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CardioBrief: More Safety Concerns on New HF Drug

— Potential for macular degeneration adds to Alzheimer's disease worries with Entresto

Ƶ MedicalToday

More safety concerns are being voiced about LCZ696 (Entresto), the new, ballyhooed heart failure drug from Novartis. Fueling these concerns is a mix of speculation, worry about the FDA's rapid approval of the drug, and a long-running feud between two leading heart failure researchers.

The concerns, raised in a by heart failure expert , of Temple University in Philadelphia, and co-authors, focus on the possibility that a key mechanism of the drug, neprilysin inhibition, may have troubling repercussions in the central nervous system and the eye. Entresto is a combination of the novel neprilysin inhibitor sacubitril and the older, well-established angiotensin receptor antagonist valsartan.

Neprilysin plays a central role in the degradation of beta-amyloid in the brain and the eye, so the concern is that inhibition of neprilysin might then lead to an increased risk for Alzheimer's disease and age-related macular degeneration.

The macular degeneration issue is new and has not been raised in the cardiology community until now, as a possible role for beta-amyloid in macular degeneration was only recently discovered.

The concern about Alzheimer's disease is not entirely new, having been aired earlier this year in the , as I . But although the drug is now approved, the concern about beta-amyloid has not been eliminated and has been "largely absent from public discussions about the beneficial effects of valsartan/sacubitril," Feldman and co-authors wrote.

An Observational Study?

At the request of the FDA, the neurocognitive question is being rigorously studied in , the next big Entresto trial in heart failure patients with preserved ejection fraction.

But the viewpoint authors called for "substantive steps ... to acquire data in a more timely manner" and to assess the issue in the heart failure patients with reduced ejection fraction who are now currently taking the drug. They recommended a "public-private partnership model" for a post-market surveillance system in the current patient population.

The viewpoint authors wrote that "there is equipoise regarding the utility of valsartan/sacubitril in patients with heart failure that will likely result in a cohort of patients receiving valsartan/sacubitril and a second cohort treated with traditional therapy of an angiotensin-converting inhibitor or an angiotensin receptor antagonist."

But there is no such equipoise, , the co-principal investigator of the , responded in an interview.

Given the highly significant clinical benefits in PARADIGM-HF, he said it would be unethical to ask patients to remain on ACE inhibitors. An observational study, such as Feldman's group proposed, "would require physicians to maintain patients on an ACE inhibitor for years and years, even though there is persuasive evidence" that Entresto saves lives. "What," Packer asked, "would the informed consent look like?"

Packer also pointed to the inevitable limitations of observational studies, because it is impossible for an observational study to completely correct for confounding effects. "Randomization controls for confounding in an observational study."

In an interview, Feldman asserted that equipoise does exist because there is significant residual doubt in the heart failure community about the drug, thereby creating a "natural experiment" that can help resolve troubling questions about the drug.

Packer, though, said that the results of PARAGON-HF will be known before the observational study could even be completed. (In their viewpoint, the authors wrote that "the " of PARAGON-HF is in 2022, but Packer said the trial will be finished much earlier than that.)

Lingering Concerns

The viewpoint authors acknowledged that no suggestion of neurocognitive or ocular adverse effects were found in PARADIGM-HF, the key trial supporting the drug's use, or in other studies. But, they wrote:

"These studies do not fully dispel concern, however, because patient follow-up in PARADIGM-HF was relatively short; Alzheimer disease-specific, dementia-related adverse events were not prespecified; and executive dysfunction, a pathognomonic finding in Alzheimer disease, was not measured. Furthermore, young monkeys and normal human volunteers do not have presenile plaque or blood-brain barrier dysfunction, both of which have the potential to increase the leakage of drugs into the central nervous system. By contrast, patients with heart failure have multiple risk factors for both Alzheimer disease and blood-brain barrier disruption including older age, hypertension, elevated cholesterol levels, cerebrovascular disease, and diabetes. In addition, the duration of time necessary for patients to manifest cognitive or behavioral symptoms is not immediate and is likely dependent on whether they had preclinical amyloid plaque already present in the brain or in the eye."

For now, "the risks of neprilysin inhibition in the brain and in the eye remain speculative," Feldman's group wrote. But because "the emergence or worsening of cognitive or visual impairments would be devastating for patients with heart failure," they recommended "a prudent approach" that would "follow high-risk patients closely with cognitive assessments, amyloid positron emission tomography, and retinal imaging until definitive answers emerge."

Packer said that it is impossible to dismiss the theoretical dangers of neprilysin inhibition but argued that the unequivocal benefits of valsartan-sacubitril in PARADIGM-HF should not be dismissed. He noted that the "relatively short" follow-up period "was because the trial was terminated early by the overseeing ethical committee when it observed that fewer patients were dying when they were treated with sacubitril/valsartan." He asked: "How many excess deaths can Dr. Feldman tolerate to justify his desire for clarity? I can assure him that -- with greater follow-up -- his fears might be justified, but only because it is not possible for dead patients to develop dementia."

The Middle of the Journey

It is worth noting here that the JAMA viewpoint will almost certainly not be the last attempt to raise questions about the role of Entresto in clinical practice. I have heard a rumor that a major journal will be soon publishing a paper raising more questions about PARADIGM-HF.

It is also worth noting that this is not the first dance for Feldman and Packer. They have been at odds for more than 20 years. Back in 1993, Packer wrote a critical of a studying vesnarinone, a novel heart failure drug that ultimately failed.

In response to a version of this story published on , Packer sent the following statement:

"It is really important to understand the difference between evidence and speculation. The PARADIGM-HF trial provides conclusive evidence that sacubitril/valsartan reduces cardiovascular mortality more effectively than guideline-recommended doses of enalapril. None of the clinical trials to date with neprilysin inhibition have noted any concerns about cognition or vision. Therefore, Dr. Feldman's opinion piece should be regarded for what it is: pure speculation.

"The question is: what purpose does it serve? If Dr. Feldman wants to raise questions about what might happen to patients whose lives are prolonged by sacubitril/valsartan, I have no problem with that. But it would be irresponsible for him to rely on such speculation to suggest that sacubitril/valsartan not be used instead of ACE inhibitors to prolong life in the first place."