lipophilic statins and studies of Kjekshus [ 18] (2007), Tavazzi (2008) [ 22] hydrophilic statins.

Table 1 Main characteristics of studies included in the study

Table 2 Main characteristics of patients enrolled among trials included in the meta-analysis

Clinical outcomes

Follow-up ranged from 12 to 40 months, with a mean of 36 months. Compared with non-statin users, statin users showed a lower risk of all-cause mortality (HR 0.77, 95% confidence interval [CI], 0.72-0.83, P < 0.0001, I ² = 63%, Fig. 2), CV mortality (HR 0.82, 95% Cl: 0.76-0.88, P < 0.000, I ² = 63%) and CV hospitalization (HR 0.78, 95% Cl: 0.69-0.89, P = 0.0003, I ² = 36%, Fig. 3 a and b).

Association of statin versus non-statin use with a) CV mortality, and b) CV hospitalizations

Subgroup analyses

In comparison to non-statin users, all-cause mortality was reduced in statin users in both EF < 40%and EF ≥40% groups (HR 0.77, 95% Cl: 0.68-0.86, p < 0.00001, and HR0.75, 95% Cl: 0.69-0.82, p < 0.00001, respectively, Fig. 4). CV mortality was also reduced in both EF groups using statins (HR 0.86, 95% Cl: 0.79-0.93, p = 0.0003, and HR 0.83, 95% Cl: 0.77-0.90, respectively, Fig. 5) with no differences between EF subgroups. Similar reduced were observed for CV hospitalizations - they were reduced in statin users in both EF groups (HR 0.80 95CI: 0.64-0.99, p = 0.04, and HR 0.76 95% CI: 0.61-0.93, p = 0.009, respectively, Fig. 6). Statin effects on all primary outcomes were confirmed when only perspective cohort studies were analyzed (after withdrawal of 2 RCTs) (Additional file 1: Figures. S1 to S6).

Effect on all-cause mortality was higher for lipophilic compared to hydrophilic statins (HR 0.59, 95%Cl: 0.37-0.93, p = 0.02 and HR 0.97, 95%Cl: 0.88-1.07, p = 0.60, respectively, Fig. 7). Significant decreases of cardiovascular outcomes were also observed only with lipophilic statins- CV mortality (HR 0.79, 95%Cl: 0.74-0.88, P ≤ 0.00001 vs HR 0.94, 95% Cl: 0.85-1.05, P = 0.28, Fig. 8) and CV hospitalizations (HR 0.60, 95%Cl: 0.45-0.86, P = 0.003 vs HR 0.78, 95% Cl: 0.50-1.22, P = 0.28, Fig. 9).

Risk of bias assessment.

The two included RCTs had low risk of bias (Additional file 1: Table S1). Many of the cohorts have good quality, about 20% of them that have fair quality (Additional file 1: Table S2).

Discussion

This systematic review evaluated large cohort of HF patients from studies comparing the effect of statin therapy with non-statin therapy on clinical outcomes. Statin treatment decreased all-cause mortality, CV mortality and CV hospitalization in HF with either LVEF ≥40% or LVEF < 40%. Effects of statin use were similar in both EF groups, and also after excluding trials with randomization. Finally, lipophilic (e.g. atorvastatin) and no hydrophilic statins (e.g. rosuvastatin or pravastatin) showed significant reductions in clinical outcomes.

Statins are able to decrease vascular and myocardial oxidative stress [ 30, 31] and possess anti-inflammatory properties [ 32, 33]. A lot of available studies have shown that they limit signal transmission from membrane receptors and slow down pathologic heart and vessels remodeling, inhibit the action of angiotensin II, and process of apoptosis [ 31]. Statins might also change myocardial action potential plateau by modulation of Kv1.5 and Kv4.3 channels activity and inhibition of sympathetic nerve activity and in the consequence suppress arrhythmogenesis [ 34]. Those beneficial effects of statin therapy might be negated by increases in collagen turnover markers as well as a reduction in plasma coenzyme Q10 (CoQ10) levels in chronic heart failure (CHF) patients [ 35, 36, 37].

There has been a large discussion on the role of lipid-lowering therapy in HF patients. Available knowledge has indicated that statins might be potentially harmful in HF due to decreased endotoxin defense, diminishing thereby the potentially beneficial pleiotropic effects. There is some suggestive evidence that statins might reduce muscle strength and alter energy metabolism during aerobic exercise [ 38]. Based on our recent hypothesis this pro-sarcopenic effect of statins might be responsible of their limited efficacy in HF patients [ 38]. On the other hand, some available data indicate that statins may even have beneficial effects by preserving or even increasing lean mass and exercise performance [ 38]. Large trials with hydrophilic rosuvastatin did not indicate a significant role for statins in patients with chronic HF, although the drug did reduce the number of CV hospitalizations in the CORONA trial [ 39, 40]. Although the abovementioned RCTs using hydrophilic rosuvastatin showed no beneficial effect on all-cause mortality, other studies like Anker et al. [ 41] reported that patients with chronic HF in the Evaluation of Losastan In The Elderly-2 (ELITE 2) study who received statin therapy at baseline had lower mortality. The authors drew the conclusion that in chronic HF, treatment with statins was related to lower mortality, independent of cholesterol levels, disease etiology and clinical status [ 41, 42]. The results of our meta-analysis are in line with the above conclusions, as we also clearly showed significantly lower mortality in HF patients on statin therapy.

The significant decrease in CV hospitalization seen with rosuvastatin in the CORONA trial should not be overlooked [ 39, 40]. Based on the data of 5000 patients with ischemic HF, the authors concluded that the lack of statin benefits in the treatment of HF patients could have been associated with some specific patients' characteristics [ 40]. Some criticism was associeted to the fact that the study participants were too old (mean age: 73 years); moreover, a large majority was in advanced HF stages [ 40]. In another important trial - the Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (GISSI-HF), patients on statins were not included, which may have resulted in more patients with severe ischemia being excluded (individuals with ischemic HF represented only 40% of patients). Finally, patients receiving cardiac resynchronization therapy were either excluded or represented a small percentage of the studied population. It is important as there are some avaiable data, including a retrospective analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, suggesting that statin therapy might be associated with improved survival in HF patients receiving resynchronization therapy [ 43]. The GISSI-HF trial also had a relatively large number of patients who discontinued therapy for reasons other than adverse drug reactions (31%) compared with only 10% in the CORONA trial, raisingthe question of whether this might have impacted the final results of the study. The investigators of GISSI-HF also suggested that there were too few acute ischemic events in heart failure patients for a statin to show a benefit [ 39]. An alternative theory to explain the controversial results between real-life cohorts and the large RCTs was based on observation that in the CORONA trial the lowest N-terminal pro-B-type natriuretic peptide tertile did benefit from rosuvastatin therapy, with a significant reduction in the primary outcome. It has been suggested that in patients with less advanced HF, statin therapy might be benefitial in reduction of coronary events, whereas in severe HF, it is too late to for the potential benefits from statin therapy due to progressive loss of pump function [ 44].

The main finding from the meta-analysis of Preiss et al. [ 45] was a significant reduction in non-fatal MI and a modest (however still significant) reduction in first non-fatal HF hospitalizations [ 45]. The composite outcome of HF death and HF hospitalizations was also significantly reduced in the statin groups, but was driven exclusively by a reduction in HF hospitalizations. A noteworthy finding from the Preiss et al. study [ 45] concerns the mechanisms, by which statin therapy reduced the risk of HF hospitalizations. Interestingly, neither a reduced risk of non-fatal MI nor a decrease in LDL-C correlated with the risk of HF hospitalizations. These results raise the possibility that statins might have exerted beneficial effects on HF hospitalizations through their pleiotropic properties [ 45]. The results of our meta-analysis are consistent with the referred meta-analysis [ 45] and support a positive influence of the pleiotropic properties of statins on HF outcomes. What is worth emphasizing, recent evidence suggests that there is no class effect for statin use in the setting of HF, and we should expect different effects for hydrophilic and lipophylic statins [ 46].

It seems that one of the most important mechanisms of statins in this group of patients could be to rapidly affect signaling pathways in myocardial cell membranes and/or the autonomic nervous system, and in the consequence protecting them from life-threatening arrhythmias. The lipophilic statins (e.g. atorvastatin and simvastatin) become easily embedded in the cell membrane, having overlapping locations in the hydrocarbon core adjacent to the phospholipid head groups [ 47, 48, 49]. Evidence from a meta-analysis of RCTs by Lipinski et al. of statins in HF showed a significant benefit of hydrophilic atorvastatin on all-cause mortality, LVEF, and hospitalization due to HF, whereas similar effects were not observed in patients randomized to the hydrophilic rosuvastatin [ 50]. We have recently seen the same results for statin types as per our pro-sarcopenic hypothesis [ 38]. Our findings also support the findings by Liu et al. in patients with HF, which indicated a significant reduction in risk of all-cause mortality, CV mortality and hospitalization for worsening HF using lipophilic statins [ 50, 51]. Based on the available data it is known that lipophilic statins are to be much more susceptible to oxidative metabolism by the CYP450 system, and those metabolized by this system are more likely to produce muscle toxicity because of the risk of drug interactions with many drugs that inhibit CYP450 [ 38]. However based on the results of our study lipophilic statins revealed better outcomes in HF patients.

Recent ESC guidelines on HF have introduced a new phenotype based on LVEF, mid-range HF (HFmrEF) that falls between the classical HFrEF and HFpEF phenotypes [ 2, 7]. Therefore, statins might improve outcomes in these types of HF [ 53] through exerting beneficial effects on inflammation, LV hypertrophy, interstitial fibrosis, endothelial dysfunction and arterial stiffness, all of which contribute to the pathophysiology of HF with LVEF ≥40% [ 52, 54]. In the study of Alehagen et al. [ 55], 9140 patients in the prospective Swedish Heart Failure Registry with HF and EF ≥50% were divided into those treated with statins ( n = 3427) and untreated with statins (n = 5713). Statins were associated with better one-year survival (85% vs 80%; p < 0.001), reduced CV death and composite all-cause mortality or CV hospitalization [ 55]. In a meta-analysis, Fukuta et al. [ 56] assessing the effect of statin therapy on mortality in patients with HF with LVEF≥45% with the use of propensity score analysis, showed that investigated therapy was associated with reduced mortality, which suggests the potential mortality benefit of statins in HFpEF [ 56]. Another meta-analysis included a total of 11 eligible studies with 17,985 patients with HF and EF > 45% [ 6]. Statin use was associated with a 40% lower risk of mortality (RR 0.60, 0.49-0.74, p < 0.001). Finally, cumulative meta-analysis by Liu et al. showed an obvious trend of reduction in mortality with statins [ 57, 58]. The results of our analysis in patients with HF and LVEF ≥40% are consistent with the results of Fukuta et al. and Liu et al. [ 56, 57].

There are some obvious limitations associated with this systematic review. First, there was limited information available on patient characteristics such as compliance with statin therapy or statin dosage. Included studies did not have enough data to check the correlations with cholesterol level and other variables like body mass index (BMI). The solubility of statins was a variable that was also not available in most of the trials, despite the fact the authors of this analysis asked all investigators of included studies about this; therefore, analyses by solubility was performed only based on limited number of studies with that information and hydrophilic statin arm included only two RCT studies while the other included only observational studies [ 59, 60, 61]. Most studies included in our meta-analysis were performed before 2016 when there was no fixed LVEF cut-off points for HFpEF and HFmrEF; that is why we combined HFpEF and HFmrEF patients in one group of patients with LVEF ≥40%. The HFmrEF patients, as a new and distinct group, had many intermediate characteristics compared with HFrEF and HFpEF subjects.

Conclusions

Statins may have beneficial effect on main CV outcomes in HF patients irrespective of the different etiologies and EF levels. Lipophilic statins, and not hydrophilic statins might be favorable for patients with heart failure independently from their postulated prosarcopenic effects [ 38]. The present meta-analysis emphasizes the need for a new, well-design randomized study of the effect of statins, in particular lipophilic, in HF patients. There will also be a need for additional analyses assessing the impact of cholesterol levels, BMI, type and doses of statin, and body mass compartments on outcomes. This information could establish a target group of patients with HF who will benefit the most from statin therapy as well as the type and dose of statins that are optimal in these patients.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its supplementary information files.

Change history

20 September 2020

An amendment to this paper has been published and can be accessed via the original article.

Abbreviations

ACC/AHA:

American College of Cardiology/American Heart Association

BMI:

body mass index

CAD:

coronary artery disease

CHF:

chronic heart failure

CI:

confidence interval

CoQ10:

coenzyme Q10

CV:

cardiovascular

DM:

diabetes mellitus

EAS:

European Society of Atherosclerosis

HF:

heart failure

HFmrEF:

heart failure with mid-range left ventricular ejection fraction

HFpEF:

heart failure with preserved ejection fraction

HFrEF:

heart failure with reduced left ventricular ejection fraction

HR:

hazard ratio

HTN:

arterial hypertension

IRB:

Institutional Review Board

LDL:

low density cholesterol

LVEF:

left ventricular ejection fraction

MI:

myocardial infarction,

NLA:

National Lipid Association

RCTs:

randomized controlled trials

SD:

standard deviation

SElogHR:

standard errors of the log HR

TC:

total cholesterol

TGs:

triglycerides

References

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Author information

Author notes

Agata Bielecka-Dabrowa & Ibadete Bytyçi contributed equally to this paper

Affiliations

1. Department of Hypertension, Medical University of Lodz, Rzgowska, 281/289; 93-338, Łódź, Poland

Agata Bielecka-Dabrowa & Maciej Banach

2. Department of Cardiology and Congenital Diseases of Adults, Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland

Agata Bielecka-Dabrowa & Maciej Banach

3. Clinic of Cardiology, University Clinical Centre of Kosovo, Prishtina, Republic of Kosovo

Ibadete Bytyçi & Gani Bajraktari

4. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

Ibadete Bytyçi & Gani Bajraktari

5. Department of Cardiology and Pneumology, University Medical Center Gottingen (UMG), Gottingen, Germany

Stephan Von Haehling

6. Charité-Universitätsmedizin Berlin, Berlin, Germany

Stefan Anker

7. Department of Family Medicine and Public Health, Institute of Medicine, University of Opole, Opole, Poland

Jacek Jozwiak

8. Department of Nephrology, Hypertension and Family Medicine, Medical University of Lodz, Lodz, Poland

Jacek Rysz

9. Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut School of Pharmacy, Storrs, CT, USA

Adrian V. Hernandez

10. School of Medicine, Universidad Peruana de Ciencias Aplicadas (UPC), Lima, Peru

Adrian V. Hernandez

11. Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK

Dimitri P. Mikhalidis

Contributions

AB-D, SH, SA and MB are resposible for the concept of all manuscript. AB-D, IB, JJ independently evaluated each article separately. Disagreements were resolved by discussion with a third party (MB). IB, GB, JR performed statistical analysis. AB-D, IB, AH, MB, DM analyzed and interpreted data and were major contributor in writing the manuscript. All authors read, improved and approved the final manuscript.

Corresponding author

Correspondence to Maciej Banach.

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Competing interests

ABD, IB, JR, JJ, SvH, and AVH have no conflicts of interest to disclose; DPM has given talks and attended conferences sponsored by MSD, AstraZeneca and Libytec; SDA reports personal fees from Bayer, Boehringer Ingelheim, Vifor, Servier and Novartis, outside the submitted work; MB has served on the speakers bureau of Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Sanofi-Aventis, Servier and Valeant, and has served as a consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Lilly, MSD, Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant.

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Bielecka-Dabrowa, A., Bytyçi, I., Von Haehling, S. et al. Association of statin use and clinical outcomes in heart failure patients: a systematic review and meta-analysis. Lipids Health Dis 18, 188 (2019). https://doi.org/10.1186/s12944-019-1135-z
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DOI: https://doi.org/10.1186/s12944-019-1135-z

Keywords

Statins

Heart failure

Mortality

Hospitalization

Meta-analysis

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Association of statin use and clinical outcomes in heart failure patients: a systematic review and meta-analysis - Lipids in Health and Disease

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Background The role of statins in patients with heart failure (HF) of different levels of left ventricular ejection fraction (LVEF) remains unclear especially in the light of the absence of prospective data from randomized controlled trials (RCTs) in non-ischemic HF, and taking into account potential statins' prosarcopenic effects.

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TITULO: Inhibidores de PCSK9 para el tratamiento del hipercolesterolemia

TIPO: Opinión de expertos

AÑO: 2020

CONCLUSION: PCSK9-I es eficaz para reducir los eventos ateroscleróticos a través de su importante acción reductora de LDL-C de manera similar a las estatinas. Además, estos fármacos pueden considerarse seguros y bien tolerados. Sin embargo, persisten algunas controversias con respecto a su eficacia para reducir la mortalidad y la escasez de datos sobre los efectos pleiotrópicos y la seguridad a largo plazo de estos fármacos. Sin embargo, los estudios futuros se centrarán en comprender los efectos de los niveles muy bajos de colesterol en la salud.

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ABSTRACT
Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.

Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.

Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.

Article highlights

Dyslipidemia and LDL-C are well-known modifiable CV risk factors for acute coronary syndromes (ACS).

The discovery that PCSK9 interacts with LDL receptor constituted a further step forward in the comprehension of the pathophysiology of dyslipidemia and laid the groundwork for the concept that limiting PCSK9 action could be a successful strategy for the management of hypercholesterolemic patients.

The efficacy of evolocumab and alirocumab, two PCSK9-I, in reducing LDL-C has been confirmed in several phase III trials, except for patients affected by Homozygous Familial Hypercholesterolemia (Ho-FH) with receptor-negative mutations.

In clinical trials, they reduce LDL-C levels of about 60% without being influenced by the background lipid-lowering therapy.

Several pooled analyses, systematic reviews, and meta-analyses of phase II and III studies on these drugs have been performed. Overall, the rate of adverse events (AEs) leading to treatment discontinuation was similar in PCSK9-I groups and in control groups.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee has received honoraria from Sanofi. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.

# data[].attributes.attachment_link.description
ABSTRACT Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.

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https://pubmed.ncbi.nlm.nih.gov/29402522/
TÍTULO:

Ensayo clínico de fase III, multicéntrico, aleatorizado, doble ciego, con comparador activo para comparar la eficacia y la seguridad de la terapia combinada con ezetimiba y rosuvastatina frente a la monoterapia con rosuvastatina en pacientes con hipercolesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) aleatorizado y controlado Juicio

AÑO DE PUBLICACIÓN: 2018

TIPO DE ESTUDIO: ECA

RESULTADOS: La eficacia reductora del LDL-C de cada una de las combinaciones de ezetimiba/rosuvastatina fue superior a la de cada una de las dosis respectivas de rosuvastatina. El cambio porcentual medio en el nivel de LDL-C en todos los grupos de combinación de ezetimiba/rosuvastatina fue >50 %. El número de pacientes que alcanzaron los niveles objetivo de C-LDL en la semana 8 fue significativamente mayor en el grupo de ezetimiba/rosuvastatina (180 [92,3 %] de 195 pacientes) que en el grupo de monoterapia con rosuvastatina (155 [79. 9%] de 194 pacientes) (P < 0,001).

CONCLUSIONES :Las combinaciones de dosis fijas de ezetimiba/rosuvastatina mejoraron significativamente los perfiles de lípidos en pacientes con hipercolesterolemia en comparación con la monoterapia con rosuvastatina. Todos los grupos tratados con rosuvastatina y ezetimiba informaron una disminución en el nivel medio de LDL-C> 50%.

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A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial - PubMed

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Fixed-dose combinations of ezetimibe/rosuvastatin significantly improved lipid profiles in patients with hypercholesterolemia compared with rosuvastatin monotherapy. All groups treated with rosuvastatin and ezetimibe reported a decrease in mean LDL-C level >50%. The safety and tolerability of eze …

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TÍTULO: Seguridad y eficacia de ezetimiba: un metanálisis

TIPO DE ESTUDIO: Metaanálisis

AÑO: 2015

AUTOR: Savarese, G., De Ferrari, G. M., Rosano, G. M., & Perrone-Filardi, P.

RESULTADOS: Se incluyeron en el análisis 7 ensayos con 31 048 pacientes (mediana de seguimiento de 34,1 ± 26,3 meses; 70 % de mujeres; edad media de 61 ± 8 años). En comparación con la terapia de control, ezetimiba redujo significativamente el riesgo de infarto de miocardio en un 13,5 % (RR: 0,865, IC del 95 %: de 0,801 a 0,934, p<0,001) y el riesgo de cualquier accidente cerebrovascular en un 16,0 % (RR: 0,840, IC del 95 %: 0,744 a 0,949, p=0,005), sin ningún efecto sobre la mortalidad por todas las causas y CV (RR: 1,003, IC 95%: 0,954 a 1,055, p=0,908; RR: 0,958, IC 95%: 0,879 a 1,044, p= 0,330; respectivamente) y riesgo de cáncer nuevo (RR: 1,040, IC 95%: 0,965 a 1,120, p=0,303).

CONCLUSIONES: Ezetimibe reduce significativamente el riesgo de infarto de miocardio y accidente cerebrovascular sin ningún efecto sobre la mortalidad por todas las causas y CV y ​​el riesgo de cáncer.

https://pubmed.ncbi.nlm.nih.gov/26301648/

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Affiliations

¹ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.

² Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

³ Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

⁴ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. Electronic address: fpperron@unina.it.

Affiliations

¹ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.

² Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

³ Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

⁴ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. Electronic address: fpperron@unina.it.

Abstract

Background: The addition of ezetimibe to statin therapy has been widely demonstrated to significantly reduce low-density lipoprotein cholesterol levels. However, the efficacy of ezetimibe in reducing CV events and its safety has been less investigated. The aim of the current meta-analysis was to report efficacy and safety of ezetimibe from randomized clinical trials.

Methods: Randomized clinical trials with a follow-up of at least 24 weeks, enrolling more than 200 patients, comparing ezetimibe versus placebo or ezetimibe plus another hypolipidemic agent versus the same hypolipidemic drug alone and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of cancer were included in the analysis.

Results: 7 trials enrolling 31,048 patients (median follow-up 34.1 ± 26.3 months; 70% women; mean age 61 ± 8 years) were included in the analysis. Compared to control therapy, ezetimibe significantly reduced the risk of MI by 13.5% (RR: 0.865, 95% CI: 0.801 to 0.934, p<0.001) and the risk of any stroke by 16.0% (RR: 0.840, 95% CI: 0.744 to 0.949, p=0.005), without any effect on all-cause and CV mortality (RR: 1.003, 95% CI: 0.954 to 1.055, p=0.908; RR: 0.958, 95% CI: 0.879 to 1.044, p=0.330; respectively) and risk of new cancer (RR: 1.040, 95% CI: 0.965 to 1.120, p=0.303).

Conclusions: Ezetimibe significantly reduces the risk of MI and stroke without any effect on all-cause and CV mortality and risk of cancer.

Keywords: Cardiovascular events; Cholesterol; Ezetimibe; Mortality; Statins.

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1 Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. 2 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 3 Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

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TÍTULO: Eficacia y seguridad de rosuvastatina frente a atorvastatina en pacientes chinos de alto riesgo con hipercolesterolemia: un estudio aleatorizado, doble ciego, con control activo
AUTOR:Shuiping Zhao, Daoquan Peng. 2018
RESULTADOS: En total 414 pacientes (edad media: 59,5 ± 9,51 años, 59,4% mujeres, C-LDL medio: 4,242 ± 0,676 mmol/L (rosuvastatina 5 mg), 4,13 ± 0,682 mmol/L (rosuvastatina 10 mg) y 4,213 ± Se analizaron 0,662 mmol/L (atorvastatina 10 mg) En comparación con atorvastatina 10 mg, rosuvastatina 5 mg (-41,70 % vs. -38,67 %, p = 0,132) y rosuvastatina 10 mg mostraron una mayor reducción del C-LDL (-46,28 % vs. -38,67 %, p = 0,0002). Las tasas de consecución del objetivo de C-LDL con rosuvastatina 5 mg, rosuvastatina 10 mg y atorvastatina 10 mg fueron del 61,0 %, 79,1 % y 58,3 % en la fase aleatorizada. En la fase abierta , el objetivo de C-LDL se logró en >40 % con ambas dosis de rosuvastatina La tasa de ≥1 evento adverso fue similar con rosuvastatina 5 mg (12,4 %), 10 mg (11,7 %) y atorvastatina 10 mg (8,9 %).
CONCLUSION: Rosuvastatina 5 mg demostró no inferioridad y rosuvastatina 10 mg demostró superioridad a atorvastatina 10 mg para reducir el LDL-C en pacientes chinos de alto riesgo con dislipidemia, que se mantuvo durante la fase abierta.
https://pubmed.ncbi.nlm.nih.gov/28836458/

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Abstract

Objective: To evaluate and compare the efficacy and safety of rosuvastatin versus atorvastatin in a high-risk Chinese population with hypercholesterolemia.

Research design and methods: This 6 week, prospective, multicenter, double-blind, three-arm, parallel-group, active-controlled study randomized adult Chinese patients (low-density lipoprotein cholesterol [LDL-C] ≥ 130-<250 mg/dL statin-naive and ≥100-<160 mg/dL in statin treated) to receive rosuvastatin (5 mg or 10 mg) or atorvastatin 10 mg. Patients not achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL-C targets in the randomized phase were administered rosuvastatin 10 mg and 20 mg in the open-label phase.

Results: In total 414 patients (mean age: 59.5 ± 9.51 years, 59.4% females, mean LDL-C: 4.242 ± 0.676 mmol/L (rosuvastatin 5 mg), 4.13 ± 0.682 mmol/L (rosuvastatin 10 mg) and 4.213 ± 0.662 mmol/L (atorvastatin 10 mg) were analyzed. Compared with atorvastatin 10 mg, rosuvastatin 5 mg (-41.70% vs. -38.67%, p = .132) and rosuvastatin 10 mg showed greater LDL-C reduction (-46.28% vs. -38.67%, p = .0002). LDL-C target achievement rates with rosuvastatin 5 mg, rosuvastatin 10 mg and atorvastatin 10 mg were 61.0%, 79.1% and 58.3% in the randomized phase. In the open-label phase, LDL-C target achievement occurred in >40% with both doses of rosuvastatin. The rate of ≥1 adverse event was similar with rosuvastatin 5 mg (12.4%), 10 mg (11.7%) and atorvastatin 10 mg (8.9%).

Conclusion: Rosuvastatin 5 mg demonstrated non-inferiority and rosuvastatin 10 mg demonstrated superiority to atorvastatin 10 mg for lowering LDL-C in high-risk Chinese patients with dyslipidemia, which was maintained through the open-label phase.

Clinical trial registration: NCT00683618.

Keywords: Atorvastatin; coronary heart disease; hypercholesterolemia; low-density lipoprotein cholesterol; rosuvastatin.

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Título:

Eficacia y seguridad de alirocumab y evolocumab: revisión sistemática y metanálisis de ensayos controlados aleatorios

Año: 2019
Tipo: Metaanálisis de ECA
Resultados:
Se incluyeron 39 ECA con 66 478 pacientes, de los cuales 35 896 fueron tratados con inhibidores de la proproteína convertasa subtilisina-kexina tipo 9 (PCSK9) (14 639 con alirocumab y 21 257 con evolocumab) y 30 582 con controles. El tiempo medio de seguimiento ponderado entre los ensayos fue de 2,3 años con un tiempo de exposición de 150 617 años-paciente. En general, los efectos de la inhibición de PCSK9 sobre la muerte por todas las causas y la muerte cardiovascular no fueron estadísticamente significativos (p = 0,15 y p = 0,34, respectivamente). Los inhibidores de la proproteína convertasa subtilisina-kexina tipo 9 se asociaron con un menor riesgo de infarto de miocardio (1,49 frente a 1,93 por 100 pacientes-año; RR 0,80, IC del 95 %: 0,74-0,86; I2 = 0 %; P < 0,0001), accidente cerebrovascular isquémico (0,44 0,58 por 100 pacientes-año; RR 0,78, IC 95 % 0,67-0,89; I2 = 0 %; P = 0,0005) y revascularización coronaria (2,16 frente a 2,64 por 100 pacientes-año; RR 0,83, IC 95 % 0,78 -0,89; I2 = 0%; P < 0,0001), en comparación con el grupo control. El uso de estos inhibidores de PCSK9 no se asoció con un mayor riesgo de eventos adversos neurocognitivos (P = 0,91), elevaciones de las enzimas hepáticas (P = 0,34), rabdomiolisis (P = 0,58) o diabetes mellitus de nueva aparición (P = 0,97).
Conclusiones: La inhibición de la proproteína convertasa subtilisina-kexina tipo 9 con alirocumab o evolocumab se asoció con un menor riesgo de infarto de miocardio, accidente cerebrovascular y revascularización coronaria, con un perfil de seguridad favorable.
https://sci-hub.st/10.1093/eurheartj/ehz430

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Titulo: Eficacia y seguridad del tratamiento con lovastatina en niñas adolescentes con hipercolesterolemia familiar heterocigota

Tipo de Estudio: ECA
Año: 2005
Resultados: El tratamiento con lovastatina fue eficaz para reducir el colesterol de lipoproteínas de baja densidad en un 23 % a un 27 %, el colesterol total en un 17 % a un 22 % y la apo B en un 20 % a un 23 % en las semanas 4 y 24, respectivamente. Las diferencias entre los grupos de tratamiento no fueron estadísticamente significativas para los triglicéridos, el colesterol de lipoproteínas de muy baja densidad, el colesterol de lipoproteínas de alta densidad o la apo AI. La lovastatina fue generalmente segura y bien tolerada.
Conclusión: Lovastatina ofrece una opción de tratamiento eficaz y bien tolerada para mejorar los perfiles de lípidos en niñas adolescentes con hipercolesterolemia familiar.
https://pubmed.ncbi.nlm.nih.gov/16140708/

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Abstract

Objective: The present study was designed to evaluate the lipid-altering efficacy, safety, and tolerability of lovastatin treatment in adolescent girls with heterozygous familial hypercholesterolemia.

