SNOWMASS, COLO. (FRONTLINE MEDICAL NEWS) – 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.

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.


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.


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 ).

In another secondary analysis from the PARADIGM-HF investigators, the use of the angiotensin receptor/neprilysin inhibitor was shown to prevent clinical progression of surviving patients with heart failure much more effectively than enalapril. The sacubitril/valsartan group was 34% less likely to have an emergency department visit for worsening heart failure, 18% less likely to require intensive care, and 22% less likely to receive an implantable heart failure device or undergo cardiac transplantation. The reduction in the rate of heart failure hospitalization became significant within the first 30 days ( Circulation. 2015 Jan 6;131[1]:54-61 ).

Moreover, the absolute benefit of sacubitril/valsartan in PARADIGM-HF was consistent across the full spectrum of patient risk ( J Am Coll Cardiol. 2015 Nov 10;66[19]:2059-71 ).

To put this into perspective, Dr. Desai continued, for every 1,000 HFrEF patients switched from an ACE inhibitor or ARB to sacubitril/valsartan, the absolute benefit over the course of 27 months includes 31 fewer cardiovascular deaths, 28 fewer hospitalizations for heart failure, and 37 fewer hospitalizations for any reason.

“This is potent therapy for patients with HFrEF who have the right phenotype,” he observed.

While substitution of sacubitril/valsartan for an ACE inhibitor or ARB may be appropriate in many patients with chronic HFrEF who continue to have NYHA Class II-IV symptoms on guideline-directed medical therapy, several caveats apply, according to Dr. Desai.

It’s important to be aware of the PARADIGM-HF eligibility criteria, because it’s only in patients who fit that profile that sacubitril/valsartan provides evidence-based therapy. There are as yet no data to support the drug’s use in patients with new-onset HFrEF, acute decompensated HFrEF, in patients who are immediately post-MI, or in those with advanced chronic kidney disease, he emphasized.

“I think you have to be mindful of eligibility because the label that’s applied to this drug is basically ‘patients with HFrEF who are treated with guideline-directed medical therapy.’ There’s no specific requirement that you follow the detailed eligibility criteria of the PARADIGM-HF trial, but you should realize that the drug is known to be effective only in patients who fit the PARADIGM-HF eligibility profile,” he said.

Dr. Desai gave a few clinical pearls for prescribing sacubitril/valsartan. For most patients, the initial recommended dose is 49/51 mg twice daily. In those with low baseline blood pressure and tenuous hemodynamics, it’s appropriate to initiate therapy at 24/26 mg BID. It’s important to halt ACE inhibitor therapy 36 hours prior to starting sacubitril/valsartan so as to avoid overlap and consequent increased risk of angioedema. And while serum n-terminal prohormone brain natriuretic peptide (NT-proBNP) remains a useful biomarker to monitor heart rate severity and response to treatment while a patient is on sacubitril/valsartan, BNP is not because serum levels of that biomarker rise with neprilysin inhibition.

Dr. Desai reported receiving research support from Novartis and St. Jude Medical and serving as a consultant to those companies as well as Merck and Relypsa.


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