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Heart failure affects approximately 1.5% of the adult population in developed countries and the prevalence rises to almost 10% in those over 70 years, a progressively increasing subset of the population.1 2 Sacubitril/Valsartan (an angiotensin receptor/neprilysin inhibitor—ARNi) was introduced as a novel agent for heart failure in 2014. Should this novel agent be tolerated and prove efficacious in older patients with heart failure?
Evolution of neprilysin inhibitors
ACE inhibitors were first reported as beneficial more than 25 years ago and have been the mainstay of therapy for heart failure since then.3 A combination of ACE inhibitors with beta blockers4 and aldosterone antagonists5 has contributed to best medical management during the intervening period. Therapeutic manipulation of the third neurohormonal system involving the natriuretic peptides has been evaluated over many years. While these peptides have been reported to cause effects such as vasodilation, suppression of aldosterone secretion, natriuresis and diuresis, all of which should be beneficial in heart failure, early studies in humans resulted in disappointing outcomes. For example, neprilysin inhibitors given alone did not produce clinically beneficial effects probably because neprilysin is also responsible for the breakdown of other polypeptide vasoconstrictors such as angiotensin II, thus negating any beneficial effects.6 Moreover the combination of neprilysin inhibitors and ACE inhibitors was demonstrated as potentially detrimental due to the increased propensity to angiooedema probably related to excess bradykinin (also degraded by neprilysin) levels.7 8
When the PARADIGM-HF study prospectively compared Sacubitril/Valsartan with an ACE inhibitor (enalapril), with a view to determining the impact of those therapies on mortality and morbidity in heart failure, there was a significant reduction in cardiovascular and all-cause mortality.9 Moreover, there was a significant diminution in the rate of hospitalisation with worsening heart failure and these effects are detailed in table 1.
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