Designing The Ideal Platelet Function Trial
Properly evaluating the benefit of platelet function testing in the PCI population has not proved successful, with the negative results of GRAVITAS and the early cessation of TRIGGER-PCI. These trials have hindered wider adoption of function testing, and have left physicians uncertain. As ACC Past-President Raymond J. Gibbons, MD, said in response to GRAVITAS: “The impetus to change clinical practice will not be driven by negative treatment trials, but instead by clear treatment alternatives, which are proven to be effective.”

Despite the lack of substantive data, platelet function testing recently has been added to the clinical practice guidelines update. The American College of Cardiology Foundation/American Heart Association Guideline Update has incorporated platelet function testing for the management of patients with unstable angina and non-STEMI (J Am Coll Cardiol 2011; 57:1920-1959).
Therefore, to better answer the remaining quandaries for clinical decision makers, three platelet experts have submitted their ideas for the foundation of a new trial design that could properly assess the potential benefits of platelet function testing.

Steven V. Manoukian, MD | Hospital Corporation of America, Nashville, Tenn.

“The challenges with previous trials are that the rates of adverse events have generally been low, and the randomized trial designs have not employed therapies that have significantly altered those low rates. With GRAVITAS, the incremental benefit of using high-dose clopidogrel was limited and the overall event rate in the post-PCI population was low. With TRIGGER-PCI, although all the data have not been released, it is possible that even prasugrel did not demonstrate a meaningful difference given the trial design and the sample size. However, more potent inhibition may still be proven effective in reducing adverse events.

  • Patient Population: Pre-PCI population of higher risk patients, especially those with high on-treatment platelet reactivity, based on platelet function testing. The event rates and greatest magnitude of benefit of more potent antiplatelet therapy is in higher-risk patients, such as those with an acute coronary syndrome (ACS), who are more prone to ischemic complications during PCI.  
  • Exclusionary Criteria: Patients undergoing elective PCI, especially those who do not have high on-treatment platelet reactivity.
  • Design: Randomizing high-risk patients, especially hypo-responders to a “very potent” glycoprotein IIb/IIIa inhibitor (Gp IIb/IIIa) versus placebo.  The immediate onset of action of a Gp IIb/IIIa would maintain throughput by avoiding a potential pre-PCI delay while waiting for an oral agent to exert its effect. A truncated regimen of Gp IIb/IIIa would maximize safety by attenuating bleeding complications while simultaneously minimize costs.
  • Endpoint: Cardiac events that occur during and immediately post-PCI, as well as the use of a troponin-based MI endpoint, which was recommended in a recent whitepaper (J Am Coll Cardiol 2007;50[20]:2173-2195). This latter endpoint would allow the capture of a larger number of events, and therefore, could potentially prove the value in platelet function testing to positively impact outcomes. The use of troponin-based MI endpoint, the use of peri-procedural events and exclusively assessing hypo-responders to antiplatelet therapy could reduce the required sample size to less than 1,000 patients.
  • Duration: The benefit of this study design is that follow-up could be limited to short-term, such as 30 days or even 48 hours post-PCI.  Alternatively, follow-up out to one year would further validate the prognostic impact of a troponin-based MI definition in PCI.

–This trial design is currently in the final planning stages in the U.S.

Matthew J. Price, MD | Scripps Clinic, La Jolla, Calif.

“A key take-away from GRAVITAS is that high-dose clopidogrel does not provide much pharmacodynamic effect in patients who are non-responders to standard-dose therapy; moreover, a post-hoc analysis showed that patients who achieved a low level of on-treatment platelet reactivity (<208 PRU) while receiving clopidogrel had better outcomes. However, overall event rates were low in this mostly elective population, which makes the required size of a randomized trial for this population prohibitive. An ideal trial would test the safety, efficacy and cost-effectiveness of platelet function test guided-antiplatelet approach in patients undergoing PCI for ACS compared with the current optimal therapy.
  • Patient Population: ACS patients who will undergo PCI.  
  • Exclusion Criteria: Any patient with a contraindication to prasugrel.
  • Design: Prasugrel compared with platelet-function guided therapy (clopidogrel or prasugrel). After an adequate duration of pre-PCI treatment with clopidogrel, patients will be randomized to either the non-individualized arm or individualized arm. The non-individualized arm will receive prasugrel with matched placebo. For the individualized arm, platelet function testing will be performed, and if the platelet function PRU is <208, then the patient will receive 75 mg of clopidogrel with matched placebo; if the PRU >208, then the patient will receive prasugrel with matched placebo.
  • Primary endpoints: 1) Death from any cause, MI or unplanned revascularization for ischemia; 2) Major and minor bleeding (not related to CABG); and 3) Net clinical outcome end point (defined as the occurrence of the composite ischemia end point or major or minor bleeding).
  • Duration: One year.

Steven R. Steinhubl, MD | Geisinger Health System, Danville, Pa.

“In all of the large platelet function testing trials to date, none have actually measured responsiveness to an antiplatelet agent—primarily clopidogrel. All have only measured residual platelet activity, which is impacted by a lot more than just the antiplatelet therapy including the patient’s degree of atherosclerosis and inflammatory status. If we really hope to show that we need to alter a drug dose or type based an individual’s response to a specific drug, then it will be necessary to start doing just that—measure response before and after the drug and not residual platelet reactivity.”
  • Patient Population: All-comers trial in those who will undergo planned PCI—either ACS patients or not. About 10,000 individuals would likely need to be screened to enroll approximately 2,000 non-responders into the study.
  • Exclusion Criteria: Any patient who was recently administered theinopyridine, GPIIb/IIIa antagonist or warfarin. Although statin use should not be exclusionary, researchers should stratify randomization based on statin use.
  • Design: The goal would be to determine if patients who are non-responders to clopidogrel would benefit more from receiving prasugrel (or double-dose clopidogrel or ticagrelor). These 2,000 individuals, identified as being non-responders based on their change in measured platelet function before and after receiving a loading dose of clopidogrel, would be randomized to either continue clopidogrel or switch to prasugrel, given as a loading dose at least an hour prior to planned PCI. (The definition of a non-responder, which is open to debate, would have to be clearly identified and applied across all study centers.) Randomized thienopyridine therapy would then be continued post-PCI. 

    Since the majority of events will be peri-PCI MIs, cardiac enzymes will need to be measured at baseline and sequentially every six to eight hours after PCI.
  • Duration: The study’s duration really doesn’t need to be more then three months after PCI, and probably just one month is fine.