Q&A: Why was the TRIGGER-PCI pulled so soon?

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Steven R. Steinhubl, MD, Director, Cardiovascular Wellness at Geisinger Health System
After the TRIGGER-PCI trial, which was developed to evaluate the efficacy of prasugrel and clopidogrel, was pulled due to a low rate of cardiovascular events, clinicians are left wondering how this decision could impact clinical practice, and whether platelet reactivity testing will have a role in the future of clinical practice. Cardiovascular Business News spoke with platelet expert Steven R. Steinhubl, MD, of Geisinger Health System in Danville, Pa., who was not invovled in the trial, about how the halted TRIGGER-PCI trial,compounded by negative results of the GRAVITAS trial, could impact clinical practice.

TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy with Prasugrel) was halted by Daiichi Sankyo and Eli Lilly, makers of prasugrel (Effient) only 18 months after trial enrollment began. The researchers were to evaluate adverse cardiovascular outcomes in acute coronary syndrome (ACS) patients with successful drug-eluting stent (DES) placement who were randomized to receive either 10 mg/day of prasugrel or 75 mg/day of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis).

Members of the TRIGGER-PCI steering committee determined that the number of primary endpoints would be “insufficient for clinically relevant statistical analyses.” The low number of adverse events could be attributed to the patient population—low-risk, stable CAD after uncomplicated PCI.

“Since originally designing the TRIGGER-PCI study, we’ve determined from results of other trials and the pooled TRIGGER-PCI results that event rates are too low for clinically relevant statistical analysis. Thus, continuing the study would not have allowed us to show improved clinical outcomes in this patient population,” said the trial's U.S. lead investigator Gregg W. Stone, MD, of the New York-Presbyterian Hospital.

Like TRIGGER-PCI, the results of the GRAVITAS trial, which studied the potential benefits of a double dose of clopidogrel, did not support adopting a treatment strategy of 150 mg of clopidogrel in post-PCI patients with high residual reactivity.

Steinhubl helped elucidate some of the remaining questions.

CVB: How will the halting of TRIGGER-PCI, compounded by the negative results of GRAVITAS, impact clinical practice or not impact clinical practice?

Steinhubl: It shouldn't impact clinical practice because physicians should not have been measuring platelet function outside of the research environment. Platelet function testing isn’t part of the routine clinical practice. From both GRAVITAS and stopping TRIGGER-PCI, we learn that if you are in the very small minority who is performing platelet function testing and making clinical decisions based on that, you should probably re-think that method.

CVB: Do you think platelet function testing will ever have a larger role in clinical practice?

Steinhubl: It almost has to. Antiplatelet agents are a hugely important medication family and it’s the only family of medicine that we don’t titrate to some endpoint so it would be like giving blood pressure medicines without measuring blood pressure or diabetic medicine without measuring glucose or statin or lipid medications without measuring lipid levels.

It’s the only drug or family of drugs we administer and assume that one dose fits all. We assume that that is not the case, but we don’t have the data to tell us otherwise. I am very hopeful that at some point we will figure out that platelet function testing has to be part of clinical practice, but it just might be platelet function testing that is very different than what we consider to be the right test today.

CVB: If TRIGGER had a different trial design, would it have been halted so prematurely?

Steinhubl: It’s hard to understand why the trial was halted as soon as it was. There were so few patients enrolled that it seems difficult how they could make a decision on endpoints already.

The challenge in all PCI trials is that the vast majority of the events are related to the PCI procedure itself and any trial looking at events that occur only after the PCI will be very challenging to show a significant difference.

The best example is to go back to the early stenting trials. The ultimate non-responder in the STARS [Stent Placement in Patients with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function] trial didn’t get any additional P2Y12 inhibitors and they had a less than 5 percent stent thrombosis. This means that 95 percent of the patients did just fine with no antiplatelet therapy. That was still four times worse than the patients who were administered ticlopidine [Ticlid] and aspirin, but if you are trying to do a clinical trial to discern a small difference in something that may not make a difference in 95 percent of the patients anyway, it’s a very challenging trial to do.