New anticoagulation options for patients with nonvalvular atrial fibrillation

Warfarin has been the sole oral anticoagulant in use for many decades. Multiple studies have demonstrated the superiority of therapeutic warfarin anticoagulation in stroke prophylaxis compared with various doses of aspirin and other platelet inhibitors and combinations of platelet inhibitors and low-dose warfarin in high-risk patients with atrial fibrillation.

Although guidelines suggest a target international normalized ratio (INR) of 2.5 (range, 2.0 to 3.0) for this indication, only about 50 to 60 percent of patients have an INR within the recommended range in usual clinical practice. Novel oral anticoagulants (NOACs) have provided another treatment option for these individuals.

"While these agents have been approved previously for prevention and treatment of deep venous thrombosis (DVT), recent clinical trials have demonstrated their noninferiority compared with warfarin in the prevention of thromboembolic stroke in patients with nonvalvular atrial fibrillation," according to Robert D. McBane, M.D., a cardiologist at Mayo Clinic in Rochester, Minnesota.

General characteristics of NOACs

Vitamin K antagonists such as warfarin inhibit the carboxylation of all vitamin K-dependent procoagulant factors (II, VII, IX and X), but they also have the "off-target" effect of inhibiting protein C and protein S. NOACs target specific proteins in the coagulation cascade; dabigatran inhibits thrombin, and rivaroxaban, apixaban and edoxaban are all direct inhibitors of factor Xa. Factor Xa is the point at which the intrinsic and extrinsic pathways converge to form the final common pathway of prothrombin activation.

All NOACs have rapid onset (one to three hours) and, as a result, do not require bridging; they all have similar half-lives (seven to 15 hours). They all exhibit some degree of renal metabolism. Hepatic cytochrome p450 3A4 (CYP3A4) is an important pathway of metabolism of all NOACs except for dabigatran. Strong inducers of this hepatic pathway include carbamazepine, phenytoin, rifampin, St John's wort and tipranavir-ritonavir combination therapy. Strong inhibitors include itraconazole, ketoconazole, lopinavir-ritonavir combination therapy, indinavir and voriconazole.

Summary of clinical trials

The results of four large clinical trials, each evaluating one of the four agents approved by the Food and Drug Administration (FDA) — dabigatran, rivaroxaban, apixaban and edoxaban — have been published.

All four agents demonstrated similar efficacy and improved safety (especially apixaban and edoxaban) compared with warfarin, despite significant differences in baseline patient characteristics, including CHADS2 score, history of congestive heart failure, history of prior stroke, percentage of therapeutic time in warfarin group, allowance of antiplatelet agents in the respective protocols and duration of follow-up.

"However, patients with severe renal failure were excluded from all trials," notes Waldemar E. Wysokinski, M.D., Ph.D., a cardiologist at Mayo Clinic in Rochester, Minnesota. "All trials had relatively high discontinuation rates, which had a negative impact on the reported incidence of thromboembolic events and a favorable impact on the reported incidence of major bleeding. These limitations need to be kept in mind when evaluating trial results."

Randomized evaluation of long-term anticoagulation therapy, 2009 (RE-LY)

This open, blinded-endpoint study compared dabigatran (thrombin inhibitor), 110 mg or 150 mg twice daily, to open-label, dose-adjusted warfarin. A total of 18,113 patients were enrolled. Inclusion criteria included a CHADS score of 1 or higher. There was no provision for dose adjustment. Follow-up was nearly two years.

INRs were in the therapeutic range in the warfarin group 64 percent of the time on average. The rate of all strokes in the 150-mg dabigatran group was less than that in the 110-mg dabigatran and the warfarin groups. The rate of extracranial hemorrhage was similar in all three groups.

Results were published by Stuart J. Connolly, M.D., and others in 2009 in the New England Journal of Medicine.

Rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation, 2011 (ROCKET AF)

This double-blinded, double-dummy study compared rivaroxaban (direct inhibitor of factor Xa), 20 mg once daily, with dose-adjusted warfarin. A total of 14,264 patients were enrolled. Inclusion criteria included a CHADS score of 2 or higher. In the rivaroxaban group 21 percent of patients had allowed dose adjustment. INRs were in the therapeutic range in the warfarin group 55 percent of the time on average. Follow-up was nearly two years.

Three different protocol-specified analyses were performed — per protocol/as treated, intention-to-treat and as-treated/safety analysis with differing results — leading to the conclusion that rivaroxaban was not superior but was significantly noninferior to warfarin treatment. The incidence of major hemorrhagic events did not differ significantly between groups, although the rate of intracranial hemorrhage was lower in the rivaroxaban group.

Results were published by Manesh R. Patel, M.D., and others in 2011 in the New England Journal of Medicine.

Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation, 2011 (ARISTOTLE)

This double-blinded, double-dummy study compared apixaban (direct inhibitor of factor Xa), 5 mg twice daily, with dose-adjusted warfarin. A total of 18,201 patients were enrolled. Inclusion criteria included a CHADS score of 1 or higher. INRs were in the therapeutic range in the warfarin group 62 percent of the time. Five percent of patients had allowed dose adjustment. Follow-up was nearly two years.

Apixaban reduced the risk of stroke or systemic embolism by 21 percent and the risk of major bleeding by 31 percent. Importantly, the apixaban-treated group had a significant reduction in all-cause death compared with the warfarin group (11 percent). This trial was the first to conclusively demonstrate improved overall mortality with NOAC treatment.

