Cardiac protection with phosphocreatine: a meta-analysis

Abstract

Introduction. Phosphocreatine (PCr) plays an important role in the energy metabolism of the heart and a decrease in its intracellular concentration results in alteration of myocardium energetics and work. Method. We conducted a meta-analysis of all randomised and matched trials that compared PCr with placebo or standard treatment in patients with coronary artery disease or chronic heart failure or in those undergoing cardiac surgery. We systematically searched PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar up to November 1st, 2015, for pertinent trials. The primary outcome was the longest follow-up all-cause mortality. Secondary outcomes included inotropes use, ejection fraction (EF), peak creatinine kinase-myocardial band (CK-MB) release, and the incidence of major arrhythmias, as well as spontaneous recovery of the heart performance in the subgroup of patients undergoing cardiac surgery with cardiopulmonary bypass. We pooled odds ratio (OR) and mean difference (MD) using fixed- and random effects models. We tested for heterogeneity using the Q statistic and quantified it with the I2 statistic. Meta-analysis was performed using Review Manager 5.3.5. Results. We identified 41 controlled trials, 31 of them randomised. Patients receiving PCr had lower all-cause mortality when compared to the control group (61/1731 [3.5%] vs. 177/1667 [10.6%]; OR 0.71, 95% CI 0.51-0.99; P=0.04; I2=0%; with 3,400 patients and 22 trials included). Phosphocreatine administration was associated with higher LVEF (MD 3.82, 95% CI 1.18-6.46; P=0.005; I2=98%), lower peak CK-MB release (MD -6.08, 95% CI -8.01, -4.15; P<0.001; I2=97%), lower rate of major arrhythmias (OR 0.42; 95% CI 0.27-0.66; P<0.001; I2=0%), lower incidence of inotropic support (OR 0.39, 95% CI 0.25-0.61; P<0.001; I2=56%) and a higher level of spontaneous recovery of the heart performance after cardiopulmonary bypass (OR 3.49, 95% CI 2.28-5.35; P<0.001; I2=49%) when compared with the control group. Discussion. In a mixed population of patients with coronary artery disease, chronic heart failure or in those undergoing cardiac surgery PCr administration was associated with improved cardiac outcomes and with a reduction in all-cause mortality at the longest follow up available. Due to the pharmacological plausibility of this effect and to the concordance of the beneficial effects of PCr on several secondary but important outcomes and survival, there is urgent need of a large multicentre randomised trial to confirm these findings.