SAN DIEGO, CA — The use of prasugrel (Effient, Lilly/Daiichi-Sankyo) in patients with acute coronary syndrome (ACS) undergoing PCI with stent implantation does not reduce the risk of major adverse cardiac events (MACE) compared with patients who receive clopidogrel, according to data from a new retrospective cohort analysis[1].

In the unadjusted analysis, the risk of MACE was reduced 42% at 90 days with prasugrel, but the benefit was attenuated when investigators adjusted for baseline patient characteristics. After adjustment, MACE was reduced just 11%, a reduction that was not statistically significant.

The attenuation of benefit makes sense given just how different the patients were in the two treatment arms, according to lead investigator Dr Usman Baber (Icahn School of Medicine at Mount Sinai, New York).

"In general, all major clinical risk factors, including the prevalence of prior MI, PCI, CABG, diabetes, renal disease, and so on, were significantly much less common in patients who received prasugrel, which indicates a much healthier patient profile," said Baber. In addition, the prasugrel-treated patients were 7 years younger than those who received clopidogrel.

In the TRITON-TIMI 38 trial in ACS patients undergoing PCI, investigators previously showed prasugrel lowered the risk of ischemic events compared with clopidogrel but at a cost of increased bleeding. Presenting the results of their analysis to the media here at the Society for Cardiac Angiography and Interventions (SCAI) 2015 Scientific Sessions, Baber said the safety and efficacy of prasugrel, despite the randomized data, are not well characterized in a real-world setting.

Of the 19,914 ACS patients included in the retrospective cohort study, known as PROMETHEUS, 80% were treated with clopidogrel. Of those who received prasugrel, 52.3% had unstable angina, 28.6% had non-ST-segment-elevation MI (NSTEMI), and 19.1% had STEMI. In contrast, 57.3% of the clopidogrel-treated patients had unstable angina, 26.8% had NSTEMI, and 15.8% had STEMI. As noted, the prasugrel-treated patients "were way healthier" than those who received clopidogrel, according to investigators.

"Basically every single parameter that correlates with an ischemic event or a bleeding event was less common in the prasugrel group compared with the clopidogrel-treated patients," said Baber.

In terms of clinical outcomes, the rate of MACE was reduced 44% with prasugrel at 90 days in the unadjusted analysis, while the rate of MI and all-cause mortality was reduced 49% and 79%, respectively. After adjustment for baseline variables, only the reduction in the risk of all-cause mortality remained significant (hazard ratio 0.62, P=0.04). Rates of bleeding, paradoxically, were reduced 35% with prasugrel in the unadjusted analysis. but the reduction was not significant after adjustment.

Cautious Use of Prasugrel in Real World

In terms of their findings, Baber told the media the results show that prasugrel is used very infrequently compared with clopidogrel and "that there is a profound degree of selection in terms of the patients" who receive the newer antiplatelet agent. The results of the real-world analysis also show the benefits of prasugrel are "more modest" compared with that observed in clinical practice.

"One important implication of this study is that if, perhaps, we are to recalibrate our use of prasugrel to the patient's ischemic risk, we might be able to derive a larger therapeutic benefit compared with what we see in clinical practice," said Baber.

Dr Roxana Mehran (Icahn School of Medicine at Mount Sinai), the senior investigator of the PROMETHEUS study, said academic medical centers are well aware of the clinical data supporting prasugrel, but the novel antiplatelet agents are not penetrating into practice "perhaps as well as they should."

"Do you think it's because we've scared people too much about bleeding?" she asked.

During the SCAI presentation, Dr Matthew Price (Scripps Clinic, La Jolla, CA), who was not affiliated with the study, said the retrospective study, which included academic physicians treating patients at the Cleveland Clinic, Mount Sinai Medical Center, and Duke University, among the other major centers, is a reflection of how physicians approach the risk/benefit trade-off in ACS patients.

"The study tells us that, as physicians, we'd rather do no harm than potentially provide benefit," said Price. "Much like anticoagulation, our treatment decisions are based too much on bleeding risk rather than ischemic benefit." Baber agreed, noting the data reflect prescribing patterns that are governed "more by therapeutic toxicity than by therapeutic benefit."

Price said the data reflect poorly on US physicians, noting they suggest that not only are clinicians afraid of bleeding but that it appears to "suggest they feel burned by clinical trials, and they don't trust the results of clinical trials like we used to."

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