SNOWMASS, COLO. – As William T. Abraham, MD, speaks to colleagues around the country about heart failure therapy, he has noticed that the first-in-class drug ivabradine remains below the radar of most physicians.
“I’ve found that this is an agent that very few people know about, even though it’s been FDA [Food and Drug Administration] approved for about 3 years. It’s used fairly extensively in Europe because that’s where the pivotal SHIFT trial was done, but not very much in the United States,” according to Dr. Abraham, professor of medicine, physiology, and cell biology and director of the division of cardiovascular medicine at Ohio State University in Columbus.
That’s likely to change as word spreads about the May 2016 update of the American College of Cardiology/American Heart Association Guideline for the Management of Heart Failure. The update incorporated evidence-based recommendations on the use of two important new heart failure medications: ivabradine (Corlanor), which received a moderate class IIa recommendation, meaning the drug “should be considered,” and sacubitril/valsartan (Entresto), which received the strongest class I recommendation.
In the right patients, these two oral medications improve heart failure morbidity and mortality significantly beyond what’s achievable with what has been the gold standard, guideline-directed medical therapy. Dr. Abraham described how to get started using the two medications at the Annual Cardiovascular Conference at Snowmass.
Ivabradine is a selective inhibitor of the sinoatrial pacemaker modulating I(f) current. It acts by slowing the sinus rate without reducing myocardial contractility.
“This agent does one thing and one thing alone: It lowers heart rate,” the cardiologist explained.
And that, he added, was sufficient to significantly reduce the risks of death due to heart failure and recurrent hospitalization for worsening heart failure in the pivotal SHIFT trial.
SHIFT included 6,505 patients with moderate to severe heart failure with reduced left ventricular ejection fraction (LVEF) and a resting heart rate above 70 bpm despite background guideline-directed medical therapy. Participants were randomized double blind to ivabradine titrated to a maximum of 7.5 mg twice daily or placebo and followed for a median of about 23 months. The rate of death due to heart failure was 3% with ivabradine and 5% with placebo, for a statistically significant 26% relative risk reduction favoring ivabradine.
But the drug’s main benefit was in reducing recurrent hospitalizations for heart failure, an endpoint of particular interest to health policy officials given that heart failure hospitalizations chew up a substantial proportion of the Medicare budget. Ivabradine reduced first hospitalizations for heart failure during the study period by 25%, second hospitalizations by 34%, and third hospitalizations by 29% (Eur Heart J. 2012 Nov;33:2813-20).
The ACC/AHA guideline update stresses the importance of reserving ivabradine for heart failure patients whose resting heart rate exceeds 70 bpm, despite being on their maximum tolerated dose of a beta-blocker, Dr. Abraham noted.
Ivabradine is contraindicated in the setting of acute decompensated heart failure, severe liver disease, or hypotension, in patients on any of the numerous agents that strongly inhibit the enzyme cytochrome P450 3A4, and in those who have sick sinus syndrome, have sinoatrial block, or are pacemaker dependent.
Sacubitril inhibits neprilysin, an enzyme that blocks the action of endogenous vasoactive peptides including bradykinin, substance P, and natriuretic peptides, all of which counter important maladaptive mechanisms in heart failure. Sacubitril has been combined with the angiotensin receptor blocker valsartan to form the first-in-class angiotensin receptor neprilysin inhibitor, or ARNI, formerly known as LCZ696 and now marketed as Entresto.
In the pivotal double-blind PARADIGM-HF trial, 8,442 patients with heart failure with reduced ejection fraction were randomized to the ARNI at 200 mg b.i.d. or to enalapril at 10 mg b.i.d. on top of background guideline-directed medical therapy. The trial was stopped early because of evidence of overwhelming benefit: a 20% relative risk reduction in cardiovascular death and a 21% decrease in the risk of heart failure hospitalizations in the sacubitril/valsartan group, as well as significant reductions in heart failure symptoms and physical limitations (N Engl J Med. 2014 Sep 11;371:993-1004).
The updated heart failure guidelines strongly recommend that patients with heart failure should be treated with either an ACE inhibitor, an angiotensin receptor blocker, or an ARNI. Further, patients who remain symptomatic on an ACE inhibitor or angiotensin receptor blocker should be switched to an ARNI; that’s a class Ib recommendation based upon the results of PARADIGM-HF.
In getting started using the ARNI, Dr. Abraham said it’s important to understand as background the selective nature of the PARADIGM-HF study design. During the single-blind run-in period of 5-8 weeks, roughly 10% of patients dropped out because they couldn’t tolerate enalapril at 10 mg b.i.d., and a similar percentage dropped out during the ARNI run-in. Thus, patients who couldn’t tolerate a low dose of an ACE inhibitor weren’t in the study. And patients capable of tolerating guideline-recommended full-dose ACE inhibitor therapy were not specifically sought for participation.
“So there are some unanswered questions about the ARNI. If you’re just getting started with this compound in treating your heart failure patients, my own feeling is you should maybe aim for the type of patient that was included in this trial: patients who could tolerate a moderate dose of an ACE inhibitor and had generally good blood pressure. That’s a great way to begin to get experience with this agent in heart failure,” the cardiologist advised.
He reported serving as a consultant to Abbott Vascular, Medtronic, Novartis, and St. Jude Medical.
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