![]() ![]() Race or ethnicity: White 66%, Black 5%, Asian 18%, other 11%.Demographics: Age 64 years, female 21%,."Unacceptable side effects" with ACE-inhibitors or ARBs.Potassium >5.2 mmol/L at screening or >5.4 mmol/L at randomization.SBP 25% from screening to randomization (amended to >35%).Beta blocker with stable dose for prior 4 weeks.ACE-inhibitor or ARB therapy with stable dose for prior 4 weeks, equivalent to enalapril ≥ 10 mg/day.If a HF hospitalization in prior year: BNP ≥100 pg/mL or NT proBNP ≥400 pg/mL.If no HF hospitalizations in prior year: BNP ≥150 pg/mL or NT proBNP ≥600 pg/mL.LVEF ≤40% until 2010 at which point this was reduced to ≤35%.Primary outcome: CV mortality or HF hospitalization.Median follow-up: 27 months (stopped after 3rd interim analysis).N=8,399 (8,000 needed by power calculation).Multicenter, prospective, randomized, comparative trial.Do not prescribe ARNI therapy to patients with prior angioedema (COR III, LOE C-EO).Do not prescribe ARNI therapy concomitantly with ACE-inhibitors or within 36 hours of last dose of an ACE-inhibitor (COR III, LOE B-R).In patients with NYHA Stage II-III HFrEF tolerating ACE-inhibitor or ARB, replacement with ARNI is recommended to improved morbidity and mortality (COR I, LOE B-R).GuidelinesĪCC/AHA/HFSA Guideline for the Management of Heart Failure (2016, adapted) The FDA fast tracked the valsartan/sacubitril combination pill for approval in July 2015. There was no difference in the rates of angioedema. The ARNI was generally well tolerated except for a higher rate of symptomatic hypotension, though not to an increased rate of discontinuation of the therapy due to hypotension. Importantly, the ARNI had a significant reduction in all-cause mortality (17.0% vs. 26.5% NNT 21) as well as each of the individual components. The ARNI group had a reduction in the primary outcome of CV mortality or HF hospitalization (21.8% vs. With a median follow-up of 27 months, the trial was stopped following a positive interval efficacy analysis. Published in 2014, the industry-sponsored Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial randomized 8,399 patients with HFrEF (LVEF ≤40% and ≤35% were used at different points in the trial) and NYHA class II-IV symptoms to the ARNI LCZ696 (sacubitril) 200 mg PO BID or enalapril 10 mg PO BID (the goal dose from CONSENSUS and SOLVD). A clinical trial evaluating its efficacy was lacking. The experimental ARNI named LCZ696 combines an ARB (valsartan 160 mg) with a neprilysin inhibitor (sacubitril). Use of a neprilysin inhibitor plus an ARB (termed ARNI or angiotensin receptor-neprilysin inhibitor) may provide benefit over ACE inhibitor monotherapy in treatment of HFrEF without increasing the rates of angioedema. However, omapatrilat was associated with a higher rate of angioedema. The 2002 OVERTURE trial found that use of omapatrilat (an agent that inhibits ACE, aminopeptidase P, and neprilysin) reduced mortality and hospitalization when compared to ACE-inhibitor use. Neprilysin is an endopeptidase that breaks down vasoactive peptides (BNP, bradykinin, and adrenomedullin) its inhibition may therefore reduce remodeling, vasoconstriction, and renal sodium retention and improve outcomes in HFrEF. While beta blockers and aldosterone antagonists have further improved survival, mortality remains high. It is also associated with a reduction in all-cause mortality.ĪCE inhibitor therapy reduces mortality in patients with HFrEF and has been the standard of care in this disease since the 1990s following publications of trials like CONSENSUS (1987) and SOLVD (1991), though ARBs may be substituted if ACE inhibitors are poorly tolerated. Among patients with HFrEF, does treatment with an angiotensin receptor-neprilysin inhibitor reduce CV mortality or HF hospitalizations when compared to ACE inhibitor therapy?Īmong patients with HFrEF, treatment with an angiotensin receptor-neprilysin inhibitor reduces CV mortality or HF hospitalizations when compared to enalapril. ![]()
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