SILVER SPRING, MD — Now that the first-in-class drug once best known as LCZ696 (Entresto, Novartis) has been approved by the US Food and Drug Administration (FDA) for patients with heart failure (HF), experts are voicing real excitement, along with a few lingering concerns, while asking: What happens next?
Valsartan/sacubitril, an angiotensin-receptor/neprilysin inhibitor (ARNI), was approved July 7 for HF patients with reduced ejection fraction. The approval was based on the seminal PARADIGM-HF trial and came after an expedited review and fast-track designation by the FDA, processes it reserves for drugs believed to fill an unmet medical need.
"I think this is exciting and is a great new hope for our heart-failure patients," Dr Mariell Jessup (University of Pennsylvania, Philadelphia) told heartwire from Medscape.
Jessup reported that a new committee is now being formed to update the joint American College of Cardiology-American Heart Association HF management guidelines, which were last released in 2013.
Dr Clyde Yancy (Northwestern University, Chicago, IL) will also be part of this committee. A few days after PARADIGM was first presented at the European Society of Cardiology 2014 Congress in Barcelona, Spain, Yancy told heartwire that the trial drug represented "a new day in heart failure."
"A year later, I continue to feel that this is, in fact, a reflection of a new day—for patients and for the opportunity to reenergize the community. It's also a huge endorsement for the importance of science in cardiovascular medicine."
That said, "there's still a need for more discussion because we aren't ready to offer this carte blanche to everyone who comes to our offices," added Yancy. "Especially because we didn't have the benefit of an FDA panel review, we have to stay very close to the published information."A Few Issues . . .
The >8000-person-strong PARADIGM-HF trial showed that patients with chronic HF treated with LCZ696 had a 20% decrease in CV death or HF hospitalizations vs those treated with the ACE inhibitor enalapril, as well as a significant reduction in all-cause mortality.
Initial reactions after the trial was first presented were, by and large, hugely enthusiastic. But after sitting with the findings for a while, some in the field began raising concerns, even as the overall feeling remained optimistic.
"This is a large trial with convincing results and will be important for clinical practice. We're hoping for great things," said Dr John G Cleland (Imperial College London, UK).
"However, there are a few issues that have yet to be settled. For example, it was done in a population that was tolerant of full doses of ACE inhibitors and LCZ. And it was only those patients going forward in the long-term trial," said Cleland, noting that the drug hasn't been approved yet in Europe.
Jessup added that the trial also didn't have many participants with comorbidities, which is standard in these types of studies. "They didn't have renal insufficiency and they weren't on a gazillion other drugs, like real-world patients often are."
"These patients were very stable," agreed Cleland. "But in clinical practice, cardiologists very often see patients who have had a recent admission with worsening heart failure. There will be a temptation to treat them with this drug, but we don't have evidence of the safety in this setting."
Yancy said that one question he's heard discussed is whether the trial's early termination may have led to an exaggeration of benefit and an understatement of risk, which has been seen in other early-termination trials.
"So we have to be prepared for results that may not be as robust as they were in [PARADIGM] and prepared for side effects that were not evident there," he said. "The one that is most notable, that seemingly was absent in the trial, is angioedema."
In addition, he noted that labeling calls for a 36-hour washout period, based on the trial, for switching from an ACE inhibitor to the ARNI. "We respect that and think it's correct. But what happens when someone doesn't provide that entire washout? We have to recognize that it's not a panacea. It hasn't cured the disease. But going forward, it does provide us an opportunity to make a big difference," said Yancy.
He added that there were also very little data on patients older than age 75 "and almost zero data for the African American patient. So, while the enthusiasm is appropriate, it needs to be measured by doing the right thing for the right patient at the right time."
Benefits Justify Cost?
Co–principal investigator of PARADIGM-HF, Dr Milton Packer (University of Texas Southwestern, Dallas), told heartwire that he was excited about the FDA's approval and that this was the quickest approval for a CV drug in a long time.
"I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure," said Packer.
Interestingly, Cleland defended the fact that the trial was 80% men, noting that "that's the price you pay for having a study of patients with low ejection fraction." He added that even 20% of an 8000-person study represents 1600 women. "There were more women randomized in PARADIGM than overall patients randomized in several other landmark trials."
