PARADIGM-HF Prompts a New Line of Thinking about Heart Failure

Published - Written by Chana Sacks

Your patient – a 65-year-old man with an ischemic cardiomyopathy – presents to clinic one week after discharge from another hospitalization for a heart-failure exacerbation.

He is doing much better. He remains at his discharge weight and reports good adherence to a low-salt diet and to the extensive medication regimen that you have prescribed: he takes an aspirin, ACE inhibitor, beta-blocker, aldosterone antagonist, and a diuretic.  His ejection fraction is 30%, and he has NYHA class II heart-failure symptoms.

Doc, he asks you, are there any other medications I should be taking to keep me from getting hospitalized again or from dying from this?

His question has been the decades-long challenge facing physician-scientists working on heart failure.  Over the past quarter century, significant advances have been made. In 1987, the ACE-inhibitor enalapril was demonstrated to improve survival in patients with systolic heart failure [CONSENSUS].  In 1996, the mortality benefit of the alpha and beta-blocker carvedilol was shown [Packer], and in 1999, evidence of a mortality benefit with spironolactone added aldosterone antagonists [RALES] to heart-failure therapy.

With the PARADIGM-HF trial, published in this week’s NEJM, McMurray and colleagues report that a new drug can now be added to this list.  This study shows that the novel drug LCZ696 reduces mortality and decreases hospitalizations in patients with heart failure.

LCZ696 is a combination of the old angiotensin II receptor blocker (ARB) valsartan and the new neprilysin inhibitor sacubitril.   ARBs have long been used to replace ACE-inhibitors when patients cannot tolerate them, usually because of a cough.  Neprilysin is a neutral endopeptidase that degrades bradykinin, natriuretic peptides, and adrenomedullin.  Inhibition of neprilysin increases the circulating levels of those peptides.  According to the authors, these higher levels “counter the effects of neurohormonal overactivation that contributes to vasoconstriction, sodium retention and maladaptive remodeling.”

In this industry-funded, double-blind, randomized controlled trial of 8,000 patients, LCZ696 is compared with enalapril, a drug known to reduce mortality in heart failure. After a run-in period in which all screened participants received both drugs sequentially to ensure tolerance at target doses, patients were randomized to either LCZ696 at a dose of 200mg twice daily or enalapril 10mg twice daily.  Importantly, about 20% of screened participants were excluded during the run-in, most because of intolerance to one of the drugs.  Like your patient, all patients in the study had heart failure with an ejection fraction less than 40%.  Most were men, and they were well-managed medically at baseline, with more than 90% on a beta blocker, all on an ACE inhibitor (78%) or ARB (22%), and a majority on an aldosterone blocker.

The study was terminated early, after a median follow up of 27 months, because LCZ696 was found to be superior to enalapril, with a 20% reduction in the primary outcome of cardiovascular death or first hospitalization for heart failure (21.8% in the LCZ696 group compared with 26.5% in the enalapril group, P<0.0001).  All-cause mortality was also reduced, with 17% mortality in the LCZ696 group and 19.8% in the enalapril group (P <0.001). Overall, there was more symptomatic hypotension and non-serious angioedema in the LCZ696 arm, with more cough, renal failure, and hyperkalemia in the enalapril arm.

NEJM Executive Editor Greg Curfman describes the significance of this trial:  “Not only does this new treatment represent a significant advance, but it opens a new line of thinking about heart failure. Perhaps most exciting is the research it will stimulate in the future.”

In an accompanying editorial, Mariel Jessup, M.D., agrees, noting that the “PARADIGM–HF trial may well represent a new threshold of hope for heart failure patients.”

So to your patient – do you throw out his ACE inhibitor and start LCZ696?  Well, right now, you can’t.   LCZ696 is not FDA approved and is not commercially available.  Expect this study to form the basis of Novartis’ FDA application.  Perhaps by then it will have a catchier name.