We now have the ability to further reduce morbidity and mortality for treating systolic heart failure, writes Dr Martin Brown
Stolic left ventricular heart failure, or heart failure with reduced ejection fraction (HFREF), is the inability of the heart to pump blood adequately around the body leading to reduced perfusion and congestion.
It is defined as left ventricular ejection fraction (LVEF) less than 40% and has significant morbidity and mortality. There are 280,000 Australians, or 1.3% of the population, suffering from HFREF with 30,000 new cases and 49,000 hospital admissions per year.
One-year heart-failure readmission rates are high at 32%, resulting in a burden of 200,000 bed days in NSW alone. One-year mortality in the pre-ACEi and beta-blocker era was as high as 50%. 1-3
Early pharmacological therapies
Early treatments for HFREF included diuretics, digoxin and the use of vasodilators such as nitrates and hydralazine until the studies of angiotensin converting enzyme inhibitors (ACEi) were first published in the early 1990s and showed a 16% to 40% mortality reduction depending on NYHA class (II-IV).4
The addition of beta-blockers followed in the late 1990s and showed a further 34% to 65% reduction in mortality and 27% reduction in hospitalisation.5,6
Around the same time, mineralocorticoid antagonism (MRA) with spironolactone for severe heart failure (NYHA class IV) was shown to have an additional benefit of 30% mortality reduction.8
Subsequent studies of angiotensin II receptor antagonist (A2RB) such as ELITE II Study were published in the early 2000s and showed they were as beneficial as ACEi9 but the results of combining ACEi and A2RB were mixed and therefore are not recommended.
In 2011, the EMPHASIS HF study with the aldosterone antagonist, eplenerone, showed a 24% mortality reduction and 23% reduction in heart failure hospitalisations in patients with milder heart failure (NYHA class II) but eplenerone is still not available in Australia for this indication.10
There was a hiatus of new pharmacological therapies for HFREF from the early 2000s until 2013 when the novel sinus node inhibitor, ivabradine (Coralan), became available. More recently, in June 2017 a new class of agents call neprilysin inhibitors (Sacubitril) became available in addition to a combination of this with the A2RB, valsartan (Entresto™).
Ivabradine (Coralan™)
Ivabradine is a selective, sinus node inhibitor working on the I-f channel and decreasing resting heart rate in sinus rhythm.
The SHIFT trial, published in 2010, showed that ivabradine can be added to the treatment options for heart-failure patients, reducing heart-failure admissions and death by 18%.11 This was mainly driven by the reduction in heart-failure admissions by 26%.
In subgroup analysis, there was a 19% reduction in all-cause mortality and 39% reduction in heart-failure mortality if the heart rate was greater than 77 beats per minute.
Ivabradine is now PBS listed for the treatment of chronic stable heart failure in patients with sinus rhythm, heart rate > 77bpm, LVEF < 35% and class II-III NYHA dyspnoea who have an intolerance or a contraindication to beta blockers or who are taking the maximum tolerated dose but remain with heart rate >77bpm.
Sacubitril/Valsartan (Entresto™)
Entresto™ is a new drug called an angiotensin receptor neprilysin inhibitor (ARNI). It is a combination of an angiotensin II receptor blocker (valsartan) and a novel neprilysin inhibitor (sacubitril).
Neprilysin is an enzyme responsible for the breakdown of natriuretic peptides (ANP, BNP, CNP) and other peptides such as angiotensin II, bradykinin, endothelin and substance P.
Inhibiting the function of neprilysin results in the beneficial effects of increasing natriuretic peptides, enabling greater diuresis and cardiac recovery in HFREF.
However, inhibiting the breakdown of angiotensin II, endothelin and bradykinin results in the deleterious effects of vasoconstriction, sodium and water retention, myocyte fibrosis and angioedema.
The addition of the A2RB, valsartan, aims to combat these adverse effects as well as providing the other beneficial effects of RAAS inhibition that has already been proven to reduce mortality and morbidity in heart-failure patients.12
The PARADIGM-HF study, published in 2014, compared enalapril to sacubitril/valsartan in 8442 patients with symptomatic chronic heart failure (NYHA class II–IV) who were stable on an ACEI or an ARB. This was in addition to background medical therapy with beta-blocker (93%), digoxin (29%) and mineralocorticoid antagonists (54%).
The results showed a 20% reduction in cardiovascular death, a 16% reduction in all-cause death and 21% reduction in risk of hospitalisation for heart failure.
There were more patients with symptomatic hypotension on the sacubitril/valsartan combination drug compared to the enalapril but less deterioration in renal function and hyperkalaemia.
Based on this study, the European Society of Cardiology, in its 2016 updated guidelines on the management of heart failure, stated that “sacubitril/valsartan is recommended as a replacement for an ACE-I to further reduce the risk of heart-failure hospitalisation and death in ambulatory patients with HFREF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker and an MRA” and have given it a Class IB indication.
The TGA approved this drug for use in Australia in February 2016 and it was available on PBS from 1 June this year.
To be eligible, patients must be NYHA Class II–IV, stable on ACEi, have LVEF ?40% and be receiving optimal standard chronic heart-failure treatment.
The starting dose is 49/51mg twice daily and uptitrated to 97/103mg twice daily if tolerated after two to four weeks. A lower dose of 24/26mg twice daily can be used in patients on low dose ACEi/A2RB, GFR<30mls/min/m2, moderate hepatic impairment, >75years of age or SBP 100-110mmHg.
Patients should have a 36-hour washout period if changing from ACEi to sacubitril/valsartan but this is not required if changing from an A2RB. However, ACEi and A2RB should not be given concomitantly with sacubitril/valsartan.
Monitoring of blood pressure and renal function is advised.
Summary
For many years, the cornerstone of systolic heart failure treatment has been ACEi, A2RB, beta-blockers and MRAs, with a significant reduction in morbidity and mortality. However, we now have the ability to further reduce morbidity and mortality by the use of ivabradine as add-on therapy for patients in sinus rhythm who are intolerant of or are taking maximal tolerated beta-blocker with persistent heart rate >77bpm.
Since June 2017, we also now have a new class of therapeutic drug (ARNI) which replaces ACEi and A2RBs for symptomatic patients with NYHA class II-IV dyspnoea and LVEF <40% called sacubitril/valsartan (Entresto™).
Dr Martin Brown specialises in advanced heart failure care and transplant cardiology at Sydney Cardiology and is Senior Clinical Lecturer at Macquarie University Hospital
References:
1. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. European Heart Journal (2012) 33, 1787–1847
2. Robertson J, McElduff P, Pearson SA, Henry DA, Inder KJ, Attia JR. The health services burden of heart failure: an analysis using linked population health data-sets. BMC Health Services Research 2012: 12:103;
3. Australian Institute of Health and Welfare 2011. Cardiovascular disease: Australian facts 2011. Cardiovascular disease series. Cat No. CVD 53. Canberra. AIHW
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5. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH, for the U.S. Carvedilol Heart Failure Study Group. The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med 1996; 334:1349-1355
6. The CIBIS II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999 :Volume 353, No. 9146, p9–13
7. The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
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9. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial–the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000 May 6;355(9215):1582-7.
10. Zannad F, McMurray JJV, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B for the EMPHASIS-HF Study Group. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med 2011; 364:11-21
11. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010 Sep 11;376(9744):875-85.
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14. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola V, Jankowska EA. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal, Volume 37, Issue 27, 14 July 2016, Pages 2129–2200.
