GRAVITAS Analysis: Lower Cutpoint May Enhance Functional Platelet Testing

PARIS, France—Using a lower degree of platelet aggregation to differentiate which patients are at risk for adverse events on clopidogrel could help bolster the prognostic value of platelet function tests. The late breaking results, announced Monday, August 29, at the European Society of Cardiology Congress 2011, might better enable clinicians to individually tailor antiplatelet therapy.

Matthew J. Price, MD, of the Scripps Clinic (La Jolla, CA), presented findings from a new analysis of the GRAVITAS (Gauging Responsiveness With A VerifyNow Assay-Impact On Thrombosis And Safety) trial that also were simultaneously published online ahead of print in Circulation.

GRAVITAS, originally published in March 2011 in the Journal of the American Medical Association, tested the ability of high-dose clopidogrel therapy to overcome high on-treatment platelet reactivity, defined as a P2Y12 reactivity unit (PRU) value of at least 230 on the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). Using this cutpoint, 2,214 of 5,429 stable or unstable CAD patients enrolled in the trial were considered to have high residual platelet reactivity. Among them, high-dose clopidogrel (600-mg initial dose and 150 mg daily thereafter) did not reduce the primary composite of CV death, nonfatal MI, or stent thrombosis at 6 months compared with standard clopidogrel (no additional loading dose and 75 mg daily thereafter).

For the post hoc analysis, Dr. Price and colleagues examined how setting a lower threshold—208 PRU—would affect adverse event risk.

On-Treatment Reactivity Linked to Event Risk

A total of 2,796 patients enrolled in GRAVITAS had evaluable platelet function data and complete follow-up. At 12 to 24 hours after PCI, high on-treatment reactivity was identified in 82.1% of patients in both treatment arms. By 30-day follow-up, this proportion had dropped to 54.7%.

Notably, fewer than half of the patients randomly assigned to high-dose clopidogrel (48.4%) achieved PRU less than 208 at 30 days.

Patients who had PRU less than 208 were at significantly lower risk of suffering the GRAVITAS primary endpoint at both 60 days (HR 0.18; 95% CI 0.04-0.79; P = 0.02) and 6 months (HR 0.43; 95% CI 0.23-0.82; P = 0.01). In comparison, the 230 PRU cutoff proved far less effective at predicting risk at either time point, whether 60 days (HR 0.62; 95% CI 0.25-1.51; P = 0.30) or 6 months (HR 0.71; 95% CI 0.41-1.23; P = 0.22).

“The association between a reduced risk of cardiovascular outcomes with PRU less than 208 persisted even after adjustments for other predictors of outcome, such as clinical presentation with acute coronary syndrome, diabetes, and stent length,” as well as prior MI, Dr. Price explained. Several factors related to heightened or reduced risk of 6-month adverse events were found (table 1).

Table 1. Multivariable Analysis: Risk Factors for Primary Endpoint at 6 Months


Adjusted HR

95% CI

P Value

On-Treatment Reactivity < 208 PRU








ACS Presentation




Prior MI




Prior CABG




“There may have been a host of reasons some patients had greater reactivity, including clinical factors, and genetics,” Dr. Price said. “But we show here that platelet reactivity is a predictor independent of clinical and procedural characteristics.”

Importantly, the GRAVITAS subanalysis “supports the prognostic utility of serial platelet function testing [and] provides further support for the ESC 2011 and ACCF/AHA 2011 guideline recommendations,” he concluded.

But the finding that fewer than half of the patients randomly assigned to high-dose clopidogrel met the 208 PRU cutoff “supports the hypothesis that an insufficient pharmacodynamic response may have contributed to the lack of observed clinical effect” in the overall trial, he noted. Thus, “alternative individualized strategies to improve patient outcomes after PCI merit further consideration.”


Price MJ, Angiolillo DJ, Teirstein PS, et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: A time-dependent analysis of the Gauging Responsiveness With a VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation. 2011;Epub ahead of print.



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  • GRAVITAS was funded by Accumetrics. The study drug was provided by an investigator-initiated grant from Bristol-Myers Squibb/Sanofi-Aventis.
  • Dr. Price reports receiving consulting fees from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, Daiichi Sankyo/Eli Lilly, and Medicure; speaker fees from Daiichi Sankyo/Eli Lilly; and grant support from Bristol-Myers Squibb/Sanofi-Aventis.

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