“We see a doubling in the reduction in cardiovascular mortality with this new therapy over and above that obtained with an ACE inhibitor or ARB [angiotensin receptor blocker],” Dr. McMurray emphasized.
Dr. Marvin A. Konstam
Panelist Dr. Lynne W. Stevenson wasn’t convinced.
“I don’t believe it is time to replace ACE inhibitors and ARBs. I don’t think LCZ696 is ready for a level I [treatment should be performed] indication; that is a higher bar. ... I think we could see a level IIa [treatment is reasonable to perform] indication based on the strong results that we’ve seen,” said Dr. Stevenson, director of the heart failure and cardiomyopathy program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.
She estimated that fewer than 10% of U.S. heart failure patients fit the description of PARADIGM-HF participants, with mild to moderate heart failure with reduced ejection fraction. Importantly, the run-in process employed in the study ensured that only patients with a demonstrated ability to tolerate enalapril in therapeutic doses were enrolled. And even in that filtered population, there was a substantial dropout rate in the LCZ696 arm due to hypotension during follow-up.
“I certainly don’t think we have any information about patients newly diagnosed with heart failure. I don’t think if you put new heart failure patients on LCZ696, they’d necessarily be able to stand up, and if they could stand up I’m not sure we could get them on the appropriate dose of beta blockers,” Dr. Stevenson added.
Noting that only 5% of PARADIGM-HF participants were black, she said that “clearly this is something we will need to watch as we get more experience with this drug, but there was no signal of concern.”
Dr. Marvin A. Konstam, professor of medicine at Tufts University, Boston, shared one of Dr. Stevenson’s concerns: “How do we know what will happen with ACE inhibitor virgins in the real world where you don’t get a run-in period?”
Panelist Dr. John G.F. Cleland said, “I don’t want to second-guess the guideline committees, but surely this must be a IA [data derived from multiple clinical trials or meta-analyses] indication. What intrigues me is what will the indication for ACE inhibitors look like in future guidelines? Is it also going to be IA in the same group of patients? That’s something the guidelines committees are going to have to sort out.”
“A lot of these questions and people’s concerns will either be increased or reduced once we start to get the medicine into clinical practice. What I find quite distressing is that we might be sitting here at this time next year and still not be in a position to prescribe this agent because it may still be going through the regulatory process,” said Dr. Cleland, professor of cardiology at the University of Hull (England).