Risk of major adverse cardiovascular events for concomitant use of clopidogrel and proton pump inhibitors in patients inheriting CYP2C19 loss-of-function alleles: meta-analysis.

Background Efficacy of clopidogrel may be diminished due to either co-administration of proton pump inhibitors or carrying CYP2C19 loss-of-function alleles. However, patients may be at greater risk of major adverse cardiovascular events if taking clopidogrel together with proton pump inhibitors and also inherited the CYP2C19 loss-of-function alleles which may cause further reduction of clopidogrel efficacy. This is due to the cumulative effects of drug-drug interactions and drug-gene interactions collectively referred to as multifactorial drug-gene interactions. Aim of the review The aim of this analysis was to estimate aggregated risk of major adverse cardiovascular events for either coronary heart disease or stroke patients with multifactorial drug-gene interactions versus clopidogrel alone with or without drug-gene interactions. Methods Literatures were searched using different resources based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using RevMan software following either fixed/random effects model based on the levels of heterogeneity. A p value < 0.05 (2-sided) was considered statistically significant. Results In total, five studies consisting 8,802 patients of coronary artery diseases or stroke were included in this meta-analysis in which 3,767 were prescribed clopidogrel alone, 1,931 were concomitantly taking clopidogrel and PPIs, 2,146 were carrying CYP2C19 loss-of-function alleles and 958 were taking both clopidogrel and proton pump inhibitors while also carrying CYP2C19 loss-of-function alleles. It was found that patients with multifactorial drug-gene interactions were associated with significantly increased risk of major adverse cardiovascular events compared to those taking clopidogrel alone without CYP2C19 loss-of-function alleles (12% vs. 5.8%; RR 1.73; 95% CI 1.12-2.67; p = 0.01). Patients with multifactorial drug-gene interactions were also associated with significantly increased risk of major adverse cardiovascular events compared to drug-gene interactions (RR 1.63; 95% CI 1.31-2.03; p < 0.0001). Patients taking clopidogrel with proton pump inhibitors were also associated with 35% significantly increased risk of major adverse cardiovascular events compared to those taking only clopidogrel (RR 1.35; 95% CI 1.11-1.65; p = 0.003). Conclusion Patients inheriting CYP2C19 loss-of-function alleles have significantly increased risk of major adverse cardiovascular events when taking clopidogrel and proton pump inhibitors concurrently.

Risk of major adverse cardiovascular events of CYP2C19 loss-of-function genotype guided prasugrel/ticagrelor vs clopidogrel therapy for acute coronary syndrome patients undergoing percutaneous coronary intervention: a meta-analysis.

The most effective antiplatelet treatments for acute coronary syndrome (ACS) patients carrying CYP2C19 loss-of-function (LoF) alleles undergoing percutaneous coronary intervention (PCI) is still debating and conflicting. It was aimed to compare the efficacy and safety endpoints for these patients treated with alternative P2Y12 receptor blockers (e.g. prasugrel or ticagrelor) against clopidogrel. Literature was searched in PubMed, Cochrane library, Synapse and 1000 Genomes databases following PRISMA guidelines for identifying relevant studies. Aggregated risk was estimated by RevMan software using either fixed/random-effects models where P values<0.05 (two-sided) were considered statistically significant. Nine studies comprising 16,132 ACS patients undergoing PCI were included in this analysis in which 2,746 and 2,640 patients were in the CYP2C19 LoF clopidogrel and alternatives treatment group, respectively. It was demonstrated that patients treated with prasugrel or ticagrelor significantly reduced the risk of MACEs (RR 0.58; 95% CI 0.45-0.76; P<0.0001) as compared to patients with clopidogrel where both groups carrying CYP2C19 LoF alleles. Subgroup analysis showed that prasugrel or ticagrelor significantly reduced the risk of cardiovascular death (RR 0.44; 95% CI: 0.25-0.74; P=0.002) and MI (RR 0.60; 95% CI: 0.44-0.81; P=0.0008) while other clinical outcomes were not found statistically significant between these two groups; stroke (RR 0.77; 95% CI: 0.43-1.38; P =0.39), stent thrombosis (RR 0.67; 95% CI: 0.38-1.18; P =0.17), unstable angina (RR 0.55; 95% CI: 0.13-2.33; P =0.42), revascularisation (RR 0.79; 95% CI: 0.28-2.24; P=0.66). Bleeding events were not found significantly different between these groups (RR 1.06; 95% CI: 0.88-1.28; P=0.55). Considering efficacy and safety, alternative antiplatelets (e.g. prasugrel or ticagrelor) may be regarded as better treatment option as compared to clopidogrel for ACS patients undergoing PCI.

