New antithrombotic released for stroke prophylaxis in atrial fibrillation

Atrial fibrillation is a major source of morbidity and mortality in the United States and increases the risk of ischemic stroke 5-fold, causing more than 200,000 events annually.

Warfarin therapy reduces this risk by 64%. Yet warfarin therapy can be difficult to manage because of high variability within and between patients, its narrow therapeutic range, and the interaction with diet and medications. Warfarin use requires lifelong, frequent assessment of each patient's international normalized ratio (INR) for dose adjustment and is associated with increases in the risk of major hemorrhage, particularly in elderly patients.

Collectively, these variables limit clinicians' enthusiasm for warfarin initiation in atrial fibrillation patients. Currently, only 50% of patients with atrial fibrillation who would benefit from warfarin therapy receive it, and the discontinuation rates are high. At 1 year, more than 25% of patients stop warfarin despite an ongoing indication for this drug. For these reasons, the prospect of antithrombotic prophylaxis strategies requiring neither monitoring nor dose adjustment is particularly attractive.

Dabigatran approved

Recently, an oral direct reversible thrombin inhibitor, dabigatran, was approved by the US Food and Drug Administration (FDA) for the indication of stroke prevention in patients with nonvalvular atrial fibrillation. This drug is formulated as a prodrug and is metabolized to the active compound on ingestion. The time to peak anticoagulant effect is about 1 hour, and the drug half-life is about 15 hours, with 80% of elimination through the kidney.

Dabigatran has been approved in 2 tablet strengths, 150 mg and 75 mg, given twice daily. Because of the drug's renal clearance, the 150-mg dose is indicated for patients with reasonable kidney function (creatinine clearance exceeding 30 mL/min). For patients with limited renal function (creatinine clearance of 15-30 mL/min), the 75-mg tablet strength is recommended (although this dose is untested in clinical trials). The drug should not be used in patients with more advanced kidney disease.

"At currently available prices, dabigatran is approximately 3 times more expensive than warfarin plus INR monitoring, assuming 5 mg/day warfarin dosing with once-monthly INR monitoring," according to Waldemar E. Wysokinski, M.D., Ph.D., a cardiologist in the Mayo Clinic Gonda Vascular Center.

Dabigatran can be thought of as a second-generation oral direct thrombin inhibitor. Ximelagatran was a first-generation agent, which, though effective, did not receive FDA approval, largely stemming from concerns of liver toxicity. Compared with warfarin and enoxaparin, dabigatran has no greater risk of liver function test abnormality, defined as alanine aminotransferase levels greater than 3 times the upper limit of normal.

RE-LY trial

At this point, there is no recommendation regarding liver function test monitoring for patients receiving this drug. The Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial assessed the efficacy and safety of dabigatran compared with warfarin in 18,113 patients with nonvalvular atrial fibrillation. This was a noninferiority randomized trial design, open label with respect to warfarin and blinded with respect to 2 doses of dabigatran (110 and 150 mg twice daily).

To qualify for trial participation, patients had to have nonvalvular atrial fibrillation plus at least 1 risk factor, including a prior thromboembolic event, an ejection fraction less than 40%, heart failure, or age of 75 years or older. Younger patients aged 65 to 74 years were eligible to participate if they had diabetes mellitus, coronary artery disease, or hypertension.

After a mean follow-up of 30 months, participants randomly assigned to receive dabigatran, 150 mg twice daily, experienced a significantly lower incidence of a primary end point (stroke or systemic embolism) compared with participants who received dabigatran, 110 mg twice daily, and warfarin: 1.1%/year vs 1.5%/year vs 1.7%/year.

This improvement did not come at a cost of major bleeding, which was similar for patients receiving 150 mg of dabigatran and warfarin patients: 3.1%/year vs 3.4%/year. Life-threatening bleeding was also similar between these 2 groups: 1.5%/year vs 1.9%/year. Hemorrhagic stroke was in fact significantly lower in patients receiving 150 mg of dabigatran compared with those receiving warfarin: 0.1%/year vs 0.4%/year.

In a post hoc analysis, warfarin-treated patients were divided by treatment center on the basis of the time in the therapeutic INR range (above and below the 67% median). Hazard ratios were constructed to compare patients receiving warfarin and dabigatran.

For patients receiving inadequate INR management from participating centers by this definition, the hazard was superior for dabigatran-treated patients for rate of embolism, major hemorrhage, and mortality compared with warfarin-treated patients. In contrast, for patients receiving INR management from participating centers above this median INR adequacy, there was no difference with respect to these outcomes.

The average time within the therapeutic INR range observed in patients treated with warfarin worldwide is below the 67% median achieved in the RE-LY trial. Patients receiving dabigatran do not require anticoagulant monitoring. In some circumstances, however, coagulation testing may be performed or required. Dabigatran has been shown to prolong both the activated partial thromboplastin time (aPTT) and prothrombin time. The aPTT will be about twice the control value within 1 hour of ingestion. At 12 hours after ingestion, when the next dose is taken (on a regimen of twice-daily dosing), the aPTT will still be about 1.5 times the basal values.

Previous studies showed that coagulation parameters closely followed drug concentrations. Single, orally administered doses of dabigatran (10-400 mg) led to rapid, dose-dependent increases in aPTT, mean INR, thrombin time, and ecarin clotting time, with the maximum anticoagulant effect occurring at the maximum plasma dabigatran concentration.

The aPTT may be helpful in assessing the circulating dabigatran levels in a patient for whom an invasive procedure is needed. In general, dabigatran administration should be stopped for 4 or 5 half-lives (60-75 hours) before an invasive procedure to ensure that all drug has been eliminated.

Whereas dabigatran is a small-molecule direct thrombin inhibitor, there is no antidote or reversing agent. Particularly for patients undergoing surgical procedures with a high risk of major bleeding, this is an important management point to consider. "For patients treated with dabigatran who have a major bleeding event, health care providers have several treatment options," according to Robert D. McBane, M.D., a cardiologist in the Mayo Clinic Gonda Vascular Center.

1. It is important to recall that major bleeding events are rare; between 1.3% and 2% have been reported in the large randomized trials published to date.
2. The perhaps more important point is to support the patient with red blood cell transfusion, fluids, and pressure support as needed. Equally important is the identification and correction of all sources of bleeding, which may include endoscopy, surgery, and interventional radiology (angiography and coiling) where indicated.
3. Whereas dabigatran is a small molecule, it is to some degree (60%) dialyzable.
4. Some have advocated the use of additional hemostatic agents, including factor VIII inhibitor bypass activity used for patients with factor VIII inhibitors (FEIBA), prothrombin complex concentrates, and recombinant factor VII when needed. These agents should be used with caution and only when absolutely needed as they undoubtedly swing the hemostatic pendulum toward thrombosis. It is important to recall that patients receiving dabigatran are doing so for an antithrombotic indication.

In summary, dabigatran represents a new era of anticoagulant therapy. For the indication of nonvalvular atrial fibrillation, dabigatran is a reasonable alternative to warfarin therapy. "Its use should be restricted to the FDA-approved indication of nonvalvular atrial fibrillation," says Dr. McBane.

Ideal candidates for this medication include those patients whose warfarin is difficult to manage and who have widely fluctuating INR values, those for whom good anticoagulation management is not available, and those living remotely. For those patients with ready access to good anticoagulant management, dabigatran and warfarin are likely equivalent therapies.