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Clopidogrel Not As Effective for the Diabetic Heart

A Danish registry study showed that patients with diabetes may not get as much benefit from clopidogrel (Plavix) for secondary prevention after a heart attack as nondiabetic patients…. 

Charlotte Andersson, MD, PhD, of Gentofte Hospital in Hellerup, Denmark, and colleagues found that, compared with other clopidogrel users, diabetes patients saw less of a reduction in all-cause mortality, with hazard ratios of 0.89 versus 0.75 (P<0.001 for interaction).

The group with diabetes also lost the substantial effect on cardiovascular mortality seen in those without diabetes, the group reported.

In the population-based study, diabetes patients achieved a nonsignificant 7% reduction in risk of death from cardiovascular causes compared with the significant 23% reduction seen among other clopidogrel users (P=0.01 for interaction).

Clopidogrel may still be worthwhile for diabetes patients, given their higher absolute risks of events, Andersson’s group noted.

"Available data nevertheless raise a possibility that patients with diabetes may benefit from a more potent platelet inhibitor strategy to achieve a relative risk reduction similar to patients without diabetes," they wrote.

Other drugs, such as prasugrel (Effient) and ticagrelor (Brilinta), are stronger inhibitors of the P2Y12 pathway that leads to platelet activation.

Clopidogrel also targets that pathway but often doesn’t do enough to quell the heightened P2Y12 activity in diabetes, based on platelet reactivity assay results.

Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital and the VA Boston Healthcare System, noted in an accompanying editorial that, the more potent agents have been shown more effective than clopidogrel in the PLATO and TRITON-TIMI 38 trials, and sub-analyses have indicated larger absolute benefits with no increased bleeding risk in the diabetes subgroup,

In an interview Bhatt stated that, "It’s not that clopidogrel doesn’t work in this situation." "Can we do better is the possibility this paper raises and … the answer is likely yes."

Bhatt warned against relying on nonrandomized comparisons, as in the current study, which looked at individual-level data on 58,851 patients who survived at least 30 days after an acute myocardial infarction (MI) without coronary artery bypass graft (CABG) surgery. All patients were hospitalized with incident MI between 2002 and 2009 and were listed in the Danish National Patient Register. Follow-up was done for 1 year.

CABG patients were excluded because they are likely to stop clopidogrel treatment after surgery, the authors explained.

Notably, the 12% with diabetes seemed to derive significantly less benefit from clopidogrel versus no clopidogrel for the composite endpoint of recurrent MI and all-cause mortality (HR 1.00 versus 0.91, P=0.08 for interaction)

European guidelines recommend ticagrelor or prasugrel over clopidogrel in acute coronary syndromes; U.S. guidelines suggest use of clopidogrel or prasugrel without distinction, because the increased bleeding risk with the more potent anti-platelet agent may offset its benefits.

Guidelines are unlikely to change based on an observational analysis like this one, Bhatt noted.

Practice Pearls:

  • Note that all-cause mortality was less decreased and cardiovascular mortality was not significantly reduced in the diabetics compared with nondiabetics.
  • A Danish observational study found decreased effectiveness of clopidogrel in diabetics following a myocardial infarction compared with nondiabetics.

Andersson C, et al "Association of Clopidogrel Treatment With Risk of Mortality and Cardiovascular Events Following Myocardial Infarction in Patients With and Without Diabetes" JAMA 2012; 308:882-889.