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Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.

ABSTRACT: Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier status of 9 AF-associated SNPs on the efficacy of RAS inhibition for the primary prevention of AF.We performed SNP-RAS inhibitor interaction testing with unadjusted and adjusted Cox proportional hazards models using a discovery (Cardiovascular Health Study) and a replication (Atherosclerosis Risk in Communities) cohort. Additive genetic models were used for the SNP analyses, and 2-tailed P values <.05 were considered statistically significant.Among 2,796 Cardiovascular Health Study participants, none of the 9 a priori identified candidate SNPs exhibited a significant SNP-drug interaction. Two of the 9 SNPs, rs2106261 (16q22) and rs6666258 (1q21), revealed interaction relationships that neared statistical significance (with point estimates in the same direction for angiotensin-converting enzyme inhibitor only and angiotensin II receptor blocker only analyses), but neither association could be replicated among 8,604 participants in Atherosclerosis Risk in Communities.Our study failed to identify AF-associated SNP genetic subtypes of AF that derive increased benefit from upstream RAS inhibition for AF prevention. Future studies should continue to investigate the impact of genotype on the response to AF treatment strategies in an effort to develop personalized approaches to therapy and prevention.

SUBMITTER: Roberts JD

PROVIDER: S-EPMC4873713 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.

Roberts Jason D JD Dewland Thomas A TA Glidden David V DV Hoffmann Thomas J TJ Arking Dan E DE Chen Lin Y LY Psaty Bruce M BM Olgin Jeffrey E JE Alonso Alvaro A Heckbert Susan R SR Marcus Gregory M GM

American heart journal 20160213

<h4>Background</h4>Renin-angiotensin system (RAS) inhibition via angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce the risk of developing atrial fibrillation (AF) in certain populations, but the evidence is conflicting. Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with AF, potentially identifying clinically relevant subtypes of the disease. We sought to investigate the impact of carrier sta ...[more]

PMID: 27179719

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Project description:ImportancePostoperative atrial fibrillation (POAF) is a well-known complication after cardiac surgery. Renin-angiotensin system inhibitors (RASIs) have been suggested as an upstream therapy for selected patients with AF; however, evidence in the surgical setting is limited.ObjectiveTo evaluate the role of preoperative RASIs in prevention of POAF and adverse events for patients undergoing cardiac surgery.Data sourcesThe PubMed database and the Cochrane Library from inception until December 31, 2018, were searched by using the keywords renin-angiotensin system inhibitors OR angiotensin-converting enzyme inhibitors OR angiotensin receptor blocker OR aldosterone antagonist AND cardiac surgery. ClinicalTrials.gov was searched from inception until December 31, 2018, by using the keywords postoperative atrial fibrillation.Study selectionRandomized clinical trials (RCTs) and observational studies comparing the association between preoperative RASI treatment vs no preoperative RASI treatment (control group) and the incidence of POAF were identified. Eleven unique studies met the selection criteria.Data extraction and synthesisPooled analysis was performed using a random-effects model. Sensitivity and subgroup analyses of RCTs were performed to test the stability of the overall effect. Metaregression was conducted to explore potential risk of bias.Main outcomes and measuresThe primary outcome was POAF, and the secondary outcomes included rates of stroke and mortality and duration of hospitalization.ResultsEleven unique studies involving 27 885 unique patients (74.4% male; median age, 65 years [range, 58.5-74.5 years]) were included. Compared with the control group, the RASI group did not have a significantly reduced risk of POAF (odds ratio [OR], 1.04; 95% CI, 0.91-1.19; P = .55; z = 0.60), stroke (OR, 0.86; 95% CI, 0.62-1.19; P = .37; z = 0.90; without significant heterogeneity, P = .11), death (OR, 1.07; 95% CI, 0.85-1.35; P = .56; z = 0.59; without significant heterogeneity, P = .12), composite adverse cardiac events (OR, 1.04; 95% CI, 0.91-1.18; P = .58; z = 0.56), or a reduced hospital stay (weighted mean difference, -0.04; 95% CI, -1.05 to 0.98; P = .94; z = 0.07) using a random-effects model. Pooled analysis focusing on RCTs showed consistent results. The primary overall effect was maintained in sensitivity and subgroup analyses. Metaregression showed that male sex was significantly associated with POAF (τ2 = 0.0065; z = 3.47; Q = 12.047; P < .001) and that use of β-blockers was associated with a significantly reduced risk in developing POAF (τ2 = 0.018; z = -2.24; Q = 5.0091; P = .03).Conclusions and relevanceThe findings from this study suggest that preoperative RASI treatment does not offer additional benefit in reducing the risk of POAF, stroke, death, and hospitalization in the setting of cardiac surgery. The results provide no support for conventional use of RASIs for the possible prevention of POAF and adverse events in patients undergoing cardiac surgery; further randomized data, particularly among those patients with heart failure, are needed.

Project description:AIMS:To describe the characteristics of patients hospitalized with COVID-19 (including their long-term at-home medication use), and compare them with regard to the course of the disease. To assess the association between renin-angiotensin system inhibitors (RASIs) and disease progression and critical outcomes. METHODS AND RESULTS:All consecutive hospitalized patients with laboratory-confirmed COVID-19 in a university hospital in Amiens (France) were included in this study. The primary composite endpoint was admission to an intensive care unit (ICU) or death before ICU admission. Univariable and multivariable logistic regression models were used to identify factors associated with the composite endpoint. Between 28 February 2020 and 30 March 2020, a total of 499 local patients tested positive for SARS-CoV-2. Of these, 231 were not hospitalized {males 33%; median [interquartile range (IQR)] age: 44 (32-54)}, and 268 were hospitalized [males 58%; median (IQR) age: 73 (61-84)]. A total of 116 patients met the primary endpoint: 47 died before ICU admission, and 69 were admitted to the ICU. Patients meeting the primary endpoint were more likely than patients not meeting the primary endpoint to have coronary heart disease and to have been taking RASIs; however, the two subsets of patients did not differ with regard to median age. After adjustment for other associated variables, the risk of meeting the composite endpoint was 1.73 times higher (odds ratio 1.73, 95% confidence interval 1.02-2.93) in patients treated at baseline with a RASI than in patients not treated with this drug class. This association was confirmed when the analysis was restricted to patients treated with antihypertensive agents. CONCLUSIONS:We highlighted a potential safety signal for RASIs, the long-term use of which was independently associated with a higher risk of severe COVID-19 and a poor outcome. Due to the widespread use of this important drug class, formal proof based on clinical trials is needed to better understand the association between RASIs and complications of COVID-19.

Dataset Information

Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.

Publications

Impact of genetic variants on the upstream efficacy of renin-angiotensin system inhibitors for the prevention of atrial fibrillation.

Similar Datasets

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