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Cardiac Conduction System and Understanding ECG

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How a Normal Heart Pumps Blood -- The Children's Hospital of Philadelphia

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Learn more at http://heart.chop.edu. In this animation, The Children's Hospital of Philadelphia explains how a normal heart pumps blood.

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Captopril, Losartan, Diltiazem & Nitroprusside

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Digoxin, Milrinone & Ivabradine

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Lidocaine, Propranolol & Amiodarone

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Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism

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Heparin for the treatment of acute VTE

How should heparin be initiated, including baseline laboratory tests and dosing?

While heparin therapy for VTE treatment is typically administered by continuous IV infusion, both adjusted dose and fixed dose SC injections can also be utilized. A comparative study of SC and IV heparin using the same initial dose (5000 unit IV bolus followed by 30,000 units/day) reported an increased risk of VTE recurrence with SC heparin (19.3 % vs. 5.2 %; p = 0.024), suggesting the need for higher doses with this route [ 1]. A meta-analysis comparing IV heparin to dose-adjusted SC heparin (initial dose 5000 units IV then 17,500 units SC twice daily) for initial DVT treatment found a lower risk of VTE recurrence or extension with SC heparin (relative risk [RR] 0.62, 95 % confidence interval [CI] 0.39-0.98) with a similar risk of major bleeding (RR 0.79, 95 % CI 0.42-1.48) [ 2]. Prandoni et al. conducted an open label multicenter trial in 720 patients comparing LMWH to adjusted dose SC heparin in those with acute, symptomatic VTE. SC heparin regimens were weight based with those over 70 kg receiving an initial 6000 unit IV bolus then 17,500 units twice daily. Objectively confirmed recurrent VTE, major bleeding and overall mortality were similar [ 3]. In the fixed dose heparin investigators (FIDO) trial, a randomized, open label, non-inferiority trial, fixed dose heparin (333 units/kg bolus then 250 units/kg every 12 h) was compared to LWMH for initial treatment of acute VTE [ 4]. There was no weight exclusion for the trial. Recurrent VTE at 3 months occurred in 3.8 % of heparin patients compared to 3.4 % of LMWH patients (absolute difference 0.4 %; 95 % CI −2.6 to 3.3 %) while major bleeding occurred in 1.1 % of heparin patients versus 1.4 % of LMWH patients (absolute difference, −0.3 %; 95 % confidence interval, −2.3 to 1.7 %).

The optimal initial dosing of continuous infusion heparin therapy is controversial. In 1989, the second American College of Chest Physicians (ACCP) Clinical Practice Guideline on VTE treatment recommended an initial 5000 unit bolus followed by a 1000 unit/h infusion [ 5]. In 1993, Raschke et al. compared weight based heparin dosing (80 units/kg followed by 18 units/kg/h) to a standard regimen (5000 units followed by 1000 units/h) in 115 patients with venous or arterial thrombosis [ 6]. A five-fold reduction in recurrent VTE was observed with weight-based dosing (95 % CI 1.1-21.9). Nevertheless, most VTE treatment trials incorporated a fixed dose initial heparin infusion regimen of 5000 unit bolus followed by infusion of approximately 1300 units/h [ 7]. In 1992, the ACCP VTE treatment guidelines suggested a 5000-10,000 unit bolus followed by a fixed heparin infusion of 1300 units/h (31,200 units/day) and in 1995 and 2004 they endorsed either a fixed regimen or the Raschke weight based regimen [ 8- 10]. For a 70 kg patient, the Raschke regimen translates into a heparin bolus of 5600 units followed by infusion of 1260 units/h. The 2012 version of the guidelines do not address UFH dosing in the VTE treatment chapter [ 11]. However, in the chapter on parenteral anticoagulants, UFH dosing recommendations are similar to those in 1995 and include either a weight based regimen (Raschke regimen) or a fixed regimen of 5000 unit bolus followed by a continuous infusion of at least 32,000 units/day [ 12].

The Joint Commission's National Patient Safety Goals require that a written policy stating required baseline and ongoing laboratory tests for patients on heparin be in place in healthcare institutions [ 13]. Pre-treatment hemoglobin and hematocrit are used as a baseline from which to assess subsequent changes that may reflect bleeding. A baseline platelet count is used to compare to subsequent values in order to detect the possible development of heparin-induced thrombocytopenia (HIT). Finally, an elevated pre-treatment prothrombin time (PT) or activated partial thromboplastin time (aPTT) may detect the presence of an underlying coagulation defect.

Guidance Statement

We suggest that total body weight, CBC, PT and aPTT be obtained prior to initiating heparin therapy. Heparin efficacy is related to dose regardless of route. The initial dose is more important than the aPTT in predicting efficacy. Although optimal initial dosing for bolus and continuous infusion remain uncertain, we suggest doses outlined in Table , acknowledging that these options have not been compared in head- to- head clinical trials. Internal audits to determine the dose requirement to produce therapeutic anticoagulation based upon the responsiveness of the health- system's aPTT reagent and coagulation instrument are strongly encouraged.

