Abstract
Numerous evidence-based medical and device therapies proven to reduce morbidity and mortality have advanced care for heart failure with reduced ejection fraction (HFrEF). The primacy of this approach has now been superseded by striking new data resulting in the approval of the combination of valsartan and sacubitril, a neprilysin inhibitor (also known as LCZ696), in 2015 for the treatment of HFrEF. LCZ696 is a novel heart failure drug that simultaneously inhibits the renin-angiotensin system and potentiates the natriuretic peptide system. In the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, LCZ696 significantly improved cardiovascular outcomes compared to current guideline-directed medical therapy. Compared to an angiotensin-converting enzyme (ACE) inhibitor, LCZ696 was associated with a 20% reduction in cardiovascular mortality (number needed to treat [NNT] 32) and a similar reduction in total mortality (NNT 36). Morbidity benefits of the drug were seen within 1month of initiation. However, hypotension due to enalapril or the LCZ696 regimen during a run-in phase eliminated 20% of patients. Safety concerns included the risk of angioedema and the theoretical concern of neurocognitive dysfunction due to the protean effects of neprilysin inhibition. The role of LCZ696 in patients with asymptomatic left ventricular systolic dysfunction is uncertain. LCZ696 is currently being evaluated in patients with heart failure with preserved ejection fraction, with promising initial results. LCZ696 represents a novel mechanistic approach to targeting heart failure with reduced ejection fraction, and ongoing studies will address its use in other cardiovascular populations.
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