Table 6.

Clinical studies of ARNI.

Drug	Study Population	Treatment	Primary and Secondary Endpoints	Main Findings and Conclusions
LCZ696 (PARAMOUNT trial) [112]	▪HFpEF patients with LVEF ≥ 45% and NYHA II–III. ▪NT-proBNP level > 400 pg/mL (N = 301).	LCZ696 200 mg BID or valsartan 160 mg BID for 36 weeks	Primary: ▪Changes in NT-proBNP levels Secondary: ▪Change in echocardiographic measures. ▪Change in BP. ▪Change in NYHA, clinical composite assessment, and QoL.	▪At 12 weeks, LCZ696 showed greater effects in reducing NT-proBNP levels. ▪At 36 weeks, LCZ696 was associated with left atrial reverse remodeling and improvement in NYHA functional class. ▪LCZ696 was well tolerated.
LCZ696 (PARADIGM-HF trial) [113]	▪HFrEF patients with LVEF ≤ 40% and NYHA II–IV. ▪NT-proBNP level ≥ 600 pg/mL (N = 8399).	LCZ696 200 mg BID or enalapril 10 mg BID	Primary: ▪A composite of death from CV causes or a first hospitalization with HF. Secondary: ▪Time to death from any cause. ▪Change in the clinical summary score on the KCCQ. ▪Time to a new onset of atrial fibrillation. ▪Time to first occurrence of a decline in renal function.	▪LCZ696 reduced the risks of death and hospitalization from HF. ▪LCZ696 had a higher occurrence of hypotension and non-serious angioedema compared with enalapril. ▪LCZ696 had a lower occurrence of renal impairment, hyperkalemia, and cough compared with enalapril.
Sacubitril-valsartan (PARAGON-HF trial) [114]	▪HFpEF patients with LVEF ≥ 45% and NYHA II–III. ▪Elevation of NT-proBNP level. ▪Structural heart disease (N = 4822).	Sacubitril-valsartan 200 mg BID or valsartan 160 mg BID	Primary: ▪A composite of total hospitalizations due to HF and death from CV causes. Secondary: ▪Change in the clinical summary score on the KCCQ. ▪Change in NYHA class. ▪First occurrence of a decline in renal function. ▪Death from any cause.	▪Sacubitril-valsartan did not meet the primary endpoint. ▪Sacubitril-valsartan had a higher occurrence of hypotension and angioedema. ▪Sacubitril-valsartan had a lower incidence of hyperkalemia.