The volume of distribution of heparin approximates blood volume, is related to body weight and averages 60 mL/kg [ 14]. There are no prospective trials evaluating heparin dosing regimens using different weight strategies, although a trial in obese patients (NCT01361193) is ongoing. Current dosing recommendations do not specify which weight should be used. The Raschke nomogram used actual body weight; however only 9/115 patients (<8 %) had a weight above 100 kg (range 101-131 kg) [ 6].

For the obese and morbidly obese patient, the importance of striking a balance between achieving effective anticoagulation and avoidance of bleeding is apparent. Although obese patients have a larger blood volume, the vascularity of adipose tissue is lower than that of lean body mass, raising concern for over-anticoagulation when heparin is dosed using total body weight. Under-dosing is also a concern as obese patients are at increased risk of VTE recurrence. Dose caps employed to increase safety may increase the risk of under-dosing in the obese/morbidly obese patient and contribute to treatment failures.

Guidance Statement

When a weight based heparin dosing strategy is selected, we suggest total body weight for calculating dose. For the obese/morbidly obese patient either total body weight or adjusted body weight can be used. Although no increased risk of major bleeding has been reported when morbidly obese patients are managed using total body weight, studies have not included patients weighing above 270 kg. If adjusted body weight is used, prompt attention to initial laboratory results is warranted to ensure the therapeutic threshold is exceeded in a timely manner. Empiric dose caps may increase the risk of initial under anticoagulation in obese and morbidly obese patients. If empiric dose caps are used, individualized initial dosing should be available for obese and morbidly obese patients.

Direct anti-Xa level monitoring is recommended in those with heparin resistance (see subsequent section), baseline aPTT elevation from a lupus anticoagulant or contact factor deficiency or those with markedly elevated levels of fibrinogen or factor VIII [ 24].

Guidance Statement

The optimal approach to heparin monitoring is unknown. Either aPTT or heparin anti- Xa level monitoring may be used. We suggest using anti- Xa level monitoring in patients with heparin resistance, a prolonged baseline aPTT or altered heparin responsiveness. We suggest the aPTT or anti- Xa level be checked every 6 h until two consecutive therapeutic results are obtained, after which the frequency of monitoring can be extended to once daily.
Monitoring aPTT
Despite the standard practice to monitor heparin through coagulation laboratory testing, the body of evidence supporting monitoring is surprisingly weak. In 1972, Basu et al. reported a lower rate of VTE recurrence when the aPTT was maintained between 1.5-2.5 × control [ 25]. A subsequent study using a rabbit model of thrombosis demonstrated prevention of thrombus extension with an aPTT of approximately 1.5 times control [ 26]. These data provided the foundation for an empiric aPTT therapeutic range of 1.5-2.5 times control. Over the next two decades, important concepts emerged, which challenged the accepted aPTT therapeutic range as well as the overall benefit of monitoring heparin therapy. Data supporting a relationship between sub-therapeutic aPTTs within the first 24-48 h and increased VTE recurrence at 90 days came from post hoc analysis of studies using fixed dose heparin regimens of ≤30,000 units/day [ 7]. A pooled analysis of trials using initial heparin infusion regimens of at least 30,000 units/day showed no association between sub-therapeutic aPTT and increased VTE recurrence (90 day recurrence: 6.3 % with sub-therapeutic aPTT in first 24-48 h versus 7 % in those with therapeutic aPTTs; odds ratio 0.89, 95 % CI: 0.2-4) [ 27]. In the FIDO trial of unmonitored SC heparin, recurrent VTE (at 90 days) occurred in 3.8 % of heparin patients versus 3.4 % with LMWH, absolute risk difference 0.4 (95 % CI −2.6 to 3.3) [ 4]. Although therapy was unmonitored, on day 3 an aPTT was drawn and subsequently analyzed by a central laboratory at study conclusion. None of the heparin patients with recurrent VTE had a sub-therapeutic aPTT [ 4]. Data supporting the upper limit of the heparin aPTT therapeutic range for VTE are even weaker than data supporting the lower limit [ 7, 27- 30]. Hull et al. reported bleeding events in 8.6 % of VTE patients with supratherapeutic aPTTs compared to 12.3 % of patients without [ 28]. In the FIDO trial none of the major bleeding events in the heparin group were associated with an aPTT above 85 s [ 4].
Monitoring heparin levels
Protamine sulfate titration and anti-Xa analysis are two approaches to heparin level monitoring. Early animal studies suggested a heparin level therapeutic range of 0.2-0.4 units/mL by protamine sulfate titration [ 18]. Subsequent studies from McMaster University demonstrated that this range was equivalent to a heparin anti-Xa level of approximately 0.3-0.7 units/mL [ 31]. This equivalency between assay systems was promoted by national guidelines despite data challenges to its validity [ 12, 24]. Since appearing in national guidelines, the heparin anti-Xa level therapeutic range of 0.3-0.7 unit/mL has gained widespread acceptance despite limited clinical trial outcome data [ 31]. In 2008, the ACCP VTE treatment guidelines stated "When patients are treated with an initial heparin infusion of 1250 U/h (corresponding to 30,000 U/d) or 18 units/kg/hr, it is uncertain if adjustment of heparin dose in response to the aPTT or heparin levels improves efficacy or safety [ 32]. There are no recent trials evaluating unmonitored continuous infusion heparin therapy or different levels of heparin anticoagulation.