Packer added that a new paper by his team, which was just accepted for publication, examined whether or not age was a factor that influenced the response of the agent.
"Even when we looked at age ranges above 75, the benefits were just as striking as the younger ages," he said. "Age just does not appear to be a factor. We also looked at women specifically, and there was no gender influence at all with the drug."
Another question raised about the new compound has been about pricing and whether the benefits justify the cost. A representative from Novartis told heartwire by email that each pill will cost $6.25, for a price of $12.50/day and roughly $4500/year per patient.
"If patients stay out of the hospital more and live longer, this price will be worth it. There have been other drugs that have been this costly that we've embraced, including Plavix," said Jessup, referring to the antiplatelet clopidogrel, long used for many patients with CV disease.
But when told the US price, Cleland said that that seemed quite high, especially compared with the cost of enalapril. "If they try to implement that price in Europe, I think it will make people hesitate," he said. "I strongly suspect that the reaction of the payers will be 'we'll pay what we have to,' but then you have to be very clear that the patient has fulfilled all the criteria of the clinical trial."
Yancy noted that it's hard to really answer these issues without cost-analysis data.
Abandon ACE Inhibitors?
In addition to the ARNI, the FDA also recently approved ivabradine, making these the first drugs to be approved for HF in almost a decade.
"There's now an educational process that needs to be undertaken," said Jessup. "Just as with any new drug, there's a potential that in inexperienced hands there could be some mishaps."
Yancy added that he's interested to observe how the medical education process will address two new drugs "that are very different, yet both have the ability to at least change morbidity. And LCZ696 has significant opportunity to improve mortality.
"There clearly is a need for very robust, thoughtful, and straightforward education. It can't be long discussions and very arcane presentations. It needs to be usable, palpable information that a practitioner can take and apply immediately," he said, adding that the strategies will need to be different from those used before.
"Plus, it has to be done in context with everything else you should be doing in a patient with heart failure. This isn't a conversation that can be done in a vacuum."
He also noted that clinicians shouldn’t think that benefit can’t come from other treatments. "The current suite of evidence-based therapy for [HF] is significantly beneficial." This means that with ivabradine, "background therapy needs to be intact, especially a beta-blocker." And although LCZ696 might be used in lieu of an ACE inhibitor, "everything else needs to be in place," stated Yancy.
When asked specifically if doctors will now be ready to completely abandon ACE inhibitors, he said only if it's the right patient, such as those in class 2 or 3, and if they replicate what was shown in PARADIGM. "But many patients in [HF] don't fit that profile."
Jessup agreed, stating that not every patient will be able to tolerate this drug. "For example, there weren't a lot of people with severe heart failure put into the trial," she said. "ACE inhibitors have revolutionized cardiovascular medicine. So I don't think anybody's going to abandon them. It's far too early to say that."
Still, she added that she could envision a time where clinicians would start with LCZ696 instead of with an ACE inhibitor. "But it's going to take time."
"Change the Narrative"
Last November, new Canadian heart-failure guidelines were released that included recommendations on the use of LCZ696. Cleland noted that new European Society of Cardiology HF guidelines are scheduled to appear next year. "So they must undoubtedly be considering LCZ."
Yancy reported that the US guideline committee will likely create an update of current recommendations rather than a full rewrite, to be released "hopefully" before the end of the year.
"This is just a very, very exciting time right now," said Jessup.
"When you couple what's happening with ivabradine and LCZ696, and with the pending approval of the PCSK9 drugs, you begin to recognize that . . . we really are beginning to redefine the experience of chronic diseases," said Yancy. He added that this is important because the more that diseases can be kept in the early stages, or even at a preventive stage, the better off public health will be.
All of this leads to "a great opportunity to sit down and have a new discussion about heart failure. Can we change the narrative?" asked Yancy. "I believe it's time for us to take 'failure' out of 'heart failure' and look at what we can do to generate success."
PARADIGM-HF was funded by Novartis. Yancy and Jessup reported no relevant financial disclosures. Cleland has received research support from Novartis, Amgen, Medtronic, Philips, Merck, Siemens, Servier, and Sorin. Packer has reported consulting for Novartis.
Heartwire from Medscape © 2015
Cite this: What Now, ARNI? Experts Ponder Next Steps for Newly Arrived Heart-Failure Drug - Medscape - Jul 27, 2015.