PPAR-α genetic variants influence on-treatment platelet reactivity in patients treated with clopidogrel and lipid-lowering drugs and undergoing non-urgent percutaneous coronary intervention with stent implantation

Background: Response to clopidogrel varies between patients, due to many factors, like polymorphisms in genes encoding for metabolizing enzymes. The CYP3A4∗22 polymorphism has been proven to decrease the expression of CYP3A4, while the PPAR-α genetic variants G209A and A208G have been identified as determinants that affect CYP3A4. Statins and fibrates, which are the ligands of PPAR-α as well as being metabolized by CYP3A4, might also affect the response of clopidogrel through these two proteins. Objectives: To investigate the association between on-treatment platelet reactivity and the CYP3A4∗22 allele and genetic variations of the PPAR-α genes in clopidogrel-treated patients undergoing non-urgent percutaneous coronary intervention (PCI) with stenting and to evaluate the influence of statin/fibrate co-medication on these associations. Methods: A total of 1126 patients with non-urgent PCI and stenting pre-treated with clopidogrel and aspirin were genotyped for CYP3A4∗22 and PPAR-α (G209A and A208G). Platelet reactivity was measured using the VerifyNow® P2Y12-assay, expressed in PRU. Multivariate linear regression analysis was used to assess the association between the genetic variants and platelet reactivity, adjusted for confounders, including the CYP2C19 metabolizer status. A stratified analysis was conducted for patients with statin/fibrate co-medication. A recessive model was used for all associations. Results: The CYP3A4∗22/∗22 genotype was present in 0.4% of patients, 6.8% had the PPAR-α G209A AA genotype, and 7.0% had the PPAR-α A208G GG genotype. CYP3A4∗22 was not associated with platelet reactivity. PPAR-α genetic variants were significantly associated with platelet reactivity (PPAR-α G209A AA: -23.87 PRU [-43.54, -4.19]; PPAR-α A208G GG: -23.70 PRU [-43.13, -4.27]). In patients who were on statin/fibrate co-medication, these PPAR-α genetic variants were associated with an even lower platelet reactivity (-29.74 PRU [-50.94, -8.54], and -29.38 PRU [-50.26, -8.49], respectively), while those without statin/fibrate co-medication did not show a significant change in platelet reactivity (13.00 PRU [-39.79, 65.80]). Conclusions: Two genetic variants in PPAR-α (G209A and A208G) were associated with lower platelet reactivity in patients with non-urgent PCI and stenting co-treated with clopidogrel and lipid-lowering drugs

Efficacy and safety of glycoprotein IIb/IIIa inhibitors in addition to P2Y12 inhibitors in ST-segment elevation myocardial infarction: A subanalysis of the POPular Genetics trial

Background: Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. Methods: GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. Results: In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09–0.55) and MIs (HR 0.24, 95% CI 0.08–0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27–3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43–3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19–2.57). In the PSM analysis, no significant association was found. Conclusion: In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations

Efficacy and safety of glycoprotein IIb/IIIa inhibitors in addition to P2Y(12) inhibitors in ST-segment elevation myocardial infarction:A subanalysis of the POPular Genetics trial

Background: Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. Methods: GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. Results: In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09–0.55) and MIs (HR 0.24, 95% CI 0.08–0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27–3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43–3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19–2.57). In the PSM analysis, no significant association was found. Conclusion: In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations

Effect of CYP3A4*22 and PPAR-α genetic variants on platelet reactivity in patients treated with clopidogrel and lipid-lowering drugs undergoing elective percutaneous coronary intervention

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016; A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings

Effect of CYP3A4*22 and PPAR-α genetic variants on platelet reactivity in patients treated with clopidogrel and lipid-lowering drugs undergoing elective percutaneous coronary intervention

This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016; A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings

Clopidogrel Versus Ticagrelor or Prasugrel after Primary Percutaneous Coronary Intervention According to CYP2C19 Genotype: A POPular Genetics Subanalysis

Background: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype-guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y12 inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate. Methods: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19∗2, ∗3, and ∗17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19∗17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel-treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months. Results: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19∗17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45-2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48-1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56-0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68-1.90]). Conclusions: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19∗17 polymorphism

A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI

BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y 12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y 12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y 12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.)

A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI

BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y 12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y 12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y 12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.)

Clopidogrel Versus Ticagrelor or Prasugrel After Primary Percutaneous Coronary Intervention According to CYP2C19 Genotype:A POPular Genetics Subanalysis

BACKGROUND: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype-guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y(12) inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate. METHODS: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19*2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19*17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel-treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months. RESULTS: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19*17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45-2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48-1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56-0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68-1.90]). CONCLUSIONS: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19*17 polymorphism. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/; Unique identifier: NL2872. GRAPHIC ABSTRACT: A graphic abstract is available for this article