By Anne McLeod, MD
2009-12-07
Physicians who treat patients with thrombosis have had a close
relationship with warfarin, dating back more than 50 years. Is it possible that
this relationship will be changed forever with the results of the RE-COVER
Study, presented by Dr. Sam Schulman in the first abstract of the Plenary
Session yesterday, and simultaneously published in the New England Journal
of Medicine? A replacement for the tried and true, yet finicky, warfarin
has been sought for decades, but it has proven difficult to “reverse” its place
in our hearts as the mainstay of venous thromboembolism (VTE) treatment.
Dr. Schulman, of McMaster University,
presented the first large study of a new oral agent, dabigatran etexilate, for
the treatment of deep-venous thrombosis and pulmonary embolism. In the study,
dabigatran — a direct thrombin inhibitor — was compared to warfarin in a
non-inferiority, randomized, double-blind trial of 2,539 patients with acute
VTE. Patients were treated initially with low-molecular-weight or
unfractionated heparin for five to 11 days, followed by either dabigatran
etexilate, 150 mg twice daily, or warfarin, each given for six months.
Results for the primary outcome of symptomatic recurrent
VTE or VTE-related death were that 30 (2.4%) of the patients treated with
dabigatran etexilate had recurrent VTE compared with 27 (2.2%) of patients
randomized to warfarin, at six months, which met the pre-specified
non-inferiority margin. Much concern has been raised about the lack of a
reversal agent for this new anticoagulant, yet in this study there was no
significant difference in major bleeding, and there was a significant reduction
of clinically relevant, non-major bleeding and of all bleeding events with
dabigatran compared to warfarin. The study also showed that rates of death,
acute coronary syndromes, and liver function test abnormalities were low, and
the frequency of these events was similar between the two treatment groups.
According to Dr. Schulman, “We are spearheading an
impressive set of studies in VTE with four randomized phase III trials,
including two parallel studies in acute VTE and two studies of extended
treatment — one compared to placebo and one compared to warfarin.” Dr. Schulman
also said, “We now have data from orthopedic studies, the RE-LY study in atrial
fibrillation, and the four VTE studies, and have had no studies stopped or
concerns raised about the safety of
dabigatran etexilate; in fact, the FDA has approved decreased frequency
of liver monitoring. We are dealing with a very safe compound.”
Whether dabigatran etexilate will displace warfarin
completely remains to be seen. Many questions remain about dabigatran,
including whether the agent will be cost-effective, how overdose might be
managed given the lack of a reversing agent, and whether it will be clinically
effective in high-risk groups such as patients with mechanical heart valves or
pregnant women. But there seems no doubt that there are new options for the treatment
of VTE on the horizon.
For decades, warfarin has been our “one true love” in VTE
treatment and prophylaxis in a multitude of clinical circumstances. On the
basis of the RE-COVER trial and future studies, we will face the prospect of
abandoning this monogamous partnership and forming a new, open relationship in
which we use warfarin and newer agents to satisfy our diverse clinical needs.
Dr. McLeod indicated no relevant conflicts of
interest.
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