The Role of Ivabradine in Heart Failure Management

In this segment, Sheryl Chow, PharmD, BCPS; Akshay Desai, MD; Peter L. Salgo, MD; Scott Solomon, MD; and Orly Vardeny, PharmD, MS, review the mechanism of action for ivabradine and provide insight regarding the 2016 American College of Cardiology/American Heart Association/Heart Failure Society of America heart failure treatment guideline update.

Peter L. Salgo, MD: We have guidelines, and guidelines are at least road maps to try to get from here to there. We have the 2016 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) clinical guidelines for the treatment of HFrEF (heart failure with reduced ejection fraction). What are those guidelines? How do they help you at all?

Sheryl Chow, PharmD, BCPS: Basically, those guidelines are a focused update, not a complete update. It’s just focusing on the newly approved medications, such as, as you said, ivabradine and Entresto. And the point is to discuss the rule of that in the HFrEF patient. What are the recommendations? What’s the level of evidence?

One of those options is ivabradine (or Corlanor), and this particular medication is very unusual. Actually, both of those medications have very unusual types of mechanisms. Ivabradine, in itself, is kind of unique in a way. In the 1970s, they coined the term “funny current,” and ivabradine affects that through this HCN (hyperpolarization-activated cyclic nucleotide-gated) channel. The HCN channel is just this hyperpolarized gated channel in the sinoatrial node, which is the cardiac pacemaker, and therefore, it inhibits this particular channel and actually prolongs phase 4 depolarization. And the heart rate actually goes down.

Peter L. Salgo, MD: Is its main mechanism of action simply reducing the heart rate?

Sheryl Chow, PharmD, BCPS: There’s really no significant effect on the blood pressure, so it does not cause hypotension, compared to some of the other medications that lower heart rate.

Orly Vardeny, PharmD, MS: But the key is that it doesn’t cause conduction abnormalities like some other medications that lower heart rate or contractility. It doesn’t affect inotropic activity of the heart.

Scott Solomon, MD: Beta-blockers are absolutely standard of care in heart failure, and we use beta-blockers to lower the heart rate. But the beneficial effects in beta blockers, we don’t completely understand. There is certainly an antiremodeling effect (the blockade of the central nervous system). The sympathetic nervous system is obviously extremely important. But what we don’t know exactly, is, where is that magic for beta-blockers?

What we do know is that beta-blockers reduce morality in patients with heart failure. It’s been shown in study after study. Ivabradine, which is a pure heart rate reducer, as Sheryl just talked about, was shown in 1 trial, the SHIFT trial, to reduce a composite of cardiovascular mortality and heart failure hospitalization. But that was almost all based on heart failure hospitalization. To be enrolled in that trial, you had to already be on a beta-blocker (an optimized beta-blocker) and still have an elevated heart rate. That’s the key.

Peter L. Salgo, MD: Everybody is going to be on a beta blocker if they can be?

Scott Solomon, MD: Unless they can’t tolerate it.

Peter L. Salgo, MD: If they can tolerate it. Now, ivabradine would be added if the heart rate is still too high?

Scott Solomon, MD: Right.

Akshay Desai, MD: One exception, though, is atrial fibrillation. The drug acts, as Sheryl said, on the sinus node current—this funny current. If patients don’t have a sinus mechanism for rhythm (if they’re not in sinus rhythm), the drug has no effect. And, in fact, there is actually a higher rate of atrial fibrillation in most of the trials. In the angina and the heart failure trials with atrial fibrillation, incidentally, there was atrial fibrillation among people taking ivabradine.

Peter L. Salgo, MD: Because there’s no AV (atrioventricular) node effect, at all?

Akshay Desai, MD: There is no AV node.