Dabigatran or Warfarin for Atrial Fibrillation?

Chances are, warfarin has begun its ride into the sunset.

THE SETTING

Warfarin has a long history of success in the prevention of thromboembolism in patients with atrial fibrillation (AF) and the treatment of deep venous thrombosis and pulmonary embolism; the drug is also used to prevent both venous and arterial clots and to treat several other conditions (e.g., anticardiolipin antibody syndrome). However, warfarin requires frequent monitoring of the international normalized ratio (INR) and dose adjustment; even with meticulous care, warfarin recipients often have INRs outside of the narrow therapeutic window.

Indeed, many pharmaceutical companies have been hard at work on replacements for warfarin. Warfarin is an inhibitor of thrombin synthesis. Most of the drugs currently under evaluation for preventing venous and arterial thromboembolism are direct inhibitors of factor Xa or thrombin. Ximelagatran, the first antithrombin inhibitor to undergo large-scale clinical trials, showed efficacy similar to warfarin for the prevention of thromboembolism in patients with AF; however, increased levels of liver enzyme leakage prevented FDA approval of ximelagatran for use in the U.S.

THE STORY

Now, the FDA has approved dabigatran, a direct thrombin inhibitor with peak concentrations 1 to 2 hours after ingestion and a half-life of 12 to 14 hours, for prevention of thromboembolism in patients with AF. Dabigatran exhibits very little drug–drug or drug–food interaction and is excreted renally. FDA approval was based largely on findings from the RE-LY trial involving 18,113 patients with AF and a CHADS₂ score (measuring risk for stroke) of 1 or more (JW Cardiol Sep 1 2009). In the RECOVER trial, researchers compared high-dose dabigatran with an adjusted dose of warfarin for the treatment of venous thromboembolism in 2539 patients; dabigatran demonstrated efficacy and bleeding risk similar to that of warfarin (JW Gen Med Dec 8 2009).

The major question about dabigatran has now shifted from efficacy and safety to cost. Not only insurers but also many in the medical community fear that the high price of this agent will drive up healthcare costs. Warfarin itself is inexpensive; however, its total cost also includes healthcare personnel time, laboratory expenses of frequent INR monitoring, and the costs of hospitalization for the consequences of both subtherapeutic and supertherapeutic INRs. In a recently published Markov decision model of cost-effectiveness, the cost of dabigatran compared with warfarin was approximately $50,000 per quality-adjusted life-year (JW Gen Med Dec 2 2010); the price of dabigatran has subsequently fallen.

THE DENOUEMENT

As a practicing cardiac electrophysiologist, I often find warfarin to be the bane of my care of patients with AF. The FDA's rejection of ximelagatran (which I considered promising) and fear of the high cost of a new agent made me initially somewhat pessimistic that an alternative to warfarin would ever be released. I am therefore quite pleased to have an available option with an improved safety profile, albeit at a higher economic cost. Furthermore, the cost of dabigatran will be driven down if rivaroxaban, a direct Xa inhibitor (Physician's First Watch Nov 16 2010) or other alternatives to dabigatran and warfarin prove effective and obtain FDA approval.

Other lingering concerns include the lack of tools for careful monitoring and rapid reversal of dabigatran's effects; thus, in the short term, dabigatran will be used primarily in patients who have problems with warfarin, such as those treated at institutions with low rates of INR control (JW Cardiol Aug 30 2010), or who are at high risk for bleeding or for poor compliance with warfarin treatment. But I can easily envision a future in which I transfer all of my warfarin patients to direct thrombin or Xa inhibitors and relegate warfarin to a fitting pharmaceutical graveyard.

Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009 Sep 17 ; 361:1139.