Methods: A total of 54 postmenarchal girls, aged 10 to 17 years, were enrolled in a 24-week, double-blind, randomized, placebo-controlled study. After a 4-week diet/placebo run-in period, patients were randomized to 1 of 2 groups: (1) treatment with diet plus lovastatin 20 mg/day for 4 weeks, followed by diet plus lovastatin 40 mg/day for 20 weeks, or (2) diet plus placebo for 24 weeks.

Results: Baseline values of lipids, lipoproteins, and apolipoproteins (apo) were comparable between treatment groups. Lovastatin treatment was efficacious at reducing low-density lipoprotein cholesterol by 23% to 27%, total cholesterol by 17% to 22%, and apo B by 20% to 23% at weeks 4 and 24, respectively. Between-treatment group differences were not statistically significant for triglycerides, very-low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or apo A-I. Lovastatin was generally safe and well tolerated. There were no clinically significant alterations in vital signs (blood pressure and pulse rate), anthropomorphic measurements (height, weight, and BMI), hormone levels (luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone sulfate, estradiol, and cortisol), menstrual cycle length, or tests of liver and muscle function.

Conclusions: Lovastatin offers an efficacious and well-tolerated treatment option for improving lipid profiles in adolescent girls with familial hypercholesterolemia.

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Ausina Gómez A, Gilsanz Peral A, Montero Brens C, Dalmau Serra J. Ausina Gómez A, et al. An Esp Pediatr. 1991 Nov;35(5):327-31. An Esp Pediatr. 1991. PMID: 1785747 Review. Spanish.

Update of the Brazilian Guideline for Familial Hypercholesterolemia - 2021.

Izar MCO, Giraldez VZR, Bertolami A, Santos Filho RDD, Lottenberg AM, Assad MHV, Saraiva JFK, Chacra APM, Martinez TLR, Bahia LR, Fonseca FAH, Faludi AA, Sposito AC, Chagas ACP, Jannes CE, Amaral CK, Araújo DB, Cintra DE, Coutinho EDR, Cesena F, Xavier HT, Mota ICP, Giuliano ICB, Faria Neto JR, Kato JT, Bertolami MC, Miname MH, Castelo MHCG, Lavrador MSF, Machado RM, Souza PG, Alves RJ, Machado VA, Salgado Filho W. Izar MCO, et al. Arq Bras Cardiol. 2021 Oct;117(4):782-844. doi: 10.36660/abc.20210788. Arq Bras Cardiol. 2021. PMID: 34709306 Free PMC article. English, Portuguese. No abstract available.

Cholesterol and Its Metabolites in Tumor Growth: Therapeutic Potential of Statins in Cancer Treatment.

Chimento A, Casaburi I, Avena P, Trotta F, De Luca A, Rago V, Pezzi V, Sirianni R. Chimento A, et al. Front Endocrinol (Lausanne). 2019 Jan 21;9:807. doi: 10.3389/fendo.2018.00807. eCollection 2018. Front Endocrinol (Lausanne). 2019. PMID: 30719023 Free PMC article. Review.

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anticholesteremic agents / adverse effects

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anticholesteremic agents / therapeutic use*

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hyperlipoproteinemia type ii / drug therapy*

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national center for biotechnology information

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Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia - PubMed

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Objective: The present study was designed to evaluate the lipid-altering efficacy, safety, and tolerability of lovastatin treatment in adolescent girls with heterozygous familial hypercholesterolemia. Methods: A total of 54 postmenarchal girls, aged 10 to 17 years, were enrolled in a 24-week, double-blind, randomized, placebo-controlled study.

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TITULO: Eficacia y seguridad de la rosuvastatina frente a la atorvastatina para reducir el colesterol LDL: un metanálisis de ensayos con poblaciones de Asia oriental

TIPO DE ESTUDIO:  Metaanalisis
AÑO:2020
AUTOR: Zhang, I.
RESULTADOS: En comparación con atorvastatina, los pacientes tratados con rosuvastatina tuvieron una reducción significativa en LDL-C: DMP = -7,15 mg/dl (95% intervalos de confianza [IC]: -10,71--3,60) mg/dl, p < 0,0001.
CONCLUSION: Hay una mayor eficacia de la rosuvastatina en comparación con la atorvastatina y la simvastatina en pacientes caucásicos, encontramos que la eficacia de la rosuvastatina fue superior a la de la atorvastatina en pacientes de Asia oriental con hipercolesterolemia.

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Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

² Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.

³ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. jiang.hong@zs-hospital.sh.cn.

⁴ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. ge.junbo2@zs-hospital.sh.cn.

Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

² Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.

³ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. jiang.hong@zs-hospital.sh.cn.

⁴ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. ge.junbo2@zs-hospital.sh.cn.

Abstract

Background: The VOYAGER meta-analysis reported on the low-density lipoprotein cholesterol (LDL-C)-lowering effect of commonly used statins in Caucasian subjects. As there is limited literature available on the efficacy of statins in Asian populations, the current meta-analysis compared the effects of rosuvastatin and atorvastatin on LDL-C levels in an East Asian population.

Methods: The MEDLINE, PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials comparing lipid-lowering effects of rosuvastatin and atorvastatin in an East Asian population. Data on the study design, participant characteristics, and outcomes were extracted. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences were calculated using the random-effects model.

Results: The meta-analysis comprised 16 randomized controlled trials with 5930 participants. Compared with atorvastatin, patients treated with rosuvastatin had a significant reduction in LDL-C: WMD = -7.15 mg/dl (95% confidence intervals [CI]: -10.71--3.60) mg/dl, p < 0.0001. Meta-regression analyses revealed no significant association between the superior benefits of rosuvastatin and other variables including age, sex, baseline LDL-C level, and follow-up duration. Additionally, the rosuvastatin group of patients, who were treated with half the dose of atorvastatin, achieved a significantly greater reduction in LDL-C levels (WMD = -3.57; 95% CI: -5.40--1.74 mg/dl, p < 0.001). Both rosuvastatin and atorvastatin were well tolerated, with similar incidences of adverse events.

Conclusion: Similar to the VOYAGER meta-analysis, which reported a greater efficacy of rosuvastatin in comparison with atorvastatin and simvastatin in Caucasian patients, we found that the efficacy of rosuvastatin was superior to atorvastatin in East Asian patients with hypercholesterolemia.

Keywords: Eastern Asia; Hypercholesterolemia; Low-density lipoprotein; Statins; Treatment efficacy.

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Strandberg TE, Feely J, Sigurdsson EL; DISCOVERY study group. Strandberg TE, et al. Clin Ther. 2004 Nov;26(11):1821-33. doi: 10.1016/j.clinthera.2004.11.015. Clin Ther. 2004. PMID: 15639694 Clinical Trial.

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Kumar B, Shah MAA, Kumar R, Kumar J, Memon A. Kumar B, et al. Cureus. 2019 Jun 14;11(6):e4898. doi: 10.7759/cureus.4898. Cureus. 2019. PMID: 31423377 Free PMC article.

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national center for biotechnology information

# data[].attributes.attachment_link.title
Efficacy and safety of rosuvastatin vs. atorvastatin in lowering LDL cholesterol : A meta-analysis of trials with East Asian populations - PubMed

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1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. 2 Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China. 3 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

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Resultados: Se incluyeron 181 ensayos controlados con placebo y de comparación activa que incluían a 256 827 personas. Hubo 83 ensayos controlados con placebo de dos brazos y los 98 restantes fueron ensayos con comparador activo de dos o múltiples brazos. Todas las estatinas redujeron los niveles séricos de LDL y colesterol total: las dosis más altas resultaron en mayores reducciones en las concentraciones de LDL y colesterol total antes del tratamiento. En términos absolutos, todas las estatinas redujeron significativamente los niveles de colesterol LDL en comparación con el tratamiento de control desde niveles basales promedio de aproximadamente 150 mg/dl, excepto fluvastatina en ≤20 mg/día y lovastatina en ≤10 mg/día. La atorvastatina, la rosuvastatina y la simvastatina fueron ampliamente equivalentes en términos de sus efectos reductores del colesterol LDL. Los efectos comparativos de dosis de las estatinas individuales no fueron diferentes entre aquellos con y sin enfermedad coronaria al inicio del estudio. Según los análisis de metarregresión, los efectos reductores del colesterol LDL de las estatinas individuales no se vieron afectados por las diferencias entre los ensayos en cuanto a la edad media inicial y la proporción de mujeres como participantes del ensayo. Las concentraciones de colesterol LDL previas al tratamiento tuvieron un efecto estadísticamente significativo marginal sobre el cambio de colesterol LDL desde el inicio. Las diferencias medias desde el inicio en el colesterol HDL en comparación con el tratamiento de control no fueron significativas para ninguna combinación de dosis de estatina. Los efectos reductores del colesterol LDL de las estatinas individuales no se vieron afectados por las diferencias entre los ensayos en cuanto a la edad media inicial y la proporción de mujeres como participantes del ensayo. Las concentraciones de colesterol LDL previas al tratamiento tuvieron un efecto estadísticamente significativo marginal sobre el cambio de colesterol LDL desde el inicio. Las diferencias medias desde el inicio en el colesterol HDL en comparación con el tratamiento de control no fueron significativas para ninguna combinación de dosis de estatina. Los efectos reductores del colesterol LDL de las estatinas individuales no se vieron afectados por las diferencias entre los ensayos en cuanto a la edad media inicial y la proporción de mujeres como participantes del ensayo. Las concentraciones de colesterol LDL previas al tratamiento tuvieron un efecto estadísticamente significativo marginal sobre el cambio de colesterol LDL desde el inicio. Las diferencias medias desde el inicio en el colesterol HDL en comparación con el tratamiento de control no fueron significativas para ninguna combinación de dosis de estatina.

Conclusiones: Los hallazgos de esta revisión integral brindan evidencia de apoyo para la relación dosis-respuesta de las estatinas en la reducción del colesterol LDL y total. Los efectos reductores del colesterol LDL de algunas estatinas parecen menos pronunciados que los hallazgos de metanálisis previos, lo cual es particularmente el caso de las formulaciones de dosis altas de atorvastatina y rosuvastatina. La evidencia más consistente de una reducción combinada tanto en LDL como en colesterol total se logró con atorvastatina en >40 mg/día, rosuvastatina en >10 mg/día y simvastatina en >40 mg/día, que parecen equivalentes en términos de su LDL. y efectos reductores del colesterol total.

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Abstract

Aims: The extent to which individual statins vary in terms of their impact on serum lipid levels has been studied mainly on the basis of placebo-controlled trials. Our objective was to review and quantify the dose-comparative effects of different statins on serum lipid levels using both placebo- and active-comparator trials.

Methods: We systematically reviewed randomized trials evaluating different statins in participants with, or at risk of developing, cardiovascular disease. We performed random-effects Bayesian network meta-analyses to quantify the the relative potency of individual statins across all possible dose combinations using both direct and indirect evidence. Dose-comparative effects were determined by estimating the mean change from baseline in serum lipids as compared to control treatment. (systematic review registration: PROSPERO 2011:CRD42011001470).

Results: We included 181 placebo-controlled and active-comparator trials including 256,827 individuals. There were 83 two-armed placebo-controlled trials and the remaining 98 were two- or multi-armed active-comparator trials. All statins reduced serum LDL and total cholesterol levels: higher doses resulted in higher reductions in pretreatment LDL and total cholesterol concentrations. In absolute terms, all statins significantly reduced LDL cholesterol levels as compared to control treatment from average baseline levels of approximately 150 mg/dl, except for fluvastatin at ≤20 mg/day and lovastatin at ≤10 mg/day. Atorvastatin, rosuvastatin, and simvastatin were broadly equivalent in terms of their LDL cholesterol-lowering effects. Dose-comparative effects of indivudual statins were not different between those with and without coronary heart disease at baseline. According to meta-regression analyses, LDL cholesterol-lowering effects of individual statins were not impacted by differences across trials in terms of baseline mean age and proportion of women as trial participants. Pretreatment LDL cholesterol concentrations had a marginally statistically significant effect on LDL cholesterol change from baseline. Mean differences from baseline in HDL cholesterol as compared to control treatment was not significant for any statin-dose combination.

Conclusions: The findings of this comprehensive review provide supporting evidence for the dose-response relationship of statins in reducing LDL and total cholesterol. The LDL cholesterol-reducing effects of some statins appear less pronounced than the findings of previous meta-analyses, which is particularly the case for the high-dose formulations of atorvastatin and rosuvastatin. The most consistent evidence for a combined reduction in both LDL and total cholesterol was achieved with atorvastatin at >40 mg/day, rosuvastatin at >10 mg/day, and simvastatin at >40 mg/day, which appear equivalent in terms of their LDL and total cholesterol-reducing effects.

Keywords: Statins; cholesterol; indirect comparison; meta-analysis; mixed treatment comparison; systematic review.

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Statins, Muscle Disease and Mitochondria.

Ramachandran R, Wierzbicki AS. Ramachandran R, et al. J Clin Med. 2017 Jul 25;6(8):75. doi: 10.3390/jcm6080075. J Clin Med. 2017. PMID: 28757597 Free PMC article. Review.

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cardiovascular diseases / prevention & control*

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national center for biotechnology information

# data[].attributes.attachment_link.title
Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials - PubMed

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The findings of this comprehensive review provide supporting evidence for the dose-response relationship of statins in reducing LDL and total cholesterol. The LDL cholesterol-reducing effects of some statins appear less pronounced than the findings of previous meta-analyses, which is particularly th ...

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TITULO: Efectos comparativos de las estatinas en los eventos cerebrovasculares mayores: un metanálisis de tratamientos múltiples de ensayos controlados con placebo y de comparación activa

AUTORES: H. Naci , JJ Brugts , R. Fleurence

AÑO Y TIPO DE ESTUDIO: 2013, Metanálisis

RESULTADOS: En todas las poblaciones, las estatinas fueron significativamente más
efectivas que el control para reducir los eventos cerebrovasculares importantes [ (OR): 0,82, IC del 95%: 0,77, 0,87]. También fueron eficaces en pacientes con enfermedad cardiovascular establecida (OR: 0,83, IC del 95%: 0,75, 0,91) y en aquellos sin (OR: 0,80, IC del  95%: 0,71, 0,91).  Las estatinas produjeron reducciones significativas en el riesgo de accidentes cerebrovasculares no mortales (OR: 0,77; IC del 95%: 0,71; 0,85) pero no de accidentes  cerebrovasculares mortales (OR: 0,96; IC del 95%: 0,80; 1,15).

CONCLUSIÓN: Las estatinas reducen significativamente la incidencia de eventos cerebrovasculares mayores en comparación con el control. El análisis proporcionó evidencia para confirmar el efecto de clase de las estatinas en la prevención de eventos cerebrovasculares importantes.

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Abstract

Statins are important in the prevention of major cerebrovascular events. Whether, and the extent to which, individual statins differ in terms of their effect on these outcomes has not been studied. The aim of this review was to evaluate the comparative effects of individual statins on major cerebrovascular events. We systematically reviewed 61 trials including 187 038 individuals with, or at risk of developing, cardiovascular disease. We performed pair-wise and multiple-treatments meta-analyses for major cerebrovascular events, in addition to fatal and non-fatal strokes separately. Across all populations, statins were significantly more effective than control in reducing major cerebrovascular events [odds ratio (OR): 0.82, 95% CI: 0.77, 0.87], with no differences among individual statins. Statins were also effective in patients with established cardiovascular disease (OR: 0.83, 95% CI: 0.75, 0.91) and in those without (OR: 0.80, 95% CI: 0.71, 0.91). Considering individual statins, significant risk reductions were achieved with atorvastatin (OR: 0.74, 95% CI: 0.63, 0.85), pravastatin (OR: 0.86, 95% CI: 0.76, 0.97) and simvastatin (OR: 0.75, 95% CI: 0.62, 0.88) as compared with control on major cerebrovascular events across all populations. Statins led to significant reductions in the risk of non-fatal strokes (OR: 0.77, 95% CI: 0.71, 0.85) but not of fatal strokes (OR: 0.96, 95% CI: 0.80, 1.15). Findings were not sensitive to dose differentials of individual statins across the trials. No significant heterogeneity or inconsistency was detected. Statins significantly reduce the incidence of major cerebrovascular events as compared with control. Our analysis provided evidence to confirm the class effect of statins in preventing major cerebrovascular events.

Introduction

Stroke is among the leading causes of death and disability worldwide. Annually, ∼16 million incident strokes occur globally, causing an estimated total of 5.7 million deaths. About half of stroke survivors experience physical or cognitive impairment, impacting their physical function, social function and activities of daily living. In addition to its health impact, stroke is costly to individuals, their families and the wider society-with an economic burden amounting to an estimated $65.5 billion in the USA alone.,

Although the evidence from epidemiological studies remains inconclusive,, lipid management is an important milestone in the prevention of stroke. Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, effectively reduce the risk of strokes., Recent reviews and meta-analyses of randomized controlled trials have confirmed the considerable benefits of statins in the prevention of strokes among individuals with a history of established cardiovascular disease. Previous meta-analyses showed that statins effectively reduce the risk of stroke in the elderly,, among diabetics, and in individuals with no established cardiovascular disease. According to analyses of individual patient-level data from different trials, there appear to be a significant trend towards greater proportional reductions in stroke being associated with greater mean absolute low-density lipoprotein (LDL) cholesterol reductions. Indeed, in direct comparisons of different dosing regimens, high-dose statin therapy reduces the risk of stroke to a greater extent compared with standard doses.

An important question that remains unanswered in previous meta-analyses is whether individual statins are different in terms of their effect on the risk of stroke in individuals with or without a history of established cardiovascular disease. Earlier meta-analyses did not address this question in part because their focus was to establish the class effect of statins over control treatment on the basis of placebo-controlled trials. Incidence of cerebrovascular events was not an endpoint of interest in previous reviews that compared statins head-to-head in network meta-analyses., Only one review indirectly compared statins (atorvastatin, pravastatin and simvastatin) in terms of major cerebrovascular events but this study was based on a small number of placebo-controlled trials, without making use of the valuable information from active-comparator trials of statins.

The objective of our study was to systematically review the placebo-controlled and active-comparator trials of statins, and perform a multiple-treatments meta-analysis of individual statins in terms of their effect on major cerebrovascular events across all populations, in addition to secondary and primary prevention of cardiovascular disease separately.

Methods

Systematic review methods

We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials to identify studies published between 1 January 1985 and 1 January 2011. To comprehensively identify the active-comparator trials that were not included in previous meta-analyses of placebo-controlled trials, we used the search terms 'atorvastatin', 'fluvastatin', 'simvastatin', 'lovastatin', 'pravastatin', 'rosuvastatin', 'cholesterol', 'cardiovascular disease' and 'HMG-CoA reductase inhibitors/therapeutic use'. Two researchers (BT and HT) independently performed abstract, title and full-text screening. A third researcher approved study selection (HN).

We included open-label and double-blind randomized controlled trials comparing one statin with another statin at therapeutic dose or with control (placebo, diet or usual care) for adults with, or at risk of developing, cardiovascular disease. We included trials of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin if they had more than 50 participants per trial arm, lasted longer than 4 weeks and reported major cerebrovascular events. Both fixed dose and titration designs were included. Per pre-defined criteria, we excluded trials conducted in patients with renal insufficiency.

Trials that included at least 80% of participants without established cardiovascular disease or reported data separately on a sole primary prevention group were categorized as primary prevention. Trials that included more than 80% of participants with established cardiovascular disease or reported data separately on a sole secondary prevention group were categorized as secondary prevention. All remaining trials were categorized as having a mixed patient population.

The primary outcome was major cerebrovascular events. In line with previous meta-analyses, we defined the composite of major cerebrovascular events as fatal- and non-fatal strokes and transient ischaemic attacks. As secondary endpoints, we evaluated fatal- and non-fatal strokes separately. For the analysis on non-fatal strokes, transient ischaemic attacks were not included.

We used a structured form to extract data on trial (reference, publication year, design features such as blinding and dosing regimen) and patient population characteristics (age, baseline LDL cholesterol, cardiovascular risk factors), and outcome measures. One researcher extracted data (HN) and another independently checked for accuracy (BT). To ensure quality, we checked the consistency of extracted data with previously published meta-analyses.

Statistical analysis methods

We first qualitatively summarized included trials, describing the types of direct and indirect comparisons. For each pair-wise comparison between two statins, we calculated the odds ratio (OR) with a 95% confidence interval. First, we performed classical pair-wise meta-analyses to synthesize studies that compared the same two statins using the DerSimonian Laird (random-effects) method. The random-effects meta-analysis model assumed the observed estimates of treatment effect could vary across studies because of real differences in the treatment effect in each study and sampling variability (chance). Forest plots of the relative treatment effects from the individual trials and pair-wise meta-analyses were visually inspected to search for heterogeneity. We also statistically inspected heterogeneity using the I ² statistic, which was used to estimate the percentage of total variation among studies that can be considered to be due to heterogeneity. We used rough thresholds of 25, 50 and 75% to define low, moderate and high heterogeneity, and investigated moderate and high heterogeneity by inspecting trial-level variables that may explain observed differences.

To determine the comparative effects of statins, we conducted multiple-treatments meta-analyses. In these analyses, study-level relative treatment effects were combined using random-effects models within a Bayesian framework using Markov chain Monte Carlo methods., We used the model developed by Dias et al. for the National Institute of Health Clinical Excellence Decision Support Unit in the UK. This was based on modelling the outcomes in every treatment group of every study, and specifying the relations among the relative effects across studies making different comparisons.

To obtain a comprehensive estimate of the effect of statins in major cerebrovascular events, the multiple-treatments meta-analysis pooled all primary and secondary prevention trials in addition to trials with mixed patient populations. This analysis included all placebo-controlled and active-comparator trials eligible for inclusion in this review. We also performed separate analyses for the primary and secondary prevention populations, as categorized by the criteria mentioned earlier. For the base case analysis, we included trials at all doses. We separately evaluated the impact of dose differentials across the trials by excluding high-dose trials (80 mg/day for atorvastatin, fluvastatin, lovastatin, simvastatin and ≥40 mg/day for rosuvastatin) in a sensitivity analysis and evaluating the benefits of statins at comparable doses.

Results

We included 61 trials ( Figure 1), totalling 187 038 individuals. Overall, the average trial duration was 140 weeks (2.7 years). There were 51 two-armed placebo-controlled trials and the remaining 10 were two- or multi-armed active-comparator trials. There were 28 secondary prevention and 12 primary prevention trials. The remaining were in individuals who experienced acute coronary syndromes ( n = 8) and those with mixed populations ( n = 13). Of the 15 possible pair-wise comparisons between the six statins, only five were available for the major cerebrovascular events outcome. No trial directly compared all six statins to each other ( Figure 2). Characteristics of included trials are summarized in Supplementary Table S1.

Benefit of statin therapy vs. control: findings of the pair-wise meta-analyses

In the pair-wise meta-analysis of statin therapy vs. control across all populations, 171 731 individuals contributed information on 4533 events. Overall, statin therapy was associated with a reduction in the risk of major cerebrovascular events (OR: 0.82, 95% CI: 0.77, 0.87) when compared with control ( Figure 3). Among statins, atorvastatin, pravastatin and simvastatin were associated with a significant reduction in major cerebrovascular events compared with the control, while fluvastatin, lovastatin and rosuvastatin were not.

In the secondary prevention population, statin therapy was associated with a significant reduction in major cerebrovascular events (OR: 0.83, 95% CI: 0.75, 0.91) when compared with control ( Figure 3). Only atorvastatin resulted in significantly fewer events as compared with control in this population.

In the primary prevention population, statin therapy was associated with a significant reduction in major cerebrovascular events (OR: 0.80, 95% CI: 0.71, 0.91) ( Figure 3). In this population, only atorvastatin and rosuvastatin had sufficient evidence for a significant benefit on major cerebrovascular events, while fluvastatin, lovastatin, pravastatin did not. Simvastatin did not have any trials in primary prevention.

Overall, statistical heterogeneity in pair-wise comparisons of statin therapy vs. control in all-cause mortality was low in analyses of primary prevention ( I ²: 9.2%), secondary prevention ( I ²: 0.0%) and all populations together ( I ²: 0.0%). We observed high heterogeneity in pair-wise comparisons of rosuvastatin vs. control ( I ²: 81.3%), mainly as a result of the differences in patient populations between JUPITER (primary prevention), GISSI-HF and CORONA (heart failure).

Comparative benefits of statins on major cerebrovascular events: findings of the multiple-treatments meta-analyses

In addition to the trials included in the pair-wise comparisons of statin therapy vs. control, there were 11 direct head-to-head statin comparisons, providing information on 20 072 participants. In the multiple-treatments meta-analysis, 61 placebo-controlled and active-comparator trials provided information for major cerebrovascular events analysis. In total, 187 038 individuals were included in this analysis, which provided information on 4913 events.

In this analysis, there were no significant differences among statins in terms of major cerebrovascular events when all trials of primary prevention, secondary prevention and mixed patient populations were pooled ( Figure 5). There were also no statistical differences among individual statins in terms of reducing the risk of major cerebrovascular events in primary and secondary prevention of cardiovascular disease.

The findings of the multiple-treatments meta-analysis were not sensitive to dose differentials across trials ( Figure 4). When high-dose trials were excluded from the analysis, estimated comparative benefits of individuals were not materially different and there were no statistically meaningful differences between statins ( Figure 5).

Comparative benefits of statins on non-fatal and fatal strokes

Across all populations, statins were effective in reducing the incidence of non-fatal strokes (OR: 0.77, 95% CI: 0.71, 0.85) as compared with control treatment ( Figure 6). Only rosuvastatin (OR: 0.69, 95% CI: 0.44, 0.99) and simvastatin (OR: 0.69, 95% CI: 0.45, 0.96) had sufficient statistical power to show superiority over control treatment across all populations. Statins were not effective in reducing the risk of fatal strokes (OR: 0.96, 95% CI: 0.80, 1.15) although atorvastatin was independently superior to control treatment in preventing fatal strokes (OR: 0.49, 95% CI: 0.30, 0.80). There were no statistical differences between the individual statins.

Discussion

This multiple-treatments meta-analysis of 187 038 individuals provides evidence on the statistically and clinically meaningful benefits of statins in reducing the risk of major cerebrovascular events in both individuals with or without established cardiovascular disease. Overall, statins were associated with an 18% reduction in relative odds of major cerebrovascular events across all populations. Benefits of statins in reducing the relative odds of major cerebrovascular events by ∼18% were consistent across primary and secondary prevention populations. Across all populations, given the lack of statistical difference between different statins, our analysis provided evidence to confirm the class effect of statins in preventing major cerebrovascular events.

Our overall findings reinforce and extend the results of previous meta-analyses on statin therapy. Previous reviews elucidated the importance of lipid management with statins in the prevention of strokes and found consistent evidence that would warrant advocating statin use for the prevention of incident strokes., Clinical practice guidelines also recommend statin therapy in secondary prevention of stroke for patients with non-cardioembolic stroke., As SPARCL was the only trial that investigated the benefits of statins for the secondary prevention of strokes in individuals with a history of transient ischaemic attack or stroke, we did not explore the comparative benefits of statins in this population separately. Our base-case analysis in individuals with or without a history of established cardiovascular disease did not detect significant differences among individual statins. However, it remains a possibility that there are actual differences between individual statins which could not be detected in our analysis.

Indeed, although there were no statistical differences, our review suggested that the randomized trial evidence base for some statins was more robust and consistent than it was for others. This was particularly the case for atorvastatin and simvastatin. There was essentially no detectable heterogeneity across the trials of atorvastatin and simvastatin with consistent evidence for their benefits in the prevention of major cerebrovascular events. Unlike simvastatin that did not have evidence in individuals with no history of cardiovascular disease, atorvastatin was able to reach statistical significance in both primary and secondary prevention populations (as well as across all populations) as compared with control treatment. Although atorvastatin led to a significant reduction in the risk of fatal strokes, unexpectedly, it was not associated with significantly fewer non-fatal strokes as compared with control. Trial evidence for fluvastatin and lovastatin was inconsistent across individuals with and without cardiovascular disease and there was large uncertainty around the benefits of these agents in the prevention of strokes. Finally, there was substantial heterogeneity in the evidence base for rosuvastatin. Given the small number of trials, JUPITER appeared to drive the pooled estimates for rosuvastatin, specifically for individuals without a history of cardiovascular disease.

In addition to pair-wise meta-analyses that compared statins with control treatment, we also performed multiple-treatments meta-analysis, which is a relatively new method that differs from pair-wise meta-analysis by incorporating data from both direct (from head-to-head comparisons within trials) and indirect (from comparisons between trials) sources of evidence. Using this approach, we combined the results of placebo-controlled and active-comparator trials, allowing for more informed estimates of the relative effect of individual statins that have not been compared head-to-head in clinical trials. Our analysis differed from previous multiple-treatments meta-analyses in two important aspects. First, our review incorporated data from a comprehensive list of trials irrespective of placebo or active controls. Second, we provided comparative estimates separately for populations in primary and secondary prevention of cardiovascular disease.

Findings of this study should be interpreted in light of its limitations. First, as a literature-based meta-analysis, our analysis shares the limitations of the published evidence base. There were only a few head-to-head trials of statins that were prospectively designed to capture differences in clinical outcomes as primary endpoints. Second, as a multiple-treatments meta-analysis combining direct and indirect sources of evidence, it remains a possibility that potential imbalances in the occurrence of effect modifiers across the contrasts impacted the results, potentially confounding the comparative estimates between statins.

