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: 35.29). 03/2011; 305(11):1097-105. DOI: 10.1001/jama.2011.290
Source: PubMed


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.

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Available from: Olivier F Bertrand
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    • "The consistent lack of correlation between platelet reactivity and thrombus area suggest that point of care measure of platelet reactivity does not reflect whole blood thrombogenicity which is a complex pathophysiology involving other factors in addition to platelets. Our results may in part explain the negative results of the GRAVITAS and ARCTIC studies using VerifyNow® [24,25]. "
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    ABSTRACT: Introduction Despite optimal secondary prevention therapy following non-ST elevation acute coronary syndrome (NSTE-ACS), recurrent thrombotic events are more frequent in patients with type 2 diabetes mellitus (T2DM). Materials and Methods This exploratory study was aimed to evaluate quantitative and qualitative aspects of thrombus. In 28 patients with and without T2DM treated with aspirin and clopidogrel we assessed thrombus quantity using an ex-vivo chamber, platelet reactivity, thrombus ultrastructure and thrombus kinetics one week after NSTE-ACS. Results T2DM was associated with increased thrombus [14861 (8003 to 30161) vs 8908 (6812 to 11996), μ2/mm, median (IQR), p = 0.045] and platelet reactivity. In addition, diabetic thrombus showed lower visco-elastic tensile strength [(− 0.2(− 1.7 to 0.7) vs 1.0(− 0.9 to 3.3), p = 0.044)] and was more resistant to autolysis [(27.8(11.7 to 70.7) vs 78.8(68.5 to109.6) mm/min, p = 0.002)]. On SEM, fibrin fibres in diabetes were thinner, with higher lateral interlinkage and mesh-like organisation. Thrombus quantity correlated inversely with thrombus retraction (r = − 0.450 p = 0.016) but not with platelet reactivity (r = 0.153, p = 0.544). Conclusions Despite optimal antiplatelet therapy, T2DM patients after NSTE-ACS developed increased thrombus of lower tensile strength and slower retraction. SEM revealed loosely arranged fibrin fibres. Our data showed significant differences in the magnitude as well as structural and mechanistic characteristics of thrombus in patients with T2DM.
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    • "The response unit test result may be favored over the calculated percent inhibition test result, though neither are substantially equivalent to LTA, especially at lower drug levels [White et al., 2004; Breet et al., 2010]. Although this POC test has been useful in demonstrating high levels of platelet inhibition, studies using the VerifyNow as a means for dose adjustment of P2Y 12 antagonists to reduce secondary events in CAD were not proven to be of added value [Price et al., 2011; Trenk et al., 2012]. This instrument is specifically designed to evaluate three antiplatelet drugs (aspirin, clopidogrel, or GPIIb-IIIa antagonists) individually. "
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    ABSTRACT: Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I-III Regulatory, Quality, ManufacturingPostmarketing Phase IV There is an increasing need for the standardization of platelet function and coagulation testing for the assessment of antithrombotic therapies. Investigators continue to strive to identify ideal laboratory testing and monitoring procedures for acquired and inherited platelet function defects as well as for evaluating patient status when treated with existing or emerging antithrombotics. These therapies are used primarily in the treatment of ischemic complications. In patients receiving antithrombotic therapy, the balance between hemostasis and thrombosis is a challenge as there is an ongoing risk for bleeding when patients are receiving antiplatelet agents or anticoagulants to lessen their risk for secondary thrombotic events. There are several diverse tests for monitoring anticoagulant therapy; however, as new agents are developed, more specific tests will be required to directly assess these agents in relationship to overall coagulation status. Research in the platelet biology field is ongoing to provide point-of-care methodologies for the assessment of platelet reactivity in terms of both bleeding and thrombosis risk. Currently there are no instruments that reliably assess the risk of bleeding. The challenges that routinely faced are the complexity of physiology, the need for standardization of platelet testing methodology, and the necessity for appropriate interpretation of the test results.
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    • "How to vanquish HTPR remains to be a challenge to cardiovascular researchers and physicians. Six RCTs with HTPR patients were included in this systemic review [29-31,33,34,37]. Subgroup analyses demonstrated that HTPRs obtained significant benefit of reduced recurrent ischemic events from high-maintenance-dose therapy and they did not present with more bleeding events. "
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