Efficacy and Safety of Ivabradine in Heart Failure

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The MD Magazine Peer Exchange “Managing Heart Failure Today: Current Best Practices and New Treatment Options” features a panel of physician experts discussing key factors to consider when making treatment decisions for patients with heart failure and their own clinical experiences with recently approved medications for the treatment of heart failure.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons, and an associate director of Surgical Intensive Care at New York-Presbyterian Hospital.

The panelists are:

• Michael Felker, MD, MHS, professor of medicine and chief of the Heart Failure Section at Duke University School of Medicine, in Durham, NC
• Milton Packer, MD, Distinguished Scholar in Cardiovascular Science, Baylor Heart and Vascular Hospital, Baylor University Medical Center, in Dallas, TX
• Scott Solomon, MD, Senior Physician and director of Non-Invasive Cardiology at Brigham and Women’s Hospital, and Edward D. Frohlich Distinguished Chair and professor of medicine at Harvard Medical School, in Boston, MA
• John R. Teerlink, MD, director of Heart Failure at San Francisco Veterans Affairs Medical Center and professor of medicine at UCSF in San Francisco, CA

Peter Salgo, MD: You just gave me a big word salad of all the various names for these agents. Ivabradine is the name I know. Is that a different drug or the same drug? What is it?

John R. Teerlink, MD: Ivabradine is a different drug. I’ll also include that this is one of the 2 drugs that was included in this [ACC/AHA guideline]. The ARNI (angiotensin receptor blocker/neprilysin inhibitor) was the first one. The second one is ivabradine.

Ivabradine was given a class 2 level of recommendation, saying that in the appropriate patients (patients who have symptomatic heart failure, who were already on maximal beta-blockers, already on maximal neurohormonal therapy, who have a sinus rhythm and a heart rate above 70), you can consider starting them on ivabradine with the goal of reducing the morbidity. So, it only reduces heart failure hospitalizations in these patients.

Peter Salgo, MD: Okay, tell me about ivabradine. What is it? How does it work?

John R. Teerlink, MD: Ivabradine is an interesting compound because it very selectively blocks the funny current. This current exists in 2 main cells in the body—one of which is the sinoatrial (SA) node cells, or nodal cells, and the other is in some of our retinal cells. In the SA node, this current, the funny current, helps modify the rate of depolarization of the sinoatrial node, which is in direct control of the heart rate. So, by blocking this current, you can very selectively decrease the heart rate without other off-target effects.

That is both a good-news and a bad-news thing. You know that with a beta-blocker, it also lowers heart rate. But it has many other effects—many of which we think are very beneficial. Ivabradine very specifically decreases the heart rate.

There have been 3 huge trials with ivabradine. The one that was specifically [done for] heart failure was the SHIFT trial. There were over 6500 patients. In this trial, ivabradine decreased, significantly, the rate of heart failure hospitalizations in these patients. It had no effect on overall mortality, but it did keep people out of the hospital.

Peter Salgo, MD: Again, we come to heart failure drugs that make people feel better, decrease heart failure [symptoms], but they don’t have an impact on mortality. Are they worth it?

John R. Teerlink, MD: I think, certainly, for the patients who are feeling better and staying out of the hospital, it is worth it. But, I think the big caution for me with ivabradine is that you only have so many beats per minute to spend, if you will. In terms of when you start a beta-blocker, you know they start at a heart rate of 80. Now, you advance them on the beta-blocker. You’ve now reduced their heart rate down to some range. Sometimes you’re going to be limited by how much beta-blocker you could give. If you still have a heart rate above 70 in a patient who you’ve maximized the beta-blocker on, then it’s useful to consider ivabradine as a therapy.

Scott Solomon, MD: So, how many people do you think fall into this category? Is it that physicians out there aren’t treating patients with maximally-tolerated beta-blocker doses? We know beta-blockers do reduce morbidity and mortality.

John R. Teerlink, MD: Tremendously in heart failure.

Scott Solomon, MD: We don’t want people to be giving a new drug simply because they don’t want to maximize beta-blockers.

John R. Teerlink, MD: Exactly. That was one of the biggest concerns when ivabradine first was presented in the EU, because there we heard people come up to the microphones and say, “Oh, this is great. Ivabradine is so much easier to give. I don’t have to worry about beta-blockers.”

That is terrifying to me. It’s kind of like with a cancer patient if you say, “Oh, great, I’m not going to give them the chemotherapy agents because that’s so difficult to give. I can just give them some Tylenol and vitamins.”

So, no. Clearly, ivabradine can help patients stay out of the hospital, but they have to be the appropriate patients. I think your point’s absolutely essential. They have to be optimized on beta-blockers.

Scott Solomon, MD: Optimize on beta-blocker therapy, right.

Michael Felker, MD, MHS: I think this is the key issue [we need to try] to figure out. With 2 new drugs [available], one of the things people in the audience are trying to grapple with is, “Who do I give what to?” I think what it means to be on the maximally-tolerated dose of beta-blockers is not at all clear because a lot of beta-blockers’ side effects are fairly nonspecific—fatigue, a little bit of dizziness or lightheadedness.

So, is that the maximally-tolerated dose? I think the message you’re hearing is that this really is for all heart failure management. You really need to push to be successful with these drugs—almost to the level of a little bit of discomfort of the clinicians, potentially, to feel like you’re actually going to get all the benefit. It is very dose-dependent.

Peter Salgo, MD: Before we go any further, just lay out for me the indications and contraindications, again, for ivabradine.

John R. Teerlink, MD: So, the indications are [for] patients with symptomatic heart failure who have reduced ejection fraction and who still have a heart rate above 70 beats per minute in sinus rhythm. It’s very important [to monitor patients for] atrial fibrillation, and [patients should be] taking maximally-tolerated doses [of beta-blockers].