SNOWMASS, COLO. – Ivabradine and sacubitril/valsartan are paradigm-changing drugs approved last year for the treatment of heart failure with reduced ejection fraction – and it’s entirely reasonable to begin using them now in the appropriate patients, Dr. Akshay S. Desai said at the Annual Cardiovascular Conference at Snowmass.
The impressive positive results seen in the pivotal trials for these novel agents – the SHIFT trial for ivabradine (Corlanor) and PARADIGM-HF for sacubitril/valsartan (Entresto) – have rocked the heart failure world.
Dr. Akshay S. Desai
The studies showed that, in the right patients, these two medications improve heart failure morbidity and mortality significantly beyond what’s achievable with the current gold standard, guideline-directed medical therapy. That’s exciting because even though great therapeutic strides have been made during the past 15 years, symptomatic patients with heart failure with reduced ejection fraction (HFrEF) treated with optimal guideline-directed pharmacotherapy still have substantial residual risk for heart failure hospitalization and death, noted Dr. Desai, director of heart failure disease management at Brigham and Women’s Hospital in Boston.
The U.S. heart failure guidelines panel hasn’t yet addressed the use of either of these recently approved drugs, but Dr. Desai provided his best sense of the data and how he thinks physicians might start using them now.
Ivabradine and sacubitril/valsartan are first-in-class agents with novel mechanisms of action. Ivabradine’s demonstrated safety and efficacy in the SHIFT trial confirmed the hypothesis that elevated heart rate is a legitimate therapeutic target in HFrEF.
Sacubitril/valsartan, an angiotensin II receptor/neprilysin inhibitor formerly known as LCZ696, provides what is to date a unique ability to enhance the activity of endogenous vasoactive peptides, including natriuretic peptides, bradykinin, substance P, adrenomedullin, and calcitonin gene–related peptide. These peptides are antifibrotic, antihypertrophic, and they promote vasodilation and diuresis, thus counteracting the adverse effects of neurohormonal activation. But in HFrEF, these vasoactive peptides are less active and patients are less sensitive to them.
Ivabradine
This selective sinus node inhibitor decreases heart rate and has essentially no other effects. The drug has been available for years in Europe, and the European Society of Cardiology (ESC) has had sufficient time to integrate ivabradine into its guidelines for pharmacotherapy in HFrEF.
The ESC treatment algorithm for HFrEF (Eur Heart J. 2012 Jul;33[14]:1787-847) is built upon a foundation of thiazide diuretics to relieve signs and symptoms of congestion along with a beta-blocker and an ACE inhibitor or angiotensin receptor blocker (ARB). In a patient who still has New York Heart Association class II-IV symptoms after those drugs are titrated to guideline-recommended target levels or maximally tolerated doses, a mineralocorticoid receptor antagonist – either spironolactone or eplerenone – is added. And, in a patient who still remains symptomatic, has a left ventricular ejection fraction of 35% or less, is in sinus rhythm, and has a heart rate of 70 beats per minute or more, it’s time to consider adding ivabradine.
“This is how our own guidelines may elect to incorporate ivabradine, but of course, we don’t know yet,” Dr. Desai observed.
In the randomized, double-blind SHIFT trial involving 6,558 HFrEF patients who fit the description of ivabradine candidates described in the ESC guidelines, those who received ivabradine titrated to a maximum of 7.5 mg twice daily experienced a 26% reduction in hospital admissions for worsening heart failure, compared with placebo, a 26% reduction in deaths from heart failure, and fewer adverse events than the control group (Lancet. 2010 Sep 11;376[9744]:875-85).
The important question is who should get ivabradine and who should just get a little more beta-blocker in order to slow the heart rate. The fact is, many heart failure patients simply can’t tolerate the guideline-recommended target dose of beta-blocker therapy, which is 12.5 mg twice daily of carvedilol or its equivalent. Indeed, only 26% of SHIFT participants were able to do so.
“My interpretation of the SHIFT trial is that the goal is to reduce heart rate by any means necessary; preferentially, with a beta-blocker, and with ivabradine as an adjunct in patients who can’t get to target doses,” the cardiologist said.
Sacubitril/valsartan
In the landmark double-blind, 8,442-patient PARADIGM-HF trial, the group randomized to sacubitril/valsartan had a 20% reduction in the primary endpoint of cardiovascular death or heart failure hospitalization over 27 months of follow-up, compared with controls on enalapril at the guideline-recommended dose of 10 mg twice a day. The number needed to treat (NNT) was 21. Moreover, all-cause mortality was reduced by 16% (N Engl J Med. 2014 Sep 11;37[11]:993-1004).
In a recent follow-up cause of death analysis, Dr. Desai and his coinvestigators reported that 81% of all deaths in PARADIGM-HF were cardiovascular in nature. The NNT for sacubitril/valsartan in order to prevent one cardiovascular death was 32. The risk of sudden cardiac death was reduced by 80%, while the risk of death due to worsening heart failure was decreased by 21% (Eur Heart J 2015 Aug 7;36[30]:1990-7).