Primer: The 2011 AHA/ACCF guidelines for secondary prevention for patients with known coronary disease include a Class IB recommendation for 75mg clopidogrel as an alternative antiplatelet agent for patients who do not tolerate or are allergic to aspirin; in addition, dual antiplatelet therapy with aspirin and clopidogrel is recommended for patients after stent placement. Diabetic patients have increased platelet reactivity, and subgroup analyses of large trials including CHARISMA, CREDO, and CURE have shown have suggested clopidogrel is less effective in the diabetic population. This study used registry data to compare the efficacy of clopidogrel in diabetic and non-diabetic patients.
The [retrospective] study: Andersson, et al. used administrative data from Danish registries to follow patients who were hospitalized for incident myocardial infarction and survived their initial hospitalization. Patients were followed for one year after admission or until the end of 2009. Outcome measures included all-cause mortality, cardiovascular mortality, and a composite endpoint of repeat myocardial infarction and all-cause mortality.
The authors controlled for sex, age, income, year of admission, comorbidities, PCI in the month following MI, and other medications. The authors created separate binary dummy variables for clopidogrel treatment in diabetic and non-diabetic patients and analyzed both groups in a single model, and then also performed a propensity score analysis to confirm the results. A propensity score is the probability that a given patient received treatment based on observed characteristics based on regression; the propensity score can be used to match patients from the treated and untreated groups.
58,851 patients were included in the study, of whom 12% had diabetes and 60% received clopidogrel. Adjusted all-cause mortality for patients taking clopidogrel was 0.89 (CI 0.79-1.00) for patients with diabetes and 0.75 (95% CI, 0.70-0.80) for patients without diabetes and 0.93 (95% CI, 0.81-1.06) and 0.77 (95% CI, 0.72-0.83) for cardiovascular mortality. Notably, no difference in effect was noted for aspirin for patients in this cohort. Propensity score matching identified 2005 pairs of patients with diabetes and 11,410 pairs of patients, and the authors report a statistically significant effect of clopidogrel on the outcomes in non-diabetic patients (P < .0001 for all-cause and CV mortality and P < .01 for the combined end point) and no statistically significant differences for the patients with diabetes.
In sum: This analysis further adds further evidence that clopidogrel does not provide a benefit to diabetic patients for secondary prevention, and serves as a reminder that diabetes has effects beyond vascular injury. As with all retrospective studies, this analysis cannot demonstrate causality, however, a significant strength of the study is the comprehensive nature of the registry data. The study generalizability is limited by the relatively homogenous population of Denmark.
The authors report the propensity score analysis confirms their multivariate regression. Notably, the authors did not attempt to match the diabetic and non-diabetic arms of the study in the propensity score analysis (see supplemental data) – they only matched patients within the diabetic and non-diabetic cohorts. Patients in the diabetic cohorts were more likely to have severe heart failure and less likely to undergo PCI, and there was a statistically significant (although the test is not specified) between the year of admission for the group receiving clopidogrel and those that did not. There is a built-in risk of rejecting an effect of clopidogrel in the diabetic cohort, particularly since fewer patients with diabetes were in the study population. Nevertheless, given previous study data and proposed mechanisms for the decreased effect of clopidogrel, the evidence from Denmark raises further questions about the appropriate anti-platelet therapy for diabetic patients, particularly after myocardial infarction and percutaneous intervention. The authors note TRITON-TIMI 38 suggested prasugrel was more effective than clopidogrel in patients with diabetes, and thus other thienopyridines may be more effective in this population.
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