Timing of Platelet Testing Key to Optimal Therapy After PCI for ACS

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In patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), initial response to the loading dose of clopidogrel is often a poor predictor of response to maintenance therapy, according to a study published  online August 10, 2012, ahead of print in the American Heart Journal. Because many patients with early high platelet reactivity become responders within 30 days, follow-up testing is needed to avoid potential overtreatment and ensure an appropriate longer-term regimen, the researchers suggest.

Investigators led by Thomas Cuisset, MD, PhD, of Aix-Marseille Université (Marseille, France), compared initial clopidogrel response after a 600-mg loading dose with that after 1 month of high-dose (150-mg) maintenance therapy and evaluated their relationship with ischemic and bleeding events in 475 patients with non-ST-segment elevation ACS undergoing PCI at their institution.

Using a vasodilator-stimulated phosphoprotein (VASP) assay, a platelet reactivity index (PRI) was calculated. Clopidogrel low response was defined as high on-treatment platelet reactivity with a PRI greater than 50% and hyperresponse as a PRI less than 8%.

Initial Response Unreliable

Following the clopidogrel loading dose, 44% of patients had high on-treatment platelet reactivity and 5% had hyperresponse. At 1 month, 39% had high on-treatment platelet reactivity and 3% had hyperresponse. Mean PRI declined between the initial and 3-month tests (46% ± 21% to 43% ± 19%; P = 0.04).  At 1 month, 40% of the initial poor responders had become responders. Similarly, the proportion of hyperresponders decreased from 5% to 3% at 1 month.

The occurrence of Academic Research Consortium-defined definite or probable stent thrombosis in the entire population was 1.9%. Patients with a higher PRI after the loading dose were more likely to develop stent thrombosis than those who responded to clopidogrel (62% ± 20% vs. 45 ± 21%; P = 0.02). However, at 1 month there was no association between stent thrombosis and response to maintenance clopidogrel (45% ± 24% vs. 43% ± 19%; P = 0.82).

Bleeding complications (Bleeding Academic Research Consortium classification type 2 or higher) occurred in 5.7% of the total population. Patients with a lower PRI both initially and at 30 days were more likely to experience bleeding complications than normal or poor responders (28% ± 20% vs. 47% ± 21% and 28% ± 19% vs. 44% ± 19%, respectively; both P < 0.01).

Overall, the study suggests that “initial clopidogrel response in patients with ACS is not a reliable predictor of response to maintenance therapy, [since] a large proportion of nonresponders after the loading dose become responders on the chronic therapy,” the authors write. They add that this may be explained by the ACS setting or by the fact that the single loading dose of 600 mg of clopidogrel could not reach the steady state of platelet inhibition by 12 hours in unstable patients.

Overall, the findings highlight the importance of the timing of platelet testing in ACS patients when tailoring antiplatelet therapy, Dr. Cuisset and colleagues say, and suggest that delayed testing after discharge should be considered to adjust therapy as needed.

Similarities to GRAVITAS

In a telephone interview with TCTMD, Matthew J. Price, MD, of the Scripps Clinic (La Jolla, CA), said he did not necessarily agree with the authors’ conclusion.

He said the findings “are remarkably similar” to those of GRAVITAS, which looked at platelet reactivity using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) in stable or unstable CAD patients who had received DES. Patients were randomized to either a150-mg dose of maintenance clopidogrel or the standard 75-mg dose. At 6 months, rates of the primary endpoint (composite of cardiovascular death, nonfatal MI, or stent thrombosis) were similar in the 2 groups. However, overall cardiovascular mortality was lower in the 150-mg clopidogrel group.

Dr. Price, who was the principal investigator for GRAVITAS, said the new study confirms that about 45% of patients will be identified on standard platelet function tests as having high platelet reactivity and that high maintenance dose clopidogrel provides some incremental benefit, even though only a portion of patients will have an adequate response to it.

“But one challenge of this paper is that there is no control group on standard 75-mg dose of clopidogrel,” Dr. Price added. “So applicability to current practice, at least in the United States, is challenging because clinicians don’t routinely treat their patients with 150 mg.”

While that limitation makes it difficult to make a strong argument in support of serial platelet function testing, this study and others leave little doubt that the association between reactivity and outcomes is consistent whether reactivity is measured at baseline or 30 days, he said.

“With the advent of generic clopidogrel, the potential individual and social benefit of platelet function testing is even more profound,” Dr. Price observed. “We have newer antiplatelet agents that clearly are superior to clopidogrel but cost substantially more, and the penetration of these agents in the United States is very small. Then we have this wealth of data showing that patients who respond well to clopidogrel on platelet function testing do quite well and have a low risk of cardiovascular events even after ACS.

“The important thing is that we need to focus on improving our outcomes, and there are more and more data supporting the prognostic utility of platelet function testing,” he concluded.

 

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Source:
Cuisset T, Quilici J, Loosveld M, et al. Comparison between initial and chronic response to clopidogrel therapy after coronary stenting for acute coronary syndrome and influence on clinical outcomes. Am Heart J. 2012;Epub ahead of print.

 

 

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• GRAVITAS Published: No Benefit from High-Dose Clopidogrel in Poor Responders