Association of Sex, Age, and Comorbidities with Mortality in COVID-19 Patients: A Systematic Review and Meta-Analysis.

INTRODUCTION: Although severe acute respiratory syndrome coronavirus-2 infection is causing mortality in considerable proportion of coronavirus disease-2019 (COVID-19) patients, however, evidence for the association of sex, age, and comorbidities on the risk of mortality is not well-aggregated yet. It was aimed to assess the association of sex, age, and comorbidities with mortality in COVID-2019 patients. METHODS: Literatures were searched using different keywords in various databases. Relative risks (RRs) were calculated by RevMan software where statistical significance was set as p < 0.05. RESULTS: COVID-19 male patients were associated with significantly increased risk of mortality compared to females (RR 1.86: 95% confidence interval [CI] 1.67-2.07; p < 0.00001). Patients with age ≥50 years were associated with 15.4-folds significantly increased risk of mortality compared to patients with age <50 years (RR 15.44: 95% CI 13.02-18.31; p < 0.00001). Comorbidities were also associated with significantly increased risk of mortality; kidney disease (RR 4.90: 95% CI 3.04-7.88; p < 0.00001), cereborovascular disease (RR 4.78; 95% CI 3.39-6.76; p < 0.00001), cardiovascular disease (RR 3.05: 95% CI 2.20-4.25; p < 0.00001), respiratory disease (RR 2.74: 95% CI 2.04-3.67; p < 0.00001), diabetes (RR 1.97: 95% CI 1.48-2.64; p < 0.00001), hypertension (RR 1.95: 95% CI 1.58-2.40; p < 0.00001), and cancer (RR 1.89; 95% CI 1.25-2.84; p = 0.002) but not liver disease (RR 1.64: 95% CI 0.82-3.28; p= 0.16). CONCLUSION: Implementation of adequate protection and interventions for COVID-19 patients in general and in particular male patients with age ≥50 years having comorbidities may significantly reduce risk of mortality associated with COVID-19.

Effects of the ABCB1 C3435T single nucleotide polymorphism on major adverse cardiovascular events in acute coronary syndrome or coronary artery disease patients undergoing percutaneous coronary intervention and treated with clopidogrel: A systematic review and meta-analysis.

INTRODUCTION: The effects of the ABCB1 C3435T genetic polymorphism on clopidogrel responses are conflicting and inconclusive especially in patients undergoing percutaneous coronary intervention (PCI). This study examined the pooled risk of major adverse cardiovascular events (MACE) and bleeding events associated with the ABCB1 C3435T polymorphism in acute coronary syndrome or coronary artery disease patients undergoing PCI and treated with clopidogrel. AREAS COVERED: Literature was searched in different resources for eligible studies. The pooled risk ratio was measured using RevMan software, with p<0.05 (two-sided) set as statistically significant. EXPERT OPINION: The ABCB1 C3435T homozygous mutant (TT) was associated with significantly increased risk of MACE compared to either wild type genotype (CC) or the combination of wild type and heterozygous genotypes (TT vs. CC: RR 1.33; 95% CI 1.06-1.68; p=0.02; TT vs. CC+CT: RR 1.32; 95% CI 1.10-1.60; p=0.004). Safety outcomes, i.e. bleeding events were not significantly different between the genetic models investigated (TT vs. CC: RR 1.93; 95% CI 0.86-4.35; p=0.11; TT vs. CC+CT: RR 1.36; 95% CI 0.89-2.09; p=0.16; CT+TT vs. CC: RR 1.20; 95% CI 0.59-2.44; p=0.61). It is suggested that ABCB1 C3435T genotype should be tested for ACS/CAD patients undergoing PCI to ensure optimum therapy of clopidogrel.