Efficacy and safety of sacubitril/valsartan in heart failure compared to renin-angiotensin-aldosterone system inhibitors: a systematic review and meta-analysis of randomised controlled trials

Introduction: Heart failure (HF) is still a major cause of morbidity and mortality all over the world. Aim of the study was to assess the benefits and harms of sacubitril/valsartan (S/V) compared to angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in patients with HF. Material and methods: We systematically searched for randomised controlled trials (RCTs) evaluating S/V vs. ACEI or ARB in acute or chronic HF in August 2021. Primary outcomes were HF hospitalisations and cardiovascular (CV) mortality; secondary outcomes included all-cause mortality, biomarkers, and renal function. Results: We selected 11 RCTs (n = 18766) with 2-48 months follow-up. Five RCTs had ACEIs as control, 5 RCTs had ARBs as control, and one RCT had both ACEI and ARB as control. Compared to ACEI or ARB, S/V reduced HF hospitalisations by 20% (HR = 0.80, 95% CI: 0.68-0.94; 3 RCTs; I2 = 65%; high CoE), CV mortality by 14% (HR = 0.86, 95% CI: 0.73-1.01; 2 RCTs; I2 = 57%; high CoE), and all-cause mortality by 11% (HR = 0.89, 95% CI: 0.78-1.00; 3 RCTs; I2 = 36%; high CoE). S/V reduced NT-proBNP (SMD = -0.34, 95% CI: -0.52 to -0.16; 3 RCTs; I2 = 62%) and hs-TNT (ratio of differences = 0.84, 95% CI: 0.79-0.88; 2 RCTs; I2 = 0%), and caused a decline in renal function by 33% (HR = 0.67, 95% CI: 0.39-1.14; 2 RCTs; I2 = 78%; high CoE). S/V increased hypotension (RR = 1.69, 95% CI: 1.33-2.15; 9 RCTs; I2 = 65%; high CoE). Hyperkalaemia and angioedema events were similar. Effects were in the same direction when stratified by type of control (ACEI vs. ARB). Conclusions: Sacubitril/valsartan had better clinical, intermediate, and renal outcomes in HF in comparison to ACEI or ARB. There was no difference in angioedema and hyperkalaemia events, but there were more hypotension events.