The PARADIGM-HF trial (October 2015)

TO THE EDITOR: Two considerations concerning the interpretation of the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial are not addressed in the article by Sabe et al regarding a new class of drugs for systolic heart failure.¹ First of all, the PARADIGM-HF trial compared the maximal dose of sacubitril with a less-than-maximal dose of enalapril. Secondly, sacubitril lowered blood pressure more than enalapril.

The angiotensin receptor blocker dose in sacubitril 200 mg is equivalent to valsartan 160 mg.² Accordingly, the angiotensin receptor blocker in sacubitril 200 mg twice daily is equivalent to the maximal dosage of valsartan approved by the US Food and Drug Administration. The dosage of enalapril in the PARADIGM-HF trial was 10 mg twice daily. While the target enalapril dosage for heart failure is 10 to 20 mg twice daily,³ the dosage of enalapril in PARA- DIGM-HF was half the maximal approved dosage.

In the PARADIGM-HF trial, sacubitril 200 mg twice daily reduced the incidence of cardiovascular death by 19% compared with enalapril 10 mg twice daily (the rates were 16.5% vs 13.3%, respectively).² That sacubitril lowered mean systolic blood pressure 3.2 ± 0.4 mm Hg more than enalapril^2,4 may account for much of this benefit.

A 2002 study by Lewington et al⁵ found that a 2-mm Hg decrease in systolic blood pressure reduces the risk of cardiovascular death by 7% in middle-aged adults. Granted, this study did not involve heart failure patients, but if its results are remotely applicable, a 3.2-mm Hg reduction in systolic blood pressure might be expected to reduce the rate of cardiovascular deaths by 10% to 11%.

Would sacubitril be superior to enalapril if the maximal dose of enalapril were compared to the maximal dose of sacubitril? Would sacubitril be superior to enalapril if blood pressure were lowered comparably between the two groups? These are relevant questions that the PARADIGM-HF trial fails to answer.

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