POPular Genetics: Using pharmacogenomics to guide antiplatelet management

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Claassens DMF, et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. NEJM 2019;381:1621-31.

Bottom line: Among STEMI patients undergoing primary PCI, CYP2C19 genotype-guided P2Y12 inhibitor selection (leading to targeted de-escalation to clopidogrel in 2/3 of patients) reduced the risk of minor bleeding by ~3% without increase thrombotic events over 1 year.

Patients (n=2751 randomized, n=2488 analyzed)

  • Included:

    • STEMI treated with primary PCI with stent

  • Excluded

    • Severe HTN (>180/110 mm Hg)

    • Cardiogenic shock (SBP ≤80 mm Hg for >30 min)

    • Active malignancy causing increased bleed risk (investigator’s opinion)

    • Dialysis-dependent CKD

  • Baseline

    • Age 61, female 25%

    • Prior coronary stent 8%, prior MI 7-8%

    • Prior bleed 2%

    • Current smoker 46%, HTN 42%, diabetes 11%, CrCl <60 9%

    • Treated vessel: LAD 43%, RCA 42%, bifurcation lesion ~20%

    • Drug-eluting stent in 94%

    • Total stent length 28 mm

Intervention: CYP2C19 genotype-guided P2Y12 inhibitor de-escalation x12 months

  • Assay: TaqMan StepOnePlus assay (central lab) or Spartan RX (point-of-care test) ASAP after randomization

  • Tested for CYP2C19*2 and CYP2C19*3 loss-of-function alleles

  • Genotype:

    • Extensive metabolizer (good clopidogrel response; *1/*1): 67%

    • Intermediate metabolizer (*1/*2 or *1/*3): 29%

    • Poor metabolizer (*2/*2, *2/*3 or *3/*3): 2-3%

    • Not done: 1.4%

  • Strategy:

    • If any *2 or *3: Ticagrelor or prasugrel

    • Neither (extensive metabolizer): Clopidogrel

  • Selected: Clopidogrel (61%), ticagrelor (38%), prasugrel (1%)

Comparator: Standard P2Y12 inhibitor selection x12 months

  • Selected: ticagrelor (91%), clopidogrel (7%), prasugrel (2%)

Internal Validity: Low risk of allocation & attrition bias; unclear risk of performance & detection bias

  • Computer-generated block randomization

  • Internet-based allocation

  • Open-label (patients, clinicians aware of allocation after randomization)

  • Blinded adjudication committee

  • Intention-to-treat (ITT) & per-protocol analyses (ITT for superiority, ITT+PP for non-inferiority)

  • 3 patients lost to follow-up

Outcomes @ 12 months

  • Composite

    • Definition: Death/MI/definite stent thrombosis/stroke/major bleeding (PLATO definition)

    • Genotype-guided: 5.1% vs control 5.9%

    • Hazard ratio (HR) 0.87 (95% confidence interval 0.62-1.21)

    • Absolute difference: -0.7% (-2.0% to 0.7%), meeting study’s non-inferiority criteria

  • Death: 1.5% in both groups (HR 1.00, 0.53-1.89)

  • MI: 1.5% vs 2.1% (HR 0.73, 0.41-1.32)

  • Definite stent thrombosis: 0.2% in both groups (HR 0.67, 0.11-4.01)

  • Stroke: 0.6% vs 0.9% (HR 0.73, 0.29-1.82)

  • Major or minor bleed: 9.8% vs 12.5% (HR 0.78, 0.61-0.98)

    • Major bleed: 2.3% in both groups (HR 0.97, 0.58-1.63)

    • Minor bleed: 7.6% vs 10.5% (HR 0.72, 0.55-0.94)

  • Dyspnea: Not compared between groups

Other Considerations

  • Comparator changed from clopidogrel to ticagrelor/prasugrel part-way through the trial; patients enrolled before this amendment excluded from analyses

  • Non-inferiority trial

    • Non-inferiority margin set as a 2% absolute risk increase for both primary outcomes (not well justified, large)

  • Unlike PHARMCLO, POPular Genetics did not test for CYP2C19*17 (ultra-fast metabolizer; increased clopidogrel efficacy), or ABCB 13435

Other Studies

  • Other studied de-escalation strategies include empiric de-escalation to clopidogrel after 1 month of potent P2Y12 inhibition, as well as platelet function testing-guided de-escalation

  • PHARMCLO

    • Patients: 888 ACS patients in Europe

      • Baseline:

        • Age 71, female 32%

        • STEMI 27%, NSTEMI 68%, UA 2%, no ACS 3%

        • Prior PCI 19%, prior MI 21%

        • Current smoker 22%, HTN 74%, diabetes 26%, CKD 9%

        • 96% underwent coronary angiography: 62% got PCI, 11% CABG

        • Treated vessel: LAD 54%, RCA 47%

        • Genotype (intervention group)

          • ABCB1 3435 mutation: 47%

          • CYP2C19*2 29%, *2/*2 4%

          • CYP2C19*17 31%, *17/*17 8%

    • Intervention: Genotype-guided P2Y12 inhibitor selection (immediately on ACS diagnosis) x12 months

      • Assay: ST Q3 (point-of-care test that takes ~70 min for result)

      • Tested for ABCB13435, CYP2C19*2, and CYP2C19*17 (increased clopidogrel efficacy)

      • Selected: Clopidogrel 43%, ticagrelor 43%, prasugrel 8%

    • Control: Standard P2Y12 inhibitor selection x12 months

      • Selected: Clopidogrel 51%, ticagrelor 33%, prasugrel 8%

    • Outcomes:

      • Composite (CV death, MI, stroke, major bleed (BARC 3-5): 15.9% vs 25.9% (HR 0.58, 0.43-0.78)

      • CV death/MI/stroke: 12.9% vs 21.4% (HR 0.57, 0.41-0.80)

      • Major bleed: 4.2% vs 6.8% (HR 0.62, 0.35-1.11)

    • Caveats:

      • Stopped prematurely 1/4 of the way through by ethics committee as genotyping assay not previously certified; therefore, the observed benefit of genotype-guided intervention is likely a large overestimate