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Following a myocardial infarction (MI), clopidogrel is less effective in providing secondary prevention against cardiovascular events in diabetic patients than nondiabetic patients, according to a retrospective study published in the September 5, 2012, issue of the Journal of the American Medical Association. The finding suggests that diabetic patients might benefit from a more potent antiplatelet regimen, the authors say.

Drawing on administrative data from Danish national registries, Charlotte Andersson, MD, PhD, of Gentofte Hospital (Hellerup, Denmark), and colleagues identified 58,851 patients who were hospitalized for a first MI between 2002 and 2009 and did not undergo CABG surgery within 30 days. Overall, 56% of the 7,247 patients with diabetes received clopidogrel compared with 61% of nondiabetic patients.

Clopidogrel Helps Diabetics—But Not as Much

After a median of 1 year (with follow-up starting 30 days post discharge), 25% of patients with diabetes and 15% of those without diabetes met the composite endpoint of all-cause death or MI. For diabetics, unadjusted mortality rates (events per 100 person-years) were 13.4% (95% CI 12.8-14.0) for those treated with clopidogrel and 29.3% (95% CI 29.3-30.4) for those not receiving the antiplatelet agent, while for nondiabetics the rates were 6.4% (95% CI 6.3-6.6) and 21.3% (95% CI 21.0-21.7), respectively.

After adjustment, patients with diabetes achieved a smaller relative risk reduction with clopidogrel than those without diabetes. In fact, there was an interaction between diabetic status and outcome for all-cause and cardiovascular mortality, though not for the composite endpoint (table 1).

Table 1. One-Year Risk for Patients Without vs. With Diabetes on Clopidogrel

 
When patients were stratified according to whether or not they received PCI, trends were observed toward a reduced impact of clopidogrel in diabetics vs. nondiabetics, although the difference was not statistically significant. In addition, concomitant use of aspirin did not affect outcomes in the 2 groups. And in subgroup analyses, there was no evidence of a differential effect of clopidogrel depending on whether diabetics were treated with metformin or insulin.

Moreover, 1-year Kaplan-Meier analysis of propensity-score-matched pairs of clopidogrel-treated and untreated diabetics as well as clopidogrel-treated and untreated nondiabetics showed a mortality reduction with clopidogrel in nondiabetics only.

According to the authors, the findings support previous evidence of reduced responsiveness to standard clopidogrel therapy in diabetics. The results are also in line with subgroup analyses from the large, randomized CREDO and CHARISMA trials showing no clear benefit of clopidogrel in this patient group.

Stepping up to a More Potent Antiplatelet Drug

Concerning the potential for an alternate antiplatelet agent, Dr. Andersson and colleagues observe that data from the randomized TRITON-TIMI 38 trial suggest that prasugrel may have greater clinical impact than clopidogrel following MI in diabetics. Thus, “prasugrel may constitute an attractive alternative . . . in patients with diabetes with [ACS], especially if recurrent ischemic events have occurred during clopidogrel treatment,” they say.

In an accompanying editorial, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), writes that despite the limitations of these observational data, the results are plausible, especially since diabetics are known to have higher platelet reactivity, with several platelet signaling pathways likely upregulated.

Thus, more potent antiplatelets such as prasugrel and ticagrelor are potential options in patients who require dual antiplatelet therapy after an MI, Dr. Bhatt comments, adding that the European ACS guidelines “give preference to these agents over clopidogrel, although the US cardiology guidelines leave the choice to the physician based on patient characteristics.”

However, it remains unclear as to whether the greater absolute risk reductions imparted by the newer antiplatelet agents in diabetics are due to preferentially greater effect in such patients or because diabetics have higher event rates and therefore derive more benefit from an effective therapy. “Likely, both mechanisms . . . are operative,” he concludes.

Overall, the current data highlight the increased risk of recurrent MI and cardiovascular mortality among patients with diabetes following MI, Dr. Bhatt notes. “More needs to be done to reduce these risks,” he adds, and because at least a portion of the excess risk appears to be due to platelet reactivity, “in appropriately selected patients, intensification of the antiplatelet regimen may be one method by which their outcomes might be markedly improved.” 

Making Sense of ‘Undertreatment’

In an interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), found aspects of the data puzzling. For example, he noted, 44% of diabetics with a recent MI were not given clopidogrel and about one third of those did not receive standard medications such as aspirin and a statin, while only 10% of diabetics who were not given clopidogrel underwent PCI. “That doesn’t make sense,” he remarked.

“I think the only logical explanation is that many of these patients may have had a troponin elevation and were coded as an MI, but in fact the doctors didn’t think they had an MI,” he said. “And that’s why they weren’t treated.” Even with propensity-score matching, it is challenging to adjust for this difference between the clopidogrel-treated and -untreated (ie, possibly non-MI) patients, he commented.

“It is difficult to [conclude] from these data that there is a differential effect of clopidogrel in diabetics vs. nondiabetics,” Dr. Brener observed. “In the 2 previous studies that tested this hypothesis in large populations there was no interaction with diabetes. And we know from TRITON and PLATO that diabetics have more benefit from antiplatelet therapy, not less.” Instead, it is likely that the lower risk of the diabetic patients who did not in fact have an MI diluted the expected benefit of clopidogrel, he explained.

Nonetheless, Dr. Brener said he would not hesitate to choose a more potent antiplatelet agent for diabetics after a true MI. “I wouldn’t bother with something that may or may not work when I have something that I know works,” he said, adding that “ticagrelor is probably the ideal agent because it was tested in both patients treated medically and those [who received] PCI.”

2. Bhatt DL. Antipletelet therapy following myocardial infarction in patients with diabetes. JAMA. 2012;208:921-922.

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