Patients with Peripheral Arterial Disease in the CHARISMA Trial
Patients with Peripheral Arterial Disease in the CHARISMA Trial
Aims: The aim of this study was to determine whether clopidogrel plus aspirin provides greater protection against major cardiovascular events than aspirin alone in patients with peripheral arterial disease (PAD).
Methods and Results: This is a post hoc analysis of the 3096 patients with symptomatic (2838) or asymptomatic (258) PAD from the CHARISMA trial. The rate of cardiovascular death, myocardial infarction (MI), or stroke (primary endpoint) was higher in patients with PAD than in those without PAD: 8.2% vs. 6.8% [hazard ratio (HR), 1.25; 95% CI 1.08, 1.44; P = 0.002]. Among the patients with PAD, the primary endpoint occurred in 7.6% in the clopidogrel plus aspirin group and 8.9% in the placebo plus aspirin group (HR, 0.85; 95% CI, 0.66-1.08; P = 0.18). In these patients, the rate of MI was lower in the dual antiplatelet arm than the aspirin alone arm: 2.3% vs. 3.7% (HR, 0.63; 95% CI, 0.42-0.96; P = 0.029), as was the rate of hospitalization for ischaemic events: 16.5% vs. 20.1% (HR, 0.81; 95% CI, 0.68-0.95; P = 0.011). The rates of severe, fatal, or moderate bleeding did not differ between the groups, whereas minor bleeding was increased with clopidogrel: 34.4% vs. 20.8% (odds ratio, 1.99; 95% CI, 1.69-2.34; P < 0.001).
Conclusion: Dual therapy provided some benefit over aspirin alone in PAD patients for the rate of MI and the rate of hospitalization for ischaemic events, at the cost of an increase in minor bleeding.
Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis, affecting an estimated 27million people in Europe and North America. PAD is associated with an increased risk for cardiovascular events due to coexistence of coronary artery disease (CAD) and cerebrovascular disease (CVD), such events being more frequent than ischaemic limb events. There is a 20-60% increased risk for myocardial infarction (MI), a two- to six-fold increased risk of cardiovascular death, and a 40% increased risk of stroke in patients with PAD. These adverse consequences of PAD occur, in part, because many affected patients are not diagnosed, and those with known PAD often are undertreated.
Antiplatelet therapy reduces the risk of MI, stroke, and vascular death in patients with PAD. The Antithrombotic Trialists' Collaboration meta-analysis of 42 trials including 9717 patients with PAD found a 22% odds reduction for adverse cardiovascular events (MI, stroke, or vascular death) in patients with PAD treated with antiplatelet therapy compared with those who were not treated. Both aspirin and clopidogrel are recommended for patients with PAD.
Among the 6452 patients with PAD in the CAPRIE trial, clopidogrel reduced the risk of MI, stroke, or vascular death by 23.8% more than aspirin. The combination of aspirin and clopidogrel is more effective in preventing adverse cardiovascular events than aspirin alone in high-risk groups including patients undergoing percutaneous coronary intervention, patients with acute coronary syndromes without ST-segment elevation, and patients with ST-elevation MI. It is not known, however, whether dual antiplatelet therapy with aspirin plus clopidogrel is more effective than a single antiplatelet agent in patients with PAD. Analyses derived from the CAPRIE and CURE studies suggested that the absolute benefit of clopidogrel over aspirin was amplified in certain high-risk subgroups of patients.
The combination of aspirin plus clopidogrel was most recently evaluated in the CHARISMA trial, which enrolled patients with either established atherothrombotic disease or multiple risk factors for atherothrombotic events. In CHARISMA, dual antiplatelet therapy vs. aspirin alone was associated with a non-significant 7.1% relative risk reduction in MI, stroke, or cardiovascular death over a median of 28 months. In a post hoc subgroup analysis of the CHARISMA population, patients with documented prior MI, ischaemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy.
In this context, we hypothesized and pre-specified that long-term treatment with a combination of clopidogrel plus aspirin may provide greater protection against cardiovascular events than aspirin alone in the very high-risk subgroup of patients with either symptomatic or asymptomatic PAD from the CHARISMA trial.
