The PARADIGM-HF trial was perhaps the biggest, potentially practice-changing study that came out of the ESC 2014 in Barcelona, and was the largest study of heart failure (HF) with reduced ejection fraction (EF) ever conducted. It was recently stopped early due to compelling efficacy. In this interview from the meeting, our CSWN executive editor talks with Scott David Solomon, MD, about the study. Dr. Solomon is the director of noninvasive cardiology at Brigham and Women's Hospital and a professor at Harvard Medical School.

CSWN: Let's first talk about the drug itself, which is called LCZ696 at present. What is it?

Scott David Solomon, MD: LCZ is a novel, dual-acting compound that consists of two molecular parts: an angiotensin receptor blocker (valsartan) and a neprilysin inhibitor. Neprilysin is the enzyme that is responsible for the breakdown of the biologically active natriuretic peptides. This dual-acting compound both blocks the angiotensin type 1 receptor and does all the things that we are familiar with respect to angiotensin receptor blockers, but it also blocks neprilysin. By inhibiting neprilysin, you're augmenting the naturally occurring endogenous natriuretic peptides including ANP, BNP, CNP, and a number of other vasoactive substances like adrenomedullin, substance P, and so forth. This is creating a new way to affect the hormonal systems in HF.

Describe the patient population you were looking at and some of the data.

We enrolled over 8,400 patients with predominantly Class II and III HF. We randomized them to either LCZ696 or enalapril 10 mg. It is very important to realize that this was not a trial against placebo. It was a trial against an active comparator, and, in fact, we ensured that patients were on what we consider the gold-standard bedrock of HF therapy.

We studied patients for an average of 27 months. As you know, the trial was stopped early by the DSMV for overwhelming efficacy. At the end of the trial, the average daily dose that patients were on of enalapril (the comparator) was over 18 mg and of LCZ was 375 mg, and, we found, a 20% very significantly significant reduction in the primary end point of cardiovascular death and HF hospitalization, a 20% extremely significant reduction in cardiovascular death, and a 16% significant reduction in all-cause mortality.

Those are striking findings from a trial of a new agent.

Striking because it's a new agent, but also because we went head-to-head with an active comparator. There are essentially no prior trials in HF going head-to-head with a gold-standard therapy that has shown this kind of efficacy.

Now these were people with reduced EF.

These were people with reduced EF. You had to have an EF under 40% to get in, and the mean EF was about 29% in those patients.

So, where to from here?

We're extremely excited, obviously, about these results. The trial was really designed so that, if successful, we would consider replacing the current standard of care ACE inhibitors, and by extension ARBs, with LCZ696. We believe that given not only the efficacy but also the side-effect profile, which was, for the most part, better. We saw less renal dysfunction. We saw less hyperkalemia. We saw less cough. We had a little more hypotension, but no more hypotension resulting in discontinuation. Overall, fewer people discontinued the therapy if they were on LCZ than if they were on enalapril.

When we posted the PARADIGM data on CardioSource, I did note that one of the readers of CardioSource had written, "Why didn't they compare a combination therapy for optimal therapy with the new agent plus a standard drug?" That really wouldn't have worked because of the special kind of "two hits" that you get with this new drug. Correct?

That's a very important point. You cannot give this drug together with an ACE inhibitor because it increases dramatically the risk of angioedema. That's because you're inhibiting multiple enzymes that are involved in the bradykinin pathway. This is actually the reason why a prior neprilysin inhibitor, omapatrilat, which, combined a neprilysin inhibitor with an ACE inhibitor, was not successful. There was a lot more serious angioedema and, quite frankly, it wasn't as effective in treating patients with HF.

When might we get more study information?

The paper has been published in The New England Journal of Medicine. We have several secondary publications that are almost complete and will probably be published fairly soon. We'll be presenting more data at the American Heart Association [meeting] on PARADIGM. We had a very robust ancillary study program with biomarkers that we measured, and we'll be reporting that at some point. We're also going to show data on the causes of death, and of the effects on the kidney. I think we're going to see an awful lot of PARADIGM information.

I want to add that we're starting a new trial with LCZ696. It's in HF with preserved ejection fraction, and is called PARADIGM-HF. It will be the largest HF with preserved ejection fraction study yet done.

McMurray J, Packer M, Desai A, et al. N Engl J Med. 2014;371:993-1004.

Keywords: Angiotensin Receptor Antagonists, Enalapril, Aminobutyrates, Receptor, Angiotensin, Type 1, Angiotensin-Converting Enzyme Inhibitors, Standard of Care, Hypotension, Angioedema, American Heart Association, Hyperkalemia, Pyridines, Valine, Tetrazoles, Neprilysin, Adrenomedullin, Cause of Death, Substance P, Schools, Medical, Heart Failure, Thiazepines, Cough, Hospitalization, Atrial Natriuretic Factor, Bradykinin

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