New oral anticoagulants: Prescriber beware

Issue: May 2012

ByJohn Lindsley, PharmD, BCPS

During the past 18 months, two novel oral anticoagulants were approved by the FDA for the prevention of stroke in patients with atrial fibrillation, and at least one more agent is likely to gain approval in the near future.

The advent of these new medications was long awaited by many due to some of the unattractive properties of warfarin, the standard of care in the field of anticoagulation. Warfarin therapy has high inter-individual variability; numerous food and drug interactions; frequent monitoring; and often requires a sophisticated patient to understand its complexity. Despite these obvious pitfalls, it has been the go-to medication for stroke prevention in AF for many years and has a wealth of literature and clinical experience associated with its use.

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John Lindsley

Because dosing and monitoring of warfarin can be cumbersome, novel oral anticoagulants were developed to try to eliminate monitoring and minimize interactions with other medications. These agents have been studied in venous thromboembolism prophylaxis of orthopedic procedures; treatment of VTE; stroke prevention in AF; and as an adjunct to therapy in patients with acute coronary syndromes. Currently, FDA approval for the new anticoagulants dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Janssen Pharmaceuticals) is limited to stroke prevention in AF, as well as VTE prophylaxis after orthopedic procedures. This review is focused on review of the data regarding stroke prevention.

Major trials in AF

Dabigatran, the first novel oral anticoagulant, was approved by the FDA in October 2010. It is a direct competitive inhibitor of thrombin. The RE-LY trial compared dabigatran with warfarin for the prevention of stroke in AF. Patients studied had a mean CHADS₂ score of 2.1 and 50% had prior long-term warfarin therapy. The FDA-approved dose of 150 mg twice daily proved to be superior to warfarin for the prevention of stroke or systemic embolism (1.11% per year vs. 1.69% per year; RR=0.66; 95% CI 0.53-0.82). No differences in major bleeding were noted; however, different rates of specific organ-related bleeding were found, which included increased rates of gastrointestinal bleeding in the dabigatran group and increased rates of intracranial bleeding in the warfarin group. Patients assigned dabigatran were also more likely to experience dyspepsia, possibly related to the tartaric acid formulation utilized to increase its absorption.

Rivaroxaban is an oral direct factor Xa inhibitor. The drug received FDA approval in November. The ROCKET AF trial compared rivaroxaban with warfarin in patients with a mean CHADS₂ score of 3.47; 62% of patients had been on prior warfarin therapy. Rivaroxaban proved to be noninferior to warfarin for the primary outcome of stroke or systemic embolism (HR=0.79; 95% CI, 0.66-0.96). There was no difference in overall bleeding between the groups; however, more patients in the warfarin group experienced intracranial hemorrhage and more patients in the rivaroxaban group experienced gastrointestinal bleeding, similar to the results found in the RE-LY trial.

Apixaban (Eliquis, Bristol-Myers Squibb and Pfizer), also a direct inhibitor of factor Xa, has been studied in two trials for stroke prevention in AF. The AVERROES study evaluated apixaban vs. aspirin in the prevention of stroke from AF in patients deemed unsuitable candidates for warfarin. This trial of approximately 5,500 patients was stopped early by the data and safety monitoring committee due to excess events in the aspirin group as the primary outcome exceeded 4 standard deviations with no differences in bleeding events. Apixaban was also compared with warfarin in the ARISTOTLE study for the prevention of stroke in patients with a mean CHADS₂ score of 2.1; approximately 57% of patients had prior warfarin use. The primary outcome of stroke or systemic embolism occurred significantly less frequently in the apixaban group (1.27% per year vs. 1.6% per year; HR=0.79; 95% CI, 0.66-0.95). Apixaban was associated with less bleeding in all defined categories except gastrointestinal bleeding, for which no difference was found between the two treatment arms. At this time, apixaban has not been approved for use in the United States, but it is approved in Europe for the prevention of VTE after orthopedic surgery.

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Applicability and concerns

Although these new agents have been touted as the panacea compared with warfarin and its difficult dose and monitoring profile, use has not yet become mainstream. As these oral anticoagulants continue on the market, we learn more about their use in real-world scenarios.

Since the approval of dabigatran, new warnings related to increased bleeding were issued and updates to the package labeling have been made in the dose recommendations section, specifically related to renal function and drug interactions. Also notable is the continued concern first raised in the RE-LY trial, related to an increase incidence in MI in patients treated with dabigatran vs. other anticoagulant therapy. A recent meta-analysis evaluated seven trials and found an increase in ACS with dabigatran as compared with warfarin (1.19% vs. 0.79%; OR=1.33; 95% CI, 1.03-1.71). This outcome may be related to the protective effect of warfarin in ACS, and not necessarily a negative effect of dabigatran. With this new information, it may be warranted to avoid dabigatran in those patients with risk factors or a history of CAD. This finding was also confirmed in another recent meta-analysis with dabigatran and ximelagatran, an oral direct thrombin inhibitor that did not receive FDA approval due to reports of liver toxicity.

Another worrisome challenge with the use of novel oral anticoagulants is the inability to reverse their effect. To date, data regarding reversal ability are limited and therefore problematic when patients present with hemorrhagic complications of therapy or require urgent or emergent procedures. Ongoing research with various recombinant blood factor products such as prothrombin complex concentrates shows more promise for the reversal of rivaroxaban than dabigatran, and more information may be available in the future to assist in these scenarios. Although bleeding complications may be more likely with warfarin, proven therapy exists to reverse warfarin’s effects in a timely and predictable manner.

Novel oral anticoagulants have a place in therapy, but time will be needed to fully elucidate their potential for improvement in care. As with warfarin, individualized care and patient selection becomes an important component of stroke prevention with these new oral anticoagulants.

John Lindsley, PharmD, BCPS, is a clinical pharmacy specialist at The Johns Hopkins Hospital, Baltimore.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor in the department of pharmacotherapy and translational research, College of Pharmacy, and division of cardiovascular medicine, College of Medicine, University of Florida, Gainesville. Dr. Cooper-DeHoff is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Editorial Board. For suggestions for future topics for this column, contact her at dehoff@cop.ufl.edu.

For more information:

Bauer KA. Am J Hematol. 2012;doi:10.1002.23165.
Connelly SJ. N Engl J Med. 2009;361:1139-1151.
Connolly SJ. N Engl J Med. 2011;364:806-817.
Granger CB. N Engl J Med. 2011;365:981-992.
Patel MR. N Engl J Med. 2011;365:883-891.
Uchino K. Arch Intern Med. 2012;172:397-402.

Disclosure: Dr. Lindsley reports no relevant financial disclosures.