Systolic heart failure - improving treatment
Published in MedicineWise News
Date published: About this date
- Add beta blockers in stable systolic heart failure
- Aldosterone antagonists may help those who remain symptomatic
- Remember to regularly review all medicines
- Address lifestyle factors that exacerbate heart failure
- Case study 71: Heart failure
- Heart Foundation - external link
People with systolic heart failure should be treated with angiotensin-converting enzyme (ACE) inhibitors and heart failure specific beta blockers to reduce morbidity and mortality. The most recent NPS clinical audit in heart failure patients suggests these guidelines are being followed. But there are still areas where treatment is not optimal. This NPS News outlines ways to further improve the treatment of systolic heart failure.
NPS audit data shows that almost everyone (90%) with systolic heart failure who does not have a contraindication for treatment with an ACE inhibitor or an angiotensin II-receptor antagonist is taking one. However, a considerable number were using an ACE inhibitor dose that was below the recommended target range (Table 1). ACE inhibitors have proven survival benefits at the doses used in randomised controlled trials; attempt to titrate doses to reach this range.4,5 Diuretic doses may need to be altered if patients experience worsening renal function or hypotension.6 If reaching the target dose level of the ACE inhibitor is difficult because of intolerable adverse effects, titrate to the highest tolerated dose as this may still be beneficial.4,6,7
Angiotensin II-receptor antagonists also reduce mortality and morbidity but are no more effective than ACE inhibitors.8–11 They are an acceptable alternative for people unable to tolerate ACE inhibitors.5
Most people with symptomatic heart failure will also require diuretic therapy.
Table 1: Recommended daily dose of ACE inhibitors12,13
|Drug||Starting dose||Target maintenance dose|
|captopril||6.25 mg three times daily||25–75 mg twice daily|
|enalapril||2.5 mg daily||10–20 mg twice daily|
|fosinopril||5–10 mg daily||20–40 mg daily|
|lisinopril||2.5 mg daily||20–40 mg daily|
||2.5 mg daily
||5–10 mg daily
||2 mg daily
||4–8 mg daily
||5 mg daily
||20–40 mg daily
||2.5 mg daily
||5–10 mg daily
Box 1: New York Heart Association (NYHA) grading system for heart failure symptom severity
No limitations in normal physical activity
Slight limitation of physical activity. Ordinary physical activity results in fatigue, palpitation, dyspnoea or angina pectoris
Marked limitation of physical activity. Less than ordinary activity results in symptoms
Unable to carry our any physical activity without discomfort. Symptoms present at rest
Mortality and hospital admissions can be reduced among people with stable heart failure if certain beta blockers (carvedilol, bisoprolol and metoprolol extended release) are added to an ACE inhibitor and a loop diuretic.14–16 Recently, a fourth beta blocker, nebivololA, has been approved for this indication. Nebivolol reduces the risk of a composite outcome of death or cardiovascular hospitalisation in people aged ≥ 70 years.17
Start low, go slow
Beta blockers may initially worsen heart failure symptoms.5,12,18 Start people with stable heart failure on a low dose once they are clinically euvolaemic and increase the dose slowly (every 2–4 weeks) to target (Table 2). Wait before increasing the dose if heart failure symptoms worsen, or if bradycardia or symptomatic hypotension is present — these side effects are often transitory.5,12,13,19
Cardioselective (beta1-selective) beta blockers should not be routinely withheld from people with both heart failure and COPD.20 They may be used with caution in people with mild to moderate asthma — short term use (up to 4 weeks) of cardioselective beta blockers does not appear to cause adverse respiratory effects among these people.21
Combined ACE inhibitors and angiotensin II-receptor antagonists benefit uncertain
Seek specialist advice if considering the combination of an ACE inhibitor and an angiotensin II-receptor antagonist.12 Meta-analyses show there is no mortality benefit in combining an ACE inhibitor with an angiotensin II-receptor antagonist in people with heart failure but it may reduce heart failure hospitalisations.22–24 However, many of the patients included in these meta-analyses were not using beta blockers. Thus the benefit of starting an angiotensin II-receptor antagonist in people who are already using an ACE inhibitor and a beta blocker is uncertain.
Combined ACE inhibitors angiotensin II-receptor antagonists may increase risk
Combining an ACE inhibitor and an angiotensin II-receptor antagonist increases the risk of worsening renal function, hyperkalaemia and symptomatic hypotension and significantly more people stop treatment because of adverse effects.23,25,26
Table 2: Recommended daily dose of beta blockers[12,13]
|Drug||Starting dose||Target maintenance dose|
1.25 mg once daily
10 mg once daily
3.125 mg twice daily
25 mg twice dailyC
metoprolol extended release
23.75 mg daily
190 mg once daily
1.25 mg once daily
10 mg once daily
If people taking an ACE inhibitor (or angiotensin II-receptor antagonist) and a beta blocker are still symptomatic, Australian guidelines recommend spironolactone for severe symptoms.5 While guidelines suggest consideration of eplerenone for mild symptoms it is not TGA approvedD for this indication.5 Although a trial of spironolactone has not been conducted in people with mild symptoms it is possible that it may have the same cardiovascular benefits as eplerenone.27,28
Beware of hyperkalaemia
Combining an aldosterone antagonist with an ACE inhibitor or an angiotensin II-receptor antagonist increases the risk of hyperkalaemia. Do not use an aldosterone antagonist in people with severe renal impairment or in those taking both an ACE inhibitor and an angiotensin II-receptor antagonist.6,12 Monitor potassium concentrations frequently; every week for the first month, then monthly for 2 months, then every 3 months and when indicated clinically.12
Trials suggest benefits
Two large trials of aldosterone antagonists (spironolactone and eplerenone) in people with systolic heart failure found significant reductions in mortality and rates of hospitalisation.29,30
In the first trial, spironolactone improved cardiovascular outcomes in people with moderate to severe heart failure (NYHA class III or IV) who were already taking a loop diuretic, an ACE inhibitor and digoxin. Beta blockers were not widely used for heart failure when this trial was conducted.29
More recently, eplerenone improved cardiovascular outcomes in people with mild symptomatic heart failure (NYHA class II) patients who were already using ACE inhibitors (or angiotensin II-receptor antagonists), beta blockers and, if indicated, a diuretic. However, while this group had mild symptoms they were still at high risk of cardiovascular events as all had been hospitalised because of a cardiovascular event in the previous 6 months.30,31 It is unclear whether mildly symptomatic patients who are not at such high risk would benefit from the addition of eplerenone.D. Eplerenone is TGA indicated for use in people who have evidence of heart failure and left ventricular impairment within 3 to 14 days of an acute myocardial infarction.