In spite of these limitations, this study has important methodological strengths. Our review is the largest meta-analysis on the benefits of statin therapy on cerebrovascular events to date. We included 11 direct head-to-head statin comparisons, providing information on additional 20 072 individuals that were not considered in prior meta-analyses on strokes. Our statistical models were appropriate for the evidence base as we did not detect any significant heterogeneity in the trial network. Although there was no considerable heterogeneity, we still used a random-effects model to take into account potential unexplained heterogeneity across the studies.

Acknowledgements

Authors thank Bernice Tsoi and Harleen Toor for their assistance with abstract and full-text review, data extraction and quality review of extracted data for accuracy. The authors did not receive any funding for this study.

Conflict of interest: Dr Fleurence is an employee of the Patient-Centered Outcomes Research Institute (PCORI). The views expressed in this article do not necessarily represent those of PCORI.

References

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# data[].attributes.attachment_link.title
Comparative effects of statins on major cerebrovascular events: a multiple-treatments meta-analysis of placebo-controlled and active-comparator trials

# data[].attributes.attachment_link.description
Statins are important in the prevention of major cerebrovascular events. Whether, and the extent to which, individual statins differ in terms of their effect on these outcomes has not been studied. The aim of this review was to evaluate the comparative effects of individual statins on major cerebrovascular events.

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TÍTULO: Diseño y resultados intermedios del ensayo de reducción de eventos de enfermedad arterial de las extremidades inferiores (LEADER)* de bezafibrato en hombres con enfermedad arterial de las extremidades inferiores [ISRCTN41194621].
TIPO DE ESTUDIO: ECA
AÑO: 2001
AUTOR: Meade, T. W
RESULTADOS: Se realizó un EC doble ciego con un tratamiento activo fue bezafibrato 400 mg/día en 1568 pacientes hombres, donde el bezafibrato redujo significativamente el CT un 8,0 %, c-LDL en un 9,0 %, aumentó c- HDL en un 11,0 % inicialmente, cayendo a aproximadamente un 6,0 % a los 3 años. Los TG se redujeron significativamente en un 23,0 %.

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Introduction

Accumulating epidemiological and clinical results [ 1, 2, 3] show strong associations of high plasma fibrinogen levels with both the onset and progression of arterial disease at all three main sites (ie heart, brain and lower extremities). High levels are also associated with venous thrombosis [ 4], and there is some evidence [ 5] that they impair the outcome of interventions such as percutaneous coronary angioplasty. Laboratory studies have indicated how fibrinogen affects several pathways that are known or suspected to be involved in thrombogenesis, principally the degree of blood viscosity, the amount of fibrin produced when the coagulation process is initiated, clot deformability, platelet aggregability and atherogenesis [ 6]. This evidence suggests that high fibrinogen levels are of causal significance. On the other hand, studies of polymorphisms associated with fibrinogen levels [ 7, 8] have been equivocal regarding the relationship of the former with clinical events of CHD.

Thus, the effects of lowering levels of fibrinogen need to be established through randomised trials so that the role of fibrinogen can be clarified, as well as identifying the clinical implications. This additional evidence would be necessary anyway, as it was for cholesterol, but particularly because of the view that raised fibrinogen levels are an acute-phase or chronic-phase response to the inflammatory nature of atheroma, and are therefore merely markers of underlying vessel wall disease and have no pathogenetic significance.

Apart from ancrod, which is used only in emergency situations and has to be given by infusion, there are at present no selective fibrinogen-lowering agents. However, most fibrates, including bezafibrate, lower fibrinogen levels as well as having the lipid-modifying properties for which they were originally introduced. Depending crucially on the extent to which it may or may not eventually be possible to apportion any clinical benefits between its fibrinogen-lowering and lipid-modifying effects, trials of bezafibrate may therefore offer opportunities for assessing the effects of lowering fibrinogen levels

The Lower Extremity Arterial Disease Event Reduction (LEADER) trial of bezafibrate is being carried out in men with LEAD. This condition was selected partly because raised levels of triglycerides may be contributory [ 9] and the greatest effect of bezafibrate is in lowering triglycerides, but also because of the high incidence of CHD events and strokes in patients with LEAD.

Recruitment to the trial started in 1992 and was almost completed in 1997, with a few further entrants in 1998. The present report describes the procedures and early stages of the trial, and the treatment effects of bezafibrate on fibrinogen, lipids and other variables during the first 3 years.

Method

Recruitment

LEADER is being carried out in men on the lists of 85 practices throughout the UK in the British Medical Research Council General Practice Research Framework and through nine hospital vascular clinics. In the Framework practices, patients with suspected or definite LEAD were identified either through diagnostic indices or through a listing of those taking any medications that may be used in treating LEAD and its complications. The research nurses then reviewed the notes of all of these men in order to exclude those who did not in fact have LEAD. Men with LEAD were ineligible for the following reasons: unstable angina, unless or until it was controlled; serum total cholesterol less than 3.5 mmol/l or more than 8.0 mmol/l (discussed in further detail below); significant renal or hepatic disease; a known hepatitis B or C or HIV positive status; malignant disease (other than non-melanoma skin cancer) within the past 5 years; they were taking or likely to need lipid-lowering agents or monamine oxidase inhibitors; they were unlikely to comply with trial treatment or procedures; they were in another trial; or at the discretion of the general practitioner for other reasons. There were no upper or lower age limits. Those who had had a myocardial infarct or stroke were eligible for the trial provided that their general management was stable, again at the discretion of the general practitioner.

Men were then sent an invitation to attend a screening visit for an explanation of the trial. At the following baseline medical examination at least 1 week later for those willing to proceed, eligibility for the trial was confirmed by a positive response to the Edinburgh Claudication Questionnaire administered by the research nurse. Occasional atypical responses, such as pain on walking in the thigh or buttock, but not in the calf, were assessed by the doctor, although LEAD was confirmed at a second visit for a medical examination by the doctor in all cases, typical or not. Blood was drawn to identify those with lipid levels that the general practitioner might wish to treat with non-fibrate agents, or those with evidence of renal impairment defined in these men (on expert advice) as serum creatinine of 150 μmol/l or more, because both of these situations increase the risk of muscle necrosis in those taking bezafibrate. All blood tests were performed twice before starting treatment: once at the baseline medical examination and again a day or so before the men started taking tablets.

Apart from fibrinogen (Clauss method), total cholesterol, LDL-cholesterol (calculated) and HDL-cholesterol (precipitation method) levels, triglycerides (non-fasting), creati-nine and alkaline phosphate were also measured, alkaline phosphatase providing a measure of compliance with treatment. LDL-cholesterol could not be measured directly, so there may be some imprecision in the results from men with high triglyceride levels (which were from non-fasting samples in order to ensure that as high a proportion as possible of those eligible would enter and remain in the trial).

Men completed questionnaires on symptoms, mostly the known possible side effects of bezafibrate, but also other symptoms such as impotence that are often attributed to treatment by older men, and on quality of life and use of health and related services. In some practices tests of cognitive function and of visual acuity were carried out because high fibrinogen levels may impair cerebral blood flow through its influence on viscosity [ 10] and contribute to age-related macular degeneration [ 11], either or both of which might therefore benefit from fibrinogen lowering.

Procedures in the hospital clinics were similar, apart from the initial identification of patients, which was through clinic attendance or diagnostic indices.

Trial treatment

Approximately 1 month after the medical examination, and provided that the creatinine result was within the specified limit, random assignment of trial treatment was initiated, balanced between active and placebo treatment within each practice or hospital clinic. Labels identifying containers with either active or placebo tablets were removed at the trial coordinating centre, labelled with the man's name and trial number, and sent to the practices and hospital clinics.

Active treatment was bezafibrate 400 mg/day (Bezalip-Mono; Boehringer Mannheim UK/Roche Products Ltd, Welwyn Garden City, UK) for men with creatinine levels below 135 μmol/l and was placebo controlled, with all tablets identical in appearance. Men with entry creatinine levels between 135 and 149 μmol/l took 400 mg on alternate days. In men taking daily treatment (i.e. those with cre-atinine less than 135 μmol/l at entry), this was changed to alternate day treatment if levels rose to 155 μmol/l unless or until levels rose to 170 μmol/l or more, in which case men were withdrawn from trial treatment. These changes were made for all men, whether they were on active or placebo treatment. (Raised creatinine levels generally fell to previous levels after withdrawal from trial treatment.)

The trial was approved by the 69 Local Research Ethics Committees that were responsible for the participating practices and hospitals. The question most frequently raised before final approval was given was whether men should routinely be taking statins, largely regardless of cholesterol levels, but particularly in those with high levels and those who had previously had myocardial infarcts. When the trial began, it was clear that expense would often preclude this, although participation in the trial would at least provide a 50% chance of receiving lipid-modifying treatment. Thus, after verbal and/or written exchanges with several committees, the entry criteria were accepted. As a matter of principle, no advice was given to the doctors responsible for the day-to-day management of recruited patients regarding treatments outside the requirements of the trial. However, the attention of general practitioners, whether in Framework practices or those responsible for patients recruited through the hospitals, was drawn to the results of the Scandinavian Simvastatin Survival Study [ 12], and decisions regarding treatment with a statin were left to their discretion. General practitioners and hospital doctors were also given pre-treatment cholesterol levels so that they could initiate statin treatment before trial treatment started if they wished to do so, and they were also notified regarding raised levels at follow-up visits. In 1999, the data monitoring and ethics committee of the trial recommended that reminder letters should be sent to doctors caring for all trial patients with total cholesterol levels above 7.0 mmol/l, which resulted in several men being started on statin treatment and their withdrawal from trial treatment.

Follow up and ascertainment of endpoints

Men were seen 1 month after treatment started and then at 3-month intervals to receive new supplies of tablets. Blood for repeat tests was taken at 1 and 3 months, and then at 6-month intervals. At the 1-month and 3-month visits men completed further questionnaires regarding symptoms and health service usage. At the annual visits, nurses asked about possible endpoint events (ie myocar-dial infarction and stroke). Details regarding such events were mostly provided by the Framework practices as they occurred, but were also sought at an annual check through the practice notes for each patient. Such details included events in those who had withdrawn from trial treatment, because these patients were nearly all known to the practices throughout the course of their routine clinical care. Few men moved from their addresses at the time of recruitment, and they will be followed up as described elsewhere [ 13]. In the hospitals, checks for endpoints were also made annually (as for men in the general practices). Hospital patients who withdrew from trial treatment were given change of address cards to be returned if they moved and were sent annual questionnaires about their progress. All deaths, whether in general practice or in hospital participants, were automatically notified by the National Health Service Central Registry.

All possible endpoint episodes notified were documented and assessed independently and without knowledge of trial treatment allocation [ 13]. Follow up for recording of events was continued in those who had withdrawn or been withdrawn from trial treatment. Initially, the occurrence of probable endpoints led to discontinuation of trial treatment. However, because patients who had had previous heart attacks or strokes were eligible for the trial and because of requests to continue treatment from some patients in whom treatment had been discontinued following an event, treatment was restarted after the acute episode was resolved and recurrent episodes were recorded. Thus, it will be possible to give results according to the numbers of men who experienced events and according to the number of events.

Participation in the trial was for a minimum of 3 years and sample size (indicated below) was based on participation for 4 years. Earlier trials in the Framework showed considerable advantages in a common finishing date, so those who entered the trial early on were asked to consider continuing until this date, and will therefore have been in the trial for up to 8 years. At 3 years, only 11 out of 340 (3.2%) men asked to continue declined to do so.

Cognitive function was re-assessed once, after 15 months, and visual acuity was assessed annually.

In just under 200 men, CRP was measured [ 14] at screening and trial entry (i.e. twice before treatment start), and then at 1, 3 and 6 months. Values are log-transformed and geometric means given.

Statistical analysis

Cardiovascular mortality and incidence in LEAD have been reported in several studies and estimates vary. It appears probable that approximately 13% of patients with LEAD die of major coronary events or strokes over a 4-year period [ 15]. It has been assumed that there are 1.5 nonfatal events for each fatal event, and therefore some 33% of trial patients were likely to experience an event. Increasing the duration of participation beyond 4 years for some men and including recurrences (see above) will increase the numbers of events. About two-thirds of the men were taking platelet-active agents (mostly aspirin), and this was expected to reduce the proportion of men having an event from 33% to approximately 28% in the placebo group. Allowing for a further attenuation of any treatment effect due to 15% of men withdrawing from treatment, a 30% reduction in endpoints suggests an event-rate of approximately 20% in those on active treatment compared with 28% in those in the placebo group. This effect could be detected in 1500 men at the 5% level of significance with 80% power. CHD events, fatal and nonfatal events separately, and stroke separately are secondary endpoints.

In assessing the effect of active treatment on biochemical variables, the change from baseline within each individual was calculated and differences in these changes between groups were tested by unpaired t tests.

Results

Recruitment

Recruitment is illustrated in Fig. . Of approximately 3200 men invited to attend the first or screening visit (precise numbers not recorded), either in the Framework or in the hospitals, 2505 (78%) did so. Of the 2505 men who attended 937 (37%) were excluded at screening, at the baseline medical examination or at trial entry for the reasons shown in Table . Most of the 277 men who were considered not to have LEAD came from general practice, where identification of patients was largely through prescribing information that was often not specific for LEAD (see above). The 1568 patients entered represent 86% of the 1816 who were eligible. Inadvertently, 10 men with entry cholesterol levels of more than 8.0 mmol/l were entered.

Table 1

Characteristics of participants

Table summarizes the characteristics of the men recruited. Their mean age was 69 years, ranging from 35 to 92 years. Just over 4% claimed never to have smoked. The current smokers had smoked for 49 years on average and the ex-smokers for 39 years. Approximately two-thirds were taking platelet-active agents, nearly all of which were in the form of aspirin. Over 30% had previously had myocardial infarcts or strokes or had stable angina, this figure being more than those for individual conditions because some men had a history of more than one of them. Table also shows entry values of fibrinogen and lipids.

Table 2

Symptomatic and biochemical effects of treatment

Table gives the responses from all the 15,279 on-treatment symptom questionnaires that were completed at follow-up visits up to March 2001 by men in the trial for at least 3 years. No symptoms were reported more frequently by those taking active treatment. Table shows reasons for withdrawing from trial treatment for all men (ie regardless of treatment group), because blindness on this aspect will be maintained until the main results are reported. The withdrawal rate of 37.7% at 3 years was higher than anticipated, but 80% of person-years at 3 years were spent on allocated treatment. The cumulative proportions of persons who withdrew over 3 years are shown in Fig. . One man had to withdraw because of severe muscle pain associated with a raised creatine kinase level. Nearly all those who withdrew because of incompatible medication had begun treatment with a statin. Withdrawals classified as 'patient decision' were for a variety of mostly vague and unspecified reasons.

Table 3

Fig. shows the effects of treatment on lipids graphically, and the percentage changes attributable to trial treatment on these and other variables are summarized in Table . Active treatment led to a sustained reduction in total cholesterol of approximately 8%. There was an unexplained downward 'drift' in LDL-cholesterol levels in the laboratory that analysed the samples, which is reflected in the placebo group (and in all of the hospital's routine clinical samples analysed in the laboratory concerned). Nevertheless, the effect of active treatment in raising HDL-cholesterol can be seen, although the difference declined from 10.6 to 6.2% over the 3 years. There may have been a small increase in absolute LDL-cholesterol levels as a result of the drift in HDL-cholesterol (because the calculated difference method has been used for LDL-cholesterol), but the sustained difference between the two groups represents a reduction of approximately 9% in LDL-cholesterol at 3 years attributable to active treatment. There was also a substantial reduction in triglyceride levels, as expected. Fig. shows that there was a sustained reduction of approximately 14% in plasma fibrinogen attributable to active treatment.

Table 5

Fig. shows the expected rise in creatinine due to bezafibrate administration, initially approximately 13% and falling to 10% at 3 years. Fig. shows a fall of about 33% in alkaline phosphate. Table shows the data for alkaline phosphatase according to the proportions of men with changes of the specified magnitudes, suggesting a high level of compliance in those who remained on trial treatment.

Table 6

Fig. shows effects on CRP and fibrinogen levels. There were 96 men on active treatment and 92 on placebo at each timepoint for both variables. There was no effect of active treatment on CRP levels, but the effect on fibrinogen is confirmed. (Omission of those with CRP values of over 20 mg/l at any stage - probably reflecting the further short-term effect of an inflammatory response [e.g. respiratory tract infection] - also resulted in no difference between the two groups.)

Discussion

Thus far, clinical endpoint results have been reported from two randomised trials of bezafibrate.

The Bezafibrate Infarction Prevention trial [ 16, 17] recruited 3090 male and female patients aged 45-74 years with an established history of CHD (78% with myocardial infarction), who had fasting total cholesterol levels between 180 and 250 mg/dl and triglyceride levels of less than 300 mg/dl. Follow-up was for 6.2 years on average (range 4.7-7.6 years). Overall, the 9.4% reduction in the combined primary endpoint of fatal or nonfatal myocardial infarction or sudden death was not statistically significant. In those whose triglyceride levels were 200 mg/dl or greater, the 39.5% reduction was significant ( P = 0.02), whereas there was no difference among those with lower levels. The net rise in HDL-cholesterol due to treatment was 14.4% (i.e. greater than in LEADER). The reduction of 25.2% in triglyceride levels in that study was similar to the reduction achieved in the LEADER trial, but the changes in cholesterol of 4.7%, LDL-cholesterol of 5.2% and fibrinogen of 10% were rather less than in LEADER.

The Bezafibrate Coronary Atherosclerosis Intervention Trial [ 18] was carried out in 92 survivors of myocardial infarction who were younger than 45 years with a mean serum cholesterol of at least 5.3 mmol/l and/or mean serum triglycerides of at least 1.6 mmol/l. The main purpose of that trial (which administered bezafibrate 200 mg three times a day) was to determine whether treatment could retard or prevent the progression of atherosclerotic lesions, as assessed using coronary angiography at baseline and then at 2, 3 and 5 years. This objective was achieved, and in addition three of the 47 patients receiving active treatment had coronary events as compared with 11 out of the 45 patients in the placebo group, a reduction of nearly 75% ( P = 0.019). Total cholesterol fell by 14%, LDL-cholesterol by 3.5% and triglycerides by 26.3%. HDL-cholesterol rose by 8.6%. Fibrinogen fell by 13.3%. Thus, the Bezafibrate Infarction Prevention trial and the Bezafibrate Coronary Atherosclerosis Intervention Trial suggest that bezafibrate may result in some reduction, of uncertain magnitude, in major events of CHD.

The Diabetes Atherosclerosis Intervention Study, which used micronized fenofibrate [ 19], recently reported lipid-modifying effects very similar to those found in the present study. In that study angiographic progression of coronary artery disease was reduced by active treatment, and there were 38 and 50 clinical endpoints among those on active and placebo treatment, respectively, although the difference was not significant. Two trials using gemfibrozil [ 20, 21], which has different properties from those of bezafibrate and fenofibrate, showed that it significantly reduces clinical endpoints.

Like the other fibrate trials, the LEADER trial was conducted primarily to test whether a fibrate reduces CHD and stroke by whatever mechanism(s). Assuming that bezafibrate does reduce clinical endpoints in the LEADER trial, a further question will be how far the benefit can be attributed to its fibrinogen-lowering or lipid-modifying effects, or both. Using Cox proportional hazards models, the independent contributions to the risk of CHD and stroke of changes in fibrinogen and, say, total cholesterol between recruitment and the various follow-up intervals will be estimated for all men and for those on active or placebo treatment. This approach is very similar to that used in the Veterans Affairs High-Density Lipoprotein Intervention Trial [ 22]. Analyses from that study showed that the effect of gemfibrozil treatment on HDL-cholesterol predicted a significant reduction in CHD, independent of changes in LDL-cholesterol and triglyceride levels. The possibility in the Bezafibrate Infarction Prevention trial [ 17] that bezafibrate was beneficial in those with high triglyceride levels provides an a priori hypothesis for analysing LEADER to determine whether there is an interaction between triglyceride values at entry and response to treatment, particularly because the main effect of bezafibrate is on triglycerides.

Trial participants in LEADER have come from general practices and hospital vascular clinics throughout the UK and a high proportion (some 86%) of those eligible have entered. Consequently, the main results are likely to have general applicability and the entry characteristics of the participants provide a useful profile of LEAD in the community. Nearly all men are or had been smokers, only 4% claiming never to have smoked. As expected, many had already developed clinically manifest arterial disease. Perhaps somewhat unexpectedly, entry values of fibrinogen and lipids were not grossly abnormal, entry fibrinogen and (non-fasting) triglyceride values being only moderately raised. The full reduction in fibrinogen levels in LEADER appeared to occur only after approximately 6 months on treatment (Fig. ).

Bezafibrate did not lead to any excess of the mainly gastrointestinal symptoms that are often associated with it, and other symptoms such as rashes or impotence did not differ between the groups. The proportion of patients who withdrew from randomised treatment was higher than was assumed in our estimation of the required sample size. However, extending the duration of participation for men recruited early on has to some extent offset the effect of this difference, and many withdrawals occurred after several years of participation in the trial. Thus, even at 3 years, some 80% of the person-years accrued in the trial were spent on randomly assigned treatment. The results on alkaline phosphatase indicate a high level of compliance in those continuing with treatment.

It has been suggested that fibrates may increase mortality from other conditions, including cancer [ 23], although this remains controversial. Much the greatest risk to the generally elderly men in the trial is from arterial disease, however, so that any possible increase in cancer incidence would need to be balanced against any reduction in CHD and stroke due to bezafibrate.

The extent to which the raised fibrinogen levels associated with arterial disease are due to the inflammatory characteristics of atheroma or inflammation and/or infection is debated. The contrast between the fibrinogen-lowering effect of bezafibrate and the absence of any effect on CRP is clear. CRP is a particularly sensitive index of inflammatory processes. Thus, it appears that the effect of bezafi-brate on fibrinogen is independent at any rate of this index of inflammation, suggesting that any benefit due to bezafi-brate on fibrinogen levels may not be mediated simply through a reduction in inflammatory stimuli. CRP levels in patients with LEAD are clearly raised, with the geometric mean being more than 3.5 mg/l in contrast to the median value of 0.8 mg/l in volunteer blood donors [ 24] and the geometric mean of 2.03 mg/l among 464 unselected men aged 64-75 years in the general population [ 25].

Further data on the effect of fibrates are needed for comparison with the larger body of evidence on statins and in view of recent reports that indicate that bezafibrate may raise homocysteine levels [ 26], and thus the risk of vascular events if homocysteine is eventually shown conclusively to contribute to these.

In conclusion, a high proportion (86%) of eligible patients with LEAD were recruited. Despite withdrawals from randomised treatment, 80% of person-years were spent on allocated treatment at 3 years. There were no differences between those on active and placebo treatment in anticipated side effects. As expected, active treatment led to lipid modifications that would be expected to be beneficial, particularly the lowering of triglyceride levels, and there is a strong a priori case for analysing the main clinical endpoint results to determine whether there may be an interaction between initial triglycerides level and any benefit conferred by bezafibrate. There has been a sustained reduction in plasma fibrinogen that would also be expected to be beneficial. There is, however, no clear effect of treatment on CRP. Thus, any benefit due to bezafibrate on fibrinogen may not be mediated simply through a reduction in inflammatory stimuli.

# data[].attributes.attachment_link.title
Design and intermediate results of the Lower Extremity Arterial Disease Event Reduction (LEADER)* trial of bezafibrate in men with lower extremity arterial disease [ISRCTN41194621]

# data[].attributes.attachment_link.description
Accumulating epidemiological and clinical results [ 1, 2, 3] show strong associations of high plasma fibrinogen levels with both the onset and progression of arterial disease at all three main sites (ie heart, brain and lower extremities).

# data[].attributes.body
https://sci-hub.se/10.1016/J.AHJ.2018.12.007
TÍTULO: Efectividad y seguridad comparativas de las estatinas como clase y de estatinas específicas para la prevención primaria de la enfermedad cardiovascular: una revisión sistemática, metanálisis y metanálisis en red de ensayos aleatorios con 94 283 participantes.
AUTOR: Henock G, et al.; 2018
TIPO DE ESTUDIO: Revisión sistemática, metanálisis y metanálisis en red de ensayos aleatorios.

RESULTADOS: Las estatinas como clase mostraron reducciones de riesgo estadísticamente significativas en el IM no mortal (cociente de riesgos [RR] 0,62, IC del 95%: 0,53-0,72), la mortalidad por ECV (RR 0,80, 0,71-0. 91), la mortalidad por todas las causas (RR 0,89, 0,85-0,93), el ictus no mortal (RR 0,83, 0,75-0,92), la angina inestable (RR 0,75, 0,63-0,91) y los eventos cardiovasculares mayores compuestos (RR 0,74, 0,67 0,81). Ademas, aumentaron de forma estadísticamente significativa los riesgos relativos y absolutos de miopatía (RR 1,08, 1,01-1,15; diferencia de riesgo [DR] 13, 2-24 por 10.000 personas-año); disfunción renal (RR 1,12, 1,00-1,26; DR 16, 0-36 por 10.000 personas-año); y disfunción hepática (RR 1,16, 1,02-1,31; DR 8, 1 16 por 10.000 personas-año). Los metaanálisis de red a nivel de fármacos mostraron que la atorvastatina y la rosuvastatina fueron las más eficaces para reducir los eventos de ECV, mientras que la atorvastatina parecía mejor perfil de seguridad.

CONCLUSIÓN: Todas las estatinas mostraron una reducción estadísticamente significativa del riesgo de ECV y de mortalidad por todas las causas en poblaciones de prevención primaria de prevención primaria, mientras que aumentaron el riesgo de algunos daños. Sin embargo, el perfil de beneficios y daños difiere según el tipo de estatina.

# data[].attributes.body
https://academic.oup.com/qjmed/article/106/4/299/1519374
TITULO: Efectos comparativos de las estatinas en los eventos cerebrovasculares mayores: un metaanálisis de tratamientos múltiples de ensayos controlados con placebo y de comparación activa.

OBJETIVO: Evaluar los efectos comparativos de las estatinas individuales sobre los eventos cerebrovasculares importantes.

TIPO DE ESTUDIO: metaanálisis

AÑO: 2013

RESULTADOS: Las estatinas también fueron eficaces en pacientes con enfermedad cardiovascular establecida (OR: 0,83, IC del 95 %: 0,75, 0,91) y en los que no la tenían (OR: 0,80, IC del 95 %: 0,71, 0,91). Teniendo en cuenta las estatinas individuales, se lograron reducciones de riesgo significativas con atorvastatina (OR: 0,74, IC del 95 %: 0,63, 0,85), pravastatina (OR: 0,86, IC del 95 %: 0,76, 0,97) y simvastatina (OR: 0,75, IC del 95 %: 0,62, 0,88) en comparación con el control de eventos cerebrovasculares importantes en todas las poblaciones. Las estatinas condujeron a reducciones significativas en el riesgo de accidentes cerebrovasculares no mortales (OR: 0,77, IC del 95 %: 0,71, 0,85), pero no de accidentes cerebrovasculares mortales (OR: 0,96, IC del 95 %: 0,80, 1,15).

CONCLUSIONES: Las estatinas reducen significativamente la incidencia de eventos cerebrovasculares mayores en comparación con el control. Nuestro análisis proporcionó evidencia para confirmar el efecto de clase de las estatinas en la prevención de eventos cerebrovasculares importantes.

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Abstract

Statins are important in the prevention of major cerebrovascular events. Whether, and the extent to which, individual statins differ in terms of their effect on these outcomes has not been studied. The aim of this review was to evaluate the comparative effects of individual statins on major cerebrovascular events. We systematically reviewed 61 trials including 187 038 individuals with, or at risk of developing, cardiovascular disease. We performed pair-wise and multiple-treatments meta-analyses for major cerebrovascular events, in addition to fatal and non-fatal strokes separately. Across all populations, statins were significantly more effective than control in reducing major cerebrovascular events [odds ratio (OR): 0.82, 95% CI: 0.77, 0.87], with no differences among individual statins. Statins were also effective in patients with established cardiovascular disease (OR: 0.83, 95% CI: 0.75, 0.91) and in those without (OR: 0.80, 95% CI: 0.71, 0.91). Considering individual statins, significant risk reductions were achieved with atorvastatin (OR: 0.74, 95% CI: 0.63, 0.85), pravastatin (OR: 0.86, 95% CI: 0.76, 0.97) and simvastatin (OR: 0.75, 95% CI: 0.62, 0.88) as compared with control on major cerebrovascular events across all populations. Statins led to significant reductions in the risk of non-fatal strokes (OR: 0.77, 95% CI: 0.71, 0.85) but not of fatal strokes (OR: 0.96, 95% CI: 0.80, 1.15). Findings were not sensitive to dose differentials of individual statins across the trials. No significant heterogeneity or inconsistency was detected. Statins significantly reduce the incidence of major cerebrovascular events as compared with control. Our analysis provided evidence to confirm the class effect of statins in preventing major cerebrovascular events.

Introduction

Stroke is among the leading causes of death and disability worldwide. Annually, ∼16 million incident strokes occur globally, causing an estimated total of 5.7 million deaths. About half of stroke survivors experience physical or cognitive impairment, impacting their physical function, social function and activities of daily living. In addition to its health impact, stroke is costly to individuals, their families and the wider society-with an economic burden amounting to an estimated $65.5 billion in the USA alone.,

Although the evidence from epidemiological studies remains inconclusive,, lipid management is an important milestone in the prevention of stroke. Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, effectively reduce the risk of strokes., Recent reviews and meta-analyses of randomized controlled trials have confirmed the considerable benefits of statins in the prevention of strokes among individuals with a history of established cardiovascular disease. Previous meta-analyses showed that statins effectively reduce the risk of stroke in the elderly,, among diabetics, and in individuals with no established cardiovascular disease. According to analyses of individual patient-level data from different trials, there appear to be a significant trend towards greater proportional reductions in stroke being associated with greater mean absolute low-density lipoprotein (LDL) cholesterol reductions. Indeed, in direct comparisons of different dosing regimens, high-dose statin therapy reduces the risk of stroke to a greater extent compared with standard doses.

