In the United States, there are currently four direct oral anticoagulants (DOACs). All four DOACs are approved for the treatment of venous thromboembolism (VTE) and nonvalvular atrial fibrillation (NVAF), among other indications.1-4 Despite differences in pharmacology, pharmacokinetics, and clinical trial efficacy and safety data, current guidelines do not prefer a specific DOAC. Given the lack of guideline-based recommendations for a particular DOAC, clinicians are frequently left without clear guidance of the most appropriate DOAC for a particular patient beyond the preferences of an insurance company or the availability of manufacturers’ coupons. After a careful analysis of the existing data, a very strong case can be made to make apixaban (Eliquis) the preferred DOAC for both VTE and NVAF.
What is the role of DOACs versus warfarin in VTE and NVAF?
For the treatment of venous thromboembolism (VTE), the CHEST 2016 guidelines recommend any of the four DOACs over warfarin therapy for long-term anticoagulation therapy in patients without cancer (grade 2B).5 The guidelines do not specifically endorse any DOAC, although a table is provided that outlines factors that may influence the selection of a “preferred” anticoagulant. For example, patients wanting to avoid parenteral therapy may prefer rivaroxaban or apixaban because dabigatran and edoxaban require five to ten days of parenteral therapy prior to initiation.
For the treatment of nonvalvular atrial fibrillation (NVAF), the 2014 AHA/ACC/HRS guidelines recommend warfarin (class IA) or a DOAC (class IB).6 The guidelines provide the same level of recommendation (IB) for dabigatran, rivaroxaban, and apixaban. At the time of publication, edoxaban (Savaysa) was not approved for use in the United States and was not mentioned within the guidelines.
Comparison of DOAC Efficacy and Safety in VTE Clinical Trials
To date, there are no trials directly comparing one DOAC to another for the treatment of VTE. Instead, all DOACs have been compared to warfarin in phase III trials. Although a direct DOAC comparison would be very desirable, it is unlikely that this type of clinical trial will come to fruition in the near future.
As a substitute for directly comparing DOACs, two recent indirect meta-analyses were conducted to evaluate the performance of each DOAC using warfarin as a consistent comparator.7, 8 Not surprisingly given the small number of clinical trials, both meta-analyses came to the same conclusion. All DOACs appear to be similar in efficacy with regards to the prevention of recurrent VTE or VTE-related mortality. With regards to safety, however, apixaban was shown to have the most desirable adverse effect profile with regards to bleeding. Compared to other DOACs, apixaban demonstrated a reduction in major or clinically relevant bleeding ranging from 53% less (versus rivaroxaban) to 31% less (versus dabigatran).
Given the available clinical trial data, apixaban has been shown to be equally effective in the treatment of VTE and superior in causing fewer bleeding events versus the other DOACs. With a more favorable risk:benefit ratio, one could argue that apixaban should be the preferred DOAC for the treatment of VTE.
Comparison of DOAC Efficacy and Safety in NVAF Clinical Trials
As with VTE, there are currently no trials directly comparing one DOAC to another for the treatment of NVAF. All phase III DOAC NVAF trials have used warfarin as a comparator, and it is similarly unlikely that a trial comparing two DOACs will be published in the near future.
A recent meta-analysis using indirect comparison analysis was conducted to evaluate the performance of each DOAC versus using warfarin as a consistent comparator among patients with NVAF.9 Among the DOAC doses that were eventually FDA approved, there was no difference in efficacy (stroke or systemic embolism) between any DOAC. With regards to safety, however, apixaban demonstrated a lower risk of major bleeding versus dabigatran and rivaroxaban, but was similar in major bleeding to edoxaban. Finally, apixaban was likely more “tolerable” than all other DOACs as reflected by a lower treatment discontinuation rate.
In consideration of the best available evidence, apixaban has been shown to be equally effective in preventing stroke or systemic embolism in patients with NVAF, is the most tolerable as measured by treatment discontinuation rates, and shares the lowest rate of major bleeding with edoxaban.
The Case against Dabigatran (Pradaxa) as the DOAC of Choice
Dabigatran has a concerning adverse effect profile unique to other DOACs that may impact its tolerability.1 In clinical trials, the rates of dyspepsia and GERD-like symptoms was more common than in patients taking warfarin. In addition, and more concerning, there may be a signal of a small but elevated risk of myocardial infarction events compared to warfarin in the VTE clinical trials (0.66 vs. 0.17 events per 100 patient-years).