Results were published by Christopher B. Granger, M.D., and others in the New England Journal of Medicine in 2011.

Effective anticoagulation with factor Xa next generation in atrial fibrillation — thrombolysis in myocardial infarction 48, 2013 (ENGAGE AF-TIMI 48)

This double-blinded, double-dummy study compared edoxaban (direct inhibitor of factor Xa), 30 mg or 60 mg, once daily, with dose-adjusted warfarin. A total of 21,105 patients were enrolled. Inclusion criteria included a CHADS score of 2 or higher. INRs in the warfarin group were therapeutic 68.4 percent of the time. In the edoxaban group, 25 percent of patients had allowed postrandomization dose adjustment. Follow-up was nearly three years.

Edoxaban in both doses was not inferior to warfarin for stroke prevention but showed a better safety profile.

Results were published by Robert P. Giugliano, M.D., and others in 2013 in the New England Journal of Medicine.

Individual agents

Dabigatran (Pradaxa)

Dabigatran requires twice-daily dosing. Slight fluctuations in gastric acidity may impact absorption of the prodrug. Thus, the active ingredient is incorporated into tartaric acid-coated spherules within the capsules, and the capsules must be swallowed whole. The tartaric acid may be responsible for the gastric upset experienced by 5 to 10 percent of patients.

The capsules are stored in a blister package until use, as they are susceptible to degradation by ambient moisture. The prodrug is converted to the active form by a serum esterase and therefore is not dependent on the hepatic cytochrome p450 system; however, P-glycoprotein (Pgp) inhibitors such as quinidine, verapamil and amiodarone increase serum concentrations of dabigatran.

Rivaroxaban (Xarelto)

An advantage of rivaroxaban is once-daily dosing. Hepatic CYP3A4 is an important pathway of metabolism, and the effects of other drugs that impact this pathway need to be considered. At 20-mg doses (15 mg for patients with creatinine clearance less than 50 mL/min), rivaroxaban should be taken with food to achieve better bioavailability.

Apixaban (Eliquis)

Apixaban requires twice-daily dosing. Most of the hepatic clearance of apixaban occurs without metabolism. Thus, apixaban can be coadministered with drugs that are strong CYP3A4 and Pgp inhibitors, but at a reduced dose of 2.5 mg twice daily.

Edoxaban (Savaysa)

Edoxaban has recently received FDA approval for this indication. An advantage is once-daily dosing, and it should be taken with food to optimize absorption. The FDA has included a boxed warning stating that edoxaban is less effective than warfarin in preventing stroke in patients with creatinine clearance higher than 95 mL/min, possibly due to the fact that 50 percent to 60 percent of the drug is excreted renally. It is approved for treating DVT and pulmonary embolism (PE) as well as secondary DVT and PE prophylaxis.

Knowledge gaps

Because of variations in inclusion and exclusion criteria in the four major clinical trials, the appropriate use of NOACs in patient subgroups is unknown. There are no data regarding the use of NOACs in pediatric and pregnant patients; patients with a prior history of intracranial, intraocular, spinal or traumatic arterial bleeding; and patients with severe anemia or thrombocytopenia. All of these subgroups were restricted from clinical trials.

An early concern not addressed in clinical trials is the lack of antidotes to rapidly reverse the anticoagulant effects of NOACs in the case of life-threatening hemorrhage (especially intracranial) or surgery. For unclear reasons, the incidence of intracranial hemorrhage was lower in the NOAC-treated groups than in the warfarin-treated groups in all four trials, possibly due to the single-target effect with NOACs versus the multiple factors affected by warfarin.

However, it should be noted that the hemorrhagic rate in patients on warfarin in these four trials was higher than the rate documented in the Canadian registry, which likely better represents "real life." Additionally, there are no data suggesting that reversibility is associated with improved outcome in patients with severe bleeding.

Preliminary results from a preplanned interim analysis of a study of the reversal effects of idarucizumab on active dabigatran (RE-VERSE AD) trial data indicate idarucizumab may be a safe, effective antidote to dabigatran. The study population is small and the trial is ongoing, but these early results are encouraging.

Finally, NOACs are considerably more expensive than warfarin, and insurance coverage may need to be considered. For those individuals on a stable, established warfarin regimen, there is no need to change. If a change is contemplated, Drs. McBane and Wysokinski suggest that the following factors be taken into consideration:

  • The only agent to have superior efficacy in reduction of ischemic stroke is dabigatran, 150 mg twice daily.
  • For patients at increased risk of bleeding, apixaban demonstrated a consistent reduction in bleeding across all age groups studied, regardless of indication for anticoagulation.
  • Edoxaban, 30 mg daily, is the only NOAC that has demonstrated specifically a reduced risk of gastrointestinal bleeding compared with warfarin.
  • Once-daily dosing improved compliance (rivaroxaban and edoxaban).
  • Dabigatran may cause gastrointestinal upset and should probably be avoided in individuals with severe dyspepsia and in those who have undergone vagotomy, gastric drainage, antrectomy, subtotal or total gastrectomy, or a bariatric procedure.
  • Patients with severe renal dysfunction should probably be treated with warfarin or apixaban.

For more information

Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2009;361:1139.

Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine. 2011;365:883.

Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2011;365:981.

Giugliano RP, et al. Edoxaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2013;369:2093.