Hopes that Sanofi-Aventis and Bristol-Myers Squibb could further widen the market for their blockbuster antiplatelet therapy Plavix to include primary prevention of cardiovascular events in high-risk patients have been dashed by results of a large-scale clinical trial.

But the findings of the 15,603-patient CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilisation, Management and Avoidance) study should not impact on the brand’s current success.

Plavix (clopidogrel) contributed 518 million euros to Sanofi-Aventis’ fourth-quarter sales of 7 billion euros last year, while B-MS reported Plavix sales rose 11% to just over $1 billion in the same period.

CHARISMA included a secondary prevention population of patients with established stable cardiovascular disease (CVD) and a primary prevention cohort of patients at high risk of developing CVD on account of multiple risk factors such as diabetes, hypertension and high blood cholesterol. Patients were randomised to either clopidogrel or placebo on top of low-dose aspirin and were followed for over two years.

Results showed a non-significant 7.1% relative risk reduction in the primary endpoint of heart attack, stroke and CV death among patients on dual therapy overall. Among the primary prevention cohort there was no benefit at all seen for dual therapy; patients in this subgroup experienced more bleeding and excess mortality. However, the trial did show a statistically significant 12.5% relative risk reduction in the primary endpoint among the much larger group (12,153 patients) with a history of previous CV events. These patients showed a significant increase in modest but not severe bleeding.

Commentators were agreed that CHARISMA would not impact on current prescribing practice in patient populations supported by prior landmark studies of the drug such as CAPRIE, CURE and COMMIT. Use of Plavix is predicted to increase with the rising numbers of patients undergoing percutaneous coronary intervention (PCI) procedures and receiving stents. Whether prescribing will increase for secondary prevention in stable patients with prior events is debatable.

The trial, published this week in the New England Journal of Medicine, drew criticism in an editorial by Marc Pfeffer and John Jarcho for extracting favourable P values from subgroup analyses. However the American Heart Association issued a statement highlighting the significant benefit of dual antiplatelet therapy for patients with established symptomatic disease.

Lead investigator Dr Deepak Bhatt of the Cleveland Clinic, who presented CHARISMA at the American College of Cardiology (ACC) meeting this week in Atlanta, said: “Valuable lessons have been learned from CHARISMA. We thought the benefits of dual antiplatelet therapy would extend to the populations who have shown benefits from statin and other risk reduction therapies but this was not the case.”

Both clinicians and future drug developers need to take these lessons on board, he suggested. His advice to investigators and companies developing drugs for atherothrombosis is to focus on secondary rather than primary prevention.

- The ACC is investigating how the embargoed results of CHARISMA were leaked ahead of presentation on Sunday and publication in an academic journal, affecting the company’s share price.

Source: Olwen Glynn Owen at the ACC in Atlanta, USA