New heart failure interventions face outcomes test

A history of trials where a well-reasoned heart failure intervention did not have the expected results is now coloring the way some clinicians view potential new treatments.

A couple of examples of this cautious, skeptical mindset cropped up during the annual meeting of the Heart Failure Association of the European Society of Cardiology in Florence, Italy, in May.

Dr. Martin Cowie

I previously reported on one of the major talks at the sessions, results from a pivotal trial of a phrenic nerve stimulation device in 151 patients with some type of cardiovascular disease (more than half had heart failure) and central sleep apnea. These patients generally had significant improvement in their apnea-hypopnea index while on active treatment with the phrenic nerve stimulator, designed to produce rhythmic contractions of the diaphragm to create negative chest pressure and enhance breathing in a way that mimics natural respiration and avoids the apparent danger from a positive-pressure intervention in patients with central sleep apnea and heart failure with reduced ejection fraction (HFrEF).

The positive-pressure danger in such patients occurred unexpectedly and dramatically in the form of significantly increased mortality among HFrEF patients with central sleep apnea enrolled in the SERVE-HF trial. Based on that chilling experience, “our understanding of central sleep apnea is imperfect,” said Dr. Martin R. Cowie, lead investigator of SERVE-HF, who rehashed his experience with that study during the recent meeting. “A really important message was that just because patients say they feel better [with the adaptive servo-ventilation tested in SERVE-HF], that doesn’t necessarily translate into benefit,” Dr. Cowie noted.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Mariell Jessup

Dr. Mariell L. Jessup, a leading U.S. heart failure expert, had a similar reaction when I spoke with her during the meeting.

“A lot of things made a lot of sense, including treating central sleep apnea in a patient with HFrEF with positive air pressure that made them feel better,” she said, also invoking the specter of SERVE-HF. “We have to now demand that sleep trials show benefit in clinical outcomes,” such as reduced mortality or a cut in heart failure hospitalizations, and certainly no increase in mortality. Until that’s shown for phrenic nerve stimulation she’ll stay a skeptic, she told me.

Another intervention recently available for U.S. heart failure patients that seems on track to confront this “show-me-the-outcomes” attitude involves new drugs that cut serum potassium levels by binding to potassium in the gastrointestinal tract. This class includes patiromer (Veltassa), approved by the Food and Drug Administration in October 2015. Another potassium binder, sodium zirconium cyclosilicate (ZS-9), seems on track to soon receive FDA approval.

Several speakers at the meeting spoke of the potential to use these drugs to control the hyperkalemia that often complicates treatment of heart failure patients with an ACE inhibitor, angiotensin receptor blocker, or a mineralocorticoid receptor antagonist, especially heart failure patients with concomitant renal disease. Study results showed treatment with patiromer or ZS-9 reversed hyperkalemia, thereby allowing patients to remain on these drugs that are known to significantly cut rates of mortality and heart failure hospitalizations in heart failure patients.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Bertram Pitt

“Right now, a lot of patients don’t get these lifesaving drugs” because of hyperkalemia, noted Dr. Bertram Pitt, a University of Michigan cardiologist who has been involved in several patiromer trials (and is a consultant to Relypsa, the company that markets patiromer).

The problem is that no studies of patiromer or ZS-9 treatment have so far shown that these drugs lead to reduced mortality or heart failure hospitalizations in heart failure patients. All that’s been shown is that patiromer and ZS-9 are effective at lowering potassium levels in patients with hyperkalemia out of the danger zone, levels above 5 mEq/L.

“I want to see outcome trials,” said Dr. Jessup.

Dr. Pitt agreed that outcomes data would be ideal, but also noted that currently no studies aimed at collecting these data are underway.

Without these data, clinicians need to decide whether they believe proven potassium lowering alone is a good enough reason to prescribe patiromer or ZS-9, or whether they need to see proof that these drugs give patients clinically meaningful benefits.

If they demand outcomes evidence they may need to wait quite a while.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler