PARADIGM-HF: Results and Implications

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The HCPLive Peer Exchange “Advances in Heart Failure Management” features expert opinion and analysis from leading physician specialists on the latest developments in heart failure research, diagnosis, and management.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University and an associate director of surgical intensive care at the New York-Presbyterian Hospital in New York City.

The panelists are:

• Michael Felker, MD, MHS, Professor of Medicine, Chief of the Heart Failure Section, Director of the Heart Center Clinical Research Unit, and Director of the Advanced Heart Failure Fellowship at Duke University School of Medicine
• Jim Januzzi, MD, Roman W. DeSanctis Endowed Distinguished Clinical Scholar in Medicine at Massachusetts General Hospital and Hutter Professor of Medicine at Harvard Medical School
• Christian Schulze, MD, PhD, Associate Professor of Medicine, Division of Cardiology at Columbia University Medical Center, and Director of Research for the Center of Advanced Cardiac Care at Columbia University Medical Center

In this segment of the Peer Exchange, the panelists discuss the design, results, and implications of the large randomized, controlled PARADIGM-HF trial.

According to Felker, this was the largest randomized trial ever performed with a pharmacologic agent in chronic heart failure. PARADIGM-HF compared LCZ696 (sacubitril), “which is a drug that harnesses the pharmacologic benefits of RAS inhibition with valsartan and combines it in the same pill with a neprilysin inhibitor,” says Januzzi. “Head to head against the best possible therapy based on current knowledge, which was enalapril, an ACE inhibitor,” says Felker.

PARADIGM-HF represents “a paradigm shift,” in Felker’s opinion. “What we saw in PARADIGM-HF was an incredibly impressive treatment effect, even over and above best chronic therapy, with a reduction in cardiovascular mortality, all-cause mortality, cardiovascular hospitalizations, heart failure hospitalizations, and an improvement in quality of life,” he continues. “In PARADIGM-HF, LCZ was as much better than enalapril as enalapril is than nothing,” he says, representing “a massively important result” for heart failure treatment.

To qualify for the trial, patients were required to have impaired ejection fraction, so the results apply only to this population. If one were to compare the PARADIGM-HF population to the general heart failure population seen in clinical practice, Felker explains, “the patients in general are a little younger,” with “a pretty high incidence of ischemic heart disease, which is common,” and the patients were “mostly class 2, class 3, pretty typical high-risk patients.” It should be remembered that the trial included a run-in period, “and run-in periods always select patients more likely to be able to tolerate the drug,” although he does not think this feature of the trial mitigates its “massively substantial results.”

Neprilysin inhibitors like LCZ696 (sacubitril) “block the breakdown of a number of vasoactive substances, most notably B-type natriuretic peptides (BNP),” says Januzzi. In addition to aiding in the diagnosis of heart failure and establishing its severity and prognosis, BNP has some favorable effects in the heart and vasculature. By “cautiously and modestly increasing circulating BNP concentration,” the neprilysin inhibitor “vasodilates the patient and reduces a number of the deleterious effects of heart failure,” he says, possibly contributing to the substantial improvements seen in PARADIGM-HF.

“The take-home message from the PARADIGM-HF trial,” according to Januzzi, “is that if a patient can tolerate the potent antihypertensive effects of LCZ696 with uptitration to the target doses, it’s expected that the benefits will be substantial.”