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For older patients with acute coronary syndromes (ACS) managed medically, the risk of ischemic and bleeding events is similar regardless of whether dual antiplatelet therapy includes low-dose prasugrel or clopidogrel. In addition, both types of events occur more frequently with increasing age, according to a substudy of the TRILOGY ACS trial published online July 12, 2013, ahead of print in Circulation.

In the main trial, 9,326 unstable angina/NSTEMI patients with at least 1 risk factor and no planned revascularization within 10 days were randomized to prasugrel (10 mg daily for patients under age 75 and 5 mg daily for those age 75 or older) or clopidogrel (75 mg daily). All subjects also received daily aspirin. For both the main cohort of younger patients (n = 7,243) and the overall population, no differences were seen in the composite of cardiovascular death, MI, or stroke (primary efficacy endpoint) or rates of non-CABG-related severe and life-threatening bleeding between the prasugrel and clopidogrel groups.

For the substudy, investigators led by Matthew T. Roe, MD, MHS, of the Duke Clinical Research Institute (Durham, NC), looked at the effects of age, weight, and use of  reduced-dose prasugrel specifically in patients age 75 years and older (n = 2,083). For this group, the median duration of treatment was 364 days and the median follow-up was 450 days compared with 453 and 532 days, respectively, for the younger group.

Older Patients Fare Worse

The risk of the primary efficacy endpoint rose progressively with increasing age, and at 30 months the Kaplan-Meier estimate stood at more than 2.5-fold higher in the older group compared with the younger group (HR 2.65). Similar differences were seen for MI (HR 2.37) and stroke (HR 2.66) but were proportionally higher for cardiovascular death (HR 3.25) and all-cause death (3.27; P < 0.01 for all comparisons). TIMI major bleeding also rose proportionally with age and was more than twofold higher in the older cohort (HR 2.15), while the risks of intracranial hemorrhage and fatal bleeding, though low overall (about 1.1%), increased about three- to fourfold in older patients (HR 2.67 and HR 4.31, respectively).

Moreover, the cumulative risks of the primary efficacy endpoint and its individual components were similar between patients receiving half-dose prasugrel or clopidogrel, as were rates of non-CABG TIMI major bleeding and intracranial and fatal bleeding (table 1).

Table 1. Cumulative Outcomes Through 30 Months in Patients Age 75 Years and Older

 Overall, no interaction was seen between age and treatment drug, although there was a trend for stroke (P = 0.052) and TIMI major/minor bleeding (P = 0.098).

In a platelet function substudy of 515 older patients, lower 30-day on-treatment P2Y12 reaction unit (PRU) values positively correlated with lower body weight in those treated with prasugrel (P = 0.04) but not clopidogrel (P = 0.58). However, weight did not modify the treatment effect on 30-day PRU values using an ANOVA model (P for interaction = 0.06). Median body weight was similar for patients with vs. without a non-CABG-related TIMI major/minor bleeding event in both treatment groups (P for interaction = 0.922).

Low-Dose Prasugrel Eases Safety Concern

According to the authors, the findings “highlight the similar increased relative risk of both ischemic and bleeding events in elderly patients.”

Importantly, say Dr. Roe and colleagues, the 5-mg dose of prasugrel appears to mitigate the risk of serious bleeding in older patients seen with the standard 10-mg dose observed in TRITON TIMI-38 (Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015). Still, despite its attenuated effect on platelet reactivity compared with the standard prasugrel dose, the lower dose achieved greater platelet inhibition than clopidogrel. 

“These are the first publicly reported data on use of the lower dose of prasugrel,” Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), told TCTMD in a telephone interview, “and in quite a large number of patients, it looks fine in the sense that the bleeding risk is no higher than with clopidogrel.”

Prasugrel Loses Its Rationale at Reduced Dose

The problem is that “we wanted a drug like prasugrel because it is [more effective] than clopidogrel,” Dr. Brener observed. “And now we’re saying, Take this drug that is better than clopidogrel, but take it in a low dose so that it ‘becomes’ clopidogrel. That makes no sense. If you have to sacrifice efficacy in order to preserve safety, then why not stay with [clopidogrel]?” The fact that generic clopidogrel is much less expensive than prasugrel makes the choice even easier, he added.

For the most part, the risk factors for ischemic events and bleeding overlap, Dr. Brener noted, and the question becomes whether for a given patient 1 risk is more important.

For someone with only 1 patent epicardial vessel, say, or a very poor ejection fraction, an additional ischemic event could be catastrophic, he explained. “For that person, I would use the more effective therapy, standard-dose prasugrel, accepting that there may be a little more bleeding,” he said. “For another patient, whose ejection fraction is normal and a small heart attack wouldn’t kill them but a major GI bleed would, I would choose clopidogrel.”

With regard to the larger issue behind the TRILOGY trial, Dr. Brener said the data appear to support the concept that dual antiplatelet therapy is beneficial in patients who do not receive revascularization. But evaluation is hampered by the fact that medical therapy is used in a mix of patients who are clinically quite different. The result, he said, is that “we don’t know if dual antiplatelet therapy is beneficial only in those who should have revascularization but for various reasons can’t have it, as opposed to those who simply had a troponin elevation but don’t have significant blockages and so maybe don’t need it.” 

Study Details

Compared with younger trial participants, older patients were more likely to be female, weigh less than 60 kg, have NSTEMI rather than unstable angina, present with Killip class 2 or greater, and have higher GRACE risk scores and lower baseline creatinine clearance values. They were also less likely to undergo angiography before randomization. 

 

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Source:
Roe MT, Goodman SG, Ohman EM, et al. Elderly patients with acute coronary syndromes managed without revascularization: Insights into the safety of long-term dual antiplatelet therapy with reduced-dose prasugrel vs. standard-dose clopidogrel. Circulation. 2013;Epub ahead of print.

 

 

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