Reports

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European Society of Cardiology Congress 2008

Munich, Germany / August 30-September 3, 2008

Despite proven benefit, warfarin and other vitamin K antagonists “ have an unpredictable anticoagulant response, which means that patients require frequent anticoagulation monitoring and dosage adjustments, so they are very inconvenient to use, and this leads to underuse in patients with atrial fibrillation or inadequate use with suboptimal INR volumes,” reported Dr. Jeff Weitz, Professor of Medicine and Biochemistry, McMaster University, Hamilton, Ontario. In contrast, he suggested that newer agents, including the direct thrombin inhibitors (DTIs), not only have the potential to avoid these problems but may also be more effective by binding to both free and clot-bound thrombin.

An Evolution in Anticoagulation

A phase III study of dabigatran etexilate, a novel oral DTI, for stroke prevention in patients with atrial fibrillation (AF) is nearing completion. It is part of a large clinical trials program to evaluate it for indications beyond its recently approved use in the prevention of venous thromboembolism (VTE) after orthopedic procedures. This agent is representative of a new wave of anticoagulants aimed at novel targets in the coagulation cascade. Although most of the new agents are still in development, they have the potential to significantly alter strategies to prevent thrombotic events. The potential advantages for preventing stroke in atrial fibrillation and for other cardiovascular (CV) indications are significant.

The prediction that dabigatran will lead an important evolution in AF is based on results of the phase II PETRO study published last year (Ezekowitz et al. Am J Cardiol 2007; 100:1419-26). This trial was primarily a dose-finding safety study, but it confirmed a low risk of bleeding in all tested doses except for the highest one and protection against thrombotic events was tested at all dosages but the lowest dose. The phase III study is moving forward to compare 110 mg and 150 mg b.i.d. of dabigatran against warfarin in the ongoing RE-LY study with more than 18,000 patients. Designed to provide the evidence to change clinical practice, the primary outcome of the study is stroke.

The novel DTI is being compared to warfarin in this study, due in 2009, because this agent is the first choice even if it is underused, according to Dr. Lars Wallentin, Professor of Cardiology, University Hospital, Uppsala, Sweden. “In AF patients, warfarin reduces stroke by up to 68% compared to placebo, so it is very effective. The problem is that it is not very easy to use. It is not just the inter-individual variation in metabolism but the numerous food and drug interactions that make it difficult to maintain optimal anticoagulation within the narrow therapeutic window despite frequent monitoring. This is the reason we need new therapeutic options.”

On the Horizon

DTIs are just one of the strategies being pursued in AF as well as in acute coronary syndrome (ACS), but so far they are the most promising. New results from a study of an oral factor Xa inhibitor called apixaban in ACS showed some activity, but the balance between the reduced risk of CV risk and increased risk of bleeding appeared to be relatively narrow. Even after discontinuing the two highest doses because of unacceptable bleeding rates, the remaining doses of 2.5 mg b.i.d. or 10 mg q.d. were still associated with significantly higher rates of bleeding than placebo. Although major bleeding rates between apixaban and placebo did not differ significantly, the advantage of apixaban relative to placebo for major events, including myocardial infarction (MI), stroke, and CV death, only trended in favour of the active treatment.

“The data indicate that apixaban may offer therapeutic potential, and we feel that it should be taken forward in further clinical trials,” reported the senior author of the apixaban trial Dr. John Alexander, Duke University Medical Center, Raleigh, North Carolina. “But the issue of identifying an acceptable trade-off of reduced thrombosis against an increased risk of bleeding is very important for all of these agents.”

Avoiding Liver Toxicity and Other Safety Issues

One reassuring characteristic of apixaban in the clinical trial presented at the ESC was the low risk of liver toxicity. Liver toxicity is an issue because the direct thrombin inhibitor ximelagatran was withdrawn, despite a 30% reduction in the risk of major bleeds relative to warfarin, when rates of liver toxicity were found to be unacceptable. This risk has not been shared so far by rivaroxaban, another factor Xa inhibitor in clinical testing, argatroban, a direct thrombin inhibitor that is administered intravenously, or dabigatran. In the initial phase of the RE-LY trial with dabigatran, liver function was monitored closely.

“In the first 6000 patients, the protocol called for frequent assessment of liver function tests but based on this experience the data monitoring safety board allowed the frequency of monitoring to be reduced for the remainder of patients who were enrolled,” Dr. Wallentin told the delegates. Its safety has already been well established in the series of studies that led to its approval for VTE prophylaxis early this year. It was the first new oral anticoagulant to be approved in Canada in more than 40 years. In one of the registration trials, called RE-NOVATE, dabigatran was compared to enoxaparin for prevention of VTE after total hip replacement (Eriksson et al. Lancet 2007;370:949-56). A non-inferiority trial, the novel agent was found to be just as effective and well tolerated as the injectable low weight-molecular heparin. The bleeding rates were low in both groups, while the rate of elevated liver enzymes was slightly lower on dabigatran (3% vs. 5%).

This and other comparative studies “tell us that fixed dose unmonitored dabigatran is as effective as enoxaparin for the prevention of VTE, and it has a similar safety profile, but certainly a fixed-dose oral therapy is more convenient,” Dr. Weitz noted.

One of its advantage compared to many other oral agents, particularly warfarin, is that it is not metabolized by cytochrome P450 system. Safety data are now available for more than 38,000 patients who have participated in clinical trials with dabigatran, including three pivotal trials for VTE prophylaxis, and there have not been significant interactions with drugs or food.

Due to the encouraging efficacy and safety of an oral, fixed-dose anticoagulant in VTE prophylaxis, the clinical trials program with dabigatran is being expanded to include secondary prevention of CV events in patients with ACS and in primary prevention in patients with arterial thrombosis. As with all anticoagulants, the important trial outcomes include both the efficacy in preventing vascular events but also the relative freedom from bleeding. However, the specificity of action of a direct thrombin inhibitor may have advantages for both when compared to vitamin K antagonists like warfarin and perhaps for agents aimed at other targets on the coagulation cascade.

Summary

The development of agents working on new targets in thrombus formation is a potentially important clinical advance because of the limitations of current options. Relative to warfarin, which has a narrow therapeutic window and requires frequent monitoring, one of the shared advantages of many of the new agents is their ability to be employed in fixed doses. Direct inhibition of thrombin, which has already proven to be a viable strategy in VTE prophylaxis, appears promising in CV applications. Progress for CV applications is being led by dabigatran, an oral direct thrombin inhibitor already approved in Canada for VTE prophylaxis after orthopedic surgery. Results of the first major clinical end point trial, RE-LY, being conducted in secondary stroke prevention is due next year.