Boston, MA (updated) - An analysis of the TRITON-TIMI 38 trial has shown that prasugrel (Effient, Daiichi Sankyo/Eli Lilly) significantly reduces the risk of cardiovascular events even in the setting of potent platelet inhibition with a GP IIb/IIIa inhibitor [1]. Like the overall study, bleeding risks were higher with prasugrel, but the use of a GP IIb/IIIa inhibitor did not heighten the relative risk of bleeding when compared with clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb).
Lead investigator Dr Michelle O'Donoghue (Brigham and Women's Hospital, Boston, MA) said the new analysis answers an important question because until now it was unknown whether there was any role for a more potent blockade of the platelet P2Y12 receptor, which prasugrel and clopidogrel both inhibit, in the setting of near-complete and rapid platelet inhibition with a GP IIb/IIIa inhibitor.
"The results of the current study suggest that more potent platelet inhibition with prasugrel compared with clopidogrel significantly reduces the risk of death, MI, or stroke at 30 days by 22% to 24%, regardless of whether a GP IIb/IIIa inhibitor is used," said O'Donoghue to heartwire. "Although prasugrel increased the risk of bleeding as compared with clopidogrel, the use of a GP IIb/IIIa inhibitor did not accentuate the risk of bleeding with prasugrel as compared with clopidogrel."
Glycoprotein IIb/IIIa inhibitor use not randomized
To heartwire, O'Donoghue said the current analysis was not designed to look at the question of whether there is any additional benefit for using GP IIb/IIIa inhibition in patients who are also treated with prasugrel. Since the use of glycoprotein IIb/IIIa inhibitors was left to the discretion of the treating physician and not randomized, it is not possible to directly compare outcomes for patients who did or did not receive the drugs in the TRITON-TIMI 38 population, she said. Patients treated with GP IIb/IIIa inhibitors might differ markedly from the other patients, for instance, and might have a poor angiographic result, a complicated PCI, or other baseline medical conditions that placed them at higher risk.
"For this reason, it may be misleading to compare MI or bleeding rates in patients who did or did not receive a GP IIb/IIIa inhibitor," according to O'Donoghue. "Patients treated with a GP IIb/IIIa inhibitor in TRITON-TIMI 38 had a higher incidence of [major adverse cardiac events] MACE; however, this finding is confounded by differences in other characteristics."
Full results of the TRITON-TIMI 38 study have been previously reported by heartwire. Briefly, investigators randomized 13 608 individuals with an acute coronary syndrome undergoing PCI to prasugrel or clopidogrel. Of these patients, 7414, or 54.5%, received a GP IIb/IIIa during their index hospitalization.
At 30 days, and similar to the overall findings, there was a significant benefit of prasugrel over clopidogrel in reducing the primary end point of cardiovascular death, MI, and stroke in patients who received GP IIb/IIIa inhibitors and those who did not. Like the main trial, the reduction was driven primarily by a reduction in the risk of MI. Investigators also report reductions in stent thrombosis and urgent target vessel revascularization in patients who received and those who did not receive GP IIb/IIIa inhibition.
Efficacy outcomes at 30 days stratified by use of GP IIb/IIIa inhibition
| Outcome | Hazard ratio (95% CI) |
| Cardiovascular death, MI, stroke (GP IIb/IIIa) | 0.76 (0.64-0.90) |
| Cardiovascular death, MI, stroke (no GP IIb/IIIa) | 0.78 (0.63-0.97) |
| Cardiovascular death (GP IIb/IIIa) | 0.88 (0.57-1.35) |
| Cardiovascular death (no GP IIb/IIIa) | 0.69 (0.41-1.16) |
| MI (GP IIb/IIIa) | 0.75 (0.62-0.90) |
| MI (no GP IIb/IIIa) | 0.74 (0.59-0.93) |
| Periprocedural MI (GP IIb/IIIa) | 0.83 (0.67-1.01) |
| Periprocedural MI (no GP IIb/IIIa) | 0.89 (0.69-1.16) |
| Stent thrombosis (GP IIb/IIIa) | 0.46 (0.29-0.71) |
| Stent thrombosis (no GP IIb/IIIa) | 0.34 (0.17-0.65) |
| Urgent target vessel revascularization (GP IIb/IIIa) | 0.56 (0.38-0.82) |
| Urgent target vessel revascularization (no GP IIb/IIIa) | 0.47 (0.26-0.84) |
In the overall study, prasugrel significantly increased the risk of bleeding at 30 days compared with clopidogrel. In this analysis, investigators report that patients treated with a GP IIb/IIIa inhibitor did have higher rates of bleeding than those who did not receive the drugs, but the excess risk with prasugrel was comparable in both patient groups.
