Sanofi-Aventis’ Acomplia may slow progression of coronary heart disease in abdominally obese patients, according to results of the STRADIVARIUS study, reported yesterday in Chicago at the American College of Cardiology Annual Scientific Meeting and published online in the Journal of the American Medical Association.
STRADIVARIUS randomised 839 patients with abdominal obesity (mean waist circumference 116.8cm and mean body mass index 35) and coronary heart disease to either Acomplia (rimonabant) or placebo. After 18 months, Acomplia-treated patients lost significantly more weight (mean 4.3kg versus 0.5kg for placebo) and significantly more waist circumference (4.5cm versus 1.0cm). There were also very significant improvements in the Acomplia group in metabolic risk factors for cardiovascular disease: HDL or ‘good’ cholesterol rose by 22.4%, triglycerides decreased by 20% and C-reactive protein fell by 50%.
Abdominal obesity is associated with metabolic abnormalities that are in turn associated with a higher risk of cardiovascular disease, but it is currently unclear whether treating abdominal obesity will reduce disease progression. In STRADIVARIUS, the primary endpoint of percent atheroma volume (PAV), a calculation of disease burden in the arteries, was assessed using intravascular ultrasound. Although Acomplia was numerically superior to placebo on PAV, these results failed to reach statistical significance. The drug was, however, significantly better than placebo on the predefined secondary endpoint of total atheroma volume.
Any clinical trial is judged on its primary endpoint, so STRADIVARIUS was a failed study. However, in Chicago lead investigator Dr Steve Nissen was upbeat. “I do think that the findings are important because we can tell from the secondary endpoint that something was happening. The potential for treating abdominal obesity to slow coronary disease still holds promise, but to prove it we have to perform additional trials,” he said.
Acomplia is available in Europe, but a US Food and Drug Administration advisory panel recommended against approval in 2007 because of concerns about psychiatric safety. As a result, STRADIVARIUS investigators rigorously assessed these adverse events and their results provide some reassurance. Although the study confirmed that Acomplia is associated with an increased risk of psychiatric symptoms, severe symptoms (such as major depression and attempted or completed suicide) were relatively uncommon, and their frequency was similar in patients receiving Acomplia and those treated with placebo.
Phase III trials are underway to assess the potential benefits of Acomplia beyond weight reduction, including CRESCENDO, a five-year cardiovascular outcomes study in 17,000 high-risk patients. If successful, such studies would transform the prospects for Acomplia, possibly prompting the FDA to decide that the drug’s benefits outweigh its risks in light of the burden of cardiovascular risk in the large numbers of abdominally obese patients. By Sue Lyon in Chicago
