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In many patients with stable coronary artery disease (CAD), platelet reactivity varies markedly over time despite an unchanged dose of clopidogrel, according to a subanalysis of the ELEVATE-TIMI 56 trial being published in the July 29, 2014, issue of the Journal of the American College of Cardiology.

The authors say such changes are often sufficient to shift a patient’s status from clopidogrel ‘nonresponder’ to ‘responder’ or vice versa. Thus, functional platelet testing at a single time point may be a faulty guide to therapy adjustment.

Platelet Function Varies Over Time for Some

Mean platelet reactivity as measured by both the VerifyNow and VASP assays did not differ between serial samplings on the 75-mg or 150-mg doses. Likewise, the proportion of nonresponders to clopidogrel (either PRU ≥ 230 or PRU ≥ 208) did not change between the treatment periods at the same clopidogrel dose (table 1).

Table 1. Platelet Function Testing by Treatment Period

Abbreviations: PRU, platelet reactivity units; PRI, platelet reactivity index.

In contrast, when patients were analyzed individually, 15.7% on a 75-mg dose had a change in responder status from 1 test to the next, whereas only 2.9% would have been expected to show such a shift had platelet function remained stable over that period. In fact, a change in responder status was seen in a significant proportion of patients irrespective of nonresponder definition or clopidogrel dose (P < .001 for each). 

Because even a minor change in reactivity could alter responder status, the authors say, data were also analyzed in a continuous fashion. This showed a similar shift in responder status in either direction, and over a variety of cutpoints, the number of patients with changes in reactivity was similar for both clopiodgrel doses. 

Diabetes and BMI were the only variables consistently associated with a change in platelet function over time across the assays and clopidogrel doses. 

‘Real-World’ Variability May Be Greater

The authors note that the variability in platelet reactivity was detected in the context of a carefully monitored trial setting and “would be expected to be even more pronounced in clinical practice.”

Factors that may contribute to variability, they speculate, include:

• Fluctuations in platelet production and expression of the P2Y12 receptor
• Changes in hepatic metabolism altering the level of clopidogrel bioactivation
• Unrecognized noncompliance
• Artifactual changes in measured reactivity due to biological or technical issues affecting the assays

In an accompanying editorial, Ori Ben-Yehuda, MD, of the Cardiovascular Research Foundation (CRF; New York, NY), points out both study strengths—rigorous assessment of platelet function and control for comorbidities—and limitations—the relatively short interval between platelet tests and weak correlations between the types of assays used.

Identifying high on-treatment platelet reactivity would be of critical clinical importance if it led to interventions that reduced the risk of stent thrombosis, he notes, but on the basis of at least 3 trials thus far (GRAVITAS, TRIGGER-PCI, and ARCTIC), the evidence is mixed. 

A key question is whether the temporal variability in platelet reactivity helps explain the trials’ largely negative results, Dr. Ben-Yehuda states. The most likely reasons for the failure of studies using baseline platelet reactivity assays are the low event rates and the modest incremental platelet inhibition achieved with increased clopidogrel doses, he says. “Yet any variability over time would be expected to reduce the power as well as the actual clinical efficacy of any intervention trial.”

“Further studies on [high platelet reactivity], whether observational or with a planned intervention (such as switching from clopidogrel to prasugrel or [ticagrelor]), should monitor platelet reactivity over time,” Dr. Ben-Yehuda concludes. 

Note: Dr. Ben-Yehuda is a faculty member of CRF, which owns and operates TCTMD, and serves as executive director of the CRF Clinical Trials Center.

Sources: 
1. Hochholzer W, Ruff CT, Mesa RA, et al. Variability of individual platelet reactivity over time in patients treated with clopidogrel: insights from the ELEVATE-TIMI 56 trial. J Am Coll Cardiol. 2014;64:361-368.

2. Ben-Yehuda O. The chronovariability of platelet reactivity: a hurdle in the road to personalized antiplatelet therapy [editorial]? J Am Coll Cardiol. 2014;64:369-371.

Disclosures:

• The ELEVATE-TIMI 56 trial was funded by an investigator-initiated grant from Bristol-Myers Squibb/Sanofi-Aventis.
• Dr. Mega reports receiving honoraria from American Genomics, Boehringer Ingelheim, and Janssen and research support from AstraZeneca, Bayer, Bristol-Meyers Squibb, Daiichi-Sankyo, Eli Lilly, Janssen, and Sanofi-Aventis.
• Dr. Ben-Yehuda reports no relevant conflicts of interest.

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