Should All Heart Failure Patients Be Treated With Sacubitril/Valsartan?

In an essay in the December 2016 issue of JAMA Cardiology, Dr Packer cites the PARADIGM-HF trial as he exhorts physicians to prescribe sacubitril/valsartan for heart failure patients. ¹ Dr Packer recommends that patients with heart failure currently treated with a conventional renin-angiotensin inhibitor be switched to sacubitril/valsartan in order to improve their long-term prognosis.

PARADIGM-HF demonstrated that sacubitril/valsartan 200 mg twice a day is more effective than enalapril 10 mg twice a day at reducing the risk of death and of hospitalization for heart failure. ² Because PARADIGM-HF compared the maximum dose of sacubitril/valsartan with a dose of enalapril that is half the maximum dose labeled for heart failure, the results do not justify switching heart failure patients to sacubitril/valsartan.

The earlier SOLVD trials that targeted an enalapril dose of 10 mg twice a day may have influenced the choice of enalapril dose in PARADIGM-HF. ^3,4 In addition, Dr Packer claims that enalapril 20 mg twice a day is poorly tolerated. ¹ Dr Packer provides no evidence to support this claim, but he may be referring to the CONSENSUS trial. ⁵ Only 22% of patients tolerated the target dose of 20 mg enalapril twice a day in CONSENSUS, perhaps because all patients had NYHA class IV heart failure at enrollment. By contrast, less than 1% of the patients in PARADIGM-HF had NYHA class IV heart failure at enrollment, while 94% of patients had either NYHA class II or class III heart failure. Since patients in PARADIGM-HF were healthier than those in CONSENSUS, there is reason to think that patients in PARADIGM-HF could have tolerated higher doses of enalapril.

Dr Packer states that the dose of enalapril “was mandated by regulatory agencies” but he does not specify which agencies. ¹ The Food and Drug Administration (FDA) is not one of those agencies. In a 2009 communication with Novartis prior to study enrollment, the FDA “voiced concern that the proposed dose of the active comparator (10 mg bid of enalapril) was inadequate since labeling recommended titration to a higher dose.” ⁶

A clinical review written in 2015 by members of the Division of Cardiovascular and Renal Products, FDA/Center for Drug Evaluation and Research recommended that sacubitril/valsartan not be granted a product label of superiority to enalapril. ⁷ Despite this recommendation, the FDA granted Novartis a claim in the product label that PARADIGM-HF demonstrated that sacubitril/valsartan was superior to enalapril in reducing the risk of the combined end point of cardiovascular death or hospitalization for heart failure. ⁸ This claim is unwarranted because the maximum dose of enalapril was not utilized in PARADIGM-HF.