Gauging Responsiveness with A VerifyNow Assay—Impact on Thrombosis And Safety - GRAVITAS

Description:

The goal of the trial was to evaluate treatment with an additional loading dose and higher maintenance dose of clopidogrel compared with no additional loading dose and standard maintenance dose of clopidogrel among patients with high residual platelet activity after percutaneous coronary intervention (PCI).

Hypothesis:

An additional loading dose and higher maintenance dose of clopidogrel will be more effective at preventing cardiovascular outcomes.

Study Design

  • Blinded
  • Parallel
  • Randomized
  • Placebo Controlled

Patient Populations:

  • Patients undergoing PCI with a drug-eluting stent for stable or unstable coronary syndromes
  • Trial was amended to include patients with ST-elevation myocardial infarction

    Number of screened applicants: 5,429
    Number of enrollees: 2,214
    Duration of follow-up: 6 months
    Mean patient age: 64 years
    Percentage female: 35%

Exclusions:

  • Bleeding event prior to platelet function testing
  • Recent use of a glycoprotein IIb/IIIa inhibitor
  • Planned use of anticoagulation therapy

Primary Endpoints:

  • Composite of cardiovascular death, myocardial infarction, or stent thrombosis at 6 months

Secondary Endpoints:

  • GUSTO moderate or severe bleeding
  • Rate of persistently high on-treatment reactivity at 30 days

Drug/Procedures Used:

Patients with high residual platelet activity 12-24 hours after PCI with drug-eluting stents were randomized to clopidogrel 600 mg post-PCI, then 150 mg daily (n = 1,109) versus no additional loading dose and 75 mg daily (n = 1,105).

Platelet activity was assessed by the VerifyNow P2Y12 test (Accumetrics, San Diego, CA) 12-24 hours after PCI. High residual platelet activity was defined as a platelet reactivity unit ≥230.

Concomitant Medications:

All patients received aspirin 81-162 mg daily.

Principal Findings:

Overall, 2,214 patients were randomized. In the high-clopidogrel dose group, the mean age was 64 years, 35% were women, 44% had diabetes, 60% had stable angina, and total stent length was 30 mm. 53% of patients had received a 600 mg loading dose of clopidogrel at least 2 hours before enrollment and 39% had received 75 mg daily for at least 7 days. The use of bivalirudin was 63% and unfractionated heparin was 39%. At 30 days, persistently high platelet reactivity was present in 40% of the high-clopidogrel dose group versus 62% of the standard-dose group (p < 0.001).

At 6 months, the primary outcome of cardiovascular death, myocardial infarction, or stent thrombosis occurred in 2.3% of the high-clopidogrel dose group versus 2.3% of the standard-dose group (p = 0.97). Cardiovascular death was 0.3% versus 0.7% (p = 0.14), nonfatal myocardial infarction was 1.8% versus 1.6% (p = 0.72), and stent thrombosis was 0.5% versus 0.7% (p = 0.42), respectively. The primary outcome was compared among patients with high platelet reactivity treated with standard-dose clopidogrel versus screened/nonrandomized patients who had low platelet reactivity: 2.3% versus 1.4% (p = 0.20).

At 6 months, GUSTO moderate or severe bleeding occurred in 1.4% versus 2.3% (p = 0.10), whereas any GUSTO bleeding occurred in 12% versus 10.2% (p = 0.18), respectively.

Interpretation:

Among patients with high residual platelet reactivity after PCI with drug-eluting stents, treatment with high-dose clopidogrel was not beneficial. An extra loading dose and higher maintenance dose clopidogrel for 6 months did not reduce the primary ischemic outcome; nor did it increase GUSTO moderate or severe bleeding. At the present time, routine testing of platelet reactivity after PCI is not warranted. It is unknown if a more potent antiplatelet agent (for example, prasugrel or ticagrelor) would have achieved different results.

References:

Price MJ, Berger PB, Teirstein PS, et al., on behalf of the GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: The GRAVITAS randomized trial. JAMA 2011;305:1097-1105.

Presented by Dr. Matthew Price at the American Heart Association Scientific Sessions, Chicago, IL, November 16, 2010.

Clinical Topics: Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Chronic Angina

Keywords: Myocardial Infarction, Platelet Aggregation Inhibitors, Angina, Stable, Thrombosis, Drug-Eluting Stents, Thiophenes, Heparin, Ticlopidine, Blood Platelets, Piperazines, Diabetes Mellitus, Percutaneous Coronary Intervention


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