An important question that remains unanswered in previous meta-analyses is whether individual statins are different in terms of their effect on the risk of stroke in individuals with or without a history of established cardiovascular disease. Earlier meta-analyses did not address this question in part because their focus was to establish the class effect of statins over control treatment on the basis of placebo-controlled trials. Incidence of cerebrovascular events was not an endpoint of interest in previous reviews that compared statins head-to-head in network meta-analyses., Only one review indirectly compared statins (atorvastatin, pravastatin and simvastatin) in terms of major cerebrovascular events but this study was based on a small number of placebo-controlled trials, without making use of the valuable information from active-comparator trials of statins.

The objective of our study was to systematically review the placebo-controlled and active-comparator trials of statins, and perform a multiple-treatments meta-analysis of individual statins in terms of their effect on major cerebrovascular events across all populations, in addition to secondary and primary prevention of cardiovascular disease separately.

Methods

Systematic review methods

We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials to identify studies published between 1 January 1985 and 1 January 2011. To comprehensively identify the active-comparator trials that were not included in previous meta-analyses of placebo-controlled trials, we used the search terms 'atorvastatin', 'fluvastatin', 'simvastatin', 'lovastatin', 'pravastatin', 'rosuvastatin', 'cholesterol', 'cardiovascular disease' and 'HMG-CoA reductase inhibitors/therapeutic use'. Two researchers (BT and HT) independently performed abstract, title and full-text screening. A third researcher approved study selection (HN).

We included open-label and double-blind randomized controlled trials comparing one statin with another statin at therapeutic dose or with control (placebo, diet or usual care) for adults with, or at risk of developing, cardiovascular disease. We included trials of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin if they had more than 50 participants per trial arm, lasted longer than 4 weeks and reported major cerebrovascular events. Both fixed dose and titration designs were included. Per pre-defined criteria, we excluded trials conducted in patients with renal insufficiency.

Trials that included at least 80% of participants without established cardiovascular disease or reported data separately on a sole primary prevention group were categorized as primary prevention. Trials that included more than 80% of participants with established cardiovascular disease or reported data separately on a sole secondary prevention group were categorized as secondary prevention. All remaining trials were categorized as having a mixed patient population.

The primary outcome was major cerebrovascular events. In line with previous meta-analyses, we defined the composite of major cerebrovascular events as fatal- and non-fatal strokes and transient ischaemic attacks. As secondary endpoints, we evaluated fatal- and non-fatal strokes separately. For the analysis on non-fatal strokes, transient ischaemic attacks were not included.

We used a structured form to extract data on trial (reference, publication year, design features such as blinding and dosing regimen) and patient population characteristics (age, baseline LDL cholesterol, cardiovascular risk factors), and outcome measures. One researcher extracted data (HN) and another independently checked for accuracy (BT). To ensure quality, we checked the consistency of extracted data with previously published meta-analyses.

Statistical analysis methods

We first qualitatively summarized included trials, describing the types of direct and indirect comparisons. For each pair-wise comparison between two statins, we calculated the odds ratio (OR) with a 95% confidence interval. First, we performed classical pair-wise meta-analyses to synthesize studies that compared the same two statins using the DerSimonian Laird (random-effects) method. The random-effects meta-analysis model assumed the observed estimates of treatment effect could vary across studies because of real differences in the treatment effect in each study and sampling variability (chance). Forest plots of the relative treatment effects from the individual trials and pair-wise meta-analyses were visually inspected to search for heterogeneity. We also statistically inspected heterogeneity using the I ² statistic, which was used to estimate the percentage of total variation among studies that can be considered to be due to heterogeneity. We used rough thresholds of 25, 50 and 75% to define low, moderate and high heterogeneity, and investigated moderate and high heterogeneity by inspecting trial-level variables that may explain observed differences.

To determine the comparative effects of statins, we conducted multiple-treatments meta-analyses. In these analyses, study-level relative treatment effects were combined using random-effects models within a Bayesian framework using Markov chain Monte Carlo methods., We used the model developed by Dias et al. for the National Institute of Health Clinical Excellence Decision Support Unit in the UK. This was based on modelling the outcomes in every treatment group of every study, and specifying the relations among the relative effects across studies making different comparisons.

To obtain a comprehensive estimate of the effect of statins in major cerebrovascular events, the multiple-treatments meta-analysis pooled all primary and secondary prevention trials in addition to trials with mixed patient populations. This analysis included all placebo-controlled and active-comparator trials eligible for inclusion in this review. We also performed separate analyses for the primary and secondary prevention populations, as categorized by the criteria mentioned earlier. For the base case analysis, we included trials at all doses. We separately evaluated the impact of dose differentials across the trials by excluding high-dose trials (80 mg/day for atorvastatin, fluvastatin, lovastatin, simvastatin and ≥40 mg/day for rosuvastatin) in a sensitivity analysis and evaluating the benefits of statins at comparable doses.

Results

We included 61 trials ( Figure 1), totalling 187 038 individuals. Overall, the average trial duration was 140 weeks (2.7 years). There were 51 two-armed placebo-controlled trials and the remaining 10 were two- or multi-armed active-comparator trials. There were 28 secondary prevention and 12 primary prevention trials. The remaining were in individuals who experienced acute coronary syndromes ( n = 8) and those with mixed populations ( n = 13). Of the 15 possible pair-wise comparisons between the six statins, only five were available for the major cerebrovascular events outcome. No trial directly compared all six statins to each other ( Figure 2). Characteristics of included trials are summarized in Supplementary Table S1.

Benefit of statin therapy vs. control: findings of the pair-wise meta-analyses

In the pair-wise meta-analysis of statin therapy vs. control across all populations, 171 731 individuals contributed information on 4533 events. Overall, statin therapy was associated with a reduction in the risk of major cerebrovascular events (OR: 0.82, 95% CI: 0.77, 0.87) when compared with control ( Figure 3). Among statins, atorvastatin, pravastatin and simvastatin were associated with a significant reduction in major cerebrovascular events compared with the control, while fluvastatin, lovastatin and rosuvastatin were not.

In the secondary prevention population, statin therapy was associated with a significant reduction in major cerebrovascular events (OR: 0.83, 95% CI: 0.75, 0.91) when compared with control ( Figure 3). Only atorvastatin resulted in significantly fewer events as compared with control in this population.

In the primary prevention population, statin therapy was associated with a significant reduction in major cerebrovascular events (OR: 0.80, 95% CI: 0.71, 0.91) ( Figure 3). In this population, only atorvastatin and rosuvastatin had sufficient evidence for a significant benefit on major cerebrovascular events, while fluvastatin, lovastatin, pravastatin did not. Simvastatin did not have any trials in primary prevention.

Overall, statistical heterogeneity in pair-wise comparisons of statin therapy vs. control in all-cause mortality was low in analyses of primary prevention ( I ²: 9.2%), secondary prevention ( I ²: 0.0%) and all populations together ( I ²: 0.0%). We observed high heterogeneity in pair-wise comparisons of rosuvastatin vs. control ( I ²: 81.3%), mainly as a result of the differences in patient populations between JUPITER (primary prevention), GISSI-HF and CORONA (heart failure).

Comparative benefits of statins on major cerebrovascular events: findings of the multiple-treatments meta-analyses

In addition to the trials included in the pair-wise comparisons of statin therapy vs. control, there were 11 direct head-to-head statin comparisons, providing information on 20 072 participants. In the multiple-treatments meta-analysis, 61 placebo-controlled and active-comparator trials provided information for major cerebrovascular events analysis. In total, 187 038 individuals were included in this analysis, which provided information on 4913 events.

In this analysis, there were no significant differences among statins in terms of major cerebrovascular events when all trials of primary prevention, secondary prevention and mixed patient populations were pooled ( Figure 5). There were also no statistical differences among individual statins in terms of reducing the risk of major cerebrovascular events in primary and secondary prevention of cardiovascular disease.

The findings of the multiple-treatments meta-analysis were not sensitive to dose differentials across trials ( Figure 4). When high-dose trials were excluded from the analysis, estimated comparative benefits of individuals were not materially different and there were no statistically meaningful differences between statins ( Figure 5).

Comparative benefits of statins on non-fatal and fatal strokes

Across all populations, statins were effective in reducing the incidence of non-fatal strokes (OR: 0.77, 95% CI: 0.71, 0.85) as compared with control treatment ( Figure 6). Only rosuvastatin (OR: 0.69, 95% CI: 0.44, 0.99) and simvastatin (OR: 0.69, 95% CI: 0.45, 0.96) had sufficient statistical power to show superiority over control treatment across all populations. Statins were not effective in reducing the risk of fatal strokes (OR: 0.96, 95% CI: 0.80, 1.15) although atorvastatin was independently superior to control treatment in preventing fatal strokes (OR: 0.49, 95% CI: 0.30, 0.80). There were no statistical differences between the individual statins.

Discussion

This multiple-treatments meta-analysis of 187 038 individuals provides evidence on the statistically and clinically meaningful benefits of statins in reducing the risk of major cerebrovascular events in both individuals with or without established cardiovascular disease. Overall, statins were associated with an 18% reduction in relative odds of major cerebrovascular events across all populations. Benefits of statins in reducing the relative odds of major cerebrovascular events by ∼18% were consistent across primary and secondary prevention populations. Across all populations, given the lack of statistical difference between different statins, our analysis provided evidence to confirm the class effect of statins in preventing major cerebrovascular events.

Our overall findings reinforce and extend the results of previous meta-analyses on statin therapy. Previous reviews elucidated the importance of lipid management with statins in the prevention of strokes and found consistent evidence that would warrant advocating statin use for the prevention of incident strokes., Clinical practice guidelines also recommend statin therapy in secondary prevention of stroke for patients with non-cardioembolic stroke., As SPARCL was the only trial that investigated the benefits of statins for the secondary prevention of strokes in individuals with a history of transient ischaemic attack or stroke, we did not explore the comparative benefits of statins in this population separately. Our base-case analysis in individuals with or without a history of established cardiovascular disease did not detect significant differences among individual statins. However, it remains a possibility that there are actual differences between individual statins which could not be detected in our analysis.

Indeed, although there were no statistical differences, our review suggested that the randomized trial evidence base for some statins was more robust and consistent than it was for others. This was particularly the case for atorvastatin and simvastatin. There was essentially no detectable heterogeneity across the trials of atorvastatin and simvastatin with consistent evidence for their benefits in the prevention of major cerebrovascular events. Unlike simvastatin that did not have evidence in individuals with no history of cardiovascular disease, atorvastatin was able to reach statistical significance in both primary and secondary prevention populations (as well as across all populations) as compared with control treatment. Although atorvastatin led to a significant reduction in the risk of fatal strokes, unexpectedly, it was not associated with significantly fewer non-fatal strokes as compared with control. Trial evidence for fluvastatin and lovastatin was inconsistent across individuals with and without cardiovascular disease and there was large uncertainty around the benefits of these agents in the prevention of strokes. Finally, there was substantial heterogeneity in the evidence base for rosuvastatin. Given the small number of trials, JUPITER appeared to drive the pooled estimates for rosuvastatin, specifically for individuals without a history of cardiovascular disease.

In addition to pair-wise meta-analyses that compared statins with control treatment, we also performed multiple-treatments meta-analysis, which is a relatively new method that differs from pair-wise meta-analysis by incorporating data from both direct (from head-to-head comparisons within trials) and indirect (from comparisons between trials) sources of evidence. Using this approach, we combined the results of placebo-controlled and active-comparator trials, allowing for more informed estimates of the relative effect of individual statins that have not been compared head-to-head in clinical trials. Our analysis differed from previous multiple-treatments meta-analyses in two important aspects. First, our review incorporated data from a comprehensive list of trials irrespective of placebo or active controls. Second, we provided comparative estimates separately for populations in primary and secondary prevention of cardiovascular disease.

Findings of this study should be interpreted in light of its limitations. First, as a literature-based meta-analysis, our analysis shares the limitations of the published evidence base. There were only a few head-to-head trials of statins that were prospectively designed to capture differences in clinical outcomes as primary endpoints. Second, as a multiple-treatments meta-analysis combining direct and indirect sources of evidence, it remains a possibility that potential imbalances in the occurrence of effect modifiers across the contrasts impacted the results, potentially confounding the comparative estimates between statins.

In spite of these limitations, this study has important methodological strengths. Our review is the largest meta-analysis on the benefits of statin therapy on cerebrovascular events to date. We included 11 direct head-to-head statin comparisons, providing information on additional 20 072 individuals that were not considered in prior meta-analyses on strokes. Our statistical models were appropriate for the evidence base as we did not detect any significant heterogeneity in the trial network. Although there was no considerable heterogeneity, we still used a random-effects model to take into account potential unexplained heterogeneity across the studies.

Acknowledgements

Authors thank Bernice Tsoi and Harleen Toor for their assistance with abstract and full-text review, data extraction and quality review of extracted data for accuracy. The authors did not receive any funding for this study.

Conflict of interest: Dr Fleurence is an employee of the Patient-Centered Outcomes Research Institute (PCORI). The views expressed in this article do not necessarily represent those of PCORI.

References

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# data[].attributes.attachment_link.title
Comparative effects of statins on major cerebrovascular events: a multiple-treatments meta-analysis of placebo-controlled and active-comparator trials

# data[].attributes.attachment_link.description
Statins are important in the prevention of major cerebrovascular events. Whether, and the extent to which, individual statins differ in terms of their effect on these outcomes has not been studied. The aim of this review was to evaluate the comparative effects of individual statins on major cerebrovascular events.

# data[].attributes.body
Título:

Ezetimiba para la prevención de la enfermedad cardiovascular y los eventos de mortalidad por todas las causas.

Tipo de Estudio: Metaanálisis de ECA
Año: 2018
Conclusiones:  La Ezetimiba tiene efectos beneficiosos moderados sobre el riesgo de variables de evaluación de ECV, principalmente debido a una reducción del IM no fatal y el accidente cerebrovascular no fatal. Además, El beneficio cardiovascular de la Ezetimiba podría implicar la reducción del LDL‐C, el colesterol total y los triglicéridos.

# data[].attributes.attachment_link.title
Ezetimibe for the prevention of cardiovascular disease and all‐cause mortality events - Zhan, S - 2018 | Cochrane Library

# data[].attributes.body
Título: Eficacia y seguridad de rosuvastatina en el tratamiento de la dislipidemia
Tipo de estudio: ECA
Año: 2005
Conclusión: La rosuvastatina tiene mayor eficacia en la reducción de las concentraciones de colesterol LDL y colesterol no HDL que las otras estatinas. Se ha demostrado que permite que más pacientes alcancen sus objetivos de colesterol LDL que otras estatinas y hacerlo con un perfil de seguridad aceptable.

# data[].attributes.attachment_link.readable_text
Abstract

Purpose: The chemistry, pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, dosage and administration, and place in therapy of rosuvastatin are reviewed.

Summary: Rosuvastatin, the latest statin to receive approved labeling by the Food and Drug Administration, has shown superior efficacy in lowering low-density-lipoprotein (LDL) cholesterol. At daily doses of 5-40 mg, rosuvastatin produces mean reductions in plasma LDL cholesterol of 45-63%, statistically greater than those achieved with equivalent doses of atorvastatin, simvastatin, and pravastatin. Rosuvastatin also improves triglyceride, non-high-density lipoprotein (HDL)-cholesterol, and HDL cholesterol levels to produce a more favorable lipid profile. Rosuvastatin's safety was studied in more than 10,000 patients, exceeding the number of patients evaluated before the launch of any other statin. Many of these patients took the drug for up to 96 weeks. With regard to muscle, renal, and hepatic toxicity and the withdrawal rate due to adverse events, rosuvastatin demonstrates a safety profile similar to that of the other marketed statins. Rosuvastatin undergoes only minor metabolism (10% of the administered dose) by the cytochrome P-450 2C9 isoenzyme. Significant drug interactions were reported with cyclosporine, gemfibrozil, warfarin, and antacids. Evidence suggests that rosuvastatin will be a valuable addition to the choices for treatment of patients with dyslipidemia.

Conclusion: Rosuvastatin has greater efficacy in lowering LDL cholesterol and non-HDL-cholesterol concentrations than the other statins. It has been shown to enable more patients to reach their LDL cholesterol goals than other statins and to do so with an acceptable safety profile.

# data[].attributes.attachment_link.keywords[]
fluorobenzenes / administration & dosage

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Efficacy and safety of rosuvastatin in treatment of dyslipidemia - PubMed

# data[].attributes.attachment_link.description
Rosuvastatin has greater efficacy in lowering LDL cholesterol and non-HDL-cholesterol concentrations than the other statins. It has been shown to enable more patients to reach their LDL cholesterol goals than other statins and to do so with an acceptable safety profile.

# data[].attributes.body
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044319/
Título:  Agregar ezetimiba a la terapia con estatinas: evidencia más reciente e implicaciones clínicas
Año: 2018
Autor: Marija Vavlukis , MD, PhD, FESC ¹ y Ana Vavlukis , MSc
Tipo de Estudio: Revisión sistemática
Resultados:
Se evidencia que la agregación de ezetimibe al tratamiento con estatinas aumenta la eficacia en cuanto a la reducción LDL-C lo cual se traduce por la reducción del riesgo de ASCVD, Ezetimibe es de los pocos medicamentos hipolipemiantes que inducen a la reducción adicional del riesgo de ASCVD.

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Results

HMG-CoA reductase inhibitors - statins

Statins are reversible inhibitors of the microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate - an early rate-limiting step in cholesterol biosynthesis. The HMG-CoA reductase inhibition decreases intracellular cholesterol biosynthesis, leading to upregulated HMG-CoA reductase production and cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-C from the blood. Given the previous situation, plasma LDL-C is the main clinical variable evaluated in statin pharmacodynamic studies, which takes about 4 to 6 weeks to show a reduction after the start of treatment, with a dose-dependent relationship. 3 Even though the statin group shares a common mechanism of action, members differ in terms of their chemical structures, pharmacokinetic profiles, and lipid-modifying efficacy. 4

The chemical structure of the statins is constituted by two components - the pharmacophore, which is a dihydroxyheptanoic acid segment, and its moiety - composed of a ring system with different substituents. The ring system is a complex hydrophobic structure involved in the binding interactions to the HMG-CoA reductase. The structure of the ring can be a partially reduced naphthalene (lovastatin, simvastatin, and pravastatin), a pyrrole (atorvastatin), an indole (fluvastatin), a pyrimidine (rosuvastatin), or a quinolone (pitavastatin). The substituents on the rings define the solubility of the statin, along with many of their pharmacological properties. Among the statins mentioned, lovastatin, simvastatin, atorvastatin, and fluvastatin are lipophilic, whereas pravastatin and rosuvastatin are more hydrophilic. 5

Statins are administrated orally as active hydroxy acids, except for lovastatin and simvastatin, which are administrated as lactone prodrugs and then hydrolysed to hydroxy acid form. The percentage of absorption is between 30 and 98% and the time to reach peak plasma concentration (T max) is within 4 hours after administration. Their bioavailability varies; pitavastatin has a bioavailability of 80%, whereas fluvastatin between 19 and 29%. 5 Statins are predominantly metabolized by the cytochrome P450 (CYP450) enzyme family. The CYP3A4 isoenzyme is responsible for the metabolism of the majority of human drugs, including lovastatin, simvastatin, and atorvastatin. A proportion of their HMG-CoA reductase inhibitory activity is attributable to their active metabolites - 2-hydroxy- and 4-hydroxy-atorvastatin acid from atorvastatin and β-hydroxy simvastatin acid and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives from simvastatin. Fluvastatin is chiefly metabolized by the CYP2C9 isoenzyme, while pravastatin, pitavastatin, and rosuvastatin do not undergo substantial metabolism by CYP450 pathways. The predominant route of elimination for the majority of statins is via the bile after metabolism by the liver. Pravastatin is eliminated by both the kidney and liver, mostly as an unchanged drug. Rosuvastatin is also eliminated, largely unchanged, by both the kidney and liver. 6

Cholesterol absorption inhibitors - ezetimibe

Ezetimibe is a cholesterol-lowering drug from the class of cholesterol absorption inhibitors that acts at the brush border of the small intestine. It appears to bind to a critical mediator of cholesterol absorption, the Niemann-Pick C1-Like 1 (NPC1L1) transporter protein on the gastrointestinal tract epithelial cells as well as in the hepatocytes. Ezetimibe blocks the absorption of dietary and biliary cholesterol and plant sterols resulting in intracellular cholesterol depletion. 7, 8

Following oral administration, ezetimibe is rapidly absorbed and extensively metabolized (>80%) to the pharmacologically active ezetimibe glucuronide. Total ezetimibe (sum of 'parent' ezetimibe plus ezetimibe glucuronide) concentrations reach a maximum 1-2 hours post-administration. The estimated half-life of ezetimibe and ezetimibe glucuronide is approximately 22 hours. The major metabolic pathway for ezetimibe is glucuronidation of the 4-hydroxyphenyl group by uridine 5′-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the feces, predominantly as ezetimibe. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolemia, such as statins, except for fibrates and cyclosporine. Described adverse effects are also rare, as monotherapy - upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain in extremity - or in combination with statins - nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and diarrhea. 9- 11

The recommended ezetimibe dosage is 10 mg daily, with or without food, taken either 2 hours before or 4 hours after bile acid sequestrants (BAS) if used in combination. 11, 12 When administered as monotherapy or coadministered with statins, timing of administration has no effect on their potency. This was confirmed by the study of Hyung Sik Yoon, who tested the therapeutic efficacy and safety of a fixed-dose combination of ezetimibe 10 mg and simvastatin 20 mg, in terms of morning versus evening administration. Morning administration was reported to be noninferior to evening administration. 13

Ezetimibe has a potency to decrease LDL-C by 10-18% and Apo B by 11-16%, while in combination therapy with statins, an additional LDL-C lowering of 25% or total reduction of 34-61% is observed. In combination with fenofibrate, a 20-22% LDL-C and 25-26% Apo B lowering can be achieved, with an increase of high-density lipoprotein cholesterol (HDL-C) as well. 8, 11, 14

Effects of statins

Statins have been proven to be very effective in reducing ASCVD risk, with no apparent threshold at which LDL-C lowering is not associated with reduced risk. The Atherosclerosis Risk in Communities (ARIC) study, performed on 13,342 individuals, provided evidence that protection against ASCVD happens in a graded fashion with LDL-C level, and a meta-analysis by the Cholesterol Treatment Trialists' (CTT) Collaboration on statin, suggested that a 1.0 mmol/L LDL-C reduction is associated with a 10% reduction of all-cause mortality, 24% reduction of major adverse cardiac events (MACE), and 15% stroke reduction. These benefits are irrespective of baseline cholesterol concentration 1 and in direct proportion to the magnitude of LDL-C lowering. High-intensity statin treatment (atorvastatin 80 mg) in the Treating to New Targets (TNT) trial, the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) trial, and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial, demonstrated an additional 11 to 23% relative risk reduction of major cardiovascular disease (CVD) events when compared with moderate-intensity statin therapy (atorvastatin 10 mg, simvastatin 20 to 40 mg, or pravastatin 40 mg). Nonetheless, the atorvastatin 80 mg treated patients still experienced a major CVD event during the trials (ranging from 4 to 11% per year). Mean LDL-C levels in the atorvastatin 80 mg groups ranged from 1.6 to 2.1 mmol/L. This data suggest that further reductions in LDL-C may be justified. 14, 15

The question of residual risk

A significant on-treatment residual risk of major CV events still exists. The meta-analysis of statin trials shows a significant 22% relative risk for 5-year major CV events among individuals with prior CVD and 10% among those without prior disease. Even with LDL-C levels < 2 mmol/L, there is still a residual CVD event risk. The aforementioned TNT trial, conducted on patients with stable coronary artery disease (CAD), described an 8.7% incidence of a major event over 5 years in patients receiving atorvastatin 80 mg, with on-treatment LDL-C concentrations of 1.8-2.6 mmol/L. 1

Findings like this point to the unmet needs of patients treated with statins. Several cholesterol treatment guidelines recommend a LDL-C treatment goal of <2.6 or <1.8 mmol/L, depending on the level of risk. However, in the everyday clinical practice, many high-risk patients fail to reach the LDL-C goal of <2.6 mmol/L, and/or few patients on high-intensity statin therapy achieve LDL-C levels <1.8 mmol/L. 15

The most recent guidelines of the professional associations from both sides of the Atlantic Ocean, the 2016 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) Guidelines for the management of Dyslipidaemias and the 2017 Guidelines of the American Association of Clinical Endocrinologists and the American College of Endocrinology for Management of Dyslipidaemia and Prevention of Cardiovascular Disease, have recommended similar target LDL-C levels, which should provide clinicians with the confidence to aim for specific and low LDL-C targets. 10, 14 This is a major difference from the risk profile treatment approach in the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guidelines. 16

The particular developments in these guidelines are the inclusion of specific LDL-C targets and the suggestion of combination therapy (ezetimibe and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) to achieve these targets in situations in which maximally tolerated statin monotherapy is insufficient (). 1, 10

Table 1

Risk profile of the patient

Treatment target goal of LDL-C

Very high CV risk

<1.8 mmol/L, or at least 50% reduction if the baseline LDL-C ¹ is 1.8-3.5 mmol/L

I/B

High CV risk

<2.6 mmol/L, or at least 50% reduction if the baseline LDL-C is 2.6-5.2 mmol/L

I/B

Low/moderate CV risk

LDL-C goal of <3.0 mmol/L

IIa/C

There is one significant difference in the American Association of Clinical Endocrinologists (AACE) guidelines, where an additional 'extreme high-risk' category is defined, which is not recognized by the ESC/EAS, and an additional treatment target of LDL-C of <1.4 mmol/L is set. This 'extreme high-risk' group consists of patients with progressive disease despite an LDL-C of <1.8 mmol/L while on statin therapy. Of paramount importance is that both sets of guidelines have recommended similar target LDL-C levels that should provide clinicians with the confidence to aim for specific and low LDL-C targets. 17

The rationale of such an approach is in the individualisation of the total CV risk reduction that can be better done if goals are defined. Treatment goals are defined and tailored to the total CV risk level of each individual patient. The 'individualized approach' may possibly result with better patient adherence to the therapy. Available evidence suggests that lowering of LDL-C beyond the guidelines-set goals may lead to further reduction of CVD events. Therefore, it seems appropriate to reduce LDL-C as low as possible, especially in patients at very high CV risk. 10

Furthermore, the IMPROVE-IT (Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin versus Simvastatin) trial demonstrated that not only such low levels are safe but such levels are also beneficial, in terms of additional CV risk reduction. Current studies demonstrate LDL-C reduction as low as 0.5 mmol/L is not only therapeutically effective but also safe. 15, 17, 18

Combination therapy: ezetimibe add-on to statin

Ezetimibe add-on to statin treatment

The unmet needs in terms of LDL-C targets and ASCVD protection raised the question of statin combination therapy. It only needed right clinical settings for such a combination to be defined. It was done in the 2016 ESC/EAS Guidelines for the Management of Dyslipidemias () 10 and in the 2016 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-C lowering in the management of atherosclerotic CVD risk. This guideline is a continuation of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, and there the role of ezetimibe is clearly positioned. 11

Table 2

Hypercholesterolemia
If the goal is not reached with statins add-on ezetimibe

IIa/B

Depends on the risk profile of the individual patient

I/A

FH
Intense-dose statin, often in combination with ezetimibe

I/C

<2.6 mmol/L, or <1.8 mmol/L in presence of CVD

IIa/C

ASC
If the goal is not reached with the highest tolerable statin dose, use ezetimibe add-on in post-ACS patients

IIa/B

<1.8 mmol/L, or a reduction of at least 50% if the baseline LDL-C ¹ is 1.8-3.5 mmol/L

CKD stages 3-5
These include high or very high CV risk patients.
The use of statins or ezetimibe add-on to statin is indicated in nondialysis dependent patients

I/A

Depends on the risk profile of the individual patient

I/A

Effects of ezetimibe add-on to statins on LDL-C

In clinical studies, ezetimibe as monotherapy reduces LDL-C in hyperlipidemic patients by 15-22%. Combined therapy with statins provides an incremental reduction in LDL-C levels of 15-20%, leading to the total LDL-C reduction by 34-61%, as previously mentioned. 10

The most comprehensive data analysis for LDL-C lowering efficiency was performed by the group of Descamps, published in 2015. Twenty-seven differently designed trials (double-blind placebo and/or active controlled studies) in which statins (type of statin, statin brand, potency, or different dose) were compared with ezetimibe add-on to statin were included, with over 21,671 patients, analyzing variables such as variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for percentage change from baseline in LDL-C. In this very comprehensive data analysis, ezetimibe add-on to statin was found to lead to a significantly more pronounced LDL-C lowering, as compared to statin monotherapy. 19

Data from a large retrospective observational study (more than 27,000 patients), published in 2014 by Toth, demonstrate a more pronounced LDL-C lowering effect of ezetimibe add-on to statin therapy and higher percentage of goal attainment (with respect to the risk profile of the patients), with one third of the patients not being able to attain the recommended LDL-C goal of <1.8 mmol/L. However, it was realized that there is a low prescription frequency of high-dose statins. Half of the patients (50.9%) remained on the same statin monotherapy, irrespective of the achievement of treatment goal. 20 The significance of this study is even bigger given that it is a real-life situation, and not a randomized study with strictly predefined inclusion criteria, study population, and so forth.

