Sacubitril/Valsartan in HFrEF Patients: Assessing the Benefits-Harms Balance

Background

Although treatment with angiotensin receptor neprilysin inhibitor (ARNI) - sacubitril/valsartan demonstrated a favorable benefits-to-harms balance in adults with heart failure (HF) in randomized controlled trials (RCTs), there has been no systematic appraisal for the quality of evidence regarding patient-centered outcomes in HF patients treated with sacubitril/valsartan.

Aim

To critically appraise the available evidence related to the benefits and harms of sacubitril/valsartan in HF patients.

Patients Profile

• Adult patients with HF treated with either ARNI or any control treatments

Methods

Study Design

• Systematic literature review

Study Selection

• Existing systematic reviews, published and unpublished RCTs and nationally representative controlled observational studies that reported adjusted effect estimates were included in this systematic review.
• The quality of evidence was rated as high, moderate, low, or very low, using the “Grading of Recommendations Assessment, Development and Evaluation” methodology

Outcomes

• All-cause mortality
• Mortality caused by HF
• Treatment utilization (hospitalization, office visits, emergency department visits)
• Quality of life (measured using validated scales)
• All adverse events

Results

• Sacubitril/valsartan reduced all-cause and cardiovascular mortality, hospitalization, emergency visits, and serious adverse events, and improved the quality of life vs. enalapril in adult patients with HF and reduced ejection fraction (HFrEF).
• As per a planned subgroup analysis, sacubitril/valsartan reduced the composite outcome of mortality, cardiovascular causes of hospitalization, or worsening HF in all patients except those with severe HF (New York Heart Association [NYHA] class III or IV, significant interaction effect). Similarly, benefits in terms of reduced cardiovascular mortality were evident in all subgroups of patients except those with diabetes (significant interaction effect).
• The incidence of cardiovascular death with sacubitril/valsartan in women, elderly, and non-white patients might be similar to that observed with enalapril. This issue however needs to be investigated further through appropriate studies.
• Conservative titration of sacubitril/valsartan over 6 weeks rather than condensed titration over 3 weeks might lower the incidence of adverse events.
• The postmarketing surveillance revealed more than 500 case reports of hypotension (851) and dizziness (651) in patients treated with sacubitril/valsartan along with other drugs for hypertension and HF.

Conclusions

• Sacubitril/valsartan demonstrated a favorable benefits-to-harms balance vs. enalapril in adult patients with HFrEF.
• Patients with severe HF (NYHA class III or IV) and those with diabetes had a relatively lesser improvement in terms of survival.
• The evidence on the long-term safety of sacubitril/valsartan in patents with HFrEF is currently inadequate.
• Practitioners may recommend sacubitril/valsartan over angiotensin-converting enzyme inhibitors, while meticulously monitoring the adverse events, renal function, and potassium levels in their patients.

Am J Cardiol.  Jul 14, 2017 [Epub ahead of print]; doi: 10.1016/j.amjcard.2017.06.062.