March 17, 2006
The CHARISMA trial, whose results were released simultaneously in the latest on-line issue of the New England Journal of Medicine, and at the 2006 Scientific Sessions of the American College of Cardiology, was a great disappointment to cardiologists, patients, and especially to Sanofi Aventis.
This study examined the use of clopidogrel (Plavix) along with aspirin as preventative therapy in patients who either had established vascular disease or who had multiple risk factors for cardiovascular disease. Aspirin alone in these patients, by reducing the "stickiness" of blood platelets and thus making blood clots less likely to occur, is known to help prevent heart attacks. Clopidogrel is commonly used in acute coronary syndromes and after stent placement for the same purpose, and has proven effective in these clinical circumstances.
However, in the CHARISMA trial, the use of clopidogrel was not beneficial. There was a suggestion of a differential effect in the two patient populations studied, however. In the patients with known cardiovascular disease, there was a trend toward benefit with clopidogrel, but it was not statistically significant. In perhaps the most surprising finding in this study, patients with multiple risk factors but no definite vascular disease there was a non-statistically-significant trend toward harm (the harm being death from cardiovascular causes) with clopidogrel. Nobody had a plausible theory as to why the drug may be producing excess harm in this subgroup.
DrRich comments:
The CHARISMA trial was an attempt to extend the benefits seen with clopidogrel in other populations of patients (i.e., patients with acute heart attacks, angioplasty or stents) to less-acute patients with known or suspected cardiovascular disease. Single drug anti-platelet therapy with aspirin is widely accepted as an effective preventative in these patients. Given the benefits provided by clopidogrel in "sicker" patients, it was strongly suspected that it could only add to the benefit of using aspirin alone to these more stable patients. However this was not seen.
The trend toward excess mortality seen with clopidogrel in the subgroup of patients with multiple risk factors (but no known vascular disease) is difficult to explain. These "extra" deaths were not due to excessive bleeding as one might suspect from an aggressive anti-platelet drug regimen. Instead they appear to be due to cardiovascular causes, such as heart attack. No explanation for this phenomenon immediately suggests itself to the experts who discussed this study at the ACC meetings, much less to DrRich.
So now we know that dual anti-platelet therapy should not be used in these two groups of patients. However, it is important that patients who are now taking clopidogrel (Plavix) for currently approved indications continue to do so unless instructed otherwise by their doctors. (If you have questions about the appropriateness of this drug in your own case, by all means talk to your doctor.) As the drug is currently being used, it has been shown to significantly decrease the risk of cardiovascular events. The CHARISMA trial did not at all address these situations - it attempted to extend the use of this drug to new populations, and it failed to do so.
