Among patients with diabetes compared with patients without diabetes, the use of conventional clopidogrel treatment after MI was associated with lower reduction in the risk of all-cause death and cardiovascular death in a registry of nearly 60,000 patients. The results were published Sept. 5 in the Journal of the American Medical Association. However, editorialist Deepak L. Bhatt, MD, MPH, told Cardiovascular Business that registry results need to be taken in stride, compared with randomized controlled trials (RCTs).
“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,” wrote the study authors, led by Charlotte Andersson, MD, PhD, of the department of cardiology at Gentofte Hospital in Hellerup, Denmark.
By individual-level linkage of the Danish nationwide administrative registries between 2002 and 2009, the researchers included patients who were hospitalized with incident MI and who had survived and not undergone CABG surgery 30 days after discharge. They were followed for as long as one year (maximally until Dec. 31, 2009). The main outcome measures were all-cause mortality, cardiovascular mortality and a composite endpoint of recurrent MI and all-cause mortality.
Of the 58,851 patients included in the study, 12 percent had diabetes and 60 percent received clopidogrel. In total, 1,790 patients with diabetes and 7,931 patients without diabetes met the composite endpoint.
Among these patients, the investigators reported that 17 percent with and 10 percent without diabetes died. In total, 80 percent of patients with and 76 percent of patients without diabetes died of events of cardiovascular origin.
“Previous randomized, controlled trials have shown that diabetics have fairly high risk of future MIs and dying,” said Bhatt, “and this carefully conducted registry demonstrates that this finding seems to be true, which is an important, but confirmatory finding.”
For patients with diabetes who were treated with clopidogrel, the unadjusted mortality rates (events/100 person-years) were 13.4 vs. 29.3 for those not treated. For patients without diabetes who were treated with clopidogrel, the unadjusted mortality rates were 6.4 compared with 21.3 for those not treated.
“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 MI 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 endpoint in patients with diabetes,” the authors wrote.
In his editorial, Bhatt wrote, “it is a bit puzzling that the association of clopidogrel use with clinical outcomes seems stronger for mortality than for MI. The degree of mortality benefit associated with clopidogrel reported in this study also exceeds that reported in randomized clinical trials.”
In an interview with Cardiovascular Business, he said this could have occurred for several reasons: the finding is spurious; real-world patients are more sick than patients in RCTs; or that MI is captured very closely in RCTs and death is more effectively captured in registries.
However, Andersson et al also acknowledged “that no definite conclusions on causal mechanisms can be drawn from observational studies.”
What this registry and other studies do indicate, according to Bhatt, is that something different is going on with diabetes and antiplatetelets, which needs to be explored further in future trials. The registry also confirms that diabetic patients who have had MI don’t benefit as much from clopidogrel.
Thus, he hypothesized that diabetics might benefit from novel antiplatets, such as ticagrelor (Brilinta) or prasugrel (Effient)—even though it is outside the scope of the registry findings.
He recommended that physicians consider this dual-antiplatelet therapy approach with ticagrelor or prasugrel plus aspirin, “assuming that these are available and affordable.”
However, physicians need to consider these aspects when taking this approach:
- Bleeding risk because the newer agents are more potent;
- Compliance because ticagrelor is a reversible agent,