br Angiotensin receptor neprilysin inhibitors Sacubitril val

Angiotensin receptor-neprilysin inhibitors Sacubitril/valsartan is the first-in-class ARNI, comprising of molecular moieties of valsartan (ARB) and a neprilysin inhibitor prodrug, sacubitril (AHU377) [51]. Upon ingestion, sacubitril is rapidly metabolised into an active neprilysin inhibitor, sacubitrilat (LBQ657). Pharmacokinetic and pharmacodynamic studies of the target dose of 97/103 mg BD, reported equivalent plasma concentrations of valsartan as valsartan 160 mg BD (the dose studied in the Valsartan Heart Failure Trial [Val-HeFT]) and rises in cyclic guanosine monophosphate (cGMP) representing an increase in ANP secondary to effective neprilysin inhibition [3,52]. Importantly, the risk of angioedema with an ARNI was thought to be lower due to the discovery that sacubitrilat does not inhibit aminopeptidase p, unlike omapatrilat [50]. PARADIGM-HF compared sacubitril/valsartan (target dose 97/103 mg twice daily) to the gold-standard ACE inhibitor, enalapril (target dose 10 mg BD), in reducing the primary composite endpoint of CV death or HF hospitalisation in patients with chronic, ambulatory, symptomatic HFrEF [20,53,54]. Prior to randomisation, all patients underwent a mandatory 6–8 week active run-in PEG Virus Precipitation Kit to ensure tolerance of firstly enalapril 10 mg BD, followed by sacubitril valsartan 97/103 mg BD [53]. If no unacceptable side-effects occurred, patients were then randomised 1:1 to double-blind treatment with sacubitril/valsartan 97/103 mg BD or enalapril 10 mg BD. In March 2014, on the recommendation of the data-safety monitoring board, the trial was terminated early after a median follow-up of 27 months due to overwhelming evidence of benefit with treatment of sacubitril/valsartan compared to enalapril. Sacubitril/valsartan was associated with a twenty percent reduction in the composite primary endpoint of CV death or HF hospitalisation compared to treatment with enalapril (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73–0.87; p < 0.001 [Fig. 2]) [20]. Significant reductions in both components of the primary endpoint, CV death and HF hospitalisation, were reported with HR of 0.80 (95% CI 0.71–0.89; p < 0.001) and 0.79 (95% CI 0.71–0.89; p < 0.001), respectively (Fig. 2). The two predominant modes of CV death, sudden and pump-failure death, were significantly reduced to a similar degree [55]. The secondary endpoint of all-cause mortality was also significantly reduced in the sacubitril/valsartan group (HR 0.84; 95% CI, 0.76 to 0.93; p < 0.001) [20]. The benefit seen with sacubitril/valsartan was consistent across all prespecified sub-groups [20]. These results mean that for every 1000 patients converted from enalapril to sacubitril, 46 fewer primary endpoints, 31 fewer CV deaths, 27 fewer patients hospitalised with worsening HF (and 52 fewer total HF hospitalisations), and 28 fewer deaths from any cause would occur over a median of 27 months. Sacubitril/valsartan was well tolerated with low rates of discontinuation due to adverse effects (Fig. 3) [20]. The presence of an active run-in period prior to randomisation ensured initial tolerability and maximised the number of patients able to attain target doses of both study drugs. Angioedema was numerically more common with sacubitril/valsartan than enalapril (19 [0.5%] cases vs. 10 [0.2%]) however this difference did not reach statistical significance (p = 0.13). Additionally, no cases of angioedema with associated airway compromise were reported. There was a statistically significant difference (p < 0.001) in the occurrence of symptomatic hypotension with sacubitril/valsartan (14%) compared to enalapril (9%), but this rarely resulted in treatment discontinuation (0.9% vs. 0.7% respectively; p = 0.38). The occurrence of elevations in serum creatinine (≥2.5 mg/dl), potassium (>6 mmol/l), and cough was less frequent with sacubitril/valsartan than enalapril.