September 2, 2008 (Munich, Germany) — If an increased bleeding risk is the price of using prasugrel (Eli Lilly/Daiichi Sankyo) instead of clopidogrel (Plavix/Iscover, Bristol-Myers Squibb/Sanofi-Aventis) to cut the risk of ischemic events in patients with ACS treated with PCI, diabetics may find a bargain in prasugrel, suggested a newly released follow-up analysis of the TRITON-TIMI 38 trial .
Its diabetic patients who received prasugrel, which remains investigational on both sides of the Atlantic, showed a superior reduction in the rate of the composite end point relative to those who received clopidogrel, but comparable rates of major or minor bleeding and of major bleeding, compared with nondiabetics, report the authors, led by Dr Stephen D Wiviott (Brigham and Women's Hospital, Boston, MA). Their results were published online August 31, 2008 by Circulation, and Wiviott presented the findings the same day at the European Society of Cardiology Congress 2008 [ 2].
Considered together, according to the researchers, their ischemic-event and bleeding results point to a significantly increased overall "net clinical benefit" from prasugrel relative to clopidogrel among the trial's diabetics compared with its nondiabetics. That's different from what was seen in the primary analysis of the overall population.
As previously published [ color="blue">3] and covered then by heartwire , prasugrel was associated with a 19% lower rate of CV death, nonfatal MI, or nonfatal stroke that was somewhat countered by a 32% rise in risk of major bleeding (excluding CABG-related bleeding per trial definition), compared with outcomes with clopidogrel, over a median follow-up of 14.5 months.
Coauthor Dr Elliott M Antman (Brigham and Women's Hospital) told heartwire that with the diabetes subanalysis as well as a separate one that compared the two antiplatelet agents solely in patients with ST-segment-elevation MI (STEMI), who also showed an increased net benefit from prasugrel , the message from TRITON-TIMI 38 remains as it was when the primary analysis was first released: the drug's potential for reduced ischemic risk is big compared with the small absolute risk of bleeding. "The relative benefit compared with the relative risk is what clinicians need to think about, and there is a profound treatment benefit with prasugrel."
Dr Robert A Harrington (Duke University, Durham, NC), who wasn't associated with TRITON-TIMI 38, said the overall trial suggests that in the clinical setting that was studied, prasugrel offers better efficacy than clopidogrel. "But that better efficacy comes at a price. What has to be figured out now is how to take advantage of that efficacy while having tolerable bleeding," he said.
"To me, the next series of analyses really needs to figure out, with the TRITON data, what is the risk for both ischemia and bleeding at any one time," Harrington said. "And then, can we construct a way of thinking about prasugrel, assuming it's approved, that will allow us to use it? And I think this [analysis in diabetics] adds to that story."
Of the trial's 13 608 randomized PCI-eligible patients with moderate- to high-risk STEMI, unstable angina, or non-ST-segment-elevation MI (NSTEMI), 3146 had diabetes; about one-fourth of those were on insulin. Prasugrel was given as a 60-mg loading dose plus maintenance at 10 mg/day, and clopidogrel as 300 mg initially plus 75 mg/day maintenance. Everyone received aspirin.
CV death or nonfatal MI or stroke occurred in 9.9% of the 10 462 patients without diabetes, 13.4% of the 2370 diabetics not on insulin, and 18.3% of the 776 insulin-treated diabetics (p for trend <0.0001). The adjusted hazard ratio (HR) for the composite end point for prasugrel vs clopidogrel was 0.74 for diabetics not on insulin and 0.63 among diabetics on insulin (p=0.009 for both subgroups).
