Direct Thrombin Inhibitor for Atrial Fibrillation
Direct Thrombin Inhibitor for Atrial Fibrillation
Abstact & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant. This article originally appeared in the November 2009 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Ethan Weiss,
Source: Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009:361: 1139-1151.
Dabigatran etexilate is an oral compound that is converted after absorption by a serum esterase to dabigatran, a direct competitive inhibitor of thrombin. Dabigatran has previously been evaluated and found to be effective in patients with venous thrombolism. In this study, Connolly et al report a large, randomized trial comparing dabigatran, 110 mg or 150 mg twice daily, with adjusted-dose warfarin for prevention of thromboembolic events in patients with atrial fibrillation. The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial enrolled patients from 951 clinical centers in 44 countries. Eligible patients had atrial fibrillation documented on an ECG within the previous six months and at least one of the following risk factors for thromboembolism: previous stroke or transient ischemic attack, left-ventricular ejection fraction less than 40%, New York Heart Association Class II or higher heart failure symptoms, age greater than 75, or age 65 to 75 plus diabetes, hypertension, or coronary artery disease. Patients with valvular heart disease, recent stroke, increased baseline risks for bleeding, renal and hepatic dysfunction, and pregnancy were excluded. The patients were randomly assigned to receive either open-label, adjusted-dose warfarin or blinded-dose dabigatran, 110 or 150 mg twice daily. For patients on warfarin, the international normalized ratio (INR) target was 2.0-3.0, with the INR measured at least monthly. Follow-up visits occurred at two weeks, one and three months, and then every three months thereafter. Liver function tests were performed monthly during the first year of the follow-up for the first 6,000 patients in the study and subsequently at regular study visits.
The primary study outcome was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in the hemoglobin level of at least 20 g/liter, a need for transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. The study was designed as a noninferiority comparison between the two doses of dabigatran and warfarin.
A total of 18,113 patients were enrolled over a two-year period. The mean age for the entire group was 71 years; 63.3% were men. Approximately equal proportions of patients with persistent, paroxysmal, and permanent atrial fibrillation were enrolled. The mean CHADS2 score was 2.1. Seventy-nine percent of the patients had a history of hypertension and 23% a history of diabetes mellitus. Approximately 50% had previously been treated with a vitamin K antagonist. For patients taking warfarin, the mean percentage of time during which the INR was between 2.0 and 3.0 was 64%.
The annual rates for stroke or systemic embolism were 1.3% for patients receiving 110 mg of dabigatran, 1.11% for patients receiving 150 mg of dabigatran, and 1.69% for patients on warfarin. Both doses satisfied criteria for noninferiority compared to warfarin, and the 150 mg dose was also superior to warfarin (relative risk, 0.66; 95% confidence interval, 0.53-0.82: p < 0.001). Hemorrhagic stroke occurred at an annual rate of 0.3% in the warfarin group, compared to 0.12% in the 110 mg dabigatran group (p < 0.001) and 0.1% in the 150 mg dabigatran group (p < 0.001). Total mortality was 4.13% per year with warfarin, compared to 0.375% per year with 110 mg dabigatran and 3.64% per year with 150 mg dabigatran. These mortality reductions with both doses of dabigatran were not statistically significant. Slightly higher myocardial infarction rates were seen in patients on dabigatran as compared to warfarin.
Major bleeding occurred at an annual rate of 3.36% per year with warfarin, compared to 2.71% per year in the 110 mg dabigatran group (p = 0.003) and 3.11% per year in the 150 mg dabigatran group (p = 0.31).
Dyspepsia was more common with dabigatran than with warfarin, occurring at rates of 11.8% and 11.3% in the 100 mg and 150 mg dose groups, respectively, compared to a rate of 5.8% in the warfarin group. Increase in liver function test values and interactions with creatinine clearance were not noted. After two years of therapy, 21% of the patients receiving both doses of dabigatran had discontinued therapy, compared to 17% of those receiving warfarin.
Connolly et al conclude that in comparison with warfarin, dabigatran 110 mg twice daily was associated with similar rates of stroke and systemic embolism and lower rates of major hemorrhage, and that the 150 mg dose of dabigatran had lower rates of stroke and embolism with a similar rate of major hemorrhage.
Commentary
Stroke and systemic embolism are major complications of atrial fibrillation. Numerous trials have established the role of warfarin therapy in atrial fibrillation. However, many factors can make warfarin therapy difficult for patients. Warfarin response is often influenced by dietary factors, and many drugs have interactions with warfarin metabolism. Warfarin metabolism is highly variable in the population. Even in a well-run clinical-trial setting, only about two-thirds of INR values are within the desired range. The need for frequent INR monitoring is costly and inconvenient for patients. Bleeding, both major and minor, is frequently seen with warfarin, particularly during early-dose titration. The RE-LY trial results show that an orally effective, direct thrombin inhibitor, dabigatran etexilate, may provide a potential alternative to warfarin therapy.
In RE-LY, both the efficacy data and safety data were in favor of dabigatran, particularly with the 110 mg, twice-daily dose. If dabigatran is approved for general use, these data, plus the convenience of predictable dosing without the need for frequent blood tests, will make it the preferred choice for many patients and physicians.
There are now several other alternatives to warfarin in various stages of clinical development. These include other thrombin inhibitors, oral and injectable Factor Xa inhibitors, and warfarin congeners with more predictable metabolism. Hopefully, within the next few years, we will be able to offer patients a safer and more reliable approach to chronic anticoagulation.
Dabigatran etexilate is an oral compound that is converted after absorption by a serum esterase to dabigatran, a direct competitive inhibitor of thrombin.Subscribe Now for Access
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