The amount of LDL-C reduction that was achieved in the large randomized study IMPROVE-IT, including 18,144 patients, was about 24%. 21 In the I-ROSETTE study (The Compare the Efficacy and Safety of a Combination Therapy of Ezetimibe and Rosuvastatin Versus Monotherapy of Rosuvastatin in Hypercholesterolemia Patients), the effect of ezetimibe add-on to rosuvastatin was analyzed in 396 patients. During the 8 weeks' treatment period, six treatment regiments were compared (5, 10, and 20 mg rosuvastatin monotherapy versus same-dose regimens rosuvastatin add-on 10 mg ezetimibe). The percentage change from baseline in adjusted mean LDL-C level after 8 weeks treatment was −57.0% (2.1%) and −44.4% (2.1%) in the total ezetimibe/rosuvastatin and total rosuvastatin groups, respectively ( p<0.001). The LDL-C-lowering efficacy of each of the ezetimibe/rosuvastatin combinations was superior to that of each of the respective doses of rosuvastatin. 22

The pleiotropic properties of ezetimibe have been confirmed in several clinical trials in addition to the beneficial effect on the lipid profile. A small-scale Japanese study by Uemura and colleagues in 39 patients, compared two arm regimens: 10 mg atorvastatin plus 10 mg ezetimibe versus 20 mg atorvastatin in high-risk patients with CAD and type 2 diabetes mellitus (T2DM). Besides a statistically significantly more pronounced improvement of the lipid profile in terms of total cholesterol, LDL-C, and HDL-C ( p=0.005), a significant effect on the Apo B/Apo A-I ratio and remnant-like particle cholesterol was observed only in the atorvastatin add-on ezetimibe treatment group. However, the most powerful information obtained from this study was more pronounced effect on oxidized LDL-C [malondialdehyde-modified LDL (MDA-LDL)], a form that is responsible for the proatherogenic effects of LDL-C with the atorvastatin add-on ezetimibe treatment ( p=0.0006). 23 Another Japanese study was performed by Tobaru and colleagues again on high-risk profile patients (with CAD) who remained above targeted LDL-C level after pretreatment with statins and who were subjected to ezetimibe add-on statin therapy. Besides a significant additional decrease of total cholesterol, LDL-C, remnant lipoprotein (LP) cholesterol, and LDL/HDL-C ratio, an increase of the percentage of patients who achieved target LDL-C level to 65.4% ( p=0.001) in the ezetimibe add-on to statin group was also observed. Although no significant effect was achieved on high-sensitivity C-reactive protein (hsCRP) and oxidative stress markers, a significant reduction of tumor necrosis factor-α (TNF-α), 1.36 versus 0.96 ( p=0.042), was observed. 24 The analysis of the data from the IMPROVE-IT trial, in which two laboratory targets were set: LDL-C (<1.8 mmol/L) and hsCRP (<2 mg/L), confirmed that ezetimibe add-on to statin treatment was far more successful in achieving both targets, and it was concluded as follows: Significantly more patients treated with ezetimibe/simvastatin met prespecified dual LDL-C and hsCRP targets, than patients treated with simvastatin alone (50 versus 29%, p<0.001). Reaching both LDL-C and hsCRP targets was associated with improved outcomes after multivariable adjustment (38.9 versus 28.0%; adjusted hazard ratio (HR), 0.73; 0.66-0.81; p<0.001). 21

Translation of pleiotropic effect of ezetimibe when add-on statins in improved endothelial function and vascular reactivity was proven by Yunoki and colleagues, with measurement of flow-mediated dilatation (FMD) of the brachial artery in 109 patients with CAD and measurement of LP fractions as well. The significance of this study lies in the fact that triglycerides (TG) and HDL-C lipoproteins were found to be independently associated with endothelial dysfunction in CAD patients (as measured by FMD). However, the ezetimibe add-on to statin treatment (in the subgroup with high TG, irrespective of LDL-C level), significantly improved TG level and endothelial function as well. 25 This is in concordance with the fact that although LDL-C is the main treatment target, other LP fractions also contribute to atherosclerosis, and their downregulation results with improvement of endothelial function (as an early manifestation of atherosclerosis).

Effects of ezetimibe add-on to statins on ASCVD outcome

The potential benefits of adding an additional lipid-lowering agent - i.e. ezetimibe - to statin therapy for CVD prevention and risk reduction has been confirmed in several clinical trials.

The Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial evaluated the effects of ezetimibe add-on to atorvastatin versus atorvastatin monotherapy on the lipid profile and coronary atherosclerosis in Japanese patients who underwent percutaneous coronary intervention (PCI). The combination therapy resulted in lower LDL-C levels than atorvastatin monotherapy (1.6 versus 1.9 mmol/L; p<0.001) and, at the same time, coronary plaque regression was observed in significantly higher percentage of patients (78 versus 58%; p=0.004). 26

In the Study of Heart and Renal Protection (SHARP) (Simvastatin plus ezetimibe) trial, high-risk patients with diabetes and chronic kidney disease (CKD) with/without requiring dialysis constituted 23% of the study population. The combination therapy demonstrated superiority over statin monotherapy in LDL-C reduction, translated in a reduction of the primary endpoint of the first major ASCVD event - nonfatal myocardial infarction (MI) or CV death, nonhemorrhagic stroke, or any arterial revascularization procedure - over a median follow-up of 4.9 years. 10, 20, 27

However, another ezetimibe add-on to statin (simvastatin) study - the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study - did not demonstrate superiority in terms of ASCVD risk reduction. The baseline hypothesis of this study was that hypolipemic medications will decrease the progression of aortic stenosis. Asymptomatic patients (1873) with mild-to-moderate aortic valvular stenosis (AS) with different LDL-C pretreatment levels were treated with ezetimibe add-on to simvastatin. In a nonprespecified post hoc analysis, slower progression of aortic stenosis was observed only in the patients with higher pretreatment LDL-C levels with mild aortic stenosis (0.06 m/s per year slower progression versus placebo in peak aortic jet velocity, 95% CI: 0.01-0.11, p=0.03), while the overall study results didn't support the hypothesis. 28

The landmark trial on ezetimibe plus statin combination therapy, the largest and the longest one with ezetimibe, is the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). A total of 18,144 patients with acute coronary syndrome (ACS) were randomized to ezetimibe (10 mg) or placebo, all receiving 40 mg simvastatin, which was increased to 80 mg if LDL-C on treatment was >2.04 mmol/L. The average LDL-C during the study was 1.8 mmol/L in the simvastatin group and 1.4 mmol/L in the ezetimibe add-on to simvastatin group. The event rates for the primary endpoint at 7 years were 32.7% in the simvastatin-ezetimibe group and 34.7% in the simvastatin-monotherapy group, with an absolute risk reduction of 2% (HR 0.936; 95% CI: 0.89-0.99; p=0.016). Ischemic stroke was reduced by 21% ( p<0.008). Nevertheless, no benefit in reducing all-cause mortality or deaths from CV causes was observed, which was not unexpected, as prior trials of intensive- versus standard-dose statin therapy also did not demonstrate a benefit in terms of mortality. As elaborated by the authors, the study was not powered to detect a difference in mortality. This was the first in the row of studies that provided information on the safety of reducing LDL-C levels down to 1.4 mmol/L. Although the absolute benefit in this group of patients (already treated with statins to reach the goal) from the added ezetimibe was small, it was statistically significant and supportive for the proposition that LDL-C lowering by means other than statins is beneficial in terms of residual risk reduction and can be performed without adverse effects. 1, 10, 11, 21, 29

The diabetic subgroup analysis in the IMPROVE-IT trial, provided the outcomes in 4933 (27%) patients with diabetes, one of the prespecified subgroups in the trial. In this patient subset, ezetimibe add-on to statin therapy decreased LDL-C at 1 year by 1.1 mmol/L, as compared to 0.6 mmol/L with statin monotherapy. Diabetic patients on ezetimibe add-on to statin therapy had a 14% relative risk reduction, or 5.5% absolute reduction, compared with a 2% absolute risk reduction for nondiabetics. The most notable reductions were seen regarding ischemic stroke (39%), MI (24%), and the composite of death due to CV causes, MI, or stroke (20%). These CV effects of ezetimibe add-on to statin therapy are a result of the more prominent reduction of LDL-C (mean 0.5 versus 1.4 mmol/L in simvastatin monotherapy). This substudy analysis demonstrated superiority of the ezetimibe add-on to statin therapy in CV prevention in high-risk diabetic subset of patients. 14, 21

Another significant effect of ezetimibe add-on to statin therapy is cerebrovascular protection. The 2013 ACC/AHA cholesterol guideline, as previously commented, had a risk-targeted approach. 16 In stroke patients <75 years of age, a high-intensity statin treatment was recommended in the absence of safety concerns, including a history of hemorrhagic stroke, in which, as in the cases of age >75 years, a moderate-intensity statin treatment was recommended. According to the same guidelines, if there was a need for nonstatin treatment for additional LDL-C lowering, ezetimibe is the only drug that demonstrated further reduction of ASCVD risk when added on statin therapy. 30 The problem with high-dose statin therapy in this subset of patients, as pointed out by Lovadi and colleagues, is that special precautions should be borne in mind in patients with prior intracerebral hemorrhage and ischemic cerebro-vascular insultus (CVI) that goes through hemorrhagic transformation. And again, the advantage of ezetimibe add-on to statin therapy can be expected, and it was observed in the IMPROVE-IT study. The highest risk benefit was observed in the subgroup of patients with ischemic CVI with a 21% relative reduction of ischemic stroke ( p<0.008). The addition of ezetimibe as a nonstatin type drug to statin treatment contributed to further reduction of LDL-C, which translated into additional decrease in reoccurrence and mortality of/from cerebrovascular events. Achieving target values with ezetimibe add-on to statin combination allows administration of low- to moderate-dose statin, which decreases the risks of adverse effects related to high-dose statin therapy. 31

It is obvious from trial results that the higher the risk profile of the patient, the greater is the benefit in terms of risk reduction when ezetimibe is added to statin treatment. Taken together, all of the studies support the decision to propose ezetimibe as a second-line therapy in association with statins when the therapeutic goal is not achieved at the maximal tolerated statin dose or in patients intolerant or with contraindications to these drugs. 10, 11

Safety profile of ezetimibe add-on to statins combination therapy

The relationship between lipid-lowering medications, glycemic control, insulin resistance, and new-onset diabetes has been studied since the introduction of hypolipemic medications. We know that glycemic control is impaired not only by statin treatment but also with niacin. In contrast, BAS demonstrate moderate lipid- and glucose-lowering effects, and fibrates (particularly bezafibrate) may produce beneficial effects on glucose metabolism and insulin sensitivity. The fact that statins are the most widely used hypolipemic drugs, makes this an important issue. Statins lead to a mild elevation of glycated hemoglobin A1c (HgbA1c) and fasting plasma glycose (FPG) and increase the incidence of new-onset diabetes, an effect known to be dose and agent dependent (pravastatin and pitavastatin have less diabetogenic effect and positive impact on insulin sensitivity), and is most pronounced in patients with baseline impaired fasting blood glucose (FBG), at older age, and with metabolic syndrome. However, it has been demonstrated that the risk of new-onset diabetes is overweighed by the benefit of CV risk reduction. 10

For a long period of time, there was a lack of clinical trials addressing the same question in ezetimibe treatment, but the data were gathered from experimental animal studies that described how ezetimibe ameliorates metabolic markers such as hepatic steatosis and insulin resistance. The process is via inhibition of intestinal cholesterol absorption, and at the hepatic level, inhibition of the NPC1L1 leads to decreased hepatic insulin resistance, improved glycemic control, and improved insulin sensitivity, especially in metabolic disorders (obesity and hepatic steatosis). A protective function to pancreatic beta cells was also found in diabetic mice. Ezetimibe treatment was shown to reduce weight gain in animals fed with diabetogenic diet. Suggested possible mechanisms at the cellular level are improved insulin signaling (evidenced by the increase in Akt phosphorylation, upregulation of SHP [small heterodimer partner], and the downregulation of sterol regulatory element binding protein-1c [SREBP-1c] expressions) in high-fat-diet-induced obese mice and possible involvement of incretin glucagon-like peptide-1 (GLP-1). This was harder to prove in humans, as ezetimibe is usually used as statin cotherapy and individual impact of ezetimibe cannot be evaluated. A recent pooled analysis of 27 randomized trials assessing efficacy and safety of ezetimibe-statin combination therapy was unable to investigate the effects of ezetimibe on glycemia due to limitations in the design of the studies. However, there are reports from several small studies in humans with ezetimibe as monotherapy that demonstrate a significant reduction of parameters of insulin resistance and fatty liver. A small study of Hiramitsy reported significant decrease of HgbA1c (−0.3%; p<0.05) and fasting insulin level, without significant difference in FBG, although the same results were not confirmed in other human studies. 8, 32

In a recently published systematic review of randomized clinical trials, performed by Wu and colleagues on 2440 patients, experimental data were confirmed. Ezetimibe did not cause any adverse effects in terms of increased levels of FBG and hemoglobin A1c (HbA1c). Compared with high-dose statin therapy, ezetimibe add-on to low-dose statin for more than 3 months may even have beneficial effects on glycemic control. 33

Statin-associated muscle symptoms are a very common side effect, also known to be dose dependent. It seems that ezetimibe add-on to low-dose statin therapy is one of the possibilities to achieve good LDL-C control and CV risk reduction with lesser side effects as demonstrated with myalgia. 34 This finding found its place in the most recent guidelines - namely, in the 2016 ESC/EAS Guidelines for the Management of Dyslipidemias, ezetimibe is to be considered in combination with low-dose statin or second- or third-line statin in order to manage statin-attributed muscle symptoms. 10

# data[].attributes.attachment_link.title
Adding ezetimibe to statin therapy: latest evidence and clinical implications

# data[].attributes.attachment_link.description
Statins are reversible inhibitors of the microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which converts HMG-CoA to mevalonate - an early rate-limiting step in cholesterol biosynthesis. The HMG-CoA reductase inhibition decreases intracellular cholesterol biosynthesis, leading to upregulated HMG-CoA reductase production and cell surface LDL receptors.

# data[].attributes.body
Titulo: Eficacia y seguridad de la rosuvastatina frente a la atorvastatina para reducir el colesterol LDL: un metanálisis de ensayos con poblaciones de Asia oriental

TIPO DE ESTUDIO: Metanalisis
Año: 2018
Compararar los efectos hipolipemiantes de la rosuvastatina y la atorvastatina en una población de Asia oriental.
RESULTADOS: En comparación con atorvastatina, los pacientes tratados con rosuvastatina tuvieron una reducción significativa en LDL-C: DMP = -7,15 mg/dl (95% intervalos de confianza [IC]: -10,71--3,60) mg/dl, p < 0,0001. Los análisis de metarregresión no revelaron una asociación significativa entre los beneficios superiores de la rosuvastatina y otras variables, como la edad, el sexo, el nivel inicial de LDL-C y la duración del seguimiento. Además, el grupo de pacientes con rosuvastatina, que fueron tratados con la mitad de la dosis de atorvastatina, logró una reducción significativamente mayor en los niveles de LDL-C (DMP = -3,57; IC 95%: -5,40--1,74 mg/dl, p < 0,001 ). Tanto la rosuvastatina como la atorvastatina fueron bien toleradas, con incidencias similares de eventos adversos.

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Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

² Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.

³ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. jiang.hong@zs-hospital.sh.cn.

⁴ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. ge.junbo2@zs-hospital.sh.cn.

Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

² Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.

³ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. jiang.hong@zs-hospital.sh.cn.

⁴ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. ge.junbo2@zs-hospital.sh.cn.

Abstract

Background: The VOYAGER meta-analysis reported on the low-density lipoprotein cholesterol (LDL-C)-lowering effect of commonly used statins in Caucasian subjects. As there is limited literature available on the efficacy of statins in Asian populations, the current meta-analysis compared the effects of rosuvastatin and atorvastatin on LDL-C levels in an East Asian population.

Methods: The MEDLINE, PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials comparing lipid-lowering effects of rosuvastatin and atorvastatin in an East Asian population. Data on the study design, participant characteristics, and outcomes were extracted. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences were calculated using the random-effects model.

Results: The meta-analysis comprised 16 randomized controlled trials with 5930 participants. Compared with atorvastatin, patients treated with rosuvastatin had a significant reduction in LDL-C: WMD = -7.15 mg/dl (95% confidence intervals [CI]: -10.71--3.60) mg/dl, p < 0.0001. Meta-regression analyses revealed no significant association between the superior benefits of rosuvastatin and other variables including age, sex, baseline LDL-C level, and follow-up duration. Additionally, the rosuvastatin group of patients, who were treated with half the dose of atorvastatin, achieved a significantly greater reduction in LDL-C levels (WMD = -3.57; 95% CI: -5.40--1.74 mg/dl, p < 0.001). Both rosuvastatin and atorvastatin were well tolerated, with similar incidences of adverse events.

Conclusion: Similar to the VOYAGER meta-analysis, which reported a greater efficacy of rosuvastatin in comparison with atorvastatin and simvastatin in Caucasian patients, we found that the efficacy of rosuvastatin was superior to atorvastatin in East Asian patients with hypercholesterolemia.

Keywords: Eastern Asia; Hypercholesterolemia; Low-density lipoprotein; Statins; Treatment efficacy.

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# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Efficacy and safety of rosuvastatin vs. atorvastatin in lowering LDL cholesterol : A meta-analysis of trials with East Asian populations - PubMed

# data[].attributes.attachment_link.description
1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. 2 Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China. 3 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

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https://pubmed.ncbi.nlm.nih.gov/19721860/La eficacia y seguridad de ezetimiba y simvastatina en dosis bajas como tratamiento primario para la dislipidemia en receptores de trasplante renal

Tipo: ECA
Resultados: La ezetimiba y la simvastatina en dosis bajas disminuyeron significativamente los niveles de colesterol total (34,6 %), triglicéridos (16,0 %) y colesterol unido a lipoproteínas de baja densidad (LDL-C) (47,6 %), y el 82,5 % de los pacientes alcanzaron el nivel objetivo de LDL-C de <100 mg/dL. No se produjeron cambios significativos en los niveles mínimos de inhibidores de la calcineurina ni en la función del aloinjerto, y no se observaron efectos adversos graves. Catorce pacientes (18,2%) suspendieron el tratamiento; ocho pacientes (11,7 %) desarrollaron dolor muscular o debilidad sin un aumento en los niveles de creatinina quinasa, y dos pacientes (2,6 %) desarrollaron niveles elevados de transaminasas hepáticas. Los niveles de proteinuria y hsCRP no cambiaron significativamente.

Conclusiones: El tratamiento con ezetimiba y estatinas a dosis bajas es seguro y eficaz como tratamiento primario de la dislipemia en pacientes trasplantados renales.

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Abstract

Background/aims: The efficacy and safety of a combination of ezetimibe and low-dose statin as primary treatment for dyslipidemia in renal transplant patients were evaluated prospectively.

Methods: The study enrolled 77 renal transplant recipients with dyslipidemia. They were given ezetimibe (10 mg) and simvastatin (10 mg) for 6 months as the initial treatment for dyslipidemia. Efficacy and safety were evaluated using lipid profiles, trough calcineurin inhibitor levels, allograft function, and adverse effects. The effects on proteinuria and high sensitivity C-reactive protein (hsCRP) levels were also evaluated.

Results: Ezetimibe and low-dose simvastatin significantly decreased the levels of total cholesterol (34.6%), triglyceride (16.0%), and low-density lipoprotein cholesterol (LDL-C) (47.6%), and 82.5% of the patients reached the target LDL-C level of <100 mg/dL. No significant change in the trough calcineurin inhibitor levels or allograft function occurred, and no serious adverse effects were observed. Fourteen patients (18.2%) discontinued treatment; eight patients (11.7%) developed muscle pain or weakness without an increase in creatinine kinase levels, and two patients (2.6%) developed elevated liver transaminase levels. The proteinuria and hsCRP levels did not change significantly.

Conclusions: Ezetimibe and low-dose statin treatment is safe and effective as a primary treatment for dyslipidemia in renal transplant patients.

Keywords: Dyslipidemias; Ezetimibe; Kidney transplantation; Statin.

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[Dual inhibition of cholesterol using the drug combination ezetimibe/simvastatin?].

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Jardine AG, Fellström B, Logan JO, et al. Cardiovascular risk and renal transplantation: post hoc analyses of the Assessment of Lescol in Renal Transplantation (ALERT) Study. Am J Kidney Dis. 2005;46:529-536. - PubMed

Kasiske BL, Guijarro C, Massy ZA, Wiederkehr MR, Ma JZ. Cardiovascular disease after renal transplantation. J Am Soc Nephrol. 1996;7:158-165. - PubMed

Kasiske B, Cosio FG, Beto J, et al. Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: a report from the Managing Dyslipidemias in Chronic Kidney Disease Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Am J Transplant. 2004;4(Suppl 7):13-53. - PubMed

Akhlaghi F, McLachlan AJ, Keogh AM, Brown KF. Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients. Br J Clin Pharmacol. 1997;44:537-542. - PMC - PubMed

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national center for biotechnology information

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The efficacy and safety of ezetimibe and low-dose simvastatin as a primary treatment for dyslipidemia in renal transplant recipients - PubMed

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Background/aims: The efficacy and safety of a combination of ezetimibe and low-dose statin as primary treatment for dyslipidemia in renal transplant patients were evaluated prospectively. Methods: The study enrolled 77 renal transplant recipients with dyslipidemia. They were given ezetimibe (10 mg) and simvastatin (10 mg) for 6 months as the initial treatment for dyslipidemia.

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Titulo:

Estatinas y concentración de colesterol total (no LDL) y resultado del infarto de miocardio: resultados de un metanálisis y un estudio observacional

Autor: xia sheng
Tipo de estudio: Metanálisis
Año: 2009
Resultados: En los metanálisis de los ensayos de prevención primaria y secundaria, las estatinas redujeron el CT en 1,54 mmol/l y 1,37 mmol/l frente a placebo. La reducción de CT asociada a las estatinas se tradujo en una reducción del riesgo del 18 % por mmol (RR 0,82; IC 95 % 0,72-0,93) para la prevención secundaria y del 24 % por mmol (RR 0,76; IC 95 % 0,62-0,93) para la prevención primaria. En el estudio de cohorte, el uso de estatinas redujo el CT en 0,98 mmol/L en comparación con el uso sin estatinas. El uso de estatinas se asoció con una reducción del 28 % (HR ajustado 0,72; IC del 95 %: 0,51-0,98) para el infarto de miocardio recurrente.
Concluciones: Las mediciones de colesterol total se pueden usar con confianza en ausencia de mediciones de LDL para tomar decisiones sobre la introducción o titulación de estatinas. Los ensayos aleatorios de la terapia con estatinas tuvieron una buena validez externa y los cambios en el colesterol y los resultados en los ensayos fueron comparables a los observados en el ámbito de la atención habitual.

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Abstract

Purpose: The purpose of this study was to evaluate how total cholesterol (TC) concentration in subjects treated with statins predicts myocardial infarction (MI) risk in the absence of low density lipoprotein cholesterol (LDL-C) measurement in clinical trials and in the setting of usual care.

Methods: A systematic review of published English language randomised clinical trials comparing statins with placebo that reported TC changes in subjects with or without prior MI between 1993 and 2008 was carried out using Medline, the Cochrane Library, Web of Science and the ISI Web of Knowledge. In addition, a cohort study of MI patients who had at least two TC measurements in Tayside, Scotland, between 1989 and 2002 was performed. The main outcome was TC concentration changes and risk of subsequent MI.

Results: In the meta-analyses of secondary and primary prevention trials statins decreased TC by 1.54 mmol/L and 1.37 mmol/L versus placebo. Statin-associated TC reduction translated into a risk reduction of 18% per mmol (RR 0.82; 95%CI 0.72-0.93) for secondary prevention and 24% per mmol (RR 0.76; 95%CI 0.62-0.93) for primary prevention. In the cohort study, statin use reduced TC by 0.98 mmol/L compared with non statin-use. Statin use was associated with a 28% reduction (adjusted HR 0.72; 95%CI 0.51-0.98) for recurrent MI.

Conclusions: Total cholesterol measurements can be used with confidence in the absence of LDL measurements to make decisions about statin drug introduction or titration. Randomised trials of statin therapy had good external validity and cholesterol changes and outcomes in trials were comparable to those observed in the setting of usual care.

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Sheng X, Murphy MJ, MacDonald TM, Wei L. Sheng X, et al. Eur J Clin Pharmacol. 2012 Aug;68(8):1201-8. doi: 10.1007/s00228-012-1234-5. Epub 2012 Feb 22. Eur J Clin Pharmacol. 2012. PMID: 22354153

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MacIntyre CR, Mahimbo A, Moa AM, Barnes M. MacIntyre CR, et al. Heart. 2016 Dec 15;102(24):1953-1956. doi: 10.1136/heartjnl-2016-309983. Epub 2016 Sep 29. Heart. 2016. PMID: 27686519 Free PMC article. Review.

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myocardial infarction / prevention & control*

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national center for biotechnology information

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Statins and total (not LDL) cholesterol concentration and outcome of myocardial infarction: results from a meta-analysis and an observational study - PubMed

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Total cholesterol measurements can be used with confidence in the absence of LDL measurements to make decisions about statin drug introduction or titration. Randomised trials of statin therapy had good external validity and cholesterol changes and outcomes in trials were comparable to those observed ...

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https://www.sciencedirect.com/science/article/abs/pii/S0149291803801625

TITULO:Efectos comparativos de simvastatina y atorvastatina en pacientes hipercolesterolémicos con características de síndrome metabólico

AÑO: 2003
RESULTADOS: De 808 pacientes evaluables, 212 (26,2 %) se clasificaron con EM al inicio del estudio. En comparación con el subgrupo sin EM, los pacientes con EM eran ligeramente mayores y tenían más probabilidades de ser mujeres. También tenían niveles más altos de IMC, SBP/DBP, FSG y TG, y niveles más bajos de HDL-C y apo AI que los pacientes sin EM. El grupo de simvastatina contenía 99 pacientes; el grupo de atorvastatina, 113 pacientes. Ambos fármacos produjeron grandes reducciones en el colesterol total, LDL-C, no-HDL-C, TG y apo B, y la atorvastatina produjo reducciones ligeramente mayores en TG. Sin embargo, la simvastatina produjo aumentos consistentemente mayores en el HDL-C y la apo AI que la atorvastatina, especialmente en dosis más altas. Después de 36 semanas de tratamiento, el 47,7 % y el 48,5 % de los grupos de simvastatina y atorvastatina, respectivamente, ya no cumplían ≥3 de los criterios de EM.

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Fluvastatin for lowering lipids - PubMed

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Fluvastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose-dependent linear fashion. Based on the effect on LDL cholesterol, fluvastatin is 12-fold less potent than atorvastatin and 46-fold less potent than rosuvastatin. This review did not provide a good estimate of the…

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https://pubmed.ncbi.nlm.nih.gov/29857919/

Titulo: Eficacia y seguridad del tratamiento combinado con ezetimiba y rosuvastatina frente a la monoterapia con rosuvastatina en pacientes con hipercolesterolemia primaria

Autor: Woohyun kim y Col.
Año: 2018
Tipo de estudio: ECA
Resultado: En el estudio principal, se comparó la eficacia  de una combinación de rosuvastatina (5, 10 y 20 mg) con ezetimiba (10 mg) con las de rosuvastatina (5, 10 y 20 mg) sola, como resultado final del estudio principal (semana 8), los niveles de LDL-C fueron significativamente más bajos en los sujetos que recibieron terapia combinada que en los que recibieron monoterapia con rosuvastatina. Otros perfiles de lípidos también mejoraron significativamente en el grupo de terapia combinada. Estas mejoras continuaron en el estudio de extensión. La terapia combinada de rosuvastatina y ezetimiba fue generalmente bien tolerada. Como conclusión la terapia combinada de ezetimiba 10 mg con dosis variables de rosuvastatina que se usan comúnmente en el campo clínico mejoró el perfil de lípidos y permitió que más sujetos alcanzaran la meta de C-LDL en la hipercolesterolemia primaria en comparación con la monoterapia con rosuvastatina. Además, la la terapia combinada se mantuvo durante el período prolongado.

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Affiliations

¹ Department of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea.

² Department of Cardiology, Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

³ Division of Cardiology, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea.

⁴ Division of Cardiology, Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.

⁵ Division of Cardiology, Heart Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

⁶ Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea.

⁷ Division of Cardiology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

⁸ Division of Cardiology, Gachon University Gil Medical Center, Incheon, Republic of Korea.

⁹ Division of Cardiology, Department of Internal Medicine, Kyung Hee University, Kyung Hee University Hospital, Seoul, Republic of Korea.

¹⁰ Cardiovascular Center, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.

¹¹ Division of Cardiology, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea.

¹² Division of Cardiology, Asan Medical Center, Seoul, Republic of Korea.

¹³ Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.

¹⁴ Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea.

¹⁵ Division of Cardiology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea.

¹⁶ Department of Cardiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.

¹⁷ Division of Cardiology, Department of Internal Medicine, Hallym University Dontan Sacred Heart Hospital, Hwaseong, Republic of Korea.

¹⁸ Division of Cardiology, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea.

¹⁹ Division of Cardiology, Department of Internal Medicine, Chungnam National University College of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.

²⁰ Division of Cardiology, Department of Internal Medicine, Hanyang University Hospital, Seoul, Republic of Korea.

²¹ Department of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea. Electronic address: parkcg@kumc.or.kr.

Affiliations

¹ Department of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea.

² Department of Cardiology, Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

³ Division of Cardiology, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea.

⁴ Division of Cardiology, Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.

⁵ Division of Cardiology, Heart Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

⁶ Department of Cardiology, Cardiovascular Center, Korea University Anam Hospital, Seoul, Republic of Korea.