Hazard ratios for primary and other end points, prasugrel vs clopidogrel, for nondiabetics and diabetics in TRITON-TIMI 38
|End Point||Nondiabetics, HR (95% CI)||Diabetics, HR (95% CI)||p for Interaction|
|CV death, nonfatal MI, or stroke*||0.86 (0.76–0.98)||0.70 (0.58–0.85)||0.09|
|MI||0.82 (0.72–0.95)||0.60 (0.48–0.76)||0.02|
|Major hemorrhage||1.43 (1.07–1.91)||1.06 (0.66–1.69)||0.29|
|Major or minor hemorrhage||1.32 (1.08–1.61)||1.30 (0.92–1.82)||0.93|
|All-cause death or nonfatal MI, stroke, or major hemorrhage||0.92 (0.82–1.03)||0.74 (0.62–0.89)||0.05|
*primary end point
In addition, prasugrel was associated with significantly reduced risks of the composite end point and of MI in both nondiabetics (p=0.02 and p=0.006, respectively) and diabetics (p<0.001 for both end points), with significantly increased risks of major hemorrhage (p=0.02) and of major or minor hemorrhage (p=0.006) in nondiabetics and with comparable risks of those two bleeding end points in diabetics, all compared with clopidogrel. Taken together, according to the authors, the findings point to an increased net benefit--that is, a significant reduction in the composite of all-cause mortality or nonfatal MI, stroke, or major bleeding--for prasugrel among the diabetics (p=0.001) but not nondiabetics.
Antman said the results of the two TRITON-TIMI 38 subanalyses are consistent with a state of increased platelet activation in diabetics and patients experiencing STEMI. Greater platelet aggregation means a lower bleed risk, "so if you're using a more powerful antiplatelet regimen, such as prasugrel compared with clopidogrel, in a condition where the platelets are more aggregable to begin with, the signal of increased bleeding with prasugrel vs clopidogrel is less likely to be observed."
| The TRITON-TIMI 38 STEMI Analysis
The story was much the same in an analysis of 3534 patients from the trial who had STEMI, which Dr Gilles Montalescot (Universitaire PitiÃ©-SalpÃªtriÃ¨re, Paris, France) reported in Munich: prasugrel was better than clopidogrel at preventing ischemic events but didn't show an increased risk of bleeding.
At 15 months, the age-adjusted hazard ratios for prasugrel vs clopidogrel in STEMI patients were:
The rates of all-cause death or nonfatal MI, stroke, or major non-CABG bleeding, reflecting net clinical benefit, were 12.2% for prasugrel and 14.6% for clopidogrel (p=0.02). "These data make prasugrel an especially attractive alternative to clopidogrel in angioplasty for ST-elevation myocardial infarction," Montalescot said.
TRITON-TIMI 38 was funded by Eli Lilly and Daiichi Sankyo. Many of the steering committee report receiving research, grant, and consulting fees from the two sponsors, Sanofi-Aventis, and other companies developing antiplatelet agents. Several employees of Eli Lilly and Daiichi Sankyo were on the study's steering committee. Antman reports receiving research grants and consulting or advisory board fees from Sanofi-Aventis and lecture fees and research grants from Eli Lilly and Sanofi-Aventis. Harrington said that his center has received grants from both of the trial's sponsors as well as Sanofi-Aventis and Bristol-Myers Squibb and that he has had consulting arrangements with the latter company unrelated to clopidogrel.
Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation. DOI: 10.1161/CIRCULATIONAHA.108.791061. Available at: circ.ahajournals.org.
Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater effect of intensive antiplatelet therapy with prasugrel compared with clopidogrel in diabetics in TRITON-TIMI 38. European Society of Cardiology Congress 2008; August 31, 2008; Munich, Germany. Poster 1328.
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel vs clopidogrel in patients with acute coronary syndromes. N Eng J Med 2007; 357:2001-2015. Abstract
Montalescot G. Prasugrel compared with clopidogrel in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention. European Society of Cardiology Congress 2008; August 31, 2008; Munich, Germany. Clinical Trial Update I.
The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
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Cite this: Steve Stiles. TRITON-TIMI 38 Analysis of Diabetics Finds Clinical Gains But No Bleeding Cost for Prasugrel vs Clopidogrel - Medscape - Sep 02, 2008.