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Although switching from clopidogrel to the more potent antiplatelet agent prasugrel generally eliminates high on-treatment platelet reactivity in stable patients following percutaneous coronary intervention (PCI), event rates are so low that the clinical utility of the strategy appears questionable, according to findings published online April 18, 2012, ahead of print in the Journal of the American College of Cardiology.
The study, which was terminated early on grounds of likely futility, was originally presented in November 2011 at the annual Transcatheter Cardiovascular Therapeutics scientific symposium in San Francisco, CA.
Investigators for TRIGGER-PCI (Testing platelet Reactivity In patients underGoing elective stent placement on clopidogrel to Guide alternative thErapy with pRasugrel), led by Dietmar Trenk, PhD, of Universitaets-Herzzentrum Freiburg-Bad Krozingen (Bad Krozingen, Germany), randomized 423 stable CAD patients with high on-treatment platelet reactivity after elective PCI with DES to clopidogrel (75 mg daily; n = 211) or prasugrel (10 mg daily; n = 212).
High residual platelet reactivity was defined as at least 208 P2Y12 reaction units (PRU), as assessed by the VerifyNow P2Y12 test (Accumetrics, San Diego, CA).
After an interim blinded review of data from 236 patients with 6-month follow-up showed only 1 primary endpoint event, the trial’s steering committee terminated the study prematurely. As a consequence, the final analysis included 136 patients from the prasugrel arm and 137 from the clopidogrel arm.
Only 1 Event in 6 Months
At 3 months, the median PRU had decreased 165 points in the prasugrel group (from 245 at baseline to 80; P < 0.001), while in the clopidogrel group median PRU declined only 8 points (from 249 at baseline to 241; P = 0.001; P < 0.001 for difference between the 2 arms). Accordingly, 94.1% of prasugrel patients reached the PRU threshold for adequate platelet inhibition compared with 29.6% of clopidogrel patients (P < 0.001). PRU measurements did not change significantly in either arm between 3 and 6 months.
During 6-month follow-up, events were rare in both treatment groups. For the primary composite endpoint of death or MI, 1 MI occurred in the clopidogrel arm at Day 140. Similarly, there was no difference between the prasugrel and clopidogrel arms for the secondary composite endpoint of cardiovascular death, MI, stroke or rehospitalization for cardiac ischemic events (1.0% vs. 2.9%; P = 0.404). Likewise, rates of the primary safety endpoint of non-CABG TIMI major bleeding were similar between the treatment groups (1.4% for prasugrel vs. 0.5% for clopidogrel).
More Striking Than GRAVITAS
The authors note that prasugrel achieved “unequivocal pharmacodynamic superiority” to clopidogrel. Even so, exclusion of patients with ACS, procedure-related infarctions, and peri-interventional bleeding events—as well as use of second-generation DES—resulted in a study group that “could tolerate high levels of platelet reactivity without a substantial risk of ischemic events after DES placement,” they write.
“I think the results are even more striking than with GRAVITAS,” study coauthor Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview. “We enrolled a low-risk group of patients with stable coronary artery disease who had successful PCI mostly with second-generation drug-eluting stents, and in that set of circumstances, the event rate is going to be extremely low even in patients who are hyporesponsive to clopidogrel.”
He added that TRIGGER PCI has “pretty definitively shown that platelet function testing is unlikely to be useful in patients with stable ischemic heart disease undergoing PCI, and I think the same is likely to be true for genotyping. We need to apply those technologies elsewhere.”
In a telephone interview with TCTMD, Matthew J. Price, MD, of the Scripps Clinic (La Jolla, CA), observed that when a trial is stopped early based on an interim analysis that is not prespecified, or results are based on a small proportion of the patients originally enrolled, it is prudent to be cautious in interpreting the findings. Nonetheless, he acknowledged, most study patients had very simple lesions and were even lower risk than those in GRAVITAS, so a difference in outcomes between the treatment arms is highly unlikely even had the trial been completed.
Dr. Price commented that because the trial was underpowered and was halted prematurely, what began as a clinical trial in effect ended up as a pharmacodynamic study. “This is a very nice multicenter prospective randomized assessment showing that patients who have high platelet reactivity on clopidogrel for the most part respond fully to prasugrel,” he said.
Is There Still a Role for Platelet Testing?
Going forward, Dr. Price suggested that platelet function testing should be assessed in at least 3 subsets of patients: stable patients who are at higher risk due to anatomy or other clinical factors, stable patients who experience periprocedural MI, and ACS patients.
“Unfortunately, to do an appropriately powered, definitive trial you need a lot of patients,” he said. “And funding is very challenging because the platelet testing companies aren’t big enough to sponsor a large multicenter randomized clinical trial, and it’s not in the interest of companies that make alternative pharmaceutical therapies [to do so].”
Meanwhile, Dr. Price cautioned against simply labeling TRIGGER-PCI and GRAVITAS as ‘negative studies’ for platelet function testing. In fact, in GRAVITAS a post-hoc analysis showed that patients who achieved lower platelet reactivity had better outcomes, while TRIGGER-PCI was simply underpowered to show a difference, he noted. “So, I like to say that GRAVITAS used an insufficient pharmacologic intervention, and TRIGGER-PCI had a study population that was insufficiently at risk,” he concluded.
Baseline PRU was well matched between the treatment arms. For on-treatment assessment, a blood sample was drawn between 2 and 7 hours after the first clopidogrel 75-mg maintenance dose the morning after PCI.
Second-generation DES were used in about 65% of patients, with Xience/Promus (Abbott Vascular, Santa Clara, CA; Boston Scientific, Natick, MA) stents accounting for about half of the total.
Note: Dr. Stone is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.
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