Profile of sacubitril/valsartan in the treatment of heart failure: patient selection and perspectives

Abstract

With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF.

Sacubitril/valsartan eligibility and outcomes in the ESC‐EORP‐HFA Heart Failure Long‐Term Registry: bridging between European Medicines Agency/Food and Drug Administration label, the PARADIGM‐HF trial, ESC guidelines, and real world

“…When the ACEi/ARB dose criterion (20 mg daily), which was most rare to be met, was set to half dose, the proportion of patients eligible significantly increased to 28% with either the PARADIGM‐HF or the ESC guideline criteria. Low rates of eligibility have been previously reported in smaller studies with fewer and less generalizable centres: the proportion of patients considered suitable for LCZ696 according to the FDA drug label ranged between 50% and 71% of patients, whereas the respective proportion when the PARADIGM‐HF criteria (20 mg daily ACEi/ARB dose) were applied decreased to 21–39% . However, if the 10 mg ACEi/ARB dose criterion was alternatively used, rates of eligibility again significantly rose .…”

“…Sacubitril/valsartan (LCZ696) is the first agent of the angiotensin receptor-neprilysin inhibitor (ARNI) drug class. 1 In PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), LCZ696 compared to enalapril reduced the risk of the primary outcome [cardiovascular death or heart failure (HF) hospitalization] by 20%. Notably, the risks of all-cause and cardiovascular mortality and of HF hospitalization were also significantly reduced by ARNI.…”

Sacubitril/valsartan in cardiovascular disease: evidence to date and place in therapy

“…5,51,52 Several questions and concerns have been raised by clinicians and researchers regarding the generalizability of the PARADIGM-HF trial results with regards to the study design, the effect of achieved target dose of medications on clinical outcomes, study population representativeness of the real-world HFrEF patients, and the effect of ethnic and geographic variations on outcomes. 6,53 Most of these concerns were answered in posthoc analyses and addressed in expert review articles. 53,54 Ongoing clinical trials will evaluate the safety and efficacy of sacubitril/valsartan and its effects on clinical and exercise-related outcomes, biomarker changes, and cardiac remodeling parameters in HFrEF patients in the acute HF, post-MI HF, and in those with left ventricular assist devices ( Table 2).…”

“…6,53 Most of these concerns were answered in posthoc analyses and addressed in expert review articles. 53,54 Ongoing clinical trials will evaluate the safety and efficacy of sacubitril/valsartan and its effects on clinical and exercise-related outcomes, biomarker changes, and cardiac remodeling parameters in HFrEF patients in the acute HF, post-MI HF, and in those with left ventricular assist devices ( Table 2). As patients with advanced heart failure were poorly represented in the PARADIGM-HF trial, an ongoing trial in symptomatic advanced HFrEF patients will determine if treatment with LCZ696 compared with valsartan for 24 weeks will improve NT-proBNP levels to reflect hemodynamic and clinical status.…”

Recurrent hypotension induced by sacubitril/valsartan in cardiomyopathy secondary to Duchenne muscular dystrophy: A case report

“…In addition, patients with NYHA class II accounted for approximately 70% of all the participants in the PARADIGM-HF Trial, while patients with NYHA class IV accounted for less than 1% of those in the PARADIGM-HF Trial, and most of the DMD patients were not suitable for cardiac function evaluation according to the NYHA criteria based on their loss of ambulation. Although the guidelines of the United States and Europe recommend the administration of sacubitril/valsartan in NYHA class II-IV patients, analysis of real-world eligibility data suggests that only 20%-40% of HFrEF patients will be eligible for sacubitril/valsartan initiation based on current guidelines[19]. ARNIs inhibit the RAS and enhance the activity of natriuretic peptides and bradykinin, thus demonstrating an effect on lowering blood pressure[20].…”