Abstract and Introduction
Abstract
Aims: The aim of this study was to determine whether clopidogrel plus aspirin provides greater protection against major cardiovascular events than aspirin alone in patients with peripheral arterial disease (PAD).
Methods and Results: This is a post hoc analysis of the 3096 patients with symptomatic (2838) or asymptomatic (258) PAD from the CHARISMA trial. The rate of cardiovascular death, myocardial infarction (MI), or stroke (primary endpoint) was higher in patients with PAD than in those without PAD: 8.2% vs. 6.8% [hazard ratio (HR), 1.25; 95% CI 1.08, 1.44; P = 0.002]. Among the patients with PAD, the primary endpoint occurred in 7.6% in the clopidogrel plus aspirin group and 8.9% in the placebo plus aspirin group (HR, 0.85; 95% CI, 0.66-1.08; P = 0.18). In these patients, the rate of MI was lower in the dual antiplatelet arm than the aspirin alone arm: 2.3% vs. 3.7% (HR, 0.63; 95% CI, 0.42-0.96; P = 0.029), as was the rate of hospitalization for ischaemic events: 16.5% vs. 20.1% (HR, 0.81; 95% CI, 0.68-0.95; P = 0.011). The rates of severe, fatal, or moderate bleeding did not differ between the groups, whereas minor bleeding was increased with clopidogrel: 34.4% vs. 20.8% (odds ratio, 1.99; 95% CI, 1.69-2.34; P < 0.001).
Conclusion: Dual therapy provided some benefit over aspirin alone in PAD patients for the rate of MI and the rate of hospitalization for ischaemic events, at the cost of an increase in minor bleeding.
Introduction
Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis, affecting an estimated 27million people in Europe and North America. PAD is associated with an increased risk for cardiovascular events due to coexistence of coronary artery disease (CAD) and cerebrovascular disease (CVD), such events being more frequent than ischaemic limb events. There is a 20-60% increased risk for myocardial infarction (MI), a two- to six-fold increased risk of cardiovascular death, and a 40% increased risk of stroke in patients with PAD. These adverse consequences of PAD occur, in part, because many affected patients are not diagnosed, and those with known PAD often are undertreated.
Antiplatelet therapy reduces the risk of MI, stroke, and vascular death in patients with PAD. The Antithrombotic Trialists' Collaboration meta-analysis of 42 trials including 9717 patients with PAD found a 22% odds reduction for adverse cardiovascular events (MI, stroke, or vascular death) in patients with PAD treated with antiplatelet therapy compared with those who were not treated. Both aspirin and clopidogrel are recommended for patients with PAD.
Among the 6452 patients with PAD in the CAPRIE trial, clopidogrel reduced the risk of MI, stroke, or vascular death by 23.8% more than aspirin. The combination of aspirin and clopidogrel is more effective in preventing adverse cardiovascular events than aspirin alone in high-risk groups including patients undergoing percutaneous coronary intervention, patients with acute coronary syndromes without ST-segment elevation, and patients with ST-elevation MI. It is not known, however, whether dual antiplatelet therapy with aspirin plus clopidogrel is more effective than a single antiplatelet agent in patients with PAD. Analyses derived from the CAPRIE and CURE studies suggested that the absolute benefit of clopidogrel over aspirin was amplified in certain high-risk subgroups of patients.
The combination of aspirin plus clopidogrel was most recently evaluated in the CHARISMA trial, which enrolled patients with either established atherothrombotic disease or multiple risk factors for atherothrombotic events. In CHARISMA, dual antiplatelet therapy vs. aspirin alone was associated with a non-significant 7.1% relative risk reduction in MI, stroke, or cardiovascular death over a median of 28 months. In a post hoc subgroup analysis of the CHARISMA population, patients with documented prior MI, ischaemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy.
In this context, we hypothesized and pre-specified that long-term treatment with a combination of clopidogrel plus aspirin may provide greater protection against cardiovascular events than aspirin alone in the very high-risk subgroup of patients with either symptomatic or asymptomatic PAD from the CHARISMA trial.
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