Dabigatran: An Oral Direct Thrombin Inhibitor

Pharmacology Watch

In this issue: Results from a Phase 3 study of dabigatran, intensive lipid-lowering in CVD, H1N1 vaccine dosing and efficacy, and FDA Actions.

Anticoagulation without monitoring?

Dabigatran is an oral direct thrombin inhibitor, currently being used in many countries as an alternative to warfarin. It is anxiously awaited in this country primarily because, unlike warfarin, it does not require monitoring with blood tests. The drug has been shown to be as effective as warfarin in preventing stroke in patients with atrial fibrillation (N Engl J Med 2009;361:1139-1151).

A new study published in December 2009 compares the two drugs in the treatment of acute venous thromboembolism. In a randomized, double-blind, non-inferiority trial, patients with acute venous thrombus embolism were given a median of 9 days of parenteral anticoagulation therapy, then were randomized to oral dabigatran (150 mg twice a day) or warfarin that was dose-adjusted to achieve an INR of 2.0-3.0. The primary outcome was 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Of the patients randomized to receive dabigatran, 2.4% had recurrent venous thromboembolism compared to 2.1% of patients on warfarin (difference in risk of 0.4%; 95% confidence interval [CI], -0.8 to 1.5; P < 0.001 for the prespecified non-inferiority margin). Major bleeding episodes occurred in 1.6% of patients on dabigatran vs 1.9% of patients on warfarin. Episodes of any bleeding were 16.1% with dabigatran and 21.9% with warfarin. There was no difference in the number of deaths, acute coronary syndromes, or abnormal liver function tests between the two groups. Treatment was discontinued due to adverse events in 9% of patients on dabigatran and 6.8% of patients on warfarin. The authors concluded that for treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has similar safety, but does not require laboratory monitoring (N Engl J Med 2009;361:2342-2352).

Physicians and patients alike in the United States have been awaiting an orally effective anticoagulant that doesn't require monitoring. Dabigatran, a direct thrombin inhibitor, may soon fill that role. The drug, which has the additional advantage of having minimal drug and food interactions, has been available in Canada and Europe for almost 2 years, and with the completion of Phase 3 trials such as this one, there is speculation the FDA may take action this year.

Intensive lipid-lowering and CVD

Follow-up analysis of two of the most famous lipid-lowering trials confirms that intensive lipid-lowering therapy continues to be beneficial in the longer term. The PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) trial, first published in 2004, compared moderate lipid-lowering using standard-dose pravastatin to intensive lipid-lowering with high-dose atorvastatin after acute coronary syndrome. The study showed high-dose therapy significantly reduced the occurrence of death, myocardial infarction, stroke, and unstable angina requiring hospitalization or revascularization occurring more than 30 days after the event. The new post-hoc analysis (J Am Coll Cardiol 2009; 54:2358-2362) followed patients for up to 2 years and showed continued benefit in reduction of the primary endpoint (16%; P = 0 .005) with high-dose therapy, as well as reduction of additional events (19%; P = 0.009).

The IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) study compared high-dose atorvastatin with usual dose simvastatin for the prevention of events subsequent to a first event. The study was published in 2005, and while not showing reduction in mortality in the 4.8 years of study, it did show a reduction in secondary cardiovascular outcomes with high-dose therapy. The new analysis looked at not only time to first event, but also second, third, fourth, and fifth events. High-dose therapy significantly reduced subsequent events by 17%-28%. The authors concluded that continued intensive statin therapy continues to be more effective than standard statin therapy, even beyond the first vascular event (J Am Coll Cardiol 2009;54:2353-2357).

Both these studies suggest that staying the course with intensive lipid-lowering in patients with cardiovascular disease is an effective long-term strategy.

H1N1 dosing and efficacy

Three recent studies in the Dec. 17, 2009, New England Journal of Medicine confirm that a single dose of the H1N1 vaccine is effective for most healthy adults and children age 3 and older. In the first study, 240 patients were equally divided to receive 15 mg or 30 mg of hemagglutinin antigen by IM injection. By day 21, antibody titers of 1:40 were observed in 95.0% of patients who received the 15 mg dose and 89.1% of patients who received the 30 mg dose (N Engl J Med 2009;361:2405-2413).

In the second study from China, antibody titers were done at 21 days after a first injection of 15 mg with or without adjuvant. A titer of 1:40 was achieved in 75% of subjects between age 3 and 11, 97.1% of subjects between age 12 and 17, 97.1% of subjects between age 18 and 60, and 79.1% of subjects age 61 and older. Alum adjuvant did not significantly raise antibody titers. Although a second injection at 21 days raised antibody titers, the authors conclude that a single dose of 15 mg induced a typically protective antibody response in the majority of subjects between age 12 and 60 (N Engl J Med 2009;361:2414-2423).

In the third study, standard H1N1 vaccine was compared to a MF59-adjuvanted vaccine (derived from cell culture rather than egg-based). A number of injection schedules were tested. Local reactions and muscle aches were more frequent in the MF59-adjuvanted vaccine. Although higher antibody titers were seen with the adjuvanted vaccine, significant titers were also seen within non-adjuvanted vaccine within 2-3 weeks (N Engl J Med 2009;361:2424-2435).

These findings confirm data previously published in the Lancet in the fall of 2009 confirming that one dose of the H1N1 vaccine seems adequate, although two doses may be required for younger children. Currently, the Centers for Disease Control and Prevention (CDC) recommends two doses for children younger than age 10, but the recommendations may change based on these findings.

In related news, the CDC is reporting that safety data regarding the H1N1 vaccine is "reassuring," with a rate of serious complications such as Guillain-Barré syndrome no higher than "background rates." The rate of adverse event reporting has been higher with the H1N1 vaccine compared to seasonal flu; however, most of these reports have been for mild reactions and may be attributed to the higher rate of awareness associated with the new vaccine.

FDA Actions

The FDA has approved the first generic version of donepezil (Aricept®) for the treatment of Alzheimer's disease. The new generic will be marketed as 5 mg and 10 mg orally disintegrating tablets, which dissolve on the tongue and do not need to be swallowed. Generic donepezil is expected to be available later this year.

An FDA advisory panel is recommending expansion of the indication for rosuvastatin (Crestor®) to include patients with normal cholesterol levels and no history of cardiovascular disease. The recommendation is based on the JUPITER trial, which showed a reduction in cardiovascular risk in patients with normal LDL cholesterol but high C-reactive protein who were treated with rosuvastatin.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: paula.cousin@sreliasmedia.com.