Guidance Statement

The benefit of monitoring IV heparin once a therapeutic threshold has been exceeded is not well defined. We suggest monitoring of continuous infusion heparin therapy, either using aPTT or anti- Xa, as this is considered standard of care despite the weak evidence base. Monitoring is optional in those receiving SC weight- based heparin therapy.

The Raschke study, the pivotal trial for weight based IV heparin dosing, used a fixed therapeutic aPTT interval of 46-79 s which corresponded to an aPTT ratio of 1.5-2.3 times control [ 6]. Other VTE treatment trials comparing heparin to LMWH employed a fixed aPTT ratio of 1.5-2.5 times control for heparin patients. In recognition of the variable sensitivity of different aPTT reagents to heparin, the use of an empiric fixed interval or fixed aPTT ratio for heparin monitoring is no longer recommended for treatment of VTE in national guidelines. The College of American Pathologists (CAP) and the ACCP recommend that each institution define its own therapeutic aPTT range based upon the responsiveness of the aPTT reagent and coagulometer in use [ 12, 23, 24]. The therapeutic range should be re-established with each change of reagent manufacturer, lot or coagulation instrument. Ex-vivo samples (as opposed to spiked samples) from 30 patients receiving therapeutic dose heparin should be used. A 3.2 % sodium citrate concentration is recommended for sampling. Two approaches are acceptable according to the CAP. The first is to use linear regression analysis to determine the aPTT interval which corresponds to a therapeutic heparin concentration (e.g. 0.3-0.7 anti-Xa units/mL). Although this approach was previously recommended by the ACCP, the most recent guidelines do not specify a desired therapeutic range for use of heparin in the treatment of VTE [ 11, 12, 32]. The use of a heparin concentration-calibrated aPTT therapeutic range for heparin monitoring has not been prospectively evaluated against alternative monitoring strategies.

The second approach recommended by the CAP compares aPTT results using the old and new reagent and assesses reagent drift using the cumulative summation method. Differences in aPTT results are tracked yearly and adjustments in therapeutic range are needed when the cumulative difference exceeds 7 s [ 24]. The CAP recommends the first approach to establish the initial heparin therapeutic range and the cumulative summation method for subsequent changes in reagent. If direct heparin concentration monitoring is used, a therapeutic range of 0.3-0.7 U/mL by anti-Xa analysis is widely accepted and promoted despite limited data [ 18, 24, 31, 33].

Guidance Statement

The optimal heparin therapeutic range is uncertain. The target therapeutic range is less important than ensuring an appropriate initial heparin dose. The CAP suggests the one- time establishment of a heparin concentration- derived aPTT therapeutic range. The cumulative summation method is suggested for range re- evaluation following reagent/instrument change. When anti- Xa monitoring is used, a therapeutic target of 0.3-0.7 units/mL is suggested.

Heparin resistance is a term used to describe patients who require high doses of heparin. Heparin resistance can be caused by antithrombin deficiency, increased heparin clearance or increased heparin binding proteins (often considered acute phase reactants). Patients with these conditions have a reduction in the formation of heparin-antithrombin complexes and require higher heparin doses to reach a therapeutic aPTT. Although the term heparin resistance is also used to describe patients with increased levels of factor VIII or fibrinogen, these individuals may more appropriately be described as having altered heparin responsiveness. These patients have a downward shift in the dose response curve resulting in a shortened or blunted aPTT response. Such patients may appear to be heparin resistant but increasing the heparin dose based upon the aPTT may lead to over-anticoagulation and an increased risk of bleeding [ 34].

Guidance Statement

We suggest drawing a paired aPTT and heparin anti- Xa level when heparin resistance is suspected. If the aPTT is subtherapeutic and the anti- Xa level is therapeutic, the heparin dose does not require adjustment and subsequent monitoring should occur using the anti- Xa level when feasible. If, despite serial dose increases, both the aPTT and anti- Xa level remain low, true heparin resistance may be present.

