POPular Genetics: Using pharmacogenomics to guide antiplatelet management
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
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