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 [1].

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 [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 [4], 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).

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 Piti
é-Salpêtrière, 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:

0.81 (0.66-0.99) for the primary end point.
1.19 (0.75-1.89) for major non-CABG bleeding.
1.14 (0.83-1.55) for major or minor non-CABG bleeding.

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.