Response by Dr Packer to the Letter of Dr Blankfield

Dr Blankfield agrees that the PARADIGM-HF trial demonstrated that sacubitril/valsartan 200 mg bid was more effective than enalapril 10 mg bid at reducing the risk of death and of hospitalization for heart failure. Yet, he questions whether such a finding is sufficient to mandate that physicians switch patients taking a conventional renin-angiotensin system inhibitor to sacubitril/valsartan. His skepticism is difficult to understand. Throughout the world, every regulatory agency that has examined the totality of evidence, every guideline committee that advises cardiologists, and every independent committee on cost-effectiveness has issued its highest recommendation that sacubitril/valsartan be prescribed to replace the use of ACE inhibitors and angiotensin receptor blockers in the treatment of heart failure. Why does Dr Blankfield’s view differ from all authoritative organizations that have examined the evidence? He apparently looked at the food and drug administration (FDA)-approved range of doses of enalapril and noted that there is some experience with the drug at a daily dose of 20 mg bid. Yet, he fails to realize that such experience is extraordinarily limited, that dose was tested only in a single small trial (the CONSENSUS trial) that enrolled only 253 patients who were treated for only 6 months. For the vast majority of patients with heart failure (similar to those enrolled in the PARADIGM-HF trial), the recommended target dose of enalapril for clinical use is 10 mg twice daily, because the efficacy and safety of this regimen were demonstrated in the SOLVD Treatment trial of 2569 patients with mild-to-moderate heart failure who were treated for an average of more than 3 years. For this reason, every large-scale heart failure trial that has utilized enalapril as a comparator have all uniformly designated 10 mg bid as the appropriate dosing regimen for the drug. Even if this were not true, it is noteworthy that the dose of enalapril actually achieved in the PARADIGM-HF trial was greater than those achieved in either the CONSENSUS trial or the SOLVD Treatment trials. For his concerns to be valid, Dr Blankfield must believe that enalapril 20 mg twice daily has a mortality advantage over enalapril 10 mg twice daily, but no such evidence exists. In fact, in a large-scale trial, very high doses of an ACE inhibitor do not even have a mortality advantage over very low doses of an angiotensin converting enzyme (ACE) inhibitor. So Dr Blankfield’s view is contradicted by the medical evidence. The dosing regimen of enalapril used in the PARADIGMHF was mandated by regulatory agencies, including the FDA. The reasons for their agreement is amply documented on the FDA website, but for some reason, Dr Blankfield cites not conclusions of the FDA but only discussion points of individuals. It is an FDA policy that all discussion points be documented, but in the final analysis, such documentation does not mean that they carried any weight in the final decision. The FDA approved sacubitril/valsartan as a replacement for a conventional renin-angiotensin system to reduce cardiovascular death. This approval was accomplished under both a priority review as well as a fast-track designation, such a combination is unprecedented for a cardiovascular drug. My view is that the consensus of the world’s experts (rather than Dr Blankfield’s opinions) should be relied upon to provide guidance to physicians.