September 5, 2012

New Antiplatelet Therapy Research Holds Some Surprises

Munich—With the thienopyridine class of adenosine diphosphate receptor inhibitors playing an increasingly important role in the management of cardiovascular disease and stroke, two recently published studies came up with somewhat surprising results.

The first, out of Duke University Medical Center, found no significant difference between two anticlotting drugs—prasugrel and clopidogrel—in preventing the first occurrence of death, heart attack, or stroke. The study, called TRILOGY ACS, was developed as a follow-up to the TRITON Phase III trial, published in 2007, which found that 10 mg of prasugrel was 19% more effective in preventing cardiovascular death, nonfatal heart attacks, and strokes than clopidogrel, but that prasugrel also caused a higher incidence of fatal bleeding.

The study showed no difference in serious bleeding complications at the dosages used. On the other hand, the Duke researchers observed an unexpected reduction in heart attack, stroke, and death among patients treated with prasugrel beyond 1 year of treatment and said that the phenomenon merits more exploration.

The results were presented in August at the European Society of Cardiology Scientific Sessions in Munich, Germany, and published online in the New England Journal of Medicine.

"If you look at this study as a comparison of two drugs, it doesn't tell the whole story," said E. Magnus Ohman, MD, a Duke professor of medicine and chairman of the TRILOGY ACS study. "This is a unique patient population that has never before been studied."

The study involved 9,326 participants at 966 sites in 52 countries and focused on acute coronary syndrome (ACS) patients who had not undergone revascularization procedures but were managed solely with drug therapy.

Because these patients tend to be at higher risk for repeated cardiovascular-related events, Ohman said, "Optimizing medical therapy for these patients is extremely important.”

TRILOGY ACS researchers compared up to 2.5 years of treatment with 10 mg of prasugrel daily to 75 mg of clopidogrel daily, both in combination with aspirin, in ACS patients who were younger than 75. (The prasugrel dose was reduced to 5 mg daily for patients weighing less than 60 kilograms.)

The study also looked at patients who were 75 and older receiving 5 mg of prasugrel daily versus 75 mg daily of clopidogrel. The prasugrel dose was reduced from 10 mg because of the bleeding risk found in the earlier TRITON study at that level.

After a median of 17 months of follow up, 13.9% of patients under age 75 years treated with prasugrel suffered either death, heart attack, or stroke compared to 16.0% of those with similar characteristics treated with clopidogrel.

That difference was considered nonsignificant, said the study authors. The bleeding risk, meanwhile, appeared to be tied to dosage level.

“Because we modified the prasugrel dose for patients with a higher risk of bleeding, we observed that prasugrel is as safe as clopidogrel with long-term treatment," Ohman said.

Another study, published recently in the New England Journal of Medicine, found that the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke for patients with recent lacunar strokes, yet dramatically increased the risk of bleeding and death.

The report noted that the effectiveness of antiplatelet therapy for secondary prevention has not been defined in lacunar infarcts, a frequent type of stroke caused mainly by cerebral small-vessel disease.

The double-blind, multicenter trial involved 3,020 patients in whom magnetic resonance imaging showed recent symptomatic lacunar infarcts. Participants were randomly assigned to receive 75 mg of clopidogrel or placebo daily, while also receiving 325 mg of aspirin daily.

In the mostly male participants with a mean age of 63 years, the risk of recurrent stroke—ischemic, disabling, or fatal—was not significantly reduced with aspirin and clopidogrel after a mean follow-up of 3.4 years compared to aspirin alone.

“These results must be interpreted in the context of the other component of the trial, which involved vigorous management of blood pressure,” noted the authors. “The rate of recurrent stroke among patients taking aspirin alone (2.7% per year) was substantially lower than anticipated. The use of statins by the majority of the study participants and the good blood pressure control achieved probably contributed to the low observed rate in our trial, which was similar to the rates in other recent trials testing antiplatelet therapies for the prevention of recurrent stroke.”

At the same time, the risk of major hemorrhage was almost doubled with dual antiplatelet therapy—105 hemorrhages or 2.1% per year—as compared with aspirin alone—56 or 1.1% per year. All-cause mortality also was greater.

“Dual antiplatelet therapy was associated with a trend toward a reduction in recurrent strokes attributed to atherosclerosis but not recurrent lacunar strokes, a finding that supports the hypothesis that the role of platelets is different in different types of ischemic cerebrovascular disease,” the authors write.

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