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Neurosurgery:
doi: 10.1227/01.neu.0000393591.15767.13
Science Times

Is It Time to Abandon Warfarin and Embrace Oral Direct Thrombin Inhibitors to Prevent Stroke in Patients With Atrial Fibrillation?

Rahme, Rudy J; Bernstein, Richard; Batjer, H Hunt; Bendok, Bernard R

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Stroke is the leading cause of morbidity in the United States with potential devastating consequences to individuals and their families. Atrial fibrillation (AF) accounts for 1.5% of strokes in patients between the ages of 50 to 59 years and up to 23.5% in octogenarians.1 While warfarin has been proven to be effective in reducing AF-related thromboembolic events, its use is cumbersome due to a narrow therapeutic index, unpredictable pharmacokinetics, multiple drug and food interactions, and a risk of major hemorrhage. Warfarin has been the only oral blood thinner available for 50 years, and until recently nothing has been proven more effective in patients who can tolerate the drug.

With this in mind, the RE-LY investigators (Randomized Evaluation of Long-Term Anticoagulation Therapy, N Engl J Med. 2009;361(12)) compared a new generation anticoagulant, dabigatran, to warfarin in the prevention of stroke. The dabigatran group was further divided based on the administered dose: 110 mg twice daily and 150 mg twice daily. Dabigatran is an orally administrated direct thrombin inhibitor that does not require any coagulation monitoring and has no food interactions or major drug interactions. It has rapid onset, with therapeutic drug levels achieved within 2 hours of oral administration. If proven as effective as warfarin for preventing stroke in atrial fibrillation, it has the potential to dramatically simplify long-term anticoagulation. This is important, since even in the best of circumstances, patients on warfarin are in the therapeutic range no more than 65% of the time.2-4

Between December 2008 and March 2009, the trial prospectively enrolled 18 113 patients with atrial fibrillation from 951 multinational centers. Patients randomly received either dose-adjusted warfarin or one of two fixed doses of dabigatran. Although this was an open label trial, among the dabigatran group the choice of dose was double blinded. The primary outcome of the study was the event of stroke—ischemic or hemorrhagic—or systemic embolism. The secondary outcome was death. The main safety outcome was major hemorrhage. The study aimed to establish the non-inferiority of dabigatran compared to warfarin.

The primary outcome (Table) was observed in 1.69% of patients taking warfarin, vs 1.53% in the 110 mg dabigatran group (RR = 0.91, P < .001 for noninferiority), and 1.11% in the 150 mg dabigatran group (RR = 0.66, P < .001 for superiority). The 110 mg dosage was shown to be as effective as warfarin, while 150 mg demonstrated superiority in the prevention of stroke and thromboembolic events. The rates of major bleeding were 3.36% per year in the warfarin group, vs 2.71% in the 110 mg dabigatran group (RR = 0.8, P = .003) and 3.11% in the 150 mg dabigatran group (RR = 0.93, P = .31). Compared to warfarin, the 110 mg dose of dabigatran revealed lower major bleeding events, whereas no significant difference was noted with the 150 mg dabigatran dose.

TABLE. Outcome in Re...
TABLE. Outcome in Re...
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Of particular importance to neurosurgeons, the rate of hemorrhagic stroke was almost 75% lower in both dabigatran groups than in patients taking warfarin, regardless of time in therapeutic range (0.38% per year on warfarin vs 0.12% on 110mg dabigatran and 0.10% on 150 mg dabigatran; P < .001).5 The 150 mg dabigatran group had a higher rate of gastrointestinal bleeding. No difference was detected between the 2 dabigatran groups in terms of hemorrhagic stroke. There was no significant difference in the mortality rates between the 3 groups, however the 150 mg dabigatran group had a significantly higher rate of myocardial infarction (RR to warfarin: 1.38; P = .048). The analysis of the composite outcome consisting of major vascular events, major bleeding and death revealed a rate of 7.64% per year with warfarin compared to 7.09% per year with 110 mg dabigatran (RR: 0.92, P = .10) and 6.91% per year with 150 mg dabigatran (RR:0.91, P = .04). However, this analysis may understate the true value of the drug, since it assigns equal weight to a GI bleed, which is usually an event from which patients recover, and an ischemic or hemorrhagic stroke, which is usually catastrophic. Based on this data, the Food and Drug Administration recently approved the 150 mg BID dose for patients with non-valvular atrial fibrillation.

While this study suggests that dabigatran may soon replace warfarin for stroke prevention in many patients with atrial fibrillation, many questions remain. There is currently no specific antidote for dabigatran; it is unknown how to reverse the drug in the case of acute ICH. Initiation of dabigatran was delayed in RE-LY for 6 months after disabling ischemic stroke. Therefore, there is no data on the drug's safety after recent major ischemic stroke. A practical approach might be to initiate dabigatran at the time that one would be comfortable starting intravenous heparin, although that also is an area of controversy. Finally, dabigatran cannot be used in patients with creatinine clearance <30 ml/min. Going forward, it will be important to compare the case fatality of dabigatran brain hemorrhages with that of patients with warfarin-associated brain hemorrhage.

It appears that it is not yet time to abandon warfarin for stroke prevention, but dabigatran will likely be a preferable alternative for many patients. Other thrombin inhibitors may also soon emerge. As critical members of the “stroke coalition,” neurosurgeons remain on the front line of hemorrhagic and ischemic stroke therapy and prevention. Working with our colleagues from other specialties, we will need to learn the nuances of dabigatran and possibly other thrombin inhibitors, define protocols for their administration, and create rational pathways for management of their hemorrhagic complications.

Disclosure: Dr Richard Bernstein is a consultant and on the speaker's bureau for Boehringer Ingelheim.

Rudy J. Rahme

Richard Bernstein

H. Hunt Batjer

Bernard R. Bendok

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REFERENCES

1. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics−2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):480-486.

2. Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293(6):690-698.

3. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet. 2003;362(9397):1691-1698.

4. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med. 2000;160(7):967-973.

5. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010;376(9745):975-983.

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