JACC: Does platelet testing have future in clinical practice?
Platelet reactivity found around the time of a PCI procedure was linked to long-term cardiovascular events including death, MI and stent thrombosis, according to a meta-analysis published in the Nov. 1 issue of the Journal of the American College of Cardiology. In an accompanying editorial, researchers questioned whether platelet function testing will someday be a part of routine clinical practice.

“Dual antiplatelet therapy with aspirin and a thienopyridine is essential after percutaneous coronary intervention (PCI) with stent implantation," Somjot S. Brar, MD, MHP, of Kaiser Permanente, Los Angeles, and colleagues wrote. “However, significant interindividual variability exists in clopidogrel induced inhibition of platelet activation through the P2Y12 pathway.”

To better understand platelet reactivity of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) treatment on adverse cardiovascular events, Brar et al conducted a meta-analysis to evaluate the VerifyNow P2Y12 assay (Accumetrics). The researchers searched MEDLINE, Scopus and Cochrane databases through January 2010 and selected six studies that included a total of 3,059 patients for review.

The researchers used a composite of death, MI or stent thrombosis as the study’s primary outcome. For each study, the researchers assessed clopidogrel responsiveness using the point-of-care assay post-PCI.

The patients in the cohort had an average age of 66 years; 68 percent were male; 24 percent were diabetic; 74 percent had hypertension; 64 percent had dyslipidemia and 20 percent were smokers. The mean platelet reactivity of the cohort was 196.5 P2Y12 reaction units.

The researchers reported that primary endpoints occurred more frequently in higher quartiles of P2Y12 reaction units: 5.8 percent in quartile I, 6.9 percent in quartile II, 10.9 percent in quartile III and 15.8 percent in quartile IV. Quartile I represented patients with the lowest on-treatment platelet reactivity,
whereas quartile IV represented patients with the highest on-treatment platelet reactivity.

The authors reported that event rates in quartiles III and IV were significantly greater compared to quartile I. Additionally, a 4 percent increase in the primary endpoint was reported for every 10-unit increase in P2Y12 reaction units. The highest rate of death occurred in quartile IV.

“[O]ur observations support a threshold effect for the relationship between on-treatment reactivity and ischemic events after PCI,” the authors wrote. “We identified a potential cut-off value of a PRU [P2Y12 reaction units] greater than 230 for high on-treatment platelet reactivity and the composite endpoint of death, MI, or stent thrombosis after PCI using receiver operator characteristics curve analysis.”

When the cutoff of 230 P2Y12 reaction units were used, the researchers saw a higher rate of stent thrombosis in patients with higher on-treatment platelet reactivity.

“The results of this study show that high on-treatment platelet reactivity around the time of PCI is associated with long-term cardiovascular events including death, MI, and stent thrombosis,” the authors wrote. Also, using the P2Y12 point-of-care assay, a PRU value of greater than 230 was associated with higher rates of death, MI, or stent thrombosis.”

The authors concluded that future trials are necessary to investigate the role of oral antiplatelet therapy guided by P2Y12 reactivity testing.

In an accompanying editorial, Stephen D. Wiviott, MD, and Willibald Hochholzer, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany, respectively, wrote that while clopidogrel has often been shown to reduce cardiovascular events in patients with acute coronary syndromes (ACS), patients with high residual platelet reactivity on clopidogrel may be at risk for stent thrombosis and other CV complications.

“The efficacy of such treatment is influenced by the large interindividual variability in the pharmacodynamic response to clopidogrel," Wiviott and Hochholzer wrote.

While platelet function testing may help reduce these risks, putting these types of tests in clinical practice would have limitations. For example, most data on platelet testing are single center experiences, making it difficult to generalize data outcomes. Additionally, some of the assays used in clinical trials are not widely available, which makes it more difficult to make platelet testing widely adopted.

“The widespread adoption of platelet function testing as part of clinical practice would certainly be hastened by demonstrating that therapies cannot only alter this factor but also improve clinical outcome,” Wiviott and Hochholzer wrote.

“Nearly every paper about the relationship between platelet function testing and clinical outcomes—and every editorial written about such papers—concludes with a remark that the gap needs to be bridged between treatments that inhibit P2Y12 receptors (the therapy) and platelet function tests (the risk marker) and clinical outcomes.”

Wiviott and Hochholzer added, “As similar economic pressures arise when clopidogrel becomes generic compared to newer branded therapies, will we be pushed by payors, or choose in balancing cost, to perform a similar leap of faith?”

The editorialists suggested that further studies be conducted to address the gap between platelet function and clinical outcomes.

“We believe that future economic pressures may force an increase in the use of platelet function testing without the highest level of direct evidence,” Wiviott and Hochholzer concluded.