Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial.

Scripps Clinic, La Jolla, California, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 29.98). 03/2011; 305(11):1097-105.
Source: PubMed

ABSTRACT High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined.
To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI.
Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010.
High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months.
The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days.
At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001).
Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. Identifier: NCT00645918.

  • Circulation Cardiovascular Quality and Outcomes 01/2015; · 5.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies have reported a considerable association between the VerifyNow (Accumetrics, San Diego, CA, USA) P2Y12 assay results and hematocrit. No reports, however, have described an association between the multiple electrode platelet aggregometry (MEA; Dynabyte, Munich, Germany) adenosine diphosphate (ADP) assay results and hematocrit. This study was conducted to evaluate the influence of hematocrit on the results of 2 different point-of-care platelet function tests. A total of 462 consecutive patients who were undergoing percutaneous coronary intervention were enrolled. Platelet function was evaluated with both the VerifyNow P2Y12 and MEA ADP assays. Anemic patients (n = 152, 32.9%) demonstrated a significantly higher rate of cardiac death, myocardial infarction, and stroke (5.3% vs. 2.3%, p = 0.046) during the follow-up (median: 18.8 months). Although the VerifyNow P2Y12 assay results demonstrated a significant inverse correlation with hematocrit (r = -0.409, p<0.001), there was no such correlation between the MEA ADP assay results and hematocrit (r = 0.039, p = 0.401). In the multivariate analysis, anemia was an independent predictor of high on-treatment platelet reactivity, defined as a VerifyNow P2Y12 reaction unit level of ≥252.5 (odds ratio = 2.21, 95% confidence interval = 1.39-3.52; p = 0.001). Importantly, this association was independent of an intrinsic change in platelet reactivity as measured by the MEA ADP assay. Adjusting for the influence of hematocrit improved the strength of the correlation between the VerifyNow P2Y12 and MEA ADP assay results. Hematocrit significantly influenced the VerifyNow P2Y12 assay results, a phenomenon that was presumably in-vitro. Hematocrit level should therefore be considered when interpreting results of the VerifyNow P2Y12 assay.
    PLoS ONE 11/2014; 9(11):e114053. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective. Negative results of recent randomized clinical trials testing the hypothesis of target therapy for patients with high on-treatment platelet reactivity (HOPR) have questioned its independent impact on clinical outcomes. 26 studies with 28.178 patients were included, with a median age of 66.8 (64-68) and 22.7% (22.4-27.8), of female gender. After a median follow-up of 1 year (0.1-1), cardiac adverse events occurred in 8.3% (3-11; all results are reported as median and interquartile range) of patients. Pooling all studies together, on-treatment platelet reactivity significantly increased the risk of adverse events (OR 1.33 [1.09, 1.64], I (2) = 0%). However, a sensitivity analysis showed that HOPR did not increase the risk of adverse events for patients with ACS, AMI, or stable angina as well as patients resistant to aspirin, ADP antagonists, or both. For all studies, publication bias was formally evident; after adjusting for this, HOPR did not significantly increase adverse cardiac events (OR 1.1 : 0.89-1.22, I (2) 0%). Conclusions. After adjusting for clinical confounders (like risk factors and clinical presentation) and for relevant publication bias, HOPR was not an independent prognostic indicator in unselected patients with both stable and unstable coronary disease for an adverse cardiac event. The clinical importance of HOPR for high-risk populations remains to be assessed.
    BioMed Research International 01/2014; 2014:610296. · 2.71 Impact Factor

Full-text (2 Sources)

Available from
Jun 3, 2014