ATLANTA — The treatment of acute myocardial infarction with the antithrombotic drug fondaparinux produced significant reductions in death and new ischemic events without boosting the risk of major bleeds in a large trial with more than 12,000 patients.
“For the first time, we have an antithrombotic drug that lowers the risk for hemorrhage,” Dr. Salim Yusuf said at the annual meeting of the American College of Cardiology.
Fondaparinux “is the only antithrombotic I know that saves lives, prevents new myocardial infarctions, and doesn't increase bleeding. No other antithrombotic has shown a mortality benefit,” compared with the standard agent, unfractionated heparin, said Dr. Yusuf, professor of medicine at McMaster University, Hamilton, Ont. “Its impact is as large as the difference between tissue plasminogen activator and streptokinase” for fibrinolysis of MIs.
The only flaw in fondaparinux's performance was in patients treated with coronary catheterization and percutaneous coronary intervention (PCI). In this setting, fondaparinux was inferior to heparin for preventing clots from forming in catheters, which led to no efficacy advantage for fondaparinux, compared with heparin, in patients treated with primary PCI in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) 6 trial.
Fondaparinux “looks very appealing for both unstable angina and ST-segment elevation MI, with excellent efficacy and reduced bleeding,” said Dr. Christopher P. Cannon, a cardiologist at Harvard University and Brigham and Women's Hospital in Boston. For patients treated with primary PCI, “it looks like we'll need unfractionated heparin or a low-molecular-weight heparin, but for everyone else” fondaparinux looks good, he said in an interview.
A detailed analysis of the study's results showed that during the first 3 days after treatment with fondaparinux, patients who underwent PCI had a 2.8% rate of death or repeat MI, compared with a 2.2% rate in control patients treated with placebo or unfractionated heparin, a 30% increased risk with fondaparinux that was not statistically significant. By contrast, during the following 6 days, patients treated with fondaparinux had a 32% reduction in death or MI, compared with the control patients, which suggested that treatment with fondaparinux after primary PCI might be beneficial, said Dr. Yusuf, adding that the hypothesis would need to be tested in a future trial.
Overall, during the first 9 days after treatment, 30 days after treatment, and out to the end of the study (90–180 days after treatment), patients treated with fondaparinux who then underwent primary PCI had very similar outcomes, compared with control patients.
On the basis of these findings, “fondaparinux will be more preferred in settings in which the use of angiographic-based reperfusion is not routine,” said Dr. Robert M. Califf in an editorial that accompanied online publication of the OASIS-6 results (JAMA 2006 Mar. 14 [E pub doi:10.1001/jama.295.13.jed60020]).
This caveat may make fondaparinux a harder sell in the United States, where “PCI has been established as the preferred treatment for STEMI [ST-segment elevation MI],” said Dr. Califf, a cardiologist and director of the Clinical Research Institute at Duke University, Durham, N.C. “The extra anxiety caused by the now-uncertain risk of catheter thrombosis casts a pall over the use of fondaparinux in patients for whom the intent is to use PCI to achieve reperfusion.”
OASIS-6 enrolled 12,092 patients within 12 hours of the onset of symptoms of acute MI (the first 4,300 patients were enrolled within 24 hours of symptom onset) at 447 centers in 41 countries during September 2003-January 2006. According to Dr. Califf, only 33 of these patients were treated in either the United States or Canada. Although the study was sponsored by Sanofi-Aventis, Organon, and GlaxoSmithKline, which markets fondaparinux (Arixtra), it was run independently by the Population Health Research Institute of McMaster University. Dr. Yusuf has received honoraria from, has served as a consultant to, and has received research funding from GlaxoSmithKline.
The enrolled patients were managed in three different ways, depending on their clinical presentation and decisions by their physicians. Thrombolytic therapy was administered to about 45%, primary PCI was used to treat about 29%, and about 24% did not receive any reperfusion therapy.
The patients were also divided by their treating physicians into two categories: those judged not to need antithrombotic therapy (about 47%) and who were randomized to treatment with either fondaparinux or placebo, and those who needed antithrombotic treatment (about 53%) and who were randomized to treatment with either unfractionated heparin or fondaparinux. The fondaparinux dosage was 2.5 mg subcutaneously once daily, which was continued for up to 8 days or until hospital discharge. Treatment with heparin was continued for 24–48 hours.