Ivabradine's US Approval for HF Came 'Out of the Blue'

Deborah Brauser

May 01, 2015

SILVER SPRING, MD — Response to the recent approval of the heart-rate–slowing drug ivabradine (Corlanor, Amgen) by the US Food and Drug Administration (FDA) has included cautious enthusiasm as well as surprise—not at whether it should have happened but rather how it happened.

"This particular drug allows us to control heart rate without a lot of the side effects. So I believe it definitely has a role to play," Dr Lee Goldberg (University of Pennsylvania, Philadelphia) told heartwire from Medscape. However, "it seemed like the FDA acted somewhat out of the blue, as we were expecting another big panel meeting later this summer," he added.

Dr Clyde Yancy

Dr Clyde Yancy (Northwestern University, Chicago, IL) called the approval process "awkward" and said he wished there had been a premarket panel discussion. "There wasn't the usual reliance on a deeper dive like the FDA usually exercises with both published and unpublished data," he said, noting that more research is needed postapproval to understand best practices when using the compound.

The FDA approved ivabradine on April 15 for reducing the risk for hospitalization in stable patients with HF (and a resting heart rate of at least 70 bpm on maximally tolerated beta-blockers) without first convening a Cardiovascular and Renal Drugs Advisory Committee (CRDAC) meeting.

Dr Philip Sager

"Although the usual expectation is to take new molecular entities and particular new classes to an advisory committee, it was felt that Corlanor presented no novel issues warranting discussion," said the director of the FDA's Division of Cardiovascular and Renal Products, Dr Norman Stockbridge, in an emailed statement to heartwire .

Dr Philip Sager (Stanford University School of Medicine, CA) was acting chair for a recent CRDAC meeting. He noted that he didn't see any problems with ivabradine's approval, which was based on findings from SHIFT in 2010 showing that patients with HF who were treated with the medication had an 18% decrease in risk for cardiovascular death or hospitalization over 23 months[1].

"This was an important, clinically beneficial end point. And I think this drug could be helpful to the patients who meet the indication criteria," said Sager.

"Certainly, we're all going to be looking to our guidelines writing committees to see exactly how this compound will be incorporated," added Goldberg. "I think it's going to change practice—not in lieu of another drug but as an add-on."

Lessons From Europe

An inhibitor of the lf current in the sinoatrial node, ivabradine was approved in Europe a number of years ago for angina and HF under the names Corlentor and Procoralan (Servier). However, the medication showed no significant effect on clinical outcomes in patients with stable CAD in the recent SIGNIFY trial.

More alarming, the study also showed an increase in combined death or nonfatal MI in the participants with symptomatic angina. Based on this finding, the European Medicines Agency's Pharmacovigilance Risk Assessment Committee conducted a review last fall and found that SIGNIFY participants received the medication in doses of up to 10 mg twice daily, which is higher than the currently authorized maximum dose of 7.5 mg twice daily. The committee went on to recommend closer monitoring in patients with angina.

The drug appears to have fared much better in patients with stable HF, which ivabradine was approved for in Europe in 2012.

Dr Kenneth Dickstein

However, Dr Kenneth Dickstein (University of Bergen, Stavanger University Hospital, Norway) emphasized that European approvals don't always mean it's available across Europe. The medication became readily available only recently in his country because of disagreements between the Norwegian authority and the pharmaceutical company over costs.

"I found the results from [SHIFT] really convincing. Also, once I get my hands on a drug and see how it starts to work in practice and talk with colleagues about how patients are responding, that's when we really start to see what it's about," said Dickstein. However, "it was only about a month ago that an agreement between Servier and the Norwegian authority took place, and it's just now that we can get access to the drug," he reported.

In the US, ivabradine tablets will be available in doses of 5 mg and 7.5 mg; it is reported to have a wholesale cost of $375 per month or $4500 per year[2]. Labeling information notes a starting dose of 5 mg twice daily, with adjustments after 2 weeks based on heart rate to a maximum of 7.5 mg twice daily. Patients with conduction defects "or in whom bradycardia could lead to hemodynamic compromise" should have a starting does of 2.5 mg twice daily.

Dickstein noted that he's excited to finally start using the medication regularly and thinks it could also be a good tool for US clinicians.

"I've been using ivabradine sometimes on compassionate protocol in order to get the drug for patients I believe have an inappropriate tachycardia that I want to treat. But I don't do it a lot because it hasn't been available," he said.

"Ivabradine lowers heart rate and only affects the sinus node, but it will not provide adrenergic blockade, which beta-blockers do. So I'm very fascinated to now work with some patients to see how this works and how they feel. I find the concept of pure heart-rate reduction intuitively attractive."

Heart Rate as a Target: New Territory

Dr Karl Swedberg

Interestingly, lead author of SHIFT, Dr Karl Swedberg (University of Gothenburg, Sweden), told heartwire that the message to use ivabradine has been "slow to pick up" throughout much of Europe, even though the European Society of Cardiology Congress (ESC) HF guidelines, which included recommendations about the medication, came out in 2012.

"Many physicians are not using heart rate as a target. It's a new treatment concept, so it will take time to get people to become used to it."

Swedberg added that he hopes the FDA approval means that American patients with HF "will be able to improve their situation"—and that US clinicians will assess the medication sooner than some of their European counterparts.

Implications for Beta Blocker Dosing

Yancy, however, has pointed out some problems with the study responsible for the FDA approval ever since it was first presented at an ESC meeting back in 2010. At that time, he told heartwire of concerns about the beta-blocker dosing and about the trial's participants, which he said were somewhat atypical and did not include any patients from the US.

In a recent interview, Yancy said that although he still has these concerns, "the SHIFT investigators make a very cogent argument that the principal reason for the benefits seen with ivabradine is because of the additional heart-rate slowing in patients who, despite appropriate efforts, still have an elevated resting heart rate."

"That's a provocative concept, and the investigators should be congratulated. They've made us understand that we should perhaps revisit the importance of heart-rate modulation."

"I think ultimately this will be a niche product for a unique cohort of patients. I don't think it will cover a large swath of the heart-failure community," he said, adding that there have been reassurances that the compound is safe. "And that may be the driver to explain why the FDA didn't insist on having the panel meeting."

"We're Just Trying to Figure It Out"

Dr Lee Goldberg

Overall, Goldberg noted that "this is an unbelievably exciting time in heart failure"—a comment that was echoed by Sager and to which Yancy said he'd like to "give a double thumbs up."

In addition to ivabradine, it appears likely that the new angiotensin receptor-neprilysin inhibitor (ARNI) that grabbed attention in the recent PARADIGM-HF study will be approved soon. Canadian HF guidelines released last November already included a recommendation on the use of the ARNI.

"These are the first new drugs to be introduced into heart failure in many years. So among heart-failure docs there is excitement that we have some new drugs to offer," said Goldberg.

"We're just trying to figure out, in what is already a very complicated medical regimen, how to incorporate these in the right patients in the right way."

The SHIFT trial was funded by Servier. Goldberg, Sager, Yancy, and Dickstein report no relevant financial disclosures. Swedberg reported receiving research grants and honoraria from Servier and Amgen.

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