Dose Comparisons of Clopidogrel and Aspirin in Acute Coronary Syndromes

NEJM

Clopidogrel (Plavix, Sanofi-Aventis and Bristol-Myers Squibb) and aspirin are commonly used for the treatment of cardiovascular disease, yet the optimal doses are uncertain.1,2 The benefits of clopidogrel in patients with acute coronary syndromes, as well as in those undergoing percutaneous coronary intervention (PCI), are well established.3-10 As compared with the standard dose of clopidogrel used in early trials, more recent studies have shown that doubling the loading and maintenance doses of clopidogrel leads to greater, more rapid, and more uniform platelet inhibition, which may further improve clinical outcomes.1,11-18 This hypothesis is consistent with the results of recent clinical trials, which have shown a benefit of more potent adenosine diphosphate (ADP)–receptor blockers, such as prasugrel19 and ticagrelor,20 as compared with the standard dose of clopidogrel.

Uncertainty regarding the optimal dose of aspirin for the prevention and treatment of cardiovascular disease has resulted in wide geographic variations in practice patterns.21 The European Society of Cardiology guidelines recommend low doses of aspirin (≤100 mg daily) after PCI,22 whereas the American Heart Association−American College of Cardiology guidelines23 recommend higher doses of aspirin (162 to 325 mg daily). This discrepancy reflects the lack of data from randomized trials directly comparing aspirin doses. Although indirect comparisons in trials evaluating different doses of aspirin versus placebo have shown similar reductions in vascular events,2 observational analyses have suggested a dose-dependent increase in the risk of bleeding associated with aspirin.21,24

The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT–OASIS 7) trial was designed to determine whether a doubling of the loading and initial maintenance doses of clopidogrel is superior to the standard-dose regimen and whether higher-dose aspirin (300 to 325 mg daily) is superior to lower-dose aspirin (75 to 100 mg daily) in patients with acute coronary syndromes referred for an early invasive strategy.

We randomly assigned, in a 2-by-2 factorial design, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600-mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300-mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days

Conclusions

In patients with an acute coronary syndrome who were referred for an invasive strategy, there was no significant difference between a 7-day, double-dose clopidogrel regimen and the standard-dose regimen, or between higher-dose aspirin and lower-dose aspirin, with respect to the primary outcome of cardiovascular death, myocardial infarction, or stroke. (Funded by Sanofi-Aventis and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00335452.)

Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects

The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established.

Obesity and excess weight are escalating public health concerns because they increase the prevalence of associated conditions such as diabetes mellitus and the risk of premature death.1,2 More than 80% of even highly motivated patients are unable to achieve weight loss with dietary and lifestyle modifications alone.3

Sibutramine is a norepinephrine and serotonin reuptake inhibitor that was approved for weight management in patients who are unable to lose weight by means of diet and exercise alone. Sibutramine induces satiety (resulting in reduced food intake) and an increase in energy expenditure.4,5 In some patients, sibutramine increases blood pressure, pulse rate, or both, owing to its sympathomimetic effects.6 Sibutramine is not indicated for patients with a history of cardiovascular disease; otherwise, treatment with sibutramine is recommended for no more than 1 to 2 years in patients who achieve a 5% weight loss. The Sibutramine Cardiovascular Outcomes (SCOUT) trial evaluated the long-term effects of sibutramine treatment combined with diet and exercise on the rates of cardiovascular events and cardiovascular death among subjects who were at high cardiovascular risk.

Conclusions

Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)