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

Abstract

Abstract Background Benefits and harms of the use of LCZ696 (sacubitril/valsartan, S/V), a combination of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), in heart failure (HF) are unknown. Purpose To systematically assess benefits and harms of S/V as compared to angiotensin converting enzyme inhibitors (ACEI) or ARB in patients with HF. Methods We searched for randomised controlled trials (RCTs) evaluating S/V vs. ACEI or ARB in acute or chronic HF adult patients. Primary outcomes were HF hospitalisation and cardiovascular [CV] mortality; secondary outcomes were all-cause mortality, decline in renal function, myocardial dysfunction, quality of life (QoL), systolic blood pressure (SBP), diastolic blood [DBP], and adverse events (AEs) including worsening renal function (SCr≥2 mg/dL), hyperkalaemia (K+≥5.5 mmol/L), symptomatic hypotension (SBP<100 mmHg), and angio-oedema. Inverse variance random-effects meta-analyses were conducted and effects expressed as hazard ratios (HR), relative risks (RR) or mean difference (MD) and their 95% confidence intervals (CI). GRADE methodology was used to assess the certainty of evidence (CoE). Results We selected 11 RCTs (n=18766). Follow-up times ranged between 2 and 48 months; the average age of participants was 61 to 73 years-old. Five RCTs had ACEIs as control, five RCTs had ARBs as control, and one RCT had both ACEI and ARB as control. Six RCTs had low risk of bias; five RCTs had unclear risk of bias. S/V reduced the hazard of 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) compared to ACEI or ARB control (Figure 1). S/V slightly improved KCCQ-QoL scores (MD 1.36 points, 95% CI 0.49 to 2.24; 6 RCTs; I2=54%). S/V did not affect LVEF and E/E' but reduced NTproBNP (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%). SBP and DBP were reduced by 4 mmHg and 3 mmHg, respectively, and hypotension was increased (RR 1.69, 95% CI 1.33–2.15; 9 RCTs; I2=65%; high CoE) with S/V. Also, S/V reduced the hazard of decline in renal function by 33% (HR 0.67, 95% CI 0.39–1.14; 2RCTs; I2=78%; high CoE); hyperkalaemia and angioedema events were similar between S/V and controls. Conclusions Sacubitril/valsartan had better clinical and intermediate outcomes in HF in comparison to ACEI or ARB. Decline of renal function was less frequent with S/V in comparison to controls, and there was no difference in decline of renal function or angioedema and hyperkalaemia events. However, sacubitril/valsartan was associated with more symptomatic hypotension events vs. controls. Funding Acknowledgement Type of funding sources: None.