⁷ Division of Cardiology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

⁸ Division of Cardiology, Gachon University Gil Medical Center, Incheon, Republic of Korea.

⁹ Division of Cardiology, Department of Internal Medicine, Kyung Hee University, Kyung Hee University Hospital, Seoul, Republic of Korea.

¹⁰ Cardiovascular Center, Dongguk University Ilsan Hospital, Goyang, Republic of Korea.

¹¹ Division of Cardiology, Department of Internal Medicine, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea.

¹² Division of Cardiology, Asan Medical Center, Seoul, Republic of Korea.

¹³ Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea.

¹⁴ Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea.

¹⁵ Division of Cardiology, Department of Internal Medicine, Yeungnam University Hospital, Daegu, Republic of Korea.

¹⁶ Department of Cardiology, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.

¹⁷ Division of Cardiology, Department of Internal Medicine, Hallym University Dontan Sacred Heart Hospital, Hwaseong, Republic of Korea.

¹⁸ Division of Cardiology, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea.

¹⁹ Division of Cardiology, Department of Internal Medicine, Chungnam National University College of Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea.

²⁰ Division of Cardiology, Department of Internal Medicine, Hanyang University Hospital, Seoul, Republic of Korea.

²¹ Department of Cardiology, Cardiovascular Center, Korea University Guro Hospital, Seoul, Republic of Korea. Electronic address: parkcg@kumc.or.kr.

Abstract

Purpose: The aim of this study was to evaluate the safety and efficacy of combination treatment of rosuvastatin with ezetimibe in patients with primary hypercholesterolemia.

Methods: This multicenter, randomized, double-blind study comprised a main study and an extension study. In the main study, the efficacy and safety of a combination of rosuvastatin (5, 10, and 20 mg) with ezetimibe (10 mg) were compared with those of rosuvastatin (5, 10, and 20 mg) alone. The subjects who achieved the National Cholesterol Education Program Adult Treatment Panel III LDL-C goal in the main study and agreed to a further study were enrolled for the extension study. In the extension study, ezetimibe 10 mg was also administered to subjects who had received rosuvastatin (5, 10, and 20 mg) alone in the main study, and the same treatment was continued for subjects who had received a combination of rosuvastatin with ezetimibe in the main study.

Findings: At the end of the main study (week 8), LDL-C levels were significantly lower in subjects receiving combination therapy than in those receiving rosuvastatin monotherapy. Other lipid profiles also significantly improved in the combination therapy group. These improvements continued in the extension study. The combination therapy of rosuvastatin and ezetimibe was generally well tolerated. At the end of the main study, more subjects achieved the National Cholesterol Education Program Adult Treatment Panel III LDL-C goal in the combination therapy group than in the monotherapy group. The increased dosage of rosuvastatin was also well tolerated in the combination treatment.

Implications: Combination therapy of ezetimibe 10 mg with varying doses of rosuvastatin that are commonly used in the clinical field improved the lipid profile and allowed more subjects to reach the LDL-C goal in primary hypercholesterolemia compared with rosuvastatin monotherapy. In addition, the efficacy of the combination therapy was maintained for the extended period. Additional beneficial changes were also achieved with combination therapy even in patients who responded well to rosuvastatin monotherapy. ClinicalTrials.gov identifier: NCT03288038.

Keywords: LDL-C; cardiovascular diseases; combination therapy; ezetimibe; rosuvastatin.

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anticholesteremic agents / administration & dosage*

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rosuvastatin calcium / administration & dosage*

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national center for biotechnology information

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Efficacy and Safety of Ezetimibe and Rosuvastatin Combination Therapy Versus Those of Rosuvastatin Monotherapy in Patients With Primary Hypercholesterolemia - PubMed

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Combination therapy of ezetimibe 10 mg with varying doses of rosuvastatin that are commonly used in the clinical field improved the lipid profile and allowed more subjects to reach the LDL-C goal in primary hypercholesterolemia compared with rosuvastatin monotherapy. In addition, the efficacy of the ...

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https://www.sciencedirect.com/science/article/abs/pii/S0014256510001530?via%3Dihub
TITULO :

Metaanálisis de ensayos clínicos randomizados que evalúan la eficacia de las estatinas versus placebo en la insuficiencia cardíaca

AÑO : 2010
Las estatinas son fármacos que han demostrado una gran utilidad en prevención primaria y secundaria de morbimortalidad cardiovascular. Su adición al tratamiento estándar de la IC podría tener también efectos favorables. El presente metaanálisis, nos confirma algunos de estos efectos con mejorías en la morbilidad, y posiblemente en los costes, de estos pacientes

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national center for biotechnology information

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Metaanálisis de ensayos clínicos randomizados que evalúan la eficacia de las estatinas versus placebo en la insuficiencia cardíaca - PubMed

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Metaanálisis de ensayos clínicos randomizados que evalúan la eficacia de las estatinas versus placebo en la insuficiencia cardíaca

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https://pubmed.ncbi.nlm.nih.gov/30712900/

Titulo:

Eficacia y seguridad de la terapia con estatinas en personas mayores: un metanálisis de datos de participantes individuales de 28 ensayos controlados aleatorios

Año: 2019
Tipo de estudio: Metaanálisis
Resultados: En general, la terapia con estatinas o un régimen de estatinas más intensivo produjo una reducción proporcional del 21 % (RR 0,79, IC del 95 % 0,77-0,81) en los eventos vasculares mayores por cada 1,0 mmol/L de reducción en el colesterol LDL. Observamos una reducción significativa de los eventos vasculares mayores en todos los grupos de edad. Aunque las reducciones proporcionales en los eventos vasculares mayores disminuyeron ligeramente con la edad, esta tendencia no fue estadísticamente significativa ( tendencia p=0·06). En general, las estatinas o una terapia más intensiva produjeron una reducción proporcional del 24 % (RR 0,76, IC del 95 % 0,73-0,79) en los eventos coronarios mayores por cada 1,0 mmol/L de reducción en el colesterol LDL, y con el aumento de la edad , observamos una tendencia hacia reducciones de riesgo proporcionales más pequeñas en eventos coronarios mayores (p tendencia = 0·009). Se observó una reducción proporcional del 25 % (RR 0,75, IC del 95 % 0,73-0,78) en el riesgo de procedimientos de revascularización coronaria con el tratamiento con estatinas o un régimen más intensivo con estatinas por 1,0 mmol/L de colesterol LDL más bajo , que no difirió significativamente entre los grupos de edad (p tendencia =0·6). De manera similar, las reducciones proporcionales en accidentes cerebrovasculares de cualquier tipo (RR 0·84, IC del 95% 0·80-0·89) no difirieron significativamente entre los grupos de edad (p tendencia=0·7). Después de la exclusión de cuatro ensayos que incluyeron solo a pacientes con insuficiencia cardíaca o sometidos a diálisis renal (entre los que no se ha demostrado que el tratamiento con estatinas sea eficaz), persistió la tendencia a reducciones de riesgo proporcionales más pequeñas con el aumento de la edad para los eventos coronarios importantes (p tendencia = 0 ·01), y permaneció no significativo para eventos vasculares mayores (p tendencia =0,3). La reducción proporcional de los eventos vasculares mayores fue similar, independientemente de la edad, entre los pacientes con enfermedad vascular preexistente (p tendencia = 0,2), pero pareció menor entre los individuos mayores que entre los más jóvenes sin enfermedad vascular conocida (p tendencia=0·05). Encontramos una reducción proporcional del 12% (RR 0·88, IC del 95% 0·85-0·91) en la mortalidad vascular por cada 1,0 mmol/L de reducción en el colesterol LDL, con una tendencia hacia reducciones proporcionales menores con la edad ( p tendencia = 0,004), pero esta tendencia no persistió después de la exclusión de los ensayos de insuficiencia cardíaca o diálisis (p tendencia = 0,2).
Interpretación: la terapia con estatinas produce reducciones significativas en los eventos vasculares mayores independientemente de la edad, pero hay menos evidencia directa de beneficio entre los pacientes mayores de 75 años que aún no tienen evidencia de enfermedad vascular oclusiva. Esta limitación ahora se está abordando en ensayos adicionales.

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Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials - PubMed

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Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation.

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Título: Comparación de la eficacia y la seguridad del tratamiento con estatinas en dosis intensiva y en dosis estándar para la prevención del accidente cerebrovascular: un metanálisis
Tipo de estudio: Metaanálisis.

Año:  2016

Autor: J uan wang , Dan Chen , Da Bing Li , Xinyu , Guo Bing Shi

Objetivo: Comparar la eficacia y la seguridad del tratamiento con estatinas en dosis intensivas y en dosis estándar para prevenir el accidente cerebrovascular en pacientes de alto riesgo.

Resultados: Para todas las incidencias de accidentes cerebrovasculares, el tratamiento con estatinas en dosis intensiva en comparación con el tratamiento con placebo y el tratamiento con estatinas en dosis estándar en comparación con el tratamiento con placebo mostró una reducción significativa del 21 % en el riesgo relativo (RR) (RR 0,79, intervalo de confianza (IC) del 95 %). [0,71, 0,87], P < 0,00001) y una reducción del RR del 18 % (RR 0,82, IC del 95 % [0,73, 0,93], P = 0,002) en el subgrupo sin receptores de trasplante renal y pacientes sometidos a hemodiálisis periódica por separado. Para las incidencias de accidente cerebrovascular mortal, el tratamiento con estatinas en dosis intensivas en comparación con la dosis estándar o el placebo fue eficaz para reducir el accidente cerebrovascular mortal (RR 0,61, IC del 95 % [0,39, 0,96], P = 0,03) y el RR fue de 1,01 (IC del 95 % [0,85 , 1,20], P = 0,90) en el tratamiento con estatinas en dosis estándar en comparación con el placebo.

Conclusiones:  Los resultados de este metanálisis sugieren que el tratamiento con estatinas en dosis intensivas podría ser más favorable para reducir la incidencia de todos los accidentes cerebrovasculares que el tratamiento con estatinas en dosis estándar, especialmente para pacientes mayores de 65 años en la reducción de las incidencias de todos los accidentes cerebrovasculares.

https://pubmed.ncbi.nlm.nih.gov/27684837/

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doi: 10.1097/MD.0000000000004950.

Affiliation

¹ aDepartment of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China bDepartment of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.

Free PMC article

Free PMC article

doi: 10.1097/MD.0000000000004950.

Affiliation

¹ aDepartment of Pharmacy, General Hospital of Shenyang Military Area Command, Shenyang, Liaoning, China bDepartment of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.

Abstract

Background: Previous study indicated that high-dose statin treatment might increase the risk of hemorrhagic stroke and adverse reactions. We aim to compare the efficacy and safety of intensive-dose and standard-dose statin treatment for preventing stroke in high-risk patients.

Methods: A thorough search was performed of multiple databases for publications from 1990 to June 2015. We selected the randomized clinical trials comparing standard-dose statin with placebo and intensive-dose statin with standard-dose statin or placebo for the prevention of stroke events in patients. Duplicate independent data extraction and bias assessments were performed. Data were pooled using a fixed-effects model or a random-effects model if significant heterogeneity was present.

Results: For the all stroke incidences, intensive-dose statin treatment compared with placebo treatment and standard-dose statin treatment compared with placebo treatment showed a significant 21% reduction in relative risk (RR) (RR 0.79, 95% confidence interval (CI) [0.71, 0.87], P < 0.00001) and an 18% reduction in RR (RR 0.82, 95% CI [0.73, 0.93], P = 0.002) in the subgroup without renal transplant recipients and patients undergoing regular hemodialysis separately. For the fatal stroke incidences, intensive-dose statin treatment compared with standard dose or placebo was effective reducing fatal stroke (RR 0.61, 95% CI [0.39, 0.96], P = 0.03) and the RR was 1.01 (95% CI [0.85, 1.20], P = 0.90) in standard-dose statin treatment compared with placebo.

Conclusion: The results of this meta-analysis suggest that intensive-dose statin treatment might be more favorable for reducing the incidences of all strokes than standard-dose statin treatment, especially for patients older than 65 years in reducing the incidences of all stroke incidences.

Conflict of interest statement

The authors have no funding and conflicts of interest to disclose.

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Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.

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national center for biotechnology information

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Comparison of the efficacy and safety of intensive-dose and standard-dose statin treatment for stroke prevention: A meta-analysis - PubMed

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The results of this meta-analysis suggest that intensive-dose statin treatment might be more favorable for reducing the incidences of all strokes than standard-dose statin treatment, especially for patients older than 65 years in reducing the incidences of all stroke incidences.

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TITULO:

Fibratos para la prevención secundaria de enfermedades cardiovasculares y accidentes cerebrovasculares

TIPO DE ESTUDIO: Metanálisis de ECA
AÑO:2015
RESULTADOS: Se encontró que, en comparación principalmente con placebo, los fibratos como clase de fármacos pueden tener un efecto protector para el resultado compuesto de accidente cerebrovascular no mortal, IM no mortal y muerte vascular en pacientes con antecedentes de ECV. Este efecto protector pareció ser principalmente el resultado de una reducción en los eventos de IM no fatales o fatales.
CONCLUSIONES:Se encontró evidencia de que la clase de fármacos fibratos puede tener un efecto preventivo secundario en los pacientes con ECV.

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Review question
The aim of this study was to assess the effect of fibrates for the prevention of major events including heart attacks, strokes, and circulatory disease death in people with existing circulatory disease.
Background
Fibrates have been used for many years as a treatment to prevent further heart attacks and strokes in people who already have disease of their circulatory system. Fibrates are a class of drugs that work by positively influencing fats in the the blood, that is lowering triglyceride, raising high‐density lipoprotein ('good') cholesterol and lowering the small dense fraction of low‐density lipoprotein ('bad') cholesterol. The drug class includes clofibrate, gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate. Successful adjustment of the blood fats in people with disease of their circulatory system could mean these individuals are less likely to have heart attacks, stroke, and die from their circulatory disease. There is currently no clear evidence for benefit of fibrates in such people.
Study characteristics
The duration of fibrates ranged from 12 months to 8 years.
Key results
We included 13 trials in this review with a total of 16,112 participants with a history of coronary heart disease or stroke. This review includes evidence identified up to October 2014.

Our analysis showed that when compared primarily to placebo, fibrates can be effective for prevention of composite outcome of non‐fatal stroke, non‐fatal heart attack (myocardial infarction), and death due to circulatory disease. However, this beneficial effect relies on the inclusion on data from clofibrates, a drug that was discontinued in 2002 because of safety concerns. In other words, there is no good evidence to support the use of currently available fibrates in the prevention of future heart attacks, strokes, and circulatory disease death in people with existing circulatory disease.
Quality of the evidence
In combination with clofibrate data, quality of evidence was moderate for the composite (non‐fatal stroke, non‐fatal myocardial infarction (MI), and vascular death) and MI (non‐fatal or fatal) outcomes and low for stroke (ischaemic or haemorrhagic, non‐fatal or fatal) and death from vascular or any cause during the treatment and scheduled follow‐up period. The quality of evidence without clofibrate data was moderate for MI (non‐fatal or fatal) outcome and low for the composite (non‐fatal stroke, non‐fatal MI, and vascular death), stroke (ischaemic or haemorrhagic, non‐fatal or fatal), and death from vascular or any cause outcomes during the treatment and scheduled follow‐up period.

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Fibrates for secondary prevention of cardiovascular disease and stroke

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Review question The aim of this study was to assess the effect of fibrates for the prevention of major events including heart attacks, strokes, and circulatory disease death in people with existing circulatory disease. Background Fibrates have been used for many years as a treatment to prevent further heart attacks and strokes in people who already have disease of their circulatory system.

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https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.026992

Uso de estatinas después de un accidente cerebrovascular isquémico en adultos jóvenes y su asociación con resultados a largo plazo
Ensayos , 2019
Resultados : Los usuarios de estatinas exhibieron un riesgo más bajo de mortalidad por todas las causas (cociente de riesgos instantáneos, 0,38 [IC 95 %, 0,25–0,58]) y accidente cerebrovascular recurrente (cociente de riesgos instantáneos, 0,29 [IC 95 %, 0,19–0,44]) que los no usuarios, después del ajuste por dislipidemia , subtipo de accidente cerebrovascular y otros factores de confusión.

Conclusión : El uso de estatinas se asoció de forma independiente con un menor riesgo de mortalidad por todas las causas y accidente cerebrovascular recurrente.

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TITULO:

Seguridad y eficacia de ezetimiba: un metanálisis

AÑO: 2015
TIPO DE ESTUDIO: Metaanálisis
RESULTADOS: se incluyeron en el análisis 7 ensayos con 31 048 pacientes (mediana de seguimiento de 34,1 ± 26,3 meses; 70 % de mujeres; edad media de 61 ± 8 años). En comparación con la terapia de control, ezetimiba redujo significativamente el riesgo de infarto de miocardio en un 13,5 % (RR: 0,865, IC del 95 %: de 0,801 a 0,934, p<0,001) y el riesgo de cualquier accidente cerebrovascular en un 16,0 % (RR: 0,840, IC del 95 %: 0,744 a 0,949, p=0,005), sin ningún efecto sobre la mortalidad por todas las causas y CV (RR: 1,003, IC 95%: 0,954 a 1,055, p=0,908; RR: 0,958, IC 95%: 0,879 a 1,044, p= 0,330; respectivamente) y riesgo de cáncer nuevo (RR: 1,040, IC 95%: 0,965 a 1,120, p=0,303).
https://pubmed.ncbi.nlm.nih.gov/26301648/

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Affiliations

¹ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.

² Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

³ Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

⁴ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. Electronic address: fpperron@unina.it.

Affiliations

¹ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.

² Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

³ Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

⁴ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. Electronic address: fpperron@unina.it.

Abstract

Background: The addition of ezetimibe to statin therapy has been widely demonstrated to significantly reduce low-density lipoprotein cholesterol levels. However, the efficacy of ezetimibe in reducing CV events and its safety has been less investigated. The aim of the current meta-analysis was to report efficacy and safety of ezetimibe from randomized clinical trials.

Methods: Randomized clinical trials with a follow-up of at least 24 weeks, enrolling more than 200 patients, comparing ezetimibe versus placebo or ezetimibe plus another hypolipidemic agent versus the same hypolipidemic drug alone and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of cancer were included in the analysis.

Results: 7 trials enrolling 31,048 patients (median follow-up 34.1 ± 26.3 months; 70% women; mean age 61 ± 8 years) were included in the analysis. Compared to control therapy, ezetimibe significantly reduced the risk of MI by 13.5% (RR: 0.865, 95% CI: 0.801 to 0.934, p<0.001) and the risk of any stroke by 16.0% (RR: 0.840, 95% CI: 0.744 to 0.949, p=0.005), without any effect on all-cause and CV mortality (RR: 1.003, 95% CI: 0.954 to 1.055, p=0.908; RR: 0.958, 95% CI: 0.879 to 1.044, p=0.330; respectively) and risk of new cancer (RR: 1.040, 95% CI: 0.965 to 1.120, p=0.303).

Conclusions: Ezetimibe significantly reduces the risk of MI and stroke without any effect on all-cause and CV mortality and risk of cancer.

Keywords: Cardiovascular events; Cholesterol; Ezetimibe; Mortality; Statins.

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Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis.

Savarese G, Gotto AM Jr, Paolillo S, D'Amore C, Losco T, Musella F, Scala O, Marciano C, Ruggiero D, Marsico F, De Luca G, Trimarco B, Perrone-Filardi P. Savarese G, et al. J Am Coll Cardiol. 2013 Dec 3;62(22):2090-9. doi: 10.1016/j.jacc.2013.07.069. Epub 2013 Aug 28. J Am Coll Cardiol. 2013. PMID: 23954343

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anticholesteremic agents / therapeutic use

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cardiovascular diseases* / prevention & control

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national center for biotechnology information

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Safety and efficacy of ezetimibe: A meta-analysis - PubMed

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1 Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. 2 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 3 Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

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Título:

Efecto de la ezetimiba añadida a la terapia con estatinas de alta intensidad sobre los niveles de colesterol de lipoproteínas de baja densidad: un metanálisis

Año:2021
Tipo de estudio: Metaanálisis
Resultados: En este estudio se incluyeron un total de 14 ensayos con 2007 pacientes. En comparación con la monoterapia con estatinas de alta intensidad, la DM en la reducción del C-LDL con la terapia con estatinas de alta intensidad más ezetimiba fue -14,00 % (intervalo de confianza del 95 %: -17,78 a -10,22; P < 0,001) con un grado moderado de heterogeneidad (P < 0,001, I ² = 66%). No se identificó ningún sesgo de publicación significativo entre los ensayos incluidos.

Conclusiones: Nuestro estudio encontró que agregar ezetimiba a la terapia con estatinas de alta intensidad proporcionó una reducción incremental significativa pero atenuada en los niveles de LDL-C. Si la magnitud de esta reducción adicional de los niveles de LDL-C conduciría a beneficios en los resultados clínicos cardiovasculares, se necesita más investigación

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Affiliations

¹ School of Pharmacy, Philadelphia College of Osteopathic Medicine, Suwanee, GA, USA.

² The Heart Center of Northeast Georgia Medical Center, Gainesville, GA, USA.

³ College of Pharmacy, California Health Sciences University, Clovis, CA, USA.

Free PMC article

Free PMC article

Affiliations

¹ School of Pharmacy, Philadelphia College of Osteopathic Medicine, Suwanee, GA, USA.

² The Heart Center of Northeast Georgia Medical Center, Gainesville, GA, USA.

³ College of Pharmacy, California Health Sciences University, Clovis, CA, USA.

Abstract

Background: Adding ezetimibe to high-intensity statin therapy is used for additional lowering of low-density lipoprotein cholesterol (LDL-C); however, there are little data on the efficacy of ezetimibe when combined with a high-intensity statin. A meta-analysis was performed to evaluate the efficacy of ezetimibe added to high-intensity statin therapy on LDL-C levels.

Methods: A literature search from database inception to May 2020 was performed using PubMed, EMBASE and Cochrane Central Register of Controlled Trials. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this meta-analysis, in which the random-effects model was adopted for the calculation of the mean difference (MD). The Cochrane Collaboration's tool for assessing the risk of bias was used to evaluate the quality of the included trials.

Results: A total of 14 trials with 2,007 patients were included in this study. Compared to the high-intensity statin monotherapy, the MD in LDL-C reduction with high-intensity statin therapy plus ezetimibe was -14.00% (95% confidence interval: -17.78 to -10.22; P < 0.001) with a moderate degree of heterogeneity (P < 0.001, I ² = 66%). No significant publication bias among the included trials was identified.

Conclusions: Our study found that adding ezetimibe to high-intensity statin therapy provided a significant but attenuated incremental reduction in LDL-C levels. Whether the magnitude of this additional lowering of LDL-C levels would lead to benefits in clinical cardiovascular outcomes needs further investigation.

Keywords: Coronary heart disease; Ezetimibe; High-intensity statin; Hypercholesterolemia; LDL-C.

Conflict of interest statement

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References

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT. et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019;139(25):e1082-e1143. doi: 10.1161/CIR.0000000000000698. - DOI - PMC - PubMed

Gencer B, Carballo D, Nanchen D, Koskinas KC, Klingenberg R, Raber L, Auer R. et al. Intensified lipid lowering using ezetimibe after publication of the IMPROVE-IT trial: A contemporary analysis from the SPUM-ACS cohort. Int J Cardiol. 2020;303:8-13. doi: 10.1016/j.ijcard.2019.12.011. - DOI - PubMed

Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H. et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi: 10.1056/NEJMoa1410489. - DOI - PubMed

Mikhailidis DP, Sibbring GC, Ballantyne CM, Davies GM, Catapano AL. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin. 2007;23(8):2009-2026. doi: 10.1185/030079907X210507. - DOI - PubMed

Mikhailidis DP, Lawson RW, McCormick AL, Sibbring GC, Tershakovec AM, Davies GM, Tunceli K. Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis. Curr Med Res Opin. 2011;27(6):1191-1210. doi: 10.1185/03007995.2011.571239. - DOI - PubMed

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national center for biotechnology information

# data[].attributes.attachment_link.title
Effect of Ezetimibe Added to High-Intensity Statin Therapy on Low-Density Lipoprotein Cholesterol Levels: A Meta-Analysis - PubMed

# data[].attributes.attachment_link.description
Our study found that adding ezetimibe to high-intensity statin therapy provided a significant but attenuated incremental reduction in LDL-C levels. Whether the magnitude of this additional lowering of LDL-C levels would lead to benefits in clinical cardiovascular outcomes needs further investigation ...

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310732/
TITULO: Ensayo controlado aleatorizado que compara la eficacia del tratamiento diario y cada dos días con atorvastatina y su correlación con los niveles séricos de la enzima hidroximetilglutaril-CoA reductasa en pacientes dislipidémicos sin tratamiento previo.
TIPO DE ESTUDIO: Metaanálisis
AÑO: 2018
RESULTADOS: Se incluyeron un total de 61 pacientes, de los cuales 46 completaron el estudio (24 en el grupo DR frente a 22 en el grupo EODR). La reducción media del colesterol total (CT), el colesterol de lipoproteínas de baja densidad (LDL-C) y el colesterol de lipoproteínas de no alta densidad (HDL-C) fue significativamente mayor en el grupo DR, mientras que la reducción media de los triglicéridos (TG) y el aumento en HDL-C fue similar en ambos grupos. La reducción en los niveles séricos de HMGCR fue comparable en ambos grupos (31,17 % frente a 28,19 %). El cambio en los niveles séricos de HMGCR se correlacionó más con el cambio en los índices de lípidos del grupo DR. Además, los parámetros de seguridad fueron similares entre los dos grupos.
CONCLUSIÓN: Ambos regímenes lograron objetivos terapéuticos, sin embargo, se encontró que DR fue superior ya que logró una mayor reducción en TC y LDL-C. Además, estos hallazgos están respaldados por la correlación de los índices de lípidos con los niveles séricos de HMGCR.

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Abstract

Objective

Data regarding efficacy comparison of daily regimen (DR) versus every other day regimen (EODR) atorvastatin therapy is not validated by estimation of serum hydroxymethylglutaryl-CoA reductase (HMGCR) levels and HMGCR correlation with lipid indices.

Methods

In this randomized controlled trial, we compared the efficacy of DR versus EODR by measuring lipid indices and serum HMGCR levels at baseline and after 12 weeks of 10 mg atorvastatin therapy. Primary endpoint was comparison of mean change in serum HMGCR levels and lipid indices of both groups and their correlation with each other. Secondary endpoints were assessed by estimating serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase MM (CK-MM) levels and adverse drug reactions (ADRs).

Results

A total of 61 patients were enrolled of which 46 completed the study (24 in DR vs 22 in EODR group). The mean reduction in total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and non-high density lipoprotein-cholesterol (HDL-C) was significantly higher in DR group, whereas mean reduction in triglycerides (TG) and increase in HDL-C was similar in both the groups. Reduction in serum HMGCR levels was comparable in both the groups (31.17% vs 28.19%). Change in serum HMGCR levels correlated more with change in lipid indices of DR group. Also, safety parameters were similar between the two groups.

Conclusion

Both the regimens achieved therapeutic goals, however DR was found to be superior as it achieved greater reduction in TC and LDL-C. Further, these findings are substantiated by correlation of lipid indices with serum HMGCR levels.

Keywords: Atorvastatin, Every other day atorvastatin, Dyslipidemia, Hydroxymethylglutaryl-CoA reductase enzyme

1. Introduction

Cardiovascular diseases (CVD) are the most common cause of mortality and are responsible for about 31% of all deaths in the world. 1 In the developing countries, CVD related mortality is increasing and being encountered a decade earlier than developed countries. 2 Indian population has increased propensity of CVD risk factors viz. hypertension, diabetes mellitus, dyslipidemias, tobacco use, obesity etc. 3 In addition, Indian population has lower high density lipoprotein-cholesterol (HDL-C), higher triglycerides (TG) and higher lipoprotein (a) levels as compared to the Western population which is associated with greater risk of development and progression of the atherosclerosis. 4, 5 Early initiation of statins stabilizes the atherosclerotic plaque which in turn reduces the cardiovascular-related mortality. 6, 7

Statins are usually well tolerated by patients, but could be associated with adverse drug reactions (ADRs) including myalgia (190 per 100,000 patient years), myositis (5 per 100,000 patient years), rhabdomyolysis (1.6 per 100,000 patient years) and rise in serum liver enzymes i.e. aspartate aminotransferase (AST) and alanine aminotransferase (ALT). 8, 9 Approximately 10-15% of dyslipidemic patients are intolerant to statins due to these adverse effects depriving them from pleiotropic benefits of statins. 10 Few researchers have studied every other day statin therapy (EODT) and found comparable clinical efficacy with daily statin therapy with reduced severity and frequency of associated adverse events. 11, 12, 13, 14, 15 The use of every other day statin may be justified for 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) inhibitors having longer half-life (>24 h) namely atorvastatin and rosuvastatin because of their active metabolites. 16 The benefits of every other day statin therapy claimed by studies available in the literature are not yet substantiated by extent of inhibition of serum HMGCR enzyme. 11, 12, 13, 14, 15 If the extent of inhibition of serum HMGCR enzyme is found to be similar in both daily and every other day atorvastatin therapy, every other day atorvastatin may be considered as alternative option to daily atorvastatin therapy especially for daily statin intolerant patients. Henceforth, the present study was undertaken to evaluate and compare the efficacy and safety of every other day atorvastatin with its standard daily regimen and investigated the correlation of alteration in lipid indices with serum HMGCR enzyme levels.

2. Materials and methods

This was a randomized, open-label, controlled, per protocol analysis study on statin treatment naive dyslipidemic patients after the approval of Institutional Ethics Committee (IEC) for Human Research, Lady Hardinge Medical College and Associated Hospitals, New Delhi.

