Cleveland, OH - A new post hoc subgroup analysis of the CHARISMA data has clarified which secondary-prevention patients may benefit most from dual antiplatelet therapy with clopidogrel and aspirin [1].

The authors, led by Dr Deepak Bhatt (Cleveland Clinic, OH), conclude: "Patients with documented prior MI, stroke, or symptomatic [peripheral arterial disease] PAD may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate." But they add that other patients with established cardiovascular disease who were enrolled in the main CHARISMA trial (patients with angina and documented multivessel coronary artery disease, a history of remote PCI or CABG, or those with transient ischemic attacks) may not benefit from dual antiplatelet therapy. "Thus, it seems that it is those patients who have had plaque rupture and thrombosis in the past that are most likely to derive benefit from an extended duration of dual antiplatelet therapy," they state.

The main CHARISMA trial, which was first reported at the American College of Cardiology 2006 meeting, enrolled a stable population with either established atherothrombotic disease or multiple risk factors for atherothrombotic events. The primary end point showed a nonsignificant 7.1% relative risk reduction in cardiovascular death/MI or stroke over a median of 28 months with the combination of clopidogrel and aspirin vs aspirin alone. In a prespecified subgroup analysis, the 12 153 patients with documented cardiovascular, cerebrovascular, or peripheral arterial disease (a secondary-prevention population) seemed to derive a significant benefit from combination therapy, while the 3284 patients without documented disease but with multiple risk factors (a primary-prevention population) did not derive any benefit.

The current analysis, which is published in the May 15, 2007 issue of the Journal of the American College of Cardiology, looks at a further subgroup of the secondary-prevention patients—those at the higher end of the risk stratification. The CHARISMA investigators explain that this high-risk group is similar to those patients enrolled in the previous CAPRIE study, which showed a benefit of clopidogrel monotherapy over aspirin monotherapy. They hypothesized that if the CHARISMA trial had examined only a "CAPRIE-like" high-risk secondary-prevention population instead of a broader and overall lower-risk population, as was actually done, greater benefit of dual antiplatelet therapy over aspirin might have been evident.

They therefore analyzed the results for the 9478 patients who met the CAPRIE criteria (with documented prior MI, ischemic stroke, or symptomatic PAD). Results showed that in this group, the rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel-plus-aspirin arm than in the placebo-plus-aspirin arm, as was the rate of hospitalizations for ischemia.

In terms of safety, while there was no significant difference in the rate of severe bleeding, there was a significant increase in moderate bleeding with the combination antiplatelet therapy.

Bhatt et al describe the CHARISMA trial as "an ambitious attempt" to examine dual antiplatelet therapy in a much broader population than the CAPRIE trial, with the additional inclusion of lower-risk secondary-prevention as well as primary-prevention types of patients. They add that the current post hoc subgroup analysis of patients with prior MI, stroke, or symptomatic PAD from the CHARISMA trial shows a significant 1.5% absolute risk reduction in the composite of cardiovascular death, MI, or stroke over a median of 27.6 months, which compares with a 2% absolute risk reduction in the same end point in the CURE trial in ACS patients over a median of nine months. "Thus, there appears to be a gradient of benefit for dual antiplatelet therapy depending on the risk of thrombotic events of the patient," they state.

In line with this, they report that the CURE and CREDO trials suggested that dual antiplatelet therapy would prevent 20 to 30 ischemic events per 1000 patients treated for about one year, while the CAPRIE-like cohort from the CHARISMA trial shows a more modest degree of benefit, with 14.4 episodes of cardiovascular death, MI, or stroke and 17.5 hospitalizations for ischemic events or revascularization averted over the course of an average of 27.6 months per 1000 patients treated, at a cost of 1.7 severe bleeds and 7.6 moderate bleeds (essentially, transfusions).

Bhatt et al note that several patterns emerge from examination of this data set: the benefit in preventing ischemic events is greatest early after treatment began and in patients with a recent previous ischemic event, and the bleeding excess is also "front-loaded," with more bleeding seen with dual antiplatelet therapy compared with aspirin alone in the first few months of therapy and little difference afterward.

Commenting on this analysis for heartwire, Dr Paul Armstrong (University of Alberta, Edmonton) pointed to several observations in the data that "made sense": those with more than one vascular bed affected had worse outcomes and amplification of benefit, and patients with recent MI or stroke (less than 30 days) are at greatest risk and derive greater benefit, reinforcing CURE. "This is key for me since those with remote events get much less benefit, and this makes sense as they decline into a lower-risk group," he said.

But he expressed some concern over the bleeding rates. "Although the bleeding is called moderate, transfusions are bad for your health over the long haul, and we now think they introduce proinflammatory effects."

Armstrong said that in his own practice, those with recurrent events are put on both aspirin and clopidogrel but the question is for how long. "Arguably if these results are right and are confirmed, it suggests that patents could be treated for at least for the median follow-up of this study," he added.