August 30th, 2014
Will There Be a PARADIGM Shift in Treatment of Heart Failure?
CardioExchange’s Harlan M. Krumholz interviews John J.V. McMurray and Milton Packer, the two lead authors of the PARADIGM-HF trial. The industry-funded randomized trial, comparing angiotensin–neprilysin inhibition with enalapril, is published in The New England Journal of Medicine.
Read CardioExchange’s news coverage of the trial, including a summary of the findings.
Krumholz: On a 1 to 10 scale, how likely is it, given what we know so far, that in 5 years this will be the main way we treat patients with heart failure and depressed systolic function in countries that can afford the medication?
Packer: I would say 9 to 10 that angiotensin-receptor neprilysin inhibition will be the cornerstone of treatment for patients with chronic heart failure and a reduced ejection fraction, replacing the current use of ACE inhibitors and angiotensin-receptor blockers.
McMurray: Cost is key. If this is affordable, it will be used as commonly as beta-blockers are now — 90%. This will be a class I, LOE A guideline recommendation.
Krumholz: What was most challenging about the trial?
Packer: The most challenging aspect of the trial was to design it in a way that, as a single trial standing on its own, it would be compelling enough to convince physicians to switch from a class of drugs that they have been using comfortably for 25 years.
McMurray: There were a few bumps along the road, but nothing too major. Early termination and rapid publication were quite challenging!
Krumholz: Given the relatively young age of your cohort (64 years) and that heart failure is most common in older populations, how should clinicians think about whether this trial is relevant to their patients, many of whom are not well represented in this study?
Packer: The trial recruited a very highly representative group of patients. As noted by Dr. Jessup in her NEJM editorial, the patients in this trial were quite comparable to those in other trials that changed clinical practice. Patients who were very elderly in this trial responded just as well as younger patients. Furthermore, many very elderly patients who have heart failure have a preserved ejection fraction, and these are being studied in a new trial with the acronym PARAGON.
McMurray: We had a sizeable subset of older patients, and the treatment benefit was consistent across subgroups.
Krumholz: Briefly explain for our members how you think this drug produces the observed effect.
Packer: This drug simultaneously decreases the influence of a maladaptive system (the renin-angiotensin system) while enhancing the influence of endogenous peptides that have favorable adaptive effects on the circulation. No other drug for heart failure has ever addressed the deficient response to adaptive factors (natriuretic peptides, bradykinin, adrenomedullin), which is characteristic of patients with heart failure.
McMurray: The incremental benefit was presumably due to the effect of neprilysin inhibition added to renin-aldosterone system blockade. Neprilysin inhibition augments natriuretic peptides and probably other vasoactive substances (including bradykinin). We believe that these other substances are beneficial in heart failure patients.
JOIN THE DISCUSSION
Join Dr. McMurray and Dr. Packer in reflecting on the findings from PARADIGM-HF.
To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.