Remote Ischemic Conditioning in Patients with Acute Coronary Syndromes: A Systematic Review with Meta-Analysis and Trial Sequential Analysis

Irene Sandven,1 Jan Eritsland,2 Michael Abdelnoor3,4 1Oslo Centre for Biostatistics and Epidemiology (OCBE), Oslo University Hospital, Oslo, Norway; 2Department of Cardiology, Oslo University Hospital, Oslo, Norway; 3Centre of Clinical Heart Research, Oslo University Hospital, Oslo, Norway; 4Epidemiology and Biological Statistics, Independent Health Research Unit, Oslo, NorwayCorrespondence: Irene Sandven Email uxsair@ous-hf.noObjective: To evaluate the efficacy of remote ischemic conditioning (RIC) as compared to no conditioning on clinical endpoints in acute coronary syndromes (ACS) patients undergoing percutaneous coronary intervention (PCI).Design: Systematic review of randomized clinical trials (RCTs).Material and Methods: Literature was searched up to September 13, 2019, and we identified a total of 13 RCTs. The efficacy of RIC on incidence of clinical events during follow-up was quantified by the rate ratio (RR) with its 95% confidence interval (CI), and we used fixed and random effects models to synthetize the results. Small-study effect was evaluated, and controlled for by the trim-and-fill method. Heterogeneity between studies was examined by subgroup and meta-regression analyses. The risk of false-positive results in meta-analysis was evaluated by trial sequential analysis (TSA).Results: Pooled analysis of 13 trials (7183 patients) showed that RIC compared to no conditioning revealed a non-significant risk reduction on endpoint mortality (RR=0.81, 95% CI: 0.56– 1.17) during a median follow-up time of 1 year (range: 0.08– 3.8) with low heterogeneity (I2=16%). Controlling for small-study effect showed no efficacy of RIC (adjusted RR: 1.03, 95% CI: 0.66– 1.59). Pooled effect of RIC on the incidence of myocardial infarction (MI) from 11 trials (6996 patients) was non-significant too (RR=0.85, 95% CI: 0.62– 1.18), with no observed heterogeneity (I2=0%) or small-study effect. A similar lack of efficacy was found in endpoint congestive heart failure (CHF) from 6 trials including 6098 patients (RR=0.71, 95% CI: 0.44– 1.15), with moderate heterogeneity (I2=30%). TSAs showed that the pooled estimates from the cumulative meta-analyses were true negative with adequate power.Conclusion: Evidence from this updated systematic review demonstrates no beneficial effect of RIC on the incidence of clinical endpoint mortality, MI and CHF during a median follow-up of 1 year in ACS patients undergoing PCI.Keywords: remote ischemic conditioning, mortality, myocardial infarction, congestive heart failure, meta-analysis, trial sequential analysis