TRITON-TIMI 38 Analysis: In CABG Patients, Mortality Benefit with Prasugrel Despite Higher Bleeding Risk

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Patients with acute coronary syndromes (ACS) who undergo coronary artery bypass graft (CABG) surgery have lower mortality if they have been receiving prasugrel prior to surgery rather than clopidogrel. However, the new, more potent thienopyridine also results in more bleeding, according to an analysis of the CABG cohort from the TRITON-TIMI 38 trial published online May 23, 2012, ahead of print in the Journal of the American College of Cardiology.

Originally published in the New England Journal of Medicine in 2007, TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38) found that in ACS patients scheduled for PCI, prasugrel reduces ischemic events, including stent thrombosis, but increases major bleeding, including fatal bleeding. No significant mortality difference was seen between the 2 treatment groups.

In the current subanalysis, Peter K. Smith, MD, of Duke University Medical Center (Durham, NC), and colleagues reviewed data on the 346 TRITON-TIMI 38 patients who, after randomization to aspirin plus prasugrel or clopidogrel for up to 15 months, subsequently underwent CABG at some point (typically more than 90 days after the enrolling event) during their participation in the trial from November 2004 to January 2007. Importantly, there were no ischemic events in the prasugrel group who discontinued the drug for up to 7 days while awaiting surgery.

More Bleeding, Transfusions with Prasugrel

Blood loss indicated by cumulative chest tube output in the first 12 hours after CABG, the primary safety endpoint, was higher in the prasugrel group than in the clopidogrel group. Prasugrel patients also had greater need for platelet transfusion and higher number of platelets transfused, as well as a trend toward more frequent surgical re-exploration for bleeding. However, no difference was seen between treatment arms in the need for packed red blood cell transfusion (table 1).

Table 1. Safety Endpoints

There was no difference in hospital length of stay between the 2 groups.

Overall, all-cause mortality at 30 days was reduced in the prasugrel cohort (2.31% vs. 8.67% in the clopidogrel cohort; P = 0.025). The mortality advantage for prasugrel remained after adjustment for baseline imbalances between the nonrandomized groups using both the EuroScore and the Society of Thoracic Surgeons score. Cardiovascular death at 30 days was also less common in the prasugrel group compared with the clopidogrel group (1.73% vs. 6.94%; P = 0.047) even after adjustment for baseline risk.

The mortality benefit with prasugrel was similar regardless of whether dual antiplatelet therapy was resumed after CABG.

Consistent with Previous Studies

According to the authors, the findings are consistent with other studies of antiplatelet therapy in CABG patients.

“Both abciximab and clopidogrel have been shown to have increased bleeding and transfusion outcomes compared with aspirin alone, whereas ticagrelor had similar bleeding and transfusion rates compared with clopidogrel,” Dr. Smith and colleagues write. “The observation of increased bleeding, transfusion, and re-exploration observed with the use of prasugrel in patients who require surgical intervention is an important finding for clinicians who are managing these patients in the perioperative setting.”

Better understand of bleeding, they add, “will help clinicians to be ready with respect to the potential for volume resuscitation, platelet therapy, or other hemostatic therapy for those patients who develop life-threatening bleeding after cardiac surgery.”

However, the authors also acknowledge multiple limitations of the analysis. The retrospective study involved patients who were randomized to therapy before an indication for CABG emerged, leaving open the possibility for unknown confounders. The incidence of both COPD and off-pump CABG performance differed between prasugrel and clopidogrel patients. Additionally, the decision to perform CABG and factors related to the timing of surgery are unknown. Finally, because TRITON-TIMI 38 was geared toward patients suitable for PCI, the CABG cohort had mostly 1- and 2-vessel disease. Thus, the results are less generalizable to the typical population of patients referred for CABG in whom 3-vessel disease predominates, or to patients who undergo complex or multiple operative procedures.

Study Details

Prasugrel therapy involved 60-mg loading dose followed by 10 mg daily, while clopidogrel therapy consisted of 300-mg loading dose followed by 75 mg daily.

Source:

Smith PK, Goodnough LT, Levy JH, et al. Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: Risk-adjusted retrospective data analysis. J Am Coll Cardiol. 2012;Epub ahead of print.

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