The use of a nomogram to guide heparin dosage adjustment increases the proportion of patients receiving adequate anticoagulation based on achieving a therapeutic aPTT [ 35]. Even with nomograms, however, nontherapeutic aPTTs occur in more than 25 % of patients in clinical trials [ 36]. In one study, only 29 % of patients with a therapeutic aPTT had two consecutive repeat therapeutic aPTTs [ 37]. Dose adjustment algorithms can be weight based (e.g. increase infusion rate by 2 units/kg/h) or fixed dose (e.g. increase infusion rate by 100 units/h) [ 6, 38]. Dose adjustment algorithms were not provided in the major VTE treatment trials comparing heparin to LMWH. A fixed dose algorithm may be inadequate in obese patients [ 15]. In a single center study, Cruickshank et al. evaluated the performance of a dosage adjustment nomogram by calculating the success rate for each heparin dose adjustment recommendation based upon the aPTT interval (e.g. increase heparin infusion by 80 units/h for an aPTT of 50-59 s) [ 38]. Results were used to modify the dosage adjustment algorithm. No studies are available which compare different heparin dosage adjustment algorithms. Health-systems typically adopt a published algorithm from a single center trial [ 6, 39].

Guidance Statement
We suggest that heparin dosing be guided by a dose adjustment nomogram, and that a weight based heparin dose adjustment algorithm may offer benefit over a fixed adjustment algorithm for the obese patient. More research in defining and assessing the optimal dosage adjustment nomogram is needed.
Patients with VTE who are treated with a vitamin K antagonist alone have an unacceptably high rate of VTE extension and recurrence [ 40]. The ACCP recommendations for the desired duration of overlap of a parenteral agent with warfarin over the past 15 years are summarized in Table [ 10, 11, 32, 41]. The current recommendation is to continue parenteral anticoagulation along with warfarin for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h [ 11]. The 5 day minimum is recommended to avoid a potential hypercoagulable state upon warfarin initiation. Factor II levels take a minimum of 5 days to fall while protein C (an endogenous anticoagulant) has a short half-life and is more rapidly depleted [ 42]. The recommendation for an INR of 2 or greater for at least 24 h is provided to ensure that the INR elevation indicates adequate anticoagulation and not solely a reduction in factor VII (short half-life). The ACCP recommended duration of overlap was followed in some VTE treatment trials demonstrating similar efficacy of LMWH to heparin (new VTE at 90 days in heparin patients 1.9 and 4.1 %) while others included a 6 day overlap with a single INR requirement above 2.0 (recurrent 90 day VTE in heparin patients 6.8 and 6.9 %) [ 28, 43- 45]. In a retrospective study conducted in an academic medical center, Hylek et al. reported compliance with the ACCP recommendation for overlap in only 20 % of patients with more than 40 % of surgical patients having less than a 4 day overlap [ 37]. For hospitalized patients this recommendation is often perceived to increase length of stay. Patients may be discharged on LMWH to complete the requisite period of overlap, but this temporary measure complicates the transition of care.

It is important to note that the ACCP recommendation for an INR > 2 for at least 24 h is paired with the recommendation to treat with a parenteral agent for at least 5 days (a separate level of evidence does not exist for the INR recommendation). Recently, there is noticeable movement away from requiring the INR to be above 2 for at least 24 h. The 2015 Joint Commission VTE Core Measures (VTE-3) address anticoagulant overlap requirements [ 46]. Compliance requires a minimum of 5 days of overlap with a heparin product and warfarin (or discharge on both agents or documentation of why overlap is not indicated) and a single INR above 2 prior to discontinuation of parenteral therapy. This approach has been used in recent clinical trials [ 47].

The direct acting Xa inhibitors rivaroxaban and apixaban do not require initial injectable therapy, but many patients in the clinical trials did receive an initial dose of a parenteral anticoagulant [ 51- 53].

Recommendations for transitioning from parenteral to oral anticoagulants are described in Table .

Guidance Statement

Parenteral anticoagulation with heparin should be overlapped with warfarin for at least 5 days and until a single INR is 2.0 or greater. Treatment of VTE with rivaroxaban and apixaban does not require initial parenteral anticoagulation while dabigatran and edoxaban require a minimum of 5 days of parenteral anticoagulation prior to initiation. See Table for additional details.

Guidance Statement
We suggest protamine sulfate be administered to reverse the effect of heparin when indicated. We suggest that health systems develop and implement guidelines on anticoagulant reversal and HIT evaluation and management.

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Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism

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How should heparin be initiated, including baseline laboratory tests and dosing? While heparin therapy for VTE treatment is typically administered by continuous IV infusion, both adjusted dose and fixed dose SC injections can also be utilized.

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After surviving a heart attack, celebrity fitness trainer and best-selling author Bob Harper was prescribed Brilinta. The medication is for people who have been hospitalized due to a heart attack and is designed to reduce the chance of another one by helping prevent platelets from sticking together and forming a clot.

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