Sep. 5, 2008 Data from a Phase II study of an investigational drug designed to block formation of blood clots show potential for added protection against a second heart attack or stroke among patients who are already taking state-of-the-art prevention therapy, according to researchers at the Duke Clinical Research Institute.
While the results of the study did not show a statistically significant difference in ischemic events among any of the four doses of apixaban evaluated, trends emerged that support further study, the scientists said.
Apixaban, one of several new anti-platelet agents under development, targets the activity of Factor Xa, an enzyme involved in the process of blood coagulation. Physicians say the need for safer, better anticoagulants is critical because current therapies fall short of therapeutic goals or are difficult to manage because they increase the risk of bleeding.
"One of the most vexing problems in cardiology is identifying the right combination of drugs that can inhibit clot formation but not increase the risk of serious bleeding," said study lead John Alexander, M.D., a cardiologist at Duke University Medical Center, who presented the findings September 2 at the European Society of Cardiology meeting in Munich.
Millions of patients worldwide take anti-clotting drugs on a regular basis. Most are prescribed aspirin, clopidogrel (also known as Plavix or Iscover) and/or warfarin.
"Warfarin is clearly effective as an anticoagulant, but it is especially hard to manage properly and safely," Alexander said. "What's driving research in this area is the fact that although aspirin and clopidogrel both offer heart attack patients important protection against blood clots, there is still room for improvement. Studies show that a significant number of patients taking aspirin and clopidogrel will still experience some sort of problem related to a blood clot. Adding warfarin just increases the likelihood of bleeding complications at a higher rate than anybody is comfortable with."
Alexander, along with Professor Lars Wallentin from the Uppsala Clinical Research Center in Sweden and other colleagues, studied the use of apixaban in 1,715 patients from 14 countries throughout Europe and North America who had suffered a recent heart attack. Roughly two-thirds of the patients had undergone angioplasty to clear blocked arteries and 99 percent of them were taking either aspirin or aspirin and clopidogrel.
The study (called APPRAISE) was designed to identify the optimal dose of apixaban. Participants were randomized into one of four doses of apixaban or a placebo. Researchers tracked the incidence of bleeding and recurrent heart attack, stroke, chest pain requiring hospitalization or additional procedures or death from cardiovascular problems for the following six months.
At the end of the study, researchers discovered a non-statistically significant trend suggesting that patients taking apixaban along with their regular treatment had a lower incidence of heart attack, stroke, chest pain or death from cardiovascular problems than patients taking a placebo.
But bleeding was an issue, especially among those taking the higher doses of the drug (10 milligrams twice daily or 20 milligrams once daily). Investigators discontinued those two arms of the study because patients were experiencing unacceptable rates of bleeding. Patients in the remaining arms of the study (2.5 milligrams twice daily or 10 milligrams once daily) also experienced more bleeding than those taking a placebo.
Investigators say that while the results are not conclusive, they do warrant further study.
"The data show adding 5 or 10 milligrams of apixaban to a regimen of aspirin or aspirin and clopidogrel in patients hoping to prevent a second heart attack may offer therapeutic potential," says Alexander. "But this needs to be definitively demonstrated in a statistically significant manner in large, well-controlled studies."
Apixaban is under development at Bristol-Myers Squibb, the company that sponsored the study.
Alexander and Wallentin have both received research support from Bristol-Myers Squibb.
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