Safety outcomes at 30 days stratified by use of GP IIb/IIIa inhibition
| End point | Prasugrel (%) | Clopidogrel (%) | Hazard ratio (95% CI) | p for interaction |
| TIMI major or minor bleed (GP IIb/IIIa) | 3.3 | 2.9 | 1.16 (0.89-1.50) | 0.19 |
| TIMI major or minor bleed (no GP IIb/IIIa) | 1.7 | 1.1 | 1.63 (1.05-2.52) | — |
| TIMI major bleed (GP IIb/IIIa) | 1.2 | 1.1 | 1.06 (0.69-1.64) | 0.39 |
| TIMI major bleed (no GP IIb/IIIa) | 0.9 | 0.6 | 1.47 (0.81-2.66) | — |
"The results of this study will be particularly relevant to cardiologists who may wish to use prasugrel in combination with a GP IIb/IIIa inhibitor following PCI," said O'Donoghue.
Speaking with heartwire, Dr Paul Gurbel (Johns Hopkins School of Medicine, Baltimore, MD), who was not involved in the TRITON study, said that patients receiving GP IIb/IIIa inhibition in this study were not randomized, and it is possible that there were clinical differences that accounted for the benefit of prasugrel over clopidogrel.
"It might be that demographically the patients are balanced, but angiographically they differed," added Gurbel. "What determines a lot of periprocedural infarctions and early event rates has to do with the anatomy you're dealing with in the cath lab."
Gurbel said that he agreed with the authors' conclusions that bleeding isn't accentuated with prasugrel on board with a GP IIb/IIIa inhibitor when compared with clopidogrel. Because the GP IIb/IIIa inhibitors are such potent antiplatelet agents, he said that he wouldn't expect bleeding to increase further with the addition of prasugrel, especially since events were assessed early, at 30 days. However, he said that it doesn't help him commit to prasugrel over clopidogrel, because patients will bleed more with the potent antiplatelet agent beyond 30 days.
Added benefit
To heartwire, O'Donoghue said the findings also provide some insight into platelet biology, especially since there appears to be added benefit of the more potent prasugrel in the setting of platelet-aggregation inhibition with a GP IIb/IIIa inhibitor. This may suggest that the P2Y12 receptor has a variety of downstream effects that influence clinical outcomes and yet are independent from the IIb/IIIa receptor, she noted.
"These insights into platelet biology also lend proof of concept to the idea of targeting multiple platelet receptors," she continued. "It will be interesting to see the results of ongoing trials that are evaluating drugs that inhibit other platelet receptors. For instance, the TRA2P-TIMI 50 and TRACER trials are currently evaluating the additive benefit of blocking the platelet thrombin receptor on top of a background of aspirin and/or clopidogrel."
Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA), who was not part of the study, said the authors were cautious in their conclusions but, like Gurbel, was critical of the lack of randomization in the study. Kaul told heartwire that it is only possible to determine the added benefits of GP IIb/IIIa inhibition on top of a thienopyridine in a randomized trial. The ideal trial, he said, would be a 2x2 factorial design where patients were randomized to clopidogrel or prasugrel and then randomized to a GP IIb/IIIa inhibitor or no GP IIb/IIIa inhibitor.
Various studies, among them ISAR-REACT, ISAR-REACT 2, and BRAVE-3, all studied the use of GP IIb/IIIa inhibition against the backdrop of clopidogrel pretreatment, and only ISAR-REACT 2, which studied high-risk ACS patients, showed a benefit, noted Kaul.
The Food and Drug Administration approved prasugrel for use during PCI on July 10, 2009. The drug debuted on the shelves of US pharmacies August 5, 2009.
- O'Donoghue M, Antman EM, Braunwald E, et al. The efficacy and safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention. J Am Coll Cardiol 2009; 54:678-85.
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