Factor Xa, the activated form of factor X, was identified as a viable drug target as it plays a key role in the coagulation cascade and hemostasis. Natural Xa inhibitors such as Antistasin and tick anticoagulant peptide (TAP) were isolated from Mexican leeches and soft ticks, respectively to test viability of Xa as a drug target^1,3. Due to promising results pharmaceutical companies launched programs to develop synthetic, oral Xa inhibitor. 

There are two phases of coagulation; initiation and amplification. 

Ultimately, Factor Xa inhibition results in a reduction of thrombin generation, which thins the blood and prevents clot formation³.

Figure from: January et al. J Am Coll Cardiol. 2014. Edited with PowerPoint. 

This demonstration of efficacy allowed for in vivo preclinical trials to occur.

Figures from: Gerotziafas GT et al. 2007⁵.

This study demonstrated that when Xarelto was given preventatively (orally) there was a significant reduction in clot formation relative to controls. Also, at higher dosages thrombin generation was shown to be almost completely inhibited⁶. 

The results of this study showed that Xarelto reduces thrombin generation and therefore clot formation in a dose-dependent manner⁶. 

All of the figures show that use of rivaroxaban was successful in reducing clot formation in vivo and was therefore moved to clinical trials. 

Also in studies with rabbit models, it was shown that oral rivaroxaban significantly reduced the growth of preexisting blood clots, demonstrating this drug has the potential to treat already established thrombi and emboli⁴. 

Figures from: Perzborn E, Strassburger J, Wilmen A, et al. 2005⁶.

 ODIXa-DVT

Results: The primary efficacy endpoint was achieved in 43.8–59.2% of patients receiving rivaroxaban and in 45.9% of patients receiving standard therapy.

EINSTEIN-DVT
Rivaroxaban 20, 30 or 40 mg od were assessed to standard therapy.
Study investigate the primary efficacy endpoint: the composite of symptomatic, recurrent VTE and deterioration of thrombotic burden

Results: the primary efficacy endpoint occurred in 5.4–6.6% of patients receiving rivaroxaban vs. 9.9% in the standard therapy group. 

In conclusion:  rivaroxaban 20–40 mg od had good efficacy and safety for the treatment of acute symptomatic DVT⁷.
Table from: Haas S.2009⁷

- The ease of oral administration instead of injections. ¹
- It is target-specific and it was the first direct inhibitor of factor Xa with approval for clinical settings. ¹
- Does not need any dietary restrictions because there are few interactions between this drug and food which can decrease its efficacy. It can be taken with or without food. ¹
- Decreases drug-drug interactions which occur when two different drugs are taken simultaneously and may interact with each other.  ¹

- Does not require a dose adjustment and regular coagulation monitoring because its safety and efficacy have already been analyzed and its probability of drug/food interactions is low. ¹

- Eliquis and Xarelto are both direct Xa inhibitors while Pradaxa is a direct thrombin inhibitor.
- The three of them are effective in preventing blood clots; however, some studies suggested Eliquis is slightly more effective and has the fewest side effects.
- All of them are taken orally and can be expensive. The expenses of these drugs can be covered with private health insurance or Medicare which significantly decreases their price.
- The main advantage of Xarelto over Eliquis and Pradaxa is that it is taken only once a day while the others are taken twice a day.¹⁴

Improvements of Xarelto to keep it in the market

The future of Xarelto and its expansion towards new conditions. 

The trial demonstrated a 79% RRR in total VTE and a comparable safety profile low rates of major bleeding, in patients undergoing THR surgery compared to patients  dosed with short-duration therapy with enoxaparin 

the incidence of major bleeding at 5 wks was 0.1% in both groups confirming the benefits of extended prophylaxis over short-term prophylaxis and the safety of its use9⁷.

‘Xarelto’ showed 49% RRR in total VTE in patients undergoing total knee replacement (TKR) surgery compared to enoxaparin, with a comparable safety profile including low rates of major bleeding7. 

There was  31.4% RRRin total VTE in patients undergoing TKR surgery and taking 1omg of Xarelto compared with enoxaparin, with a comparable safety profile including low rates of major bleeding7. 

Figure from Haas. 2009

The primary efficacy endpoint was observed in 23.8%, 40.4%, 10.6% and 14%, of patients assigned to rivaroxaban 10mg in the four studies. 

The primary efficacy endpoint occurred in 16.8% , 44.3%,25.2% and 17%of patients in the com- parator group. 

Meanwhile The primary safety outcome was observed in 2.5%, 0%, 0.7% and 2.2%, of patients assigned to rivaroxaban 10mg in the four studies. Compare to 0%, 1.9% and 1.5% of patients in enaxoparin⁹.

Table from: Schulman S. 2009⁹

Xarelto is also prescribed preventatively for patients that have an increased risk of developing blood clots, such as those recovering from major surgeries, especially knee and hip surgeries, and those experiencing limited mobility^1,2.

Studies concerning the use of Xarelto in children are promising. The dosage of Xarelto given to children is adjusted to their body weight¹⁰. 

There was also a need for more target-specific anticoagulants that had less interactions with other drugs and food, along with more predictable effects. Vitamin K antagonists were the only oral anticoagulant available before Xarelto's approval for clinical use in 2008^1,3. It had unpredictable pharmacokinetics, required frequent dose adjustments, and had multiple drug-drug and food interactions^1-3.