Another complicating factor of dabigatran is its precautions regarding administration and storage.1 Dabigatran capsules must be swallowed whole (not broken, crushed, chewed, or emptied); doing so will increase overall drug exposure and potentially increase the risk for bleeding. Furthermore, dabigatran should be kept in its original bottle and it expires within four months of opening.
While dabigatran can be reversed with idarucizumab (Praxbind), there is a promising new reversal agent for the other DOACs on the horizon in the form of andexanet alfa (AndexXa).
The Case against Rivaroxaban (Xarelto) as the DOAC of Choice
Rivaroxaban has many qualities that make it a desirable DOAC agent.2 Unlike dabigatran, it does not have any unique or concerning adverse effects. Rivaroxaban’s unique quality, however, is that most doses (15 or 20 mg) must be taken with food. Taking rivaroxaban with food increases drug exposure by 39% and the maximum concentration by 76%, meaning that failure to take rivaroxaban appropriately can result in low serum concentrations of the drug and a risk of therapeutic failure.
The Case against Edoxaban (Savaysa) as the DOAC of Choice
At first glance, edoxaban has many advantageous traits.4 It is taken once daily without regards to meals and does not have any of the unique adverse effects seen with dabigatran. Further, it was the only DOAC shown to have similarly low major bleeding rates to apixaban in patients with NVAF.9
Unlike all other DOACs, however, edoxaban warrants serious concern regarding its boxed warning in patients with excellent renal function (creatinine clearance above 95 mL/min). In the trial for NVAF, edoxaban was less effective (associated with a higher incidence of stroke or systemic embolism) versus warfarin among the cohort of patients with excellent renal function. There is no mention or analysis of this cohort within the VTE clinical trials, but it stands to reason that similar precaution among this patient group would be prudent.
The Final Case for Apixaban (Eliquis) as the DOAC of Choice
Apixaban embodies nearly all of the qualities desirable in a DOAC for the treatment of either VTE or NVAF. As previously mentioned:
- Apixaban is just as effective as other DOACs for the treatment of VTE and NVAF
- In the treatment of VTE, apixaban likely has the lowest bleeding risk compared to all other DOACs
- In the treatment of NVAF, apixaban and edoxaban have the lowest bleeding risk compared to the other DOACs
- In the treatment of NVAF, apixaban demonstrated the lowest discontinuation rate (a surrogate for tolerability)
Furthermore, apixaban does not require five to ten days of parenteral anticoagulation for the treatment of VTE (unlike dabigatran and edoxaban).3 It can be crushed and does not have any unique administration or storage concerns. It does not have any unique adverse effects (unlike dabigatran) and does not have any specific concerns in patients with excellent renal function (unlike edoxaban).
The most significant downside to apixaban is that it requires twice daily dosing, whereas rivaroxaban and edoxaban tout the quality of once daily administration. While this may be less convenient, it seems like a small price to pay for so many other redeeming qualities.
Given the similar efficacy, favorable safety, greater tolerability, and a lack of unique administration or storage warnings, a compelling case can be made for selecting apixaban as the DOAC of choice for the treatment of VTE or NVAF.
- Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
- Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2015.
- Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016.
- Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc; 2016.
- Kearon C, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016 Feb;149(2):315-352. doi: 10.1016/j.chest.2015.11.026.
- January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 Dec 2;64(21):e1-76. doi: 10.1016/j.jacc.2014.03.022.
- Cohen AT, Hamilton M, Mitchell SA, et al. Comparison of the Novel Oral Anticoagulants Apixaban, Dabigatran, Edoxaban, and Rivaroxaban in the Initial and Long-Term Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis. PLoS One. 2015 Dec 30;10(12):e0144856. doi: 10.1371/journal.pone.0144856.
- Mantha S, Ansell J. Indirect comparison of dabigatran, rivaroxaban, apixaban and edoxaban for the treatment of acute venous thromboembolism. J Thromb Thrombolysis. 2015 Feb;39(2):155-65. doi: 10.1007/s11239-014-1102-5.
- Lip GY, Mitchell SA, Liu X, et al. Relative efficacy and safety of non-Vitamin K oral anticoagulants for non-valvular atrial fibrillation: Network meta-analysis comparing apixaban, dabigatran, rivaroxaban and edoxaban in three patient subgroups. Int J Cardiol. 2016 Feb 1;204:88-94. doi: 10.1016/j.ijcard.2015.11.084.