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- Michael A. Shapiro, MD∗ ()
- ↵∗Cardiology/Medicine, Chalmers Wylie Veterans Administration Medical Center, 420 James Road, Columbus, Ohio 43215
The recently published preview of the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial of sacubitril/valsartan (Entresto) therapy for congestive heart failure with reserved ejection fraction (1) raised several questions. The trial’s control is good, comparing targeted full dose sacubitril/valsartan with valsartan alone targeted at the standard dosage, 160 mg twice/day. A better control would not use the standard available form of lone valsartan but would compare it to the form of valsartan used in the sacubitril/valsartan combination. Although this form of valsartan alone is not available commercially, certainly Novartis could make it available for this Novartis-funded trail, as a more honest control.
The larger question gets back to the original PARADIGM-HF (Angiotensin-Neprilysin Inhibition versus Enelapril in Heart Failure) trial (2) for heart failure with reduced ejection fraction (HFrEF). The trial of the drug for heart failure with preserved ejection fraction (HFpEF) is underway, but what is the strength of the data in HFrEF? Despite the widely published experts’ opinions, PARADIGM-HF did not have a proper control. The new agent sacubitril was paired with reliable valsartan, and the combination was not compared to usual target dosage of valsartan alone, which would have been the honest trial, but compared to enalapril targeted at one-half the usual dosage. Never mind the relative dosage issue of enalapril versus that for the new form of valsartan, the trial design violated the principle of a controlled clinical trial. The nearly universal approval of published expert opinion on PARADIGM-HF seems disingenuous.
I await the results of PARAGON-HF, and it may change my clinical management of patients with HFpEF, although at a cost increase of more than $500 per month per patient. As for sacubitril/valsartan for patients with HFrEF, I await a study with the trial design of PARAGON-HF but in the HFrEF population of the mendacious PARADIGM-HF trial.
Please note: Dr. Shapiro has reported that he has no relationships relevant to the contents of this paper to disclose.