Prasugrel: Different Mortality Trends in STEMI and Non-STEMI Patients in TRITON

April 01, 2010

April 1, 2010 (Towson, Maryland) — Further information on deaths in the TRITON trial comparing the antiplatelet agents prasugrel (Effient, Eli Lilly/Daiichi Sankyo) and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in ACS patients scheduled for PCI show that prasugrel was associated with opposite mortality trends in the STEMI and non-STEMI populations, a fact that is causing concern to at least one observer.

The additional information is found in the complete documentation set on prasugrel recently released by the US FDA, which is the subject of an article by platelet expert Dr Victor Serebruany (HeartDrug Research Laboratories, Towson, MD) published online March 22, 2010 in the American Journal of Cardiology.

Serebruany, a long-time critic of the TRITON trial, points out that mortality is trending in the wrong direction for prasugrel in the unstable-angina or non-STEMI cohort in the trial, representing 74% of TRITON's patients, while there is an early mortality benefit in patients with STEMI, followed by a late detriment.

"Discrepancy in these mortality trends dependent on the underlying acute coronary syndrome type adds more confusion to the adequate assessment of TRITON's results and may restrict prasugrel use even further," he concludes.

Commenting on this issue for heartwire , Serebruany explained that the mortality data from TRITON was particularly important, given the controversy that has surrounded the MI end point. "As the definition of MI used in this trial has been queried, the only hard outcome data we have is mortality, and the fact that this is going the wrong way in the population that makes up three-quarters of the patients treated is alarming to me," he said.

Serebruany also highlights other mortality statistics not included in the original TRITON paper but included in the documentation made available by the FDA. He writes: "Although cardiovascular deaths trended slightly in favor of prasugrel (133 vs 150), an excess in bleeding fatalities (21 vs five), and four additional cancer-related deaths after prasugrel diluted the mortality benefit almost completely. Moreover, final FDA notes revealed more deaths with unidentified causes after prasugrel (five vs two) in patients lost to follow-up without achieving primary end points but affecting all-cause mortality."

He continues: "Considering the existing black-box warning for bleeding in the United States, growing cancer risks, and the lack of an anticipated late heart-failure benefit, justification for the use of prasugrel in patients with UA or NSTEMI is seriously challenged."

Differences in "First Site-Reported" and "Centrally Adjudicated" Deaths

Serebruany explained that the FDA conducted these additional mortality analyses after it was noticed that the death rate appeared higher in the prasugrel group in a secondary analysis based on first site-reported events, rather than the primary analysis, which focused on centrally adjudicated events.

Deaths as First-Reported Site Events in TRITON

Group Prasugrel Clopidogrel Difference
UA/NSTEMI 113 83 +30
STEMI 49 58 -9
Combined 162 141 +21

Serebruany says the trend toward a higher death rate in the non-STEMI group remains when looking at the total number of centrally adjudicated deaths. "The pattern of the mortality difference was marginal but consistent, favoring clopidogrel over the course of the entire trial," he writes.

But responding to these comments, Dr Jeff Riesmeyer, senior medical director at Lilly, argued that the deaths recorded as "site-reported first events" were an incomplete analysis, as the analysis didn't include all the deaths. "This analysis is just looking at deaths if they were the first event to be reported. So if a patient had an MI or a stroke and then died, it would not be included as a death in this analysis," he explained.

Riesmeyer said the total number of deaths in STEMI/non-STEMI patients in TRITON do not show such large differences, with nine more deaths in the prasugrel group in the non-STEMI group and 18 fewer deaths in the prasugrel group in STEMI patients. Riesmeyer said these numbers were more reliable to make any judgments on as they included all deaths in the trial, not just those that were "first-reported events."

Total Deaths in TRITON Trial

Group Prasugrel Clopidogrel Difference
UA/NSTEMI 130 121 +9
STEMI 58 76 -18
Combined 188 197 -9

What About the STEMI Group?

Serebruany says the suggestion of mortality benefit in the STEMI group occurred very early and can be attributed to the inappropriately delayed loading of clopidogrel. "This advantage emerged very early in the trial and was steadily maintained until after 14 months of follow-up, when the benefit began to rapidly vanish," he writes.

But Riesmeyer told heartwire that the trend toward mortality benefit in the STEMI population was maintained throughout the trial and the blip at the end of the trial reflected a drop-off in patients in the study. "This was the end of the trial. The patient numbers being evaluated were suddenly much lower as the trial had now been finished, so this last figure will not be reliable. That probably explains the sudden disappearance of the mortality benefit," he said.

Slow Start for Prasugrel Sales?

Commenting on these issues for heartwire , Dr Sanjay Kaul, who has also been a critic of prasugrel and was famously "disinvited" from the FDA advisory panel considering the drug, said it was difficult to know whether these mortality numbers mean anything or not, as TRITON was not powered for mortality alone.

On Serebruany's article, Kaul said: "Overall, I agree with his core message that the benefits of prasugrel appear to be overestimated and the risks underestimated in TRITON. This important point seems to be reflected in the use of prasugrel in clinical practice. Most clinicians are using this drug selectively and limiting its use to a few weeks. Even though not informed by evidence, I cannot disagree with this strategy to optimize the benefit/risk balance of prasugrel."

Serebruany also maintains prasugrel usage is low, citing Wall Street statistics that suggest prasugrel accounts for just over 1% of new antiplatelet prescriptions, with clopidogrel holding on to the rest of the market.

Lilly said it could not provide any usage data, but it claims that prescriptions have accelerated over the past months. "Daiichi Sankyo and Lilly continue to be optimistic about the accelerated growth we are seeing for Effient as it is being added to formularies in hospitals and by managed-care organizations. As those positive formulary decisions are being made, we are seeing Effient prescribed more," a company spokesperson added. More information on sales of the dug will be made available when Lilly announces its first quarter results, expected on April 19.

Investigators for the TRITON trial did not respond to requests for comments on Serebruany's analysis before this story went live on theheart.org.

Serebruany is listed as an inventor and received compensation for US patent application P-17232, "Method for treating vascular diseases with prasugrel," assigned to Eli Lilly & Company. He has received funding for research studies with both prasugrel and clopidogrel. Kaul has previously disclosed owning stock, stock options, or bonds in Eli Lilly and Johnson & Johnson and has received grants for clinical research from Hoffmann-La Roche and has served as an advisor or consultant for Novo Nordisk and Hoffmann-La Roche.

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