NEJM Publishes Heart Failure Treatment History, Results of PARADIGM-HF Trial

PARADIGM-HF study results offer insight into a new heart failure treatment mechanism, neprilysin inhibition.

Two steps forward, 1 step back, with overall progress as the paradigm for treatment of heart failure (HF) has shifted and improved over the last 28 years—that’s the celebratory message in the September 4, 2014, issue of the New England Journal of Medicine (NEJM). This issue summarizes NEJM’s history of publishing critical HF research and subsequent significant changes. Since 1986, results from well-designed, carefully controlled clinical trials have helped experts craft significantly better treatment plans for patients who experience HF. The bottom-line message: patients who have HF with reduced ejection fraction can expect to live much longer if they receive key life-extending drugs at appropriate doses.

This issue is a must-read for all pharmacists who deal with HF patients. It presents 3 critical articles that offer insight into current guidelines.

First, an article describes HF treatment’s history, starting in 1986 when the 2 drugs considered the cornerstone of treatment—digoxin and diuretics—conferred no mortality benefits. A string of trials—beginning with the familiar acronyms V-HeFT I, CONSENSUS, SOLVD, and V-HEFT II—introduced new drugs into the treatment paradigm. Angiotensin-converting enzyme (ACE) inhibitors, beta-blockers (once considered counterintuitive), aldosterone antagonists, and cardiac devices have now improved survival in HF. Glycosides have moved from first-line therapy to a lesser role, being used to mitigate symptoms and reduce hospitalization in select patients. In addition, these trials have identified alternatives for patients unable to take first-line drugs. Of note, this article and the NEJM issue in general do not ignore trials with negative or equivocal results, acknowledging that even when trials seemingly fail, good researchers learn, regroup, and redirect efforts.

Second, the article includes an interactive timeline of treatment trials that shows the steady march of progress at a glance. It includes trials for drugs, but also those that validated roles for devices.

Third, NEJM published results of the recent PARADIGM-HF trial, which was stopped early when it demonstrated overwhelming benefit. This study introduces a new treatment mechanism, neprilysin inhibition. Neprilysin, a neutral endopeptidase abundant in the kidney, has a wide range of functions throughout the body, but in HF, it affects vasoactive peptide metabolism. PARADIGM-HF reports mortality reductions of 16% to 20% in patients with HF treated with a nephrilysin inhibitor and an angiotensin II receptor blockers (ARBs) as compared with enalapril at a dose shown to reduce mortality. Neprilysin inhibition, in this case using the investigational agent sacubitril in combination with the approved ARB valsartan, appears to increase natriuretic peptides, improve sodium excretion, and probably promote cardiac remodeling. Patients in the sacubitril/valsartan arm experienced more hypotension but fewer signs of renal impairment than in the enalapril arm.

It’s likely that angiotensin-receptor—neprilysin inhibitors will be the next step in HF’s constantly-changing and always improving paradigm. Pharmacists should note one important point that represents an opportunity for improvement: survival in clinical trials in HF populations remains better than in real-world situations. Until all HF patients receive life-extending drugs at adequate doses, the disparity between clinical trial survival rates and real-world survival rates will remain. Let’s promote evidence-based use of available options.