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 We assessed benefits and harms of sacubitril/valsartan (S/V) compared to angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in patients with heart failure (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, five 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 to 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 NTproBNP (SMD -0.34, 95%CI -0.52 to -0.16; 3 RCTs; I2=62%), hs-TNT (Ratio of differences 0.84, 95%CI 0.79-0.88; 2 RCTs; I2=0%), and decline in renal function by 33% (HR 0.67, 95%CI 0.39-1.14; 2RCTs; 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 hyperkalemia events, but more hypotension events.