Dyslipidemic patients with 0-1 risk factor for CVD aged more than 18 years were prescribed hypolipidemic pharmacotherapy as per National Cholesterol Education Program (NCEP), Adult Treatment Panel (ATP) III Guidelines after obtaining their informed written consent to participate in the study. 17 The patients having ALT and AST levels >3 times of upper normal limit (UNL); creatine kinase MM isoenzyme (CK-MM) >10 times UNL; diagnosis of acute coronary syndrome within the last 3 months; history of alcohol intake (>60 ml/day for more than 6 months); concurrent use of other hypolipidemic drug(s), immune-suppressant agents and azoles; history of diabetes mellitus, hypertension, hypothyroidism, pregnancy, lactation, prior hypersensitivity and/or intolerance to any HMGCR inhibitors were excluded from the study.

The baseline clinical examination and biochemical investigations i.e. AST, ALT, lipid indices i.e. total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C), LDL-C, TG, non HDL-C and serum HMGCR & CK-MM levels were recorded for the study population. Using block randomization, patients were allocated to receive 10 mg atorvastatin either daily i.e. daily regimen (DR) group or every other day i.e. every other day regimen (EODR) group orally after dinner for a period of 12 weeks. Patients included in the study were explained dietary and lifestyle modifications and a written handout was given for the same. 17 At the end of study period i.e. 12 weeks, all the baseline biochemical investigations were repeated and adverse drug events/reactions (if any) were documented as per definition and standards of Pharmacovigilance Program of India. 18 Change in the study parameters after 12 weeks of daily and every other day atorvastatin therapy were compared with their respective baseline values. Primary end point was the extent of inhibition of serum HMGCR levels in both the study regimens which were correlated with changes in lipid profile (TC, LDL-C, TG, HDL-C and non HDL-C) of patients in the respective groups. Secondary end points included mean change in serum liver enzymes (AST and ALT) levels, serum CK-MM levels and difference in reported ADR(s) between the two groups.

Lipid profile was estimated using Beckman Coulter AU-680/5800 auto-analyzer. The serum samples to estimate HMGCR and CK-MM were stored at −30° C till analysis. Serum HMGCR and CK-MM levels were estimated using BMASSAY [Human HMGCR enzyme linked immunosorbent assay (ELISA)] kit and human CK-MM ELISA kit.

3. Statistical analysis

The data have been presented as Mean ± SD and percentage and analyzed using SPSS-17 software. The comparison of lipid indices (TC, LDL-C, TG, HDL-C and non HDL-C), liver enzymes (AST and ALT), serum HMGCR and serum CK-MM levels at baseline and at the end of 12 weeks of therapy (within and in between the groups) was done by paired and unpaired student's t-test.

Paired student's t-test was used to compare within group and unpaired Student's t-test was used to compare in between the groups data of lipid indices (TC, LDL-C, TG, HDL-C and non HDL-C), liver enzymes (AST and ALT), serum HMGCR and serum CK-MM levels at baseline and at the end of 12 weeks of therapy.

Adverse drug reactions/events were compared using Chi square test with Yate's correction. Pearson's coefficient of correlation and regression was used to find the correlation between the lipid indices of the patients in both the regimens with mean serum HMGCR level. P-value less than 0.05 was considered as significant.

4. Results

Of a total of 61 patients enrolled, 46 patients completed the study. Age and gender distribution was similar in the two groups (DR: n = 24, mean age = 49.46 ± 6.84 year, male: female = 13:11; EODR: n = 22, mean age = 47.73 ± 9.09 year, male: female = 12:10). Mean weight and body mass index (BMI) of the patients were slightly increased (p value >0.05) after 12 weeks of the atorvastatin treatment from their respective baseline values in both the regimens.

In both DR and EODR group, the mean baseline levels of TC, LDL-C, non HDL-C and TG decreased while the HDL-C increased significantly (p < 0.0001) after 12 weeks of atorvastatin therapy (). On comparing the mean change in TC, LDL-C and non HLD-C levels in DR and EODR group, it was found that daily regimen was superior in reducing these values significantly (p < 0.0001), whereas the comparison between mean change in the levels of TG and HDL-C were statistically insignificant ().

Table 1

Table 2

The baseline levels of serum HMGCR in DR group and EODR group were similar (). These values at the end of 12 weeks of atorvastatin therapy were significantly reduced in both DR group and in EODR group. The percentage reduction was comparable in both the groups (31.17% vs 28.19%; p = 0.655) ().

On analysis of the correlation between change in serum HMGCR levels and change in lipid indices, we found that the correlation is better in DR group than EODR group for all the lipid indices. Also, correlation was significant for all the lipid indices in DR group but in EODR group, the correlation was significantly evident only for TC ().

Table 3

On evaluating the safety parameters of both the regimens after 12 weeks of atorvastatin treatment, we found that the rise in mean ALT and AST levels was statistically significant in DR group whereas in EODR group, only mean AST levels were significantly raised (). Also, percentage change in AST and ALT did not significantly differ between DR and EODR group (). Serum CK-MM, a marker of muscular toxicity, did not significantly change within and in between the two groups (, ). In addition, a total of 21 adverse drug reactions were reported in the DR group. Majority of these adverse drug reactions (ADRs) pertained to musculoskeletal system followed by neurological and gastrointestinal system. The frequency of the ADRs in EODR group was similar to DR group ().

Table 4

5. Discussion

Reduction in serum LDL-C, non HDL-C and TG with elevation in serum HDL-C is a cornerstone in the treatment of dyslipidemia. Conventional daily regimen of statin is well established for treating dyslipidemia by inhibiting HMGCR, the rate limiting enzyme in the synthesis of cholesterol. 16 The use of every other day statins viz. atorvastatin is advocated due to its longer duration of action (24-30 h) despite its t 1/2 of 7 h as its ortho- and parahydroxylated metabolites also have lipid lowering effect. 16

In our study, 12 weeks of atorvastatin therapy in both the regimens was significantly effective in lowering TC, TG, LDL-C & non HDL-C and increasing HDL-C (). However, efficacy benefit on TC and LDL-C with DR was significantly higher (). Similarly, a study reported higher reduction in mean percentage of LDL-C with daily than with every other day atorvastatin regimen after 6 weeks of therapy. 15 Also, in a prospective, randomized trial on CVD patients reported insignificantly higher mean reduction in TC with daily than every other day atorvastatin (31.6% vs 28.3%) after 3 months of therapy. 14 On the contrary, Jafari et al. reported no statistical difference between daily and every other day atorvastatin therapy in terms of reduction in TC and LDL-C levels after 6 weeks of treatment. 12 Since the action of atorvastatin is dose dependent, 16 the doubling of dose per week in DR group vs EODR group may provide an explanation for these findings in our study.

Assessment of non-HDL-C provides a measure of cholesterol present in atherogenic particles. 19 A meta-analysis reported positive relationship between reduction in non-HDL-C and decrease in CVD risk. 19 Our study pioneered to report significant (p < 0.0001) reduction in non HDL-C in both daily and alternate day atorvastatin regimen (). Dyslipidemia treatment guidelines of Lipid association of India recommended non-HDL-C as a co-primary target and ATP III of the US NCEP recommended it as a secondary target of therapy in persons with triglycerides ≥200 mg/dl. 20, 17 In clinical practice, the role of non-HDL-C should be considered as a vital target of dyslipidemic therapy to prevent CVD.

Further, both the groups showed significant lipid lowering efficacy in terms of mean percentage inhibition of serum HMGCR levels in DR (31.17%) and EODR (28.19%) group which was matching between the two groups (). Moreover, serum HMGCR levels in both the groups, positively correlated with TC, LDL-C, non HDL-C, TG and negativity correlated with HDL-C. However, this correlation was more apparent in DR group. No study in the literature is available to compare this finding. It appears that this lower correlation in EODR group could be due to poor adherence with alternate day therapy. Missing a single dose in DR group leads to gap of 48 h between the next atorvastatin doses, whereas in EODR group this duration will be at least of 72 h. However, it is reported that the serum levels of HMGCR enzyme achieved a plateau beyond the compliance of 60% to statin therapy. 21 In view of this, it is hypothesized that good compliance with every other day regimen of atorvastatin may achieve desired HMGCR enzyme inhibition and provide benefits comparable to that of daily regimen. This aspect was not evaluated in our study and need further studies with appropriate design.

Statins are usually well tolerated by the patients but muscle and liver toxicity may lead to discontinuation of the therapy. In our study, slight rise in liver transaminases i.e. ALT and AST was present in both the treatment groups but the levels were not high enough to modify the therapy. 22 Previous studies have shown similar asymptomatic rise in liver transaminases (ALT and AST) levels with atorvastatin therapy. 9, 23 It has been postulated that changes in the lipid components of the hepatocyte membrane increase its permeability resulted in increased liver transaminases. 23 Statin induced myalgia and myositis is a distressing condition which affects the compliance and the outcome of the therapy. In our study, myalgia was more frequently reported in DR group than EODR group (). The rise in CK-MM was also more in daily group than EODR group (). However, these findings are not statistically significant to advocate alternate day therapy in statin intolerant patients. On the contrary, few previous studies have reported no difference in number of adverse events between daily and every other day atorvastatin treatment. 11, 12 Hence larger studies are needed in this direction to support or refute this finding.

The limitations of our study were small sample size, open label study design, high dropout rate (lost to follow-up) and dose of atorvastatin per week in EODR group was half of DR group which makes comparison of these two regimens difficult, especially the safety outcomes. Therefore, we recommend a study with double dose every other day as compared to daily dose.

It is concluded that both daily and every other day atorvastatin regimen for a period of 12 weeks achieved the therapeutic goals i.e. reduction in TC, LDL-C, non HDL-C, TG and serum HMGCR and increase in HDL-C with respect to their baselines. However, these benefits were more with daily atorvastatin therapy. Alteration of lipid indices better correlated with reduction of serum HMGCR levels in patients on daily therapy. Safety parameters i.e. AST, ALT, CK-MM and ADRs did not differ significantly between the two groups. Large randomized controlled trials are advocated to further substantiate the merits of every other day atorvastatin therapy.

Conflict of interest

None.

Funding

All the authors declare no financial relationships with any organizations that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work.

References

13. Aghasadeghi K., Zare D. Efficacy of alternate day dosing of atorvastatin. Cent Eur J Med. 2007;3:163-166. [ Google Scholar]

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Randomized controlled trial comparing the efficacy of daily and every other day atorvastatin therapy and its correlation with serum hydroxymethylglutaryl-CoA reductase enzyme levels in naïve dyslipidemic patients

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Data regarding efficacy comparison of daily regimen (DR) versus every other day regimen (EODR) atorvastatin therapy is not validated by estimation of serum hydroxymethylglutaryl-CoA reductase (HMGCR) levels and HMGCR correlation with lipid indices. In this randomized controlled trial, we compared the efficacy of DR versus EODR by measuring lipid indices and serum HMGCR levels at baseline and after 12 weeks of 10 mg atorvastatin therapy.

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Titulo: Fibratos para la prevención primaria de eventos de enfermedades cardiovasculares.

Tipo de estudio: Revisión sistemática.
Año: 2016.

Resultados: Los pacientes tratados con fibratos tuvieron un riesgo reducido de resultado primario combinado de muerte por ECV, infarto de miocardio no mortal o accidente cerebrovascular no mortal en comparación con los pacientes tratados con placebo (cociente de riesgos [CR] 0,84; intervalo de confianza [IC] del 95%: 0,74 a 0,96; participantes = 16 135; estudios = 6; evidencia de calidad moderada). Para los resultados secundarios se encontraron RR para el tratamiento con fibratos en comparación con placebo de 0,79 para la muerte combinada por enfermedad coronaria o el infarto de miocardio no mortal (IC del 95%: 0,68 a 0,92; participantes = 16 135; estudios = 6; evidencia de calidad moderada); 1,01 para la mortalidad general (IC del 95%: 0,81 a 1,26; participantes = 8471; estudios = 5; evidencia de baja calidad); 1,01 para la mortalidad no ECV (IC del 95%: 0,76 a 1,35; participantes = 8471; estudios = 5; evidencia de baja calidad); y 1,38 para la interrupción del tratamiento debido a efectos adversos (IC del 95%: 0,71 a 2,68; participantes = 4805; estudios = 3; Yo² = 74%; evidencia de muy baja calidad). No hubo datos sobre la calidad de vida disponibles en ningún ensayo. Los ensayos que evaluaron los fibratos en el contexto de las estatinas (2 estudios) no mostraron beneficios en la prevención de eventos cardiovasculares.
Conclusiones: Los fibratos reducen el riesgo de eventos cardiovasculares y coronarios en la prevención primaria, pero los efectos absolutos del tratamiento en el contexto de la prevención primaria son modestos (reducciones del riesgo absoluto < 1%). Hay evidencia de baja calidad de que los fibratos no tienen ningún efecto sobre la mortalidad general o no por ECV. La evidencia de muy baja calidad indica que los fibratos no se asocian con un mayor riesgo de efectos adversos.

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Estudio: https://pubmed.ncbi.nlm.nih.gov/26301648/

Título: Seguridad y eficacia de la ezetimiba: un metanálisis

Tipo de estudio: Revisión sistemática

Año: 2015

Resultados: El presente estudio indica que la ezetimiba reduce significativamente el riesgo de infarto de miocardio en un 13,5% (RR: 0,865, IC del 95%: 0,801 a 0,934, p<0,001) y accidente cerebrovascular en un 16,0% (RR: 0,840, IC del 95%: 0,744 a 0,949, p = 0,005) sin ningún efecto significativo sobre la mortalidad total y CV y ​​el riesgo de cáncer. Sin embargo, según la búsqueda incluyeron 7 ensayos clínicos aleatorizados donde se mostró un efecto no significativo de la ezetimiba añadida a estatinas sobre la muerte por todas las causas o CV, infarto de miocardio, accidente cerebrovascular y cáncer, lo que sugiere una falta de beneficio clínico asociado con el uso de ezetimiba y estatina.

Conclusión: La ezetimiba reduce significativamente el riesgo de IM y accidente cerebrovascular sin ningún efecto sobre la mortalidad por todas las causas y CV y el riesgo de cáncer.

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Affiliations

¹ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.

² Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

³ Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

⁴ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. Electronic address: fpperron@unina.it.

Affiliations

¹ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.

² Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

³ Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

⁴ Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. Electronic address: fpperron@unina.it.

Abstract

Background: The addition of ezetimibe to statin therapy has been widely demonstrated to significantly reduce low-density lipoprotein cholesterol levels. However, the efficacy of ezetimibe in reducing CV events and its safety has been less investigated. The aim of the current meta-analysis was to report efficacy and safety of ezetimibe from randomized clinical trials.

Methods: Randomized clinical trials with a follow-up of at least 24 weeks, enrolling more than 200 patients, comparing ezetimibe versus placebo or ezetimibe plus another hypolipidemic agent versus the same hypolipidemic drug alone and reporting at least one event among all-cause and CV mortality, myocardial infarction (MI), stroke and new onset of cancer were included in the analysis.

Results: 7 trials enrolling 31,048 patients (median follow-up 34.1 ± 26.3 months; 70% women; mean age 61 ± 8 years) were included in the analysis. Compared to control therapy, ezetimibe significantly reduced the risk of MI by 13.5% (RR: 0.865, 95% CI: 0.801 to 0.934, p<0.001) and the risk of any stroke by 16.0% (RR: 0.840, 95% CI: 0.744 to 0.949, p=0.005), without any effect on all-cause and CV mortality (RR: 1.003, 95% CI: 0.954 to 1.055, p=0.908; RR: 0.958, 95% CI: 0.879 to 1.044, p=0.330; respectively) and risk of new cancer (RR: 1.040, 95% CI: 0.965 to 1.120, p=0.303).

Conclusions: Ezetimibe significantly reduces the risk of MI and stroke without any effect on all-cause and CV mortality and risk of cancer.

Keywords: Cardiovascular events; Cholesterol; Ezetimibe; Mortality; Statins.

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anticholesteremic agents / therapeutic use

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national center for biotechnology information

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Safety and efficacy of ezetimibe: A meta-analysis - PubMed

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1 Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. 2 Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 3 Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy; Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, United Kingdom.

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TITULO: Eficacia y seguridad de alirocumab y evolocumab: revisión sistemática y metanálisis de ensayos controlados aleatorios

TIPO DE ESTUDIO -AÑO: metanálisis-2019

OBJETIVO: evaluar la eficacia y seguridad de alirocumab y evolocumab en pacientes con dislipidemia o enfermedad cardiovascular aterosclerótica.

RESULTADOS: En general, los efectos de la inhibición de PCSK9 sobre la muerte por todas las causas y la muerte cardiovascular no fueron estadísticamente significativos (P = 0,15 y P = 0. 34, respectivamente). Los inhibidores de la proproteína convertasa subtilisina-kexina tipo 9 se asociaron con un menor riesgo de infarto de miocardio (1,49 frente a 1,93 por 100 pacientes-año; RR 0,80, IC del 95 %: 0,74-0,86; I2 = 0 %; P < 0,0001), accidente cerebrovascular isquémico (0,44 0,58 por 100 pacientes-año; RR 0,78, IC 95 % 0,67-0,89; I2 = 0 %; P = 0,0005) y revascularización coronaria (2,16 frente a 2,64 por 100 pacientes-año; RR 0,83, IC 95 % 0,78 -0,89; I2 = 0%; P < 0,0001), en comparación con el grupo control.

CONCLUSIONES: La inhibición de la proproteína convertasa subtilisina-kexina tipo 9 con alirocumab o evolocumab se asoció con un menor riesgo de infarto de miocardio, accidente cerebrovascular y revascularización coronaria, con un perfil de seguridad favorable.
https://pubmed.ncbi.nlm.nih.gov/31270529/

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Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials - PubMed

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Proprotein convertase subtilisin-kexin type 9 inhibition with alirocumab or evolocumab was associated with lower risk of MI, stroke, and coronary revascularization, with favourable safety profile.

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Título: Eficacia y seguridad de la coadministración de fenofibrato y ezetimiba en comparación con cada uno como monoterapia en pacientes con dislipidemia tipo IIb y características del síndrome metabólico.
Tipo de estudio: Un estudio prospectivo, aleatorizado, doble ciego, de tres brazos paralelos, multicéntrico y comparativo.
Año: 2012
Objetivo: Evaluar la eficacia y seguridad de la coadministración de fenofibrato (NanoCrystal®) y ezetimiba en pacientes con dislipidemia tipo IIb y síndrome metabólico en comparación con la administración de fenofibrato y ezetimiba solos.
Resultados: Fenofibrato/ezetimiba fue más eficaz que fenofibrato o ezetimiba para reducir el C-LDL (−36,2 % frente a −22,4 % y −22,8 %, respectivamente), C-no HDL (−36,2 % frente a −24,8 % y −20,9 %, respectivamente), colesterol total (CT) [−27,9% vs −18,9% y −17,1%, respectivamente], apolipoproteína B (−33,3% vs −24,5% y −18,7%, respectivamente), cociente CT/HDL-C (− 34,2 % frente a −23,0 % y −17,0 %, respectivamente) y relación apolipoproteína B/apolipoproteína AI (−37,5 % frente a −27,0 % y −17,7 %, respectivamente) [p<0,001 para todas las comparaciones entre fenofibrato/ezetimiba y monoterapias] .
Conclusión: En pacientes con dislipidemia tipo IIb y características del síndrome metabólico, la coadministración de 145 mg de fenofibrato y 10 mg de ezetimiba al día fue más eficaz que cualquiera de las dos monoterapias para reducir el LDL-C, el no-HDL-C, la apolipoproteína B y las proporciones de riesgo cardiovascular, y fue tan efectivo como el fenofibrato 145 mg solo para reducir los TG y aumentar el HDL-C en pacientes con niveles basales bajos de HDL-C.

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Background

Patients with type IIb, or mixed, dyslipidemia have high levels of low-density lipoprotein cholesterol (LDL-C) with predominance of small dense LDL particles, high levels of triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C). Fenofibrate significantly reduces TG and, more moderately, LDL-C, increases HDL-C and produces a shift from small to large LDL particle size; the main effect of ezetimibe is a reduction in LDL-C levels. Combined treatment with fenofibrate and ezetimibe may correct all the abnormalities of type IIb dyslipidemia.

Objective

To assess the efficacy and safety of coadministration of fenofibrate (NanoCrystal®) and ezetimibe in patients with type IIb dyslipidemia and the metabolic syndrome compared with administration of fenofibrate and ezetimibe alone (ClinicalTrials.gov Identifier: NCT00349284; Study ID: CLF178P 04 01).

Methods

This was a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study. Sixty ambulatory patients (mean age 56 years; 50% women, 50% men) were treated in each group. For inclusion in the study, patients were required to have LDL-C ≥4.13 mmol/L (≥ 160 mg/dL), TG ≥1.71 mmol/L and ≤4.57 mmol/L (≥150 mg/dL and ≤405 mg/dL), and at least two of the following National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome: low HDL-C or increased fasting plasma glucose, blood pressure, or waist circumference. Patients received fenofibrate 145 mg, ezetimibe 10 mg, or coadministration of both (fenofibrate/ezetimibe) daily for 12 weeks. The outcome measures were changes in lipids and related parameters, apolipoproteins, glucose metabolism parameters, and high-sensitivity C-reactive protein (hsCRP).

Results

Fenofibrate/ezetimibe was more effective than either fenofibrate or ezetimibe in reducing LDL-C (−36.2% vs −22.4% and −22.8%, respectively), non-HDL-C (−36.2% vs −24.8% and −20.9%, respectively), total cholesterol (TC) [−27.9% vs −18.9% and −17.1%, respectively], apolipoprotein B (−33.3% vs −24.5% and −18.7%, respectively), TC/HDL-C ratio (−34.2% vs −23.0% and −17.0%, respectively), and apolipoprotein B/apolipoprotein AI ratio (−37.5% vs −27.0% and −17.7%, respectively) [p<0.001 for all comparisons between fenofibrate/ezetimibe and monotherapies]. Fenofibrate/ezetimibe was as effective as fenofibrate and more effective than ezetimibe in reducing remnant-like particle cholesterol (−36.2% and −30.7% vs −17.3%, respectively), and in increasing LDL size ( + 2.1% and + 1.9% vs + 0.7%, respectively), apolipoprotein AI (+7.9% and + 5.1% vs +0.2%, respectively) and apolipoprotein AII ( + 24.2% and +21.2% vs + 2.7%, respectively). Fenofibrate/ezetimibe and fenofibrate were equally effective in reducing TG (both −38.3%) and in increasing HDL-C (+11.5% and + 7.9%, respectively; p = 0.282). Ezetimibe had minor effects on TG (−10.4%) and HDL-C ( + 2.2%). Among patients with low HDL-C at baseline (<1.29 mmol/L [<50 mg/dL] in women, <1.03 mmol/L [<40 mg/dL] in men), normalization of HDL-C was observed in 52.9% with fenofibrate/ezetimibe and in 58.8% with fenofibrate, compared with 20.0% with ezetimibe. Changes in hsCRP were −25.9% with fenofibrate/ezetimibe, −27.8% with fenofibrate, and −10.2% with ezetimibe (not statistically significant). None of the treatments altered glucose metabolism parameters.

Conclusion

In patients with type IIb dyslipidemia and features of the metabolic syndrome, coadministration of fenofibrate 145 mg and ezetimibe 10 mg daily was more effective than either monotherapy in reducing LDL-C, non-HDL-C, apolipoprotein B, and cardiovascular risk ratios, and was as effective as fenofibrate 145 mg alone in reducing TG and in increasing HDL-C in patients with low baseline HDL-C levels.

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Efficacy and Safety of Coadministration of Fenofibrate and Ezetimibe Compared with Each as Monotherapy in Patients with Type IIb Dyslipidemia and Features of the Metabolic Syndrome - American Journal of Cardiovascular Drugs

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Background Patients with type IIb, or mixed, dyslipidemia have high levels of low-density lipoprotein cholesterol (LDL-C) with predominance of small dense LDL particles, high levels of triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C).

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Título: Eficacia y seguridad de rosuvastatina frente a atorvastatina en pacientes chinos de alto riesgo con hipercolesterolemia: un estudio aleatorizado, doble ciego, con control activo
Autor: Shuiping Zhao y Daoquan Peng
Año: 2017
Tipo de estudio: Aleatorizado, doble ciego
Resultados: En total 414 pacientes (edad media: 59,5 ± 9,51 años, 59,4% mujeres, C-LDL medio: 4,242 ± 0,676 mmol/L (rosuvastatina 5 mg), 4,13 ± 0,682 mmol/L (rosuvastatina 10 mg) y 4,213 ± 0,662 mmol/L (atorvastatina 10 mg) En comparación con atorvastatina 10 mg, rosuvastatina 5 mg ( −41,70 % vs. vs. −38,67 %, p = 0,0002). Las tasas de consecución del objetivo de C-LDL con rosuvastatina 5 mg, rosuvastatina 10 mg y atorvastatina 10 mg fueron del 61,0 %, 79,1 % y 58,3 % en la fase aleatorizada. En la fase abierta , el objetivo de C-LDL se logró en >40 % con ambas dosis de rosuvastatina La tasa de ≥1 evento adverso fue similar con rosuvastatina 5 mg (12,4 %), 10 mg (11,7 %) y atorvastatina 10 mg (8,9 %).
Conclusión: Rosuvastatina 5 mg demostró no inferioridad y rosuvastatina 10 mg demostró superioridad a atorvastatina 10 mg para reducir el LDL-C en pacientes chinos de alto riesgo con dislipidemia, que se mantuvo durante la fase abierta.

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Efficacy and safety of rosuvastatin versus atorvastatin in high-risk Chinese patients with hypercholesterolemia: a randomized, double-blind, active-controlled study

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(2018). Efficacy and safety of rosuvastatin versus atorvastatin in high-risk Chinese patients with hypercholesterolemia: a randomized, double-blind, active-controlled study. Current Medical Research and Opinion: Vol. 34, Themed issue: Cardiometabolic, pp. 227-235.

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Título: Ezetimiba para la prevención de enfermedades cardiovasculares y eventos de mortalidad por todas las causas

Tipo de estudio: Metaanálisis
Año: 2018
Resultados: Los ensayos que informaron mortalidad por todas las causas utilizaron ezetimiba con estatina o fenofibrato y encontraron que tienen poco o ningún efecto sobre este resultado (RR 0,98; IC del 95%: 0,91 a 1,05; 21 222 participantes; 8 estudios; evidencia de alta calidad). ara los lípidos séricos, agregar ezetimiba a una estatina o fenofibrato podría reducir aún más el colesterol de lipoproteínas de baja densidad (LDL-C), los niveles de colesterol total y triglicéridos y probablemente aumenten los niveles de colesterol de lipoproteínas de alta densidad; sin embargo, se detectó heterogeneidad significativa en la mayoría de los análisis. Ninguno de los estudios incluidos informó sobre la calidad de vida relacionada con la salud.
Conclusión: El beneficio cardiovascular de ezetimiba podría implicar la reducción de LDL-C, colesterol total y triglicéridos. No hay evidencia suficiente para determinar si la ezetimiba aumenta el riesgo de eventos adversos debido a la calidad baja y muy baja de la evidencia. La evidencia de efectos beneficiosos se obtuvo principalmente de individuos con enfermedad cardiovascular aterosclerótica establecida (ASCVD, predominantemente con síndrome coronario agudo) que recibieron ezetimiba más estatinas.

https://pubmed.ncbi.nlm.nih.gov/30480766/

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Affiliation

¹ Pharmacy Department, First Affiliated Hospital of Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, China, 400038.

Free PMC article

Free PMC article

Affiliation

¹ Pharmacy Department, First Affiliated Hospital of Third Military Medical University (Army Medical University), 30 Gaotanyan Street, Shapingba District, Chongqing, China, 400038.

Abstract

Background: Cardiovascular disease (CVD) remains an important cause of mortality and morbidity, and high levels of blood cholesterol are thought to be the major modifiable risk factors for CVD. The use of statins is the preferred treatment strategy for the prevention of CVD, but some people at high-risk for CVD are intolerant to statin therapy or unable to achieve their treatment goals with the maximal recommended doses of statin. Ezetimibe is a selective cholesterol absorption inhibitor, whether it has a positive effect on CVD events remains uncertain. Results from clinical studies are inconsistent and a thorough evaluation of its efficacy and safety for the prevention of CVD and mortality is necessary.

Objectives: To assess the efficacy and safety of ezetimibe for the prevention of CVD and all-cause mortality.

Search methods: We searched the CENTRAL, MEDLINE, Embase and Web of Science on 27 June 2018, and two clinical trial registry platforms on 11 July 2018. We checked reference lists from primary studies and review articles for additional studies. No language restrictions were applied.

Selection criteria: We included randomised controlled trials (RCTs) that compared ezetimibe versus placebo or ezetimibe plus other lipid-modifying drugs versus other lipid-modifying drugs alone in adults, with or without CVD, and which had a follow-up of at least 12 months.

Data collection and analysis: Two review authors independently selected studies for inclusion, extracted data, assessed risk of bias and contacted trialists to obtain missing data. We performed statistical analyses according to the Cochrane Handbook for Systematic Reviews of Interventions and used the GRADE to assess the quality of evidence.

