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Beyond an increased risk of hemorrhage with prasugrel compared with clopidogrel as a part of dual antiplatelet therapy, other predictors of serious bleeding in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) include a mix of patient and procedural characteristics, such as female sex, use of a glycoprotein IIb/IIIa inhibitor (GPI), and femoral access. In addition, serious bleeding increases mortality almost sixfold, but the extra risk declines sharply within a few days of the event and all but disappears after 1 month.

The findings from a new analysis of TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38) were published online May 23, 2011, ahead of print in Circulation.

The main results of the trial, which randomized ACS patients to clopidogrel or the more potent P2Y12 antagonist prasugrel, showed the latter to be superior for reducing ischemic events. However, prasugrel was linked to excess major bleeding.

For the substudy, Willibald Hochholzer, MD, of Harvard Medical School (Boston, MA), and colleagues explored the factors that distinguished the 534 patients (4%) who experienced serious (TIMI major or minor) bleeding from the overall 13,430 subjects. Multivariable analyses identified the factors that most strongly predicted serious bleeding (table 1, in descending order according to strength of association).

Table 1. Independent Predictors of Non-CABG-Related Serious Bleeding Over 15 Months

The excess of serious bleeding with prasugrel was driven by a higher incidence of bleeding from surgical sites (other than CABG) and gastrointestinal bleeding. Moreover, the overall increased risk was seen for both instrumented/traumatic and spontaneous bleeding.

Time Dependence of Mortality Risk a Surprise

Serious bleeding was associated with an almost sixfold increased risk of death (adjusted HR 5.84; 95% CI 4.11-8.29). In particular, spontaneous bleeding events were associated with a higher mortality risk than were instrumented or traumatic events. However, landmark analyses showed a sharp decline in mortality risk within the first week after the bleeding event; by 40 days, bleeding no longer had a statistically significant impact on death rate.

Sunil V. Rao, MD, of Duke University Medical Center (Durham, NC), focused on the finding. “Bleeding complications are ‘front-loaded’—they tend to occur early and over time and there is a natural selection of patients who can tolerate the risk,” he told TCTMD in an e-mail correspondence.

“[Also,] bleeding with prasugrel that occurs late (ie, beyond 40 days) does not appear to be associated with increased risk. This is a bit different from what we know about late bleeding from other studies like CHARISMA, the Ontario database, etc,” Dr. Rao said. “Why this finding is different from other studies is not clear. Perhaps it's the TIMI definition of bleeding, perhaps it's something about the patients in TRITON, or perhaps it's confounding. In any case, I think clinicians can take comfort in the fact that patients who seem to tolerate the increased bleeding risk with prasugrel will likely do very well in terms of subsequent clinical events.”

New Specificity on Bleeding Risk

Most of the predictors of bleeding identified in the study “have been described before,” Dr. Hochholzer noted in an e-mail communication with TCTMD. “[But] an interesting finding was that use of a GP IIb/IIIa inhibitor, [which] is usually only used for 12 to 36 hours, showed an even stronger association with bleeding than treatment with prasugrel, which was used for the full trial period.”

“This manuscript [also] provides additional [information] regarding the different types of bleeding and their incidences with clopidogrel vs. prasugrel,” he added. “Prasugrel was associated with a higher rate of serious gastrointestinal and surgical site bleeding and minimal epistaxis and vascular access site bleeding.”

Overall, to minimize bleeding in ACS patients undergoing PCI, Dr. Rao recommended several measures:

• Avoid prasugrel in the high-risk patient groups identified on the label
• Make sure that drugs are being dosed appropriately
• Use antithrombotics associated with reduced bleeding risk
• Use radial access

 

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Source:
Hochholzer W, Wiviott SD, Antman EM, et al. Predictors of bleeding and time dependence of association of bleeding with mortality: Insights from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Circulation. 2011;Epub ahead of print.

 

 

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