An anticoagulation option for nonvalvular atrial fibrillation

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An anticoagulation option for nonvalvular atrial fibrillation

J Fam Pract. 2012 June;61(6):E1-E6

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References

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Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996;348:633-638.

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16. Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;118:2029-2037.

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TABLE 1
CHADS₂ score for stratifying risk of stroke in a patient with nonvalvular atrial fibrillation⁵

Risk factor	Score
CHF (reduced EF%)	1
Hypertension	1
Age ≥75 years	1
Diabetes mellitus	1
Stroke/TIA	2
TOTAL
CHADS₂ score	Treatment considerations^1,19,20
0	Withhold treatment, or give aspirin
1	Give an antiplatelet or anticoagulant
≥2	Give an oral anticoagulant such as warfarin, dabigatran, or rivaroxaban
CHADS₂, acronym comprising initial letters of risk factors listed; CHF, congestive heart failure; EF, ejection fraction; TIA, transient ischemic attack.

Dabigatran as an option for nonvalvular AF

Dabigatran’s approval was based on the clinical outcomes of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.²¹ This multicenter randomized noninferiority trial compared warfarin with 2 doses of dabigatran (110 and 150 mg twice daily) in patients who had AF and a risk of stroke. A total of 18,113 patients with AF, a mean age of 71 years, and a mean CHADS₂ score of 2.1 were randomly assigned in a blinded fashion to receive one of the dabigatran doses or, in nonblinded fashion, warfarin. The primary outcome was stroke or systemic embolism. The primary safety outcome was major bleeding defined as a reduction in the hemoglobin level of at least 20 g/L, a need for transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. The mean follow-up period was 2 years.

The study showed that 110 mg dabigatran twice daily was statistically not inferior to warfarin in preventing stroke and systemic embolism (1.53% vs 1.69% per year; P<.001). In addition, this dose was associated with statistically lower rates of major bleeding (2.71% vs 3.36% per year; P=.003). However, dabigatran 150 mg twice daily was statistically superior to warfarin in reducing the risk of stroke and systemic embolism by 34% per year (1.11% vs 1.69%; P<.001) with rates of major bleeding similar to warfarin (3.11% vs 3.36% per year; P=.31). The beneficial effect of dabigatran was also seen in patients with higher CHADS₂ scores of 3 to 6, who comprised one-third of the study population and were at higher risk of stroke. Interestingly, both doses of dabigatran were associated with lower rates of intracranial hemorrhage than was warfarin. The 110-mg dose of dabigatran, however, was not approved by the FDA.

A higher incidence of myocardial infarction (MI) occurred in the dabigatran group compared with warfarin, but it was not statistically significant.^21,22 A recent meta-analysis of 7 randomized controlled trials, including RE-LY, found that dabigatran was significantly associated with a higher incidence of MI or acute coronary syndrome compared with heterogeneous control groups receiving placebo, warfarin, or enoxaparin (1.19% vs 0.79%, odds ratio, 1.33; P=.03).²³

The exact reason for the difference is unknown. It may be due to a chance effect, given that the absolute number of events was small. Or warfarin may exert a protective effect against MI, as was seen in the WARIS II study, wherein warfarin, given alone or in combination with aspirin, was superior to aspirin in reducing the risk of reinfarction.²⁴ However, a true adverse effect of dabigatran cannot be ruled out. If it proves to be the case, 2 more cases of MI can be expected to occur in 1000 patients treated with dabigatran, compared with warfarin, at 1 year.

FAST TRACK

There was a statistically significant higher incidence of major gastrointestinal hemorrhage with dabigatran 150 mg twice daily compared with warfarin.

In addition, there was a statistically significant higher incidence of major gastrointestinal hemorrhage with dabigatran 150 mg twice daily compared with warfarin. Most of these bleeding events occurred in the lower gastrointestinal tract. Here, too, the exact reason for the difference is unknown.

How dabigatran prevents thrombus formation

Dabigatran directly and competitively inhibits both free and fibrin-bound thrombin, thereby preventing thrombin-mediated effects on the coagulation cascade, including cleavage of fibrinogen to fibrin, activation of factors V, VIII, XI, and XII, and thrombin-induced platelet aggregation.^25-28

The drug’s pharmacokinetic profile. Dabigatran is given as a prodrug, dabigatran etexilate. Serum esterase converts it to its active form. Peak concentration is reached within 2 to 3 hours of oral dosing, and its half-life is 12 to 17 hours. It is taken twice daily, mornings and evenings. The drug is excreted unchanged, primarily by the kidneys (~80%); the remainder is metabolized by the liver. Therefore, dabigatran is contraindicated in patients with severe renal dysfunction (creatinine clearance <15 mL/min). Compared with warfarin, dabigatran has a more predictable anticoagulant function, no need for laboratory monitoring, and less interaction with other drugs and foods (TABLE 2).^29-32 No data are available regarding heterogenous genetic response to dabigatran.

TABLE 2
How warfarin and dabigatran compare pharmacologically^29-32