Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting - ARCTIC

Description:

The goal of the trial was to evaluate a strategy of platelet function monitoring and antiplatelet dose adjustments as necessary compared with no monitoring among patients undergoing drug-eluting stent implantation.

Hypothesis:

Platelet function monitoring will improve adverse outcomes.

Study Design

  • Randomized
  • Parallel

Patient Populations:

  • Patients undergoing drug-eluting stent implantation

    Number of enrollees: 2,440
    Duration of follow-up: 1 year
    Mean patient age: 63 years
    Percentage female: 20%

Exclusions:

  • ST-segment elevation myocardial infarction
  • Planned use of glycoprotein IIb/IIIa inhibitor
  • Long-term need for anticoagulation therapy
  • Bleeding problem

Primary Endpoints:

  • Composite of death, myocardial infarction, stroke/TIA, stent thrombosis, or urgent revascularization

Secondary Endpoints:

  • Composite of stent thrombosis or urgent revascularization
  • Major bleeding (STEEPLE criteria)

Drug/Procedures Used:

Patients undergoing drug-eluting stent implantation were randomized to a strategy of platelet function monitoring with antiplatelet dose adjustments as necessary (n = 1,213) versus usual care without monitoring or drug adjustments (n = 1,227).

Randomization was performed after coronary angiography, but before stent implantation. Platelet function was assessed with the VerifyNow P2Y12 and aspirin point of care assays. High-reactivity to aspirin was defined as >550 aspirin reaction units and high-reactivity to clopidogrel was defined as >235 platelet reaction units.

High-reactivity to aspirin resulted in administration of intravenous aspirin, while high-reactivity to clopidogrel resulted in administration of a glycoprotein IIb/IIIa inhibitor during the procedure and an additional load of clopidogrel (≥600 mg) or prasugrel. Clopidogrel 150 mg daily or prasugrel 10 mg daily was used as maintenance therapy.

Concomitant Medications:

At the time of randomization, the use of angiotensin-converting enzyme inhibitor was 54%, beta-blocker 60%, and statin 68%.

Principal Findings:

Overall, 2,440 patients were randomized. The median age was 63 years, 20% were women, median body mass was 78 kg, 37% had diabetes, and 31% had a prior myocardial infarction. Clopidogrel was given before randomization in 90% of patients.

In the monitoring group, 35% of patients had high platelet reactivity to clopidogrel and 7.6% had high platelet reactivity to aspirin. Glycoprotein IIb/IIIa inhibitors were used in 30% of the monitoring group versus 6.1% of the usual care group (p < 0.001). At the last visit, 80% of the monitoring group was treated with clopidogrel versus 86% of the usual care group (p < 0.001), and 12% was treated with prasugrel versus 6.1% (p < 0.001), respectively.

At 1 year, the primary outcome of death, myocardial infarction, stroke, stent thrombosis, or urgent revascularization occurred in 34.6% of the monitoring group versus 31.1% of the usual care group (p = 0.10).

- Death or myocardial infarction: 31.7% versus 28.8% (p = 0.15), respectively
- Stent thrombosis: 1.0% versus 0.7% (p = 0.51), respectively
- Stroke/transient ischemic attack (TIA): 0.7% versus 0.6% (p = 0.78), respectively
- Major bleeding: 2.3% versus 3.3% (p = 0.15), respectively
- Major or minor bleeding: 3.1% versus 4.5% (p = 0.08), respectively

ARCTIC-GENE trial: Genetic analysis was performed in 1,394 patients and used to stratify into poor metabolizers and rapid metabolizers. In the poor metabolizer group, 40.3% had high on-treatment platelet reactivity compared with 30.9% in the rapid metabolizer group (p = 0.015). Among slow metabolizers, 50% had an increase in clopidogrel dosing at day 14, while 11.5% were on prasugrel at the last visit. Among rapid metabolizers, 39.1% had an increase in clopidogrel dosing at day 14, while 8.1% were on prasugrel at the last visit.

The composite endpoint of death, myocardial infarction, stent thrombosis, stroke/TIA, or urgent revascularization occurred in 32.7% of the poor metabolizer group vs. 32.2% of the rapid metabolizer group (p = 0.90). Major bleeding: 3.1% versus 2.2% (p = 0.38), respectively for poor versus rapid metabolizers.

Interpretation:

 Among a relatively high-risk cohort of patients undergoing drug-eluting stent implantation, a strategy to monitor platelet reactivity or genetic analysis to guide antiplatelet dosing failed to improve clinical outcomes. As a result of monitoring for platelet reactivity, fivefold more patients were treated with maintenance prasugrel therapy. Despite numerous studies documenting the adverse association of high platelet reactivity, individualized antiplatelet therapy has been unable to improve outcomes. Platelet reactivity may not be the best marker to guide therapeutic decisions.

References:

ARCTIC-GENE: Presented by Dr. Jean-Philippe Collet at the European Society of Cardiology Congress, Amsterdam, Holland, September 4, 2013.

Collet JP, Cuisset T, Range G, et al., on behalf of the ARCTIC Investigators. Bedside monitoring to adjust anti-platelet therapy for coronary stenting. N Engl J Med 2012;367:2100-2109.

Presented by Dr. Gilles Montalescot at the American Heart Association Scientific Sessions, Los Angeles, CA, November 4, 2012.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Myocardial Infarction, Stroke, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Platelet Function Tests, Drug-Eluting Stents, Thiophenes, Ticlopidine, Piperazines, Purinergic P2Y Receptor Antagonists, Coronary Angiography, Thrombosis, Diabetes Mellitus


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