Main results: We included 26 RCTs randomising 23,499 participants. All included studies assessed effects of ezetimibe plus other lipid-modifying drugs compared with other lipid-modifying drugs alone or plus placebo. Our findings were driven by the largest study (IMPROVE-IT), which had weights ranging from 41.5% to 98.4% in the different meta-analyses.Ezetimibe with statins probably reduces the risk of major adverse cardiovascular events compared with statins alone (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.90 to 0.98; a decrease from 284/1000 to 267/1000, 95% CI 256 to 278; 21,727 participants; 10 studies; moderate-quality evidence). Trials reporting all-cause mortality used ezetimibe with statin or fenofibrate and found they have little or no effect on this outcome (RR 0.98, 95% CI 0.91 to 1.05; 21,222 participants; 8 studies; high-quality evidence). Adding ezetimibe to statins probably reduces the risk of non-fatal myocardial infarction (MI) (RR 0.88, 95% CI 0.81 to 0.95; a decrease from 105/1000 to 92/1000, 95% CI 85 to 100; 21,145 participants; 6 studies; moderate-quality evidence) and non-fatal stroke (RR 0.83, 95% CI 0.71 to 0.97; a decrease 32/1000 to 27/1000, 95% CI 23 to 31; 21,205 participants; 6 studies; moderate-quality evidence). Trials reporting cardiovascular mortality added ezetimibe to statin or fenofibrate, probably having little or no effect on this outcome (RR 1.00, 95% CI 0.89 to 1.12; 19457 participants; 6 studies; moderate-quality evidence). The need for coronary revascularisation might be reduced by adding ezetimibe to statin (RR 0.94, 95% CI 0.89 to 0.99; a decrease from 196/1000 to 184/1000, 95% 175 to 194; 21,323 participants; 7 studies); however, no difference in coronary revascularisation rate was observed when a sensitivity analysis was limited to studies with a low risk of bias.In terms of safety, adding ezetimibe to statins may make little or no difference in the risk of hepatopathy (RR 1.14, 95% CI 0.96 to 1.35; 20,687 participants; 4 studies; low-quality evidence). It is uncertain whether ezetimibe increase or decrease the risk of myopathy (RR 1.31, 95% CI 0.72 to 2.38; 20,581 participants; 3 studies; very low-quality evidence) and rhabdomyolysis, given the wide CIs and low event rate. Little or no difference in the risk of cancer, gallbladder-related disease and discontinuation due to adverse events were observed between treatment groups. For serum lipids, adding ezetimibe to statin or fenofibrate might further reduce the low-density lipoprotein cholesterol (LDL-C), total cholesterol and triglyceride levels and likely increase the high-density lipoprotein cholesterol levels; however, substantial heterogeneity was detected in most analyses.None of the included studies reported on health-related quality of life.

Authors' conclusions: Moderate- to high-quality evidence suggests that ezetimibe has modest beneficial effects on the risk of CVD endpoints, primarily driven by a reduction in non-fatal MI and non-fatal stroke, but it has little or no effect on clinical fatal endpoints. The cardiovascular benefit of ezetimibe might involve the reduction of LDL-C, total cholesterol and triglycerides. There is insufficient evidence to determine whether ezetimibe increases the risk of adverse events due to the low and very low quality of the evidence. The evidence for beneficial effects was mainly obtained from individuals with established atherosclerotic cardiovascular disease (ASCVD, predominantly with acute coronary syndrome) administered ezetimibe plus statins. However, there is limited evidence regarding the role of ezetimibe in primary prevention and the effects of ezetimibe monotherapy in the prevention of CVD, and these topics thus requires further investigation.

Conflict of interest statement

Zhan Shipeng: no conflict of interest

Xia Peiyuan: no conflict of interest

Tang Min: no conflict of interest

Liu Fang: no conflict of interest

Shu Maoqin: no conflict of interest

Wu Xiaojiao: no conflict of interest

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anticholesteremic agents / adverse effects

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anticholesteremic agents / therapeutic use*

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cardiovascular diseases / prevention & control*

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myocardial infarction / prevention & control

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national center for biotechnology information

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Ezetimibe for the prevention of cardiovascular disease and all-cause mortality events - PubMed

# data[].attributes.attachment_link.description
Moderate- to high-quality evidence suggests that ezetimibe has modest beneficial effects on the risk of CVD endpoints, primarily driven by a reduction in non-fatal MI and non-fatal stroke, but it has little or no effect on clinical fatal endpoints. The cardiovascular benefit of ezetimibe might invol ...

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TITULO: Efecto de la monoterapia con ezetimiba en las concentraciones en plasma de lipoproteína (a) en pacientes con
Hipercolesterolemia.
TIPO DE ESTUDIO: Revisión sistematica y metaanálisis.
AÑO: 2018
RESULTADOS: En siete ECA con 2337 pacientes cumplieron los criterios de selección y se incluyeron en el análisis. El análisis combinado general sugirió que ezetimiba 10 mg redujo significativamente las concentraciones plasmáticas de Lp(a) en pacientes con hipercolesterolemia primaria en un -7,06 % (IC del 95 %: -11,95 a -2,18; p = 0,005) en comparación con el placebo. No se observó heterogeneidad significativa (χ 2 = 5,34; p = 0,5). La exclusión de un estudio del análisis dio lugar a diferencias insignificantes entre los dos grupos (p = 0,2). La metarregresión no encontró una asociación significativa entre los cambios porcentuales medios en Lp(a) y otras posibles variables moderadoras, que incluían los cambios porcentuales medios de las concentraciones de LDL-C (p = 0,06) y los valores medios de Lp(a) basales ( p = 0,46).
CONCLUSIONES: La monoterapia con ezetimiba (10 mg/día) mostró una pequeña (7,06%) pero estadísticamente significativa reducción en los niveles plasmáticos de Lp(a) en pacientes con hipercolesterolemia primaria.

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Effect of Ezetimibe Monotherapy on Plasma Lipoprotein(a) Concentrations in Patients with Primary Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials - PubMed

# data[].attributes.attachment_link.description
Ezetimibe monotherapy (10 mg/day) showed a small (7.06%) but statistically significant reduction in the plasma levels of Lp(a) in patients with primary hypercholesterolemia. According to current literature, this magnitude of reduction seems to have no clinical relevance. However, further studies are…

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TÍTULO: Efecto de las resinas secuestradoras de ácidos biliares en los desenlaces cardiovasculares y en los niveles séricos de lípidos
TIPO DE ESTUDIO: RS de ECA con alto riesgo de sesgo
AÑO: 2016
AUTOR: Muñoz et al.
RESULTADOS: una reducción en la incidencia de IAM del 16% significativamente (RR 0,84; IC 95% 0,67: 1,00), además el estudio mostró  que una reducción del 14% en muerte cardiovascular pero no fue significativo (RR de 0,76; IC 95% 0,5:1,15).

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http://dx.doi.org/10.1016/j.rccar.2015.04.010 Efecto de las resinas secuestradoras de ácidos biliares en los desenlaces cardiovasculares y en los niveles séricos de lípidos Effect of bile acid sequestrants on cardiovascular outcomes and seric lipids: A systematic review
Oscar M. Muñoz a, b, Néstor F. Correa a, Angélica Higuera b, Ángel A. García a,b, Álvaro J. Ruiz a,b

a Departamento de Medicina Interna, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia

b Departamento de Epidemiología Clínica y Estadística, Pontificia Universidad Javeriana, Hospital Universitario San Ignacio, Bogotá, Colombia

Recibido el 2 de octubre de 2014; Aceptado el 18 de abril de 2015

Correo electrónico: munoz@javeriana.edu.co (Oscar M. Muñoz).
Resumen
Antecedentes: Las guías internacionales recientes proponen el uso de estatinas como piedra angular del manejo de la dislipidemia en adultos. Sin embargo, no se ha definido con claridad el tratamiento de los pacientes con intolerancia o efectos adversos asociados con estas. Las resinas secuestradoras de ácidos biliares son una alternativa interesante, pese a que la evidencia que avala su uso no ha sido evaluada cuidadosamente.

Métodos: Se realizó una búsqueda de la literatura en MEDLINE, Embase y en la Biblioteca Cochrane hasta junio de 2013, acerca de artículos publicados en inglés y español, identificando experimentos clínicos aleatorizados y estudios de cohortes que evaluaran el impacto de las resinas secuestradoras de ácidos biliares en mortalidad, eventos cardiovasculares, niveles de lípidos séricos y efectos adversos. Se presenta la información de forma descriptiva.

Resultados: Se identificaron cuatro experimentos clínicos aleatorizados y un estudio de cohortes, que incluían 6.833 pacientes. Solo uno de los estudios evaluó el impacto en la mortalidad cardiovascular, evidenciando que no hay diferencia estadísticamente significativa en comparación con placebo (RR de 0,76; IC 95% 0,5:1,15), aunque se observó una reducción del 16% en la incidencia de infarto agudo de miocardio (RR 0,84; IC 95% 0,67:1,00). Tres estudios evaluaron cambios en las fracciones lipídicas, los cuales mostraron disminución moderada en los niveles de colesterol LDL, sin percibir diferencias clínicamente significativas en los niveles de colesterol HDL y triglicéridos.

Conclusión: La evidencia que respalda el uso de resinas secuestradoras de ácidos biliares es limitada y no avala su empleo como terapia de primera línea en pacientes con dislipidemia; no obstante, son una alternativa en pacientes con efectos adversos o intolerancia al manejo con estatinas.

Palabras clave: Hipercolesterolemia. Tratamiento. Mortalidad. Infarto agudo de miocardio.
Abstract
Background: Recent international guidelines have proposed statins as the corner stone of dyslipidemia management in adults. However it is not clear if they are best option for patients with statin related intolerance or what their adverse effects are. The bile acid sequestrants are an interesting alternative, however its evidence has not been carefully evaluated.

Methods: A search was conducted on MEDLINE, Embase and Cochrane library databases for articles published up to June 2013, limited to Spanish and English language. Randomized clinical trials (RCT) and cohort studies evaluating the impact of bile acid sequestrants on mortality, cardiovascular outcomes, seric lipids and adverse effects were selected. Information was presented in a descriptive way.

Results: Four RCT and one cohort study with aggregate data on 6833 people were included. Just one study evaluated cardiovascular mortality showing no statistically significant difference when compared with placebo, (RR 0.76; 95% CI 0.5:1.15), however there was a 16% reduction on acute myocardial infarction incidence. (RR 0.84; 95% IC 0.67: 1.00). Three studies evaluated seric lipids changes showing a moderate reduction in LDL levels without clinical significant differences on HDL and triglyceride levels.

Conclusions: The evidence supporting bile acid sequestrants use is lacking and not conclusive to recommend its use as first-line therapy in dyslipidemic patients; however, these are an alternative option for patients with statin-related intolerance or adverse effects.

Keywords: Hypercholesterolemia. Treatment. Mortality. Myocardial acute infarction.
Introducción
De acuerdo con el boletín epidemiológico del Instituto Nacional de Salud publicado en 2013, la enfermedad cardiovascular es la principal causa de muerte en Colombia, y ha venido en continuo crecimiento durante la última década ¹, realidad compartida tanto con países desarrollados como con otros en vía de desarrollo ². Como parte de las estrategias de control se han intensificado y aunado esfuerzos para controlar los principales factores de riesgo cardiovascular, como hipertensión arterial, tabaquismo, diabetes mellitus, dislipidemia y obesidad ³.

Recientemente, la Asociación Americana del Corazón y el Colegio Americano de Cardiología (AHA/ACC) publicaron las Guías para el tratamiento del colesterol sanguíneo con miras a reducir el riesgo aterosclerótico cardiovascular en adultos ⁴, en las que propusieron a las estatinas como el pilar fundamental del tratamiento farmacológico de las dislipidemias en la población adulta. Sin embargo, algunos grupos de pacientes presentan intolerancia o efectos secundarios que obligan a suspender dicha terapia o hay quienes no logran reducciones significativas en las fracciones lipídicas, de modo tal que se impacta de manera negativa el riesgo de presentar desenlaces cardiovasculares o cerebrovasculares.

Una de las opciones terapéuticas con la que se cuenta en este escenario clínico son las resinas secuestradoras de ácidos biliares (RSAB), que incluyen colestiramina, colestipol y colesevelam. Su mecanismo de acción estriba en la formación de un compuesto inabsorbible que termina siendo excretado por la materia fecal, lo que disminuye la circulación enterohepática de ácidos biliares, propiciando a su vez una cadena de retroalimentación positiva para la producción de nuevos ácidos biliares a partir de colesterol LDL. El hepatocito depletado de colesterol LDL, termina por expresar receptores para capturar LDL, proceso que finalmente conlleva la reducción de LDL plasmático ⁵⁻¹⁰.

A pesar de que durante varias décadas las RSAB han estado disponibles como parte de las opciones terapéuticas para el manejo de la dislipidemia, la evidencia que avala su uso nunca ha sido sintetizada y evaluada de forma sistemática. Esta publicación constituye la primera revisión sistemática de la literatura que evalúa el impacto de las RSAB en los desenlaces cardiovasculares y en los niveles séricos de lípidos.

El estudio fue desarrollado inicialmente como parte de la "Guía colombiana para la prevención, detección temprana, diagnóstico, tratamiento y seguimiento de la dislipidemia en pacientes colombianos mayores de 18 años"¹¹. Conocer esta evidencia es fundamental a la hora de definir el papel real de estos medicamentos en el manejo de la dislipidemia en pacientes adultos, tanto en prevención primaria como secundaria.
Materiales y métodos Búsqueda de la literatura
Se llevó a cabo una búsqueda sistemática de la literatura con el fin de hallar artículos relevantes, incluyendo las bases de datos MEDLINE (Pubmed), EMBASE, y la base de datos de la colaboración Cochrane (Cochrane Central Register of Controlled trials), desde la iniciación hasta junio de 2013. Los términos de búsqueda incluyeron: hiperlipidemia, dislipidemia, hipercolesterolemia, colesevelam, colestipol y colestiramina, tanto en texto libre como en términos MeSH. Se restringió la búsqueda a publicaciones en inglés o español, y adicionalmente se realizó una búsqueda manual de las referencias bibliográficas de los artículos identificados.
Selección de los estudios
Los artículos hallados se incluían en la revisión sistemática de la literatura si cumplían los siguientes criterios: pacientes mayores de 18 años que cursaran con dislipidemia, con o sin enfermedad cardiovascular incluyendo ataque cerebrovascular, infarto agudo de miocardio, angina inestable o enfermedad arterial periférica; que recibieran alguna de las resinas secuestradoras de ácidos biliares (colestiramina, colestipol o colesevelam) por lo menos durante un periodo de 24 semanas, comparando su uso contra placebo o dieta. Se incluyeron tanto estudios de cohortes como experimentos clínicos aleatorizados. Los experimentos clínicos debían contar con un mínimo de 50 pacientes en cada brazo de tratamiento y evaluar al menos uno de los desenlaces del estudio. Los desenlaces primarios fueron mortalidad de causa cardiovascular e incidencia de infarto agudo de miocardio o ataque cerebrovascular; también se incluyeron cambios en las fracciones lipídicas, adherencia a la terapia e incidencia de efectos adversos.

Se descartaron estudios que incluyeran pacientes con dislipidemias familiares, VIH u otras inmunodeficiencias, y pacientes con enfermedad renal crónica en cualesquiera de sus estadios. La selección de los estudios se hizo de forma pareada y estuvo a cargo de dos investigadores (AH y NC); las discrepancias fueron resueltas por consenso, contando con la opinión de un tercer investigador (OM).
Extracción de los datos y evaluación de calidad
Como se expresó, los datos fueron extraídos independientemente por dos investigadores (NC y AH), utilizando un formato estandarizado. Las discrepancias fueron resueltas por consenso, con la intervención de un tercer investigador (OM). Los investigadores recolectaron los siguientes datos para cada estudio: diseño del estudio, tamaño de la muestra, características basales de la población, medicamento utilizado y dosis, duración del seguimiento, resultados en los desenlaces. Cuando se trató de un experimento clínico el estimativo de resumen utilizado fue el riesgo relativo (RR), y para los estudios de cohorte se utilizó la razón de disparidad (OR). En los casos en que se disponía de más de un estudio publicado sobre la misma población se seleccionó el más reciente; a pesar de ello, se revisaron los artículos complementarios en busca de datos adicionales.

La evaluación del riesgo de sesgo de los estudios incluidos se hizo a través de los cuestionarios propuestos por el Scottish Intercollegiate Guidelines Network (SIGN 50) ¹², mediante formatos diferenciales según el diseño (estudios de cohorte o experimentos clínicos aleatorizados). Lo anterior estuvo de acuerdo con las recomendaciones de la "Guía metodológica para la elaboración de guías de práctica clínica y evaluación económica en el Sistema General de Seguridad Social colombiano"¹³. Los resultados de esta evaluación permitieron clasificar los estudios en alto, moderado o bajo riesgo de sesgo.
Análisis estadístico
Se planeó la recolección de los RR o las OR (para los estudios de cohorte) y de la reducción absoluta de riesgo, reportados en cada estudio para los desenlaces primarios, y la diferencia de medias para los cambios en el perfil lipídico, con sus respectivos intervalos de confianza del 95%. Adicionalmente, se planeó la evaluación de la heterogeneidad usando el estadístico I ². Con estos datos se planeó resumir la información contenida en los experimentos clínicos aleatorios, mediante un modelo de efectos aleatorios, considerando la evaluación de múltiples moléculas que podrían conferir heterogeneidad a los datos. Estos, a su vez, se procesaron con el programa estadístico RevMan versión 5.3.5, sugerido por la Colaboración Cochrane.
Resultados
De los 563 títulos identificados se seleccionaron 5 ¹⁴⁻¹⁸ que incluían 6.833 pacientes. Cuatro de estos estudios correspondieron a experimentos clínicos controlados ¹⁴⁻¹⁸ y uno a un estudio de cohortes ¹⁹ ( fig. 1). Dos de los estudios correspondían a una misma población en la que usaron como intervención colestiramina 14,15, en dos se utilizó colesevelam 16,17 y en uno colestipol ¹⁸.

Las características de los estudios se muestran en la tabla 1. Los estudios más grandes 14,15 fueron publicados antes de 1990, fecha en la que aún no estaban disponibles las estatinas. Todos ellos incluyeron población de prevención primaria y dos incluyeron adicionalmente una proporción de pacientes con eventos previos 17,18. El tiempo de seguimiento estuvo en el rango entre 24 semanas y 10 años.
Tabla 1
Todos los estudios tuvieron riesgo moderado de sesgo de acuerdo con la evaluación efectuada con los cuestionarios propuestos por SIGN. Las principales limitaciones detectadas fueron falta de cegamiento a los evaluadores 16,17 y alta tasa de pérdidas al seguimiento 14,15,17.
Eventos cardiovasculares y cerebrovasculares
Los desenlaces primarios evaluados fueron el impacto en la mortalidad y en las frecuencias de infarto agudo de miocardio y accidente cerebrovascular. El estudio de Dorr ¹⁸ fue el único que evaluó cambios en la mortalidad, mostrando una disminución no estadísticamente significativa (RR de 0,76; IC 95% 0,5:1,15). El impacto de la colestiramina en la incidencia de infarto agudo de miocardio fue evaluado en el estudio de Rifkind ¹⁴, The Lipids Research Clinics Coronary Primary Prevention Trial, el más grande realizado con RSAB. Fue publicado en 1986 e incluyó 1.906 pacientes que recibieron colestiramina y 1.900 a quienes se les suministró placebo, en un seguimiento entre 7 y 10 años. Se demostró una reducción en la incidencia de infarto agudo de miocardio del 16% (RR 0,84; IC 95% 0,67: 1,00) ( tabla 2). Ningún estudio publicado ha evaluado el impacto de las RSAB en la incidencia de accidente cerebrovascular.
Tabla 2 Fracciones lipídicas y efectos adversos
Tres estudios reportaron cambios en los niveles de colesterol LDL 14,16,17. Todos detectaron disminución en los niveles de colesterol LDL con la intervención, en el rango entre 21 y 28 mg/dl. En cuanto a los niveles de colesterol HDL, los resultados también tuvieron tendencias similares, ya que los tres estudios ¹⁵⁻¹⁷ determinaron que no hubo variaciones clínicamente significativas, con un aumento máximo de 5,7 mg/dl reportado en el estudio de Davidson. Por último, tres estudios más ¹⁶⁻¹⁸ presentan la información sobre el cambio en los niveles de triglicéridos y todos demuestran un aumento clínicamente no significativo en rangos entre 2 y 9,7 mg/dl. Cabe resaltar que no fue posible hacer un metaanálisis de la información puesto que los estudios originales no reportaron los intervalos de confianza. En la tabla 3 se presenta la información contenida en los estudios acerca de los cambios en las fracciones de perfil lipídico.
Tabla 3
En cuanto a efectos adversos, tres estudios ¹⁷⁻¹⁹ evaluaron este desenlace y reportaron constipación como el efecto adverso más frecuente ( tabla 4). La adherencia al medicamento solo se evaluó en un estudio de cohorte ¹⁷, en el que se mostró que el uso de este medicamento era bien tolerado, con una adherencia muy similar a la reportada para el placebo (OR 0,94; IC 95% 0,89-0,99) ( tabla 4).
Tabla 4 Discusión
De acuerdo con la evidencia disponible en la actualidad y con las guías internacionales recientes 4,6, resulta claro que las estatinas son los medicamentos de primera línea en el tratamiento de la dislipidemia en adultos. Las guías de la ACC/AHA ⁴ proponen considerar el uso de las RSAB al mismo nivel que otros grupos de medicamentos hipolipemiantes, como ezetimibe, ácido nicotínico y fibratos, dejando al clínico la decisión de cuál usar en caso de contraindicación o intolerancia a las estatinas.

La actual es la primera revisión sistemática de la literatura que evalúa de forma rigurosa la evidencia disponible en cuanto a los efectos del uso de las RSAB, denotando las serias deficiencias de la evidencia que avala su uso. El primer inconveniente radica en la antigüedad de los estudios clínicos disponibles, que se asocia con limitaciones importantes en la aplicabilidad de los datos. Un ejemplo es el estudio publicado por Rifkind en 1986 ¹⁴, que es adicionalmente el más grande y significativo de los estudios que han evaluado las RSAB en el manejo de la dislipidemia. Este dio un giro histórico a la enfermedad cardiovascular al mostrar que la disminución en los niveles de las fracciones lipídicas sanguíneas atenuaba la probabilidad de eventos cardiovasculares de origen aterotrombótico (específicamente de infarto agudo de miocardio). Sin embargo, es difícil evaluar sus resultados a la luz de los conocimientos actuales dado que ahora se dispone de múltiples intervenciones adicionales no existentes previamente, como estatinas y medicamentos antitrombóticos y antiplaquetarios. En esa población sin esos nuevos medicamentos era más sencillo demostrar cambios significativos, ya que les faltaban intervenciones que ahora son rutinarias.

Otra limitación de la evidencia disponible está dada por el pobre reporte de estos estudios, que no presentan los resultados en profundidad, lo que impide hacer un metaanálisis de la información y, por tanto fortalecer los estimativos del tamaño del efecto en las fracciones lipídicas.

Es importante resaltar que si bien la actividad hipolipemiante de las RSAB es modesta, son medicamentos con perfil de seguridad apropiado y altas tasas de adherencia. En vista de que no pasan a la circulación sistémica, los principales efectos adversos de las RSAB son gastrointestinales, entre los cuales sobresale el estreñimiento ²⁰. Su perfil de seguridad se ha comprobado en pacientes embarazadas ²¹, en quienes no solo se usan como hipolipemiantes, sino como depuradoras de medicamentos fetotóxicos como metotrexate y leflunomida ²².

Teniendo en cuenta la información presentada, el grupo desarrollador de la "Guía Colombiana para la prevención, detección temprana, diagnóstico, tratamiento y seguimiento de la dislipidemia en pacientes colombianos mayores de 18 años"¹¹, concluyó que la evidencia actual no apoya el uso de las RSAB como medicamentos de primera línea en el tratamiento de la dislipidemia, mientras que se propone su uso solamente cuando se han presentado efectos adversos serios que limiten la terapia con estatinas o cuando haya verdadera intolerancia a las mismas. Adicionalmente, son una alternativa interesante en mujeres embarazadas que requieran tratamiento.
Responsabilidades éticas Protección de personas y animales
Los autores declaran que para esta investigación no se han realizado experimentos en seres humanos ni en animales.
Confidencialidad de los datos
Los autores declaran que en este artículo no aparecen datos de pacientes.
Derecho a la privacidad y consentimiento informado
Los autores declaran que en este artículo no aparecen datos de pacientes.
Financiación
Este trabajo fue financiado por el Ministerio de la Protección Social y COLCIENCIAS.
Conflicto de intereses
Los autores declaran no tener ningún conflicto de intereses.
Bibliografía
1. Ministerio de la Protección Social. Informe sobre la situación de salud en Colombia -Indicadores de salud 2013. Colombia: Ministerio de la Protección Social; 2013. [ Links ]

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# data[].attributes.attachment_link.title
Efecto de las resinas secuestradoras de ácidos biliares en los desenlaces cardiovasculares y en los niveles séricos de lípidos: A systematic review

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http://dx.doi.org/10.1016/j.rccar.2015.04.010 Efecto de las resinas secuestradoras de ácidos biliares en los desenlaces cardiovasculares y en los niveles séricos de lípidos Effect of bile acid sequestrants on cardiovascular outcomes and seric lipids: A systematic review Oscar M. Muñoz a, b, Néstor F. Correa a, Angélica Higuera b, Ángel A. García a,b, Álvaro J.

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TITULO: Comparación de la eficacia hipolipemiante/aumentadora de 7 estatinas en pacientes con dislipidemia, enfermedades cardiovasculares o diabetes mellitus: revisión sistemática y metanálisis en red de 50 ensayos controlados aleatorios

TIPO DE ESTUDIO -AÑO: metanálisis-2020

RESULTADOS: Como resultado, se usaron para los análisis siete tratamientos de monoterapia con estatinas en 50 estudios (51956 participantes). Las estatinas incluían simvastatina (SIM), fluvastatina (FLU), atorvastatina (ATO), rosuvastatina (ROS), lovastatina (LOV), pravastatina (PRA) y pitavastatina (PIT). En términos de reducción de LDL-C, la rosuvastatina ocupó el primer lugar con un valor de superficie bajo clasificación acumulada (SUCRA) del 93,1%. La eficacia comparativa del tratamiento para la reducción de LDL-C fue ROS>ATO>PIT>SIM>PRA>FLU>LOV>PLA. Todos los demás resultados de clasificación y NMA se informaron en diagramas y tablas de clasificación de SUCRA.

CONCLUSIONES: De acuerdo con las NMA, se puede concluir que la rosuvastatina ocupó el primer lugar en LDL-C, eficacia para reducir ApoB y eficacia para aumentar ApoA1. La lovastatina ocupó el primer lugar en la eficacia de reducción de TC y TG, y la fluvastatina ocupó el primer lugar en la eficacia de aumento de HDL-C. Los resultados deben interpretarse con cautela debido a algunas limitaciones de nuestra revisión.
https://pubmed.ncbi.nlm.nih.gov/32411300/

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Affiliations

¹ Department of Pharmacy, Base for Clinical Trial, Peking University First Hospital, Beijing 100034, China.

² Department of Pharmacy, China Pharmaceutical University, Nanjing 210000, China.

³ Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.

Free PMC article

Free PMC article

Affiliations

¹ Department of Pharmacy, Base for Clinical Trial, Peking University First Hospital, Beijing 100034, China.

² Department of Pharmacy, China Pharmaceutical University, Nanjing 210000, China.

³ Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.

Abstract

Objective: The drug efficacy may differ among different statins, and evidence from head-to-head comparisons is sparse and inconsistent. The study is aimed at comparing the lipid-lowering/increasing effects of 7 different statins in patients with dyslipidemia, cardiovascular diseases, or diabetes mellitus by conducting systematic review and network meta-analyses (NMA) of the lipid changes after certain statins' use.

Methods: In this study, we searched four electronic databases for randomized controlled trials (RCTs) published through February 25, 2020, comparing the lipid-lowering efficacy of no less than two of the included statins (or statin vs. placebo). Three reviewers independently extracted data in duplicate. Firstly, mixed treatment overall comparison analyses, in the form of frequentist NMAs, were conducted using STATA 15.0 software. Then, subgroup analyses were conducted according to different baseline diseases. At last, sensitivity analyses were conducted according to age and follow-up duration. The trial was registered with PROSPERO (number CRD42018108799).

Results: As a result, seven statin monotherapy treatments in 50 studies (51956 participants) were used for the analyses. The statins included simvastatin (SIM), fluvastatin (FLU), atorvastatin (ATO), rosuvastatin (ROS), lovastatin (LOV), pravastatin (PRA), and pitavastatin (PIT). In terms of LDL-C lowering, rosuvastatin ranked 1 st with a surface under cumulated ranking (SUCRA) value of 93.1%. The comparative treatment efficacy for LDL-C lowering was ROS>ATO>PIT>SIM>PRA>FLU>LOV>PLA. All of the other ranking and NMA results were reported in SUCRA plots and league tables.

Conclusions: According to the NMAs, it can be concluded that rosuvastatin ranked 1 st in LDL-C, ApoB-lowering efficacy and ApoA1-increasing efficacy. Lovastatin ranked 1 st in TC- and TG-lowering efficacy, and fluvastatin ranked 1 st in HDL-C-increasing efficacy. The results should be interpreted with caution due to some limitations in our review. However, they can provide references and evidence-based foundation for drug selection in both statin monotherapies and statin combination therapies.

Conflict of interest statement

The authors declare no conflict of interest.

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national center for biotechnology information

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Comparative Lipid-Lowering/Increasing Efficacy of 7 Statins in Patients with Dyslipidemia, Cardiovascular Diseases, or Diabetes Mellitus: Systematic Review and Network Meta-Analyses of 50 Randomized Controlled Trials - PubMed

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According to the NMAs, it can be concluded that rosuvastatin ranked 1 st in LDL-C, ApoB-lowering efficacy and ApoA1-increasing efficacy. Lovastatin ranked 1 st in TC- and TG-lowering efficacy, and fluvastatin ranked 1 st in HDL-C-increasing efficacy. The results should ...