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:
In this segment of the Peer Exchange, the panelists discuss how angioedema was avoided in the PARADIGM-HF trial, and what might be expected from a representative real-world population.
The neprilysin inhibitor omapatrilat was associated with angioedema, which affected certain elements of how PARADIGM-HF, which studied the neprilysin inhibitor LCZ696 (sacubitril) was conducted. The protocol called for a run-in period, which could help assess whether patientstolerated the study medication, says Schulze. He adds that “it was specifically designed to combine a neprilysin inhibitor with an ARB,” and that “the enalapril was withheld for one day before initiation of LCZ696 and then the LCZ696 was stopped before randomization.” But he cautions that, “We also need to see real-live data from patients taking it in everyday practice.”
In addition to study design, there may be molecular differences between omapatrilat and LCZ696 that “probably favored the results from PARADIGM-HF,” says Januzzi. For instance, he says, “Omapatrilat has a number of effects on other vasoactive substances, including bradykinin and other substances that might play a role in the development of angioedema, whereas sacubitril does not.”
Also, one theory is related to the patient population in the trials. “The angioedema seen in the OVERTURE study, which was the study with omapatrilat, was typically seen in African Americans, and there were only 230 or so African Americans total in the PARADIGM-HF study, which was a gigantic study,” says Januzzi. Therefore, real-world data will be needed to find out its effects “in a more representative heart failure population. Regarding whether this will become an issue, he says, “The consensus is it probably won’t happen because there are biological reasons why omapatrilat seemed to cause the angioedema, but it’s something that clinicians need to watch out for.”
Despite its high potency, “In general, in PARADIGM-HF, actually, LCZ696 was better tolerated than enalapril,” says Felker. The life-threatening cases of angioedema seen with omapatrilat were not experienced in the PARADIGM-HF trial.
In discussing the differences between the clinical trial world versus the real world, Januzzi explains that the issue of patients receiving suboptimal doses of ACE inhibitor or ARBs in clinical practice is at least partially explained by the “demographics of a typical clinical trial population: they’re younger, they’re less comorbid, they have better blood pressure.” In addition, he says that “it’s very difficult for the everyday clinician to remember the targets that are articulated from these clinical trials,” and that seeing patients frequently enough to uptitrate the dose appropriately can be a challenge.
The mean dose of enalapril (the active comparator) in the PARADIGM-HF trial was 18.9 mg/day, which, according to Felker, “was actually the highest enalapril dose used in any enalapril trial.” Overall, he says, “they were able to show an improvement [with LCZ696] on top of extremely good baseline therapy, which is I think one of the remarkable things about the results.”