Pharmacogenetics of Clopidogrel in Patients With Acute Coronary Syndromes - PHARMCLO

Contribution To Literature:

The PHARMCLO trial showed that use of point-of-care genotype testing for identifying intermediate or poor clopidogrel metabolizers influenced providers’ choice of P2Y12 inhibitor post-PCI and resulted in fewer ischemic and bleeding events.

Description:

The goal of the trial was to assess the impact of point-of-care genotyping on clinical outcomes following percutaneous coronary intervention (PCI).  

Study Design

Patients presenting with acute coronary syndrome (ACS) were randomized to genotying-based P2Y12 inhibitor use (n = 448) or usual care (n = 440). The patients assigned to the strategy that included genotyping underwent genetic testing for ABCB1 3435 (7q21.1; rs1045642), CYP2C19*2 (10q24.1-q24.3; rs4244285), and CYP2C19*17 (10q24.1-q24.3; rs12248560).

  • Total number of enrollees: 888
  • Duration of follow-up: 48 months
  • Mean patient age: 70.4 years
  • Percentage female: 33%

Inclusion criteria:

  • European ancestry
  • Hospitalized because of  ST-segment elevation or non-ST-segment elevation ACS

Exclusion criteria:

  • An inability to provide informed consent or follow study procedures
  • Any contraindication to the use of P2Y12 receptor antagonists
  • Life expectancy of <1 year
  • Thrombolytic therapy within the previous 24 hours
  • Enrollment in another randomized trial or observational registry
  • Prior knowledge of the patients’ ABCB1, CYP2C19*2, or CYP2C19*17 genotype

Other salient features/characteristics:

  • ST-segment elevation myocardial infarction (STEMI): 26%
  • PCI: 62.4%, coronary artery bypass grafting: 11%
  • ABCB1 3435 allele: 47.1% heterozygous, 26.4% homozygous
  • CYP2C19*2: 29.2% heterozygous, 4.3% homozygous
  • CYP2C19*17: 31.3% heterozygous, 7.8% homozygous
  • Pharmacogenomic vs. usual care: clopidogrel 43.3% vs. 50.7%, prasugrel 7.6% vs. 8.4%, ticagrelor 42.6% vs. 32.7% (p = 0.02)

Principal Findings:

The trial was terminated early by which time <25% of estimated sample size had been enrolled. The primary outcome, composite of cardiovascular death, MI, stroke, Bleeding Academic Research Consortium (BARC) 3-5 major bleeding at 12 months, for pharmacogenomic vs. usual care, was 15.9% vs. 25.9% (hazard ratio 0.58, 95% confidence interval 0.43-0.78, p < 0.001).

  • Cardiovascular death: 6.3% vs. 7.7%
  • Major bleeding: 3.8% vs. 5.9%

Secondary outcomes:

  • Stent thrombosis: 3 vs. 5

Among clopidogrel-treated patients, major adverse cardiac events were 24.7% vs. 35.4% (p = 0.03).

Interpretation:

The results of this trial indicate that the use of point-of-care genotype testing for identifying intermediate or poor clopidogrel metabolizers influenced providers’ choice of P2Y12 inhibitor post-PCI and resulted in fewer ischemic and bleeding events.

In the ADAPT trial, knowledge of genotype was similarly able to influence prescription patterns. The magnitude of benefit in the current trial seems larger than expected, particularly when considering that the trial was terminated with <25% of its planned enrollment and differences in clopidogrel use between the two arms were comparatively small. Trials on tailoring antiplatelet therapy based on platelet function testing have been negative. These results are interesting, and will need to be replicated in other larger trials before they can influence clinical practice. It is also important to assess this strategy in patients with different racial and ethnic backgrounds.

References:

Notarangeloa FM, Magliettab G, Bevilacquaa P, et al. Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Acute Coronary Syndromes: PHARMCLO Trial. J Am Coll Cardiol 2018;Mar 11:[Epub ahead of print].

Presented by Dr. Diego Ardissino at the American College of Cardiology Annual Scientific Session (ACC 2018), Orlando, FL, March 11, 2018.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Invasive Cardiovascular Angiography and Intervention, EP Basic Science, Interventions and ACS

Keywords: ACC18, ACC Annual Scientific Session, Acute Coronary Syndrome, Adenosine, Blood Platelets, Genetic Testing, Genotype, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Pharmacogenetics, Platelet Function Tests, Point-of-Care Systems, Purinergic P2Y Receptor Antagonists, Stents, Stroke, Thrombolytic Therapy, Thrombosis


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