Danish Survey Finds Clopidogrel Less Effective In Diabetics

A large nationwide survey of MI survivors in Denmark provides new information about the efficacy of antiplatelet therapy with clopdiogrel in patients with diabetes. In a paper published in JAMACharlotte Andersson reports on 58,851 MI patients, 12% of whom had diabetes and 60% of whom received clopidogrel.

As expected, diabetics had a worse outcome than nondiabetics: the composite endpoint of recurrent MI and all-cause mortality occurred in 25% of diabetics compared with 15% of the nondiabetics. Overall mortality was 17% in the diabetic group compared with 10% in the nondiabetic group.

Clopidogrel was less effective in diabetics than in nondiabetics in reducing all-cause mortality and CV mortality:

  • All-cause mortality risk reduction: 11%for diabetics versus 25% for nondiabetics (p value for interaction = .001)
  • CV mortality risk reduction: 7% (nonsignificant) for diabetics versus 23% for nondiabetics (p value for interaction = .01)

The results lend support to the hypothesis that “there may be a difference of effect of clopidogrel among those with diabetes compared with those without it,” wrote the authors. After acknowledging that “use of clopidogrel may still translate into a significant reduction in event rates for patients with diabetes,” they then raise the “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.”

In an accompanying editorial, Deepak Bhatt lends support to their suggestion, writing that it is plausible to suspect that there is “something about patients with diabetes that makes them less likely to respond to standard antiplatelet therapy.” Compared with nondiabetics, diabetics with coronary artery disease have increased platelet reactivity.  Bhatt writes that the newer and more potent antiplatelet agents prasugrel and ticagrelor may be more effective in diabetics, though they may also cause an increase in the risk of bleeding, and they cost more than clopidogrel, which has now gone generic.

Here is the press release from JAMA:

Study Evaluates Association Between Clopidogrel Use and Mortality Risk in Heart Attack Patients With Diabetes

CHICAGO – In a study that included nearly 60,000 patients with a first-time heart attack, patients with diabetes who received conventional platelet-inhibition with clopidogrel had a lower reduction in the risk of all-cause death and cardiovascular death compared with heart attack patients without diabetes who received clopidogrel, according to a study in the September 5 issue of JAMA.

“Patients with diabetes have an increased risk of ischemic adverse events and death compared with patients without diabetes,” according to background information in the article. “Pharmacodynamic studies have shown that persistently high platelet reactivity is common in patients with diabetes in spite of clopidogrel treatment. Clinical trials have not convincingly demonstrated that clopidogrel benefits patients with diabetes as much patients without diabetes.”

Charlotte Andersson, M.D., Ph.D., of Gentofte Hospital, Hellerup, Denmark, and colleagues analyzed the outcomes associated with clopidogrel treatment after heart attack in patients with and without diabetes.  The study included data from the Danish nationwide administrative registries between 2002-2009 of patients who were hospitalized with incident heart attack and who had survived and not undergone coronary artery bypass surgery 30 days after discharge and who were followed up for as long as 1 year. Analysis was conducted to investigate the association between clopidogrel treatment in patients with and without diabetes and the outcomes of all-cause mortality, cardiovascular mortality, and a composite end point of recurrent heart attack and all-cause mortality.

Of the 58,851 patients—7,247 of whom (12 percent) had diabetes—who were included in the analyses, 35,380 (60 percent) received clopidogrel at the beginning of the study. Patients were followed up for a median (midpoint) of 365 days. In total, 1,790 patients (25 percent) with and 7,931 patients (15 percent) without diabetes met the composite end point. Of these, 1,225 (17 percent) with and 5,377 (10 percent) without diabetes died. Of the patients who died, 978 patients (80 percent) with and 4,100 patients (76 percent) without diabetes died of cardiovascular-related events.

Of patients with diabetes, those who took clopidogrel had lower crude incidence rates of all-cause mortality than those who were not taking clopidogrel. Of patients who did not have diabetes, those who took clopidogrel had lower crude incidence rates of all-cause mortality than those who did not take clopidogrel. Adjusted for other variables, patients with diabetes were found to have a smaller relative risk reduction for mortality than patients without diabetes. “When adjusted, this finding applied for the all-cause mortality end point and the cardiovascular mortality end point, but not for the composite end point,” the authors write.

“In the present analysis, clopidogrel treatment was associated with a relative risk reduction of 25 percent for all-cause mortality, 23 percent for cardiovascular mortality, and 9 percent for the combination of recurrent myocardial infarction [MI; heart attack] and all-cause mortality in patients without diabetes, and a relative risk reduction of 11  percent for all-cause mortality but no significant reduction in cardiovascular mortality or the combined end point in patients with diabetes.”

“In summary, data from previous clinical trials and data from the present analyses strongly suggest that patients with diabetes have a significantly diminished relative effectiveness of conventional platelet-inhibition with clopidogrel after MI compared with patients without diabetes. It should however be emphasized that considering the relatively higher absolute risks found for patients with diabetes, use of clopidogrel may still translate into a significant reduction in event rates for patients with diabetes, which data from the subgroup analyses supported. 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,” the researchers conclude.

(JAMA. 2012;308[9]:882-889.)

Editor’s Note: The study was funded by an internal research foundation grant at the Department of Cardiology, Gentofte Hospital. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Editorial: Antiplatelet Therapy Following Myocardial Infarction in Patients With Diabetes

Deepak L. Bhatt, M.D., M.P.H., of the VA Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston, writes in an accompanying editorial that the “study by Andersson et al highlights the elevated risk of recurrent myocardial infarction and cardiovascular mortality among patients with diabetes following MI.”

“More needs to be done to reduce these risks among such patients. At least a portion of this excess risk appears due to platelet activity and function and to the effects of antiplatelet medications in patients with diabetes. Therefore, in appropriately selected patients, intensification of the antiplatelet regimen may be one method by which their outcomes might be markedly improved.”

(JAMA. 2012;308[9]:921-922)

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