Ileana L. Piña, MD, MPH


September 12, 2014

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Hello. This is Ileana Piña, Associate Chief of Cardiology at Montefiore Einstein Hospital and Medical Center in the Bronx, New York. Today I am in the beautiful city of Barcelona at the European Society of Cardiology (ESC) Congress. More than 30,000 individuals are registered here. It is a terrific venue, with many exhibitors and important papers.

In the heart failure world, the trial called PARADIGM has taken over the news. Even before the ink was dry, the New England Journal of Medicine already had published the PARADIGM study online, with the first author being John McMurray.[1] What is this trial called PARADIGM?[2] The number-one drug of use in heart failure, according to the guidelines, is an angiotensin-converting enzyme (ACE) inhibitor, and probably the most classic and best studied of the ACE inhibitors is enalapril. Using enalapril as a comparison drug in the doses that were used in the SOLVD[3] trial (10 mg twice daily), the PARADIGM trial began with a novel drug that doesn't even have a name yet. It is known as LCZ696 and is manufactured by Novartis (Basel, Switzerland). LCZ696 is a combination of valsartan, an AT-1 receptor blocker that was shown in the Val-HeFT trial to be a positive agent and was approved by the US Food and Drug Administration (FDA) for patients who are ACE inhibitor intolerant. The other component of this combination drug is a neprilysin inhibitor.

One of the benefits of ACE inhibition is blocking the breakdown of bradykinin, which is a vasodilator. Neprilysin breaks down the natriuretic peptides. Atrial natriuretic peptides and brain natriuretic peptide (BNP) are degraded by the neprilysin enzyme, and yet these sorts of neurohormones (which now we also call biomarkers) can be vasodilators and improve sodium excretion in the kidney. So, this is a novel drug, a little different from the older drug, omapatrilat, which had more of a core of ACE inhibition plus a neprilysin inhibitor but produced large amounts of angioedema.

The PARADIGM trial involved patients with low ejection fraction heart failure who were randomly assigned to either 10 mg twice daily of enalapril or the drug LCZ696. The study was stopped early. We all heard about it, and about how excited everyone was to have a new agent with such a positive impact on the combined endpoint of mortality and hospitalization, that the Data Safety Monitoring Board stopped the study early.

PARADIGM was an international trial, but not as many North Americans were enrolled. That may come up as a question if and when this drug makes it in front of the FDA's Cardiovascular and Renal Drugs Advisory Committee. There were also very few black patients in the study. If approved, the drug will probably be available at a much higher price, because enalapril and many of the ACE inhibitors are now generic. In this era of cost reduction, it's something that we may want to think about. I encourage you to read the paper by John McMurray in the New England Journal of Medicine.

The company has decided to study preserved ejection fraction heart failure (HFpEF). We do not have a great drug for patients with HFpEF. These patients often have comorbid conditions (such as hypertension, diabetes, and obstructive sleep apnea) and often die -- not of their heart disease, but of these underlying conditions. Because we don't have a great drug and because of some baseline data and animal studies that appeared to be positive,[4] it has been decided to study this combination angiotensin receptor-neprilysin inhibitor in HFpEF. The first patient has now been enrolled internationally. At Montefiore, we will be one of the sites for PARADIGM, so stayed tuned. It's an area for which a drug was badly needed.

This is Ileana Piña, signing off. Have a great day.


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