From NPS audit data, 20% of patients with systolic heart failure take a medicine or medicines that can exacerbate heart failure — most commonly a COX-2 selective NSAID. Commonly used medicines to avoid, if possible, include:
- conventional and COX-2 selective NSAIDs
- thiazolidinediones (e.g. rosiglitazone or pioglitazone)
- corticosteroids (e.g. hydrocortisone, prednisone, fluticasone)
- anti-arrhythmic medicines (except for heart failure specific beta blockers and amiodarone)
- non-dihydropyridine calcium-channel blockers (e.g. verapamil or diltiazem)
- tricyclic antidepressants.5,12
Plan end of life care for those with advanced disease
Advanced age, NYHA class IV symptoms, repeated hospitalisations, poor renal function, cardiac cachexia, low sodium concentration and refractory hypotension requiring withdrawal of medical therapy are indicators that a person may be at high risk of dying within 12 months.5 Care of these people is aimed at improving end of life quality. Reassess all current medicines but do not withdraw heart failure specific medicines (ACE inhibitors, beta blockers, diuretics) unless there is intolerance as these medicines improve symptoms.5,32 Additional medicines to alleviate pain, anxiety and dyspnoea (e.g. diuretics, opioids, sedatives) may be needed.5
Lack of physical activity, poor diet, excessive consumption of fluids and being overweight can exacerbate heart failure. Advise patients to quit smoking, avoid drinking more than 2 L of fluid per day and to limit or stop caffeine and alcohol intake. A dietitian can help plan a diet high in fibre and low in sodium and saturated fat.5
Advise patients to weigh themselves every morning to monitor fluid retention. Let them know they should contact a health professional immediately if they gain or lose more than 2 kg over 2 days.5
Exercise-based rehabilitation significantly reduces hospitalisations from heart failure, improves quality of life and does not increase mortality in people with stable systolic heart failure.4 Refer everyone to a heart failure specific physical activity program if available. Encourage people with NYHA class I or II symptoms to walk for at least 10 to 30 minutes on most days. Other low to moderate intensity exercises include cycling on a stationary bicycle, light weights and stretching. Patients should exercise to a level that allows them to carry on a normal conversation.5
Self-management resources for patients
Encourage patients to call the Heart Foundation on 1300 362 787 to obtain a copy of the Living Well with Chronic Heart Failure booklet. This is designed to help people with chronic heart failure better understand and manage their condition.
Ask patients or carers to bring in this booklet, or download the Living Well with Chronic Heart Failure information sheet, and discuss its contents with them.
Use the Heart Foundation’s Heart Health Information Service (1300 362 787) to find, and refer patients to, heart failure specific management programs in their local area.
A/Prof John Atherton, Director of Cardiology, Royal Brisbane and Women’s Hospital, Brisbane.
Dr John Dowden, Editor, Australian Prescriber
Dr Graham Emblen, General Practitioner, Toowoomba
Dr Sarah Gani, General Practitioner and Medical Educator, Blacktown
Benafsha Khariwala, Managing Editor, Journal of Pharmacy Practice and Research
A/Prof Jennifer Martin, Head, PA-Southside Clinical School
Deborah Norton, QUM Pharmacist, Vic
Simone Rossi, Managing Editor, Australian Medicines Handbook
Any correspondence regarding content should be directed to NPS. Declarations of conflicts of interest have been sought from all reviewers. The opinions expressed do not necessarily represent those of the reviewers.
- Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000;355:1575–81.
- The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigattors. N Engl J Med 1992;327:685–91.
- Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669–77.
- National Clinical Guideline Centre. Chronic heart failure: the management of chronic heart failure in adults in primary and secondary care. London: National Clinical Guideline Centre, 2010. (accessed 16 June 2011).
- National Heart Foundation, Cardiac Society of Australia and New Zealand. Guidelines for the prevention, detection and management of chronic heart failure in Australia, updated July 2011, 2011. (accessed 17 August 2011).
- Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:e391–479.
- Dobre D, van Veldhuisen DJ, DeJongste MJ, et al. The contribution of observational studies to the knowledge of drug effectiveness in heart failure. Brit J Clin Pharmacol 2007;64:406–14.
- Jong P, Demers C, McKelvie RS, et al. Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials. J Am Coll Card 2002;39:463–70.
- Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360:752–60.
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893–906.
- Pitt B, Poole-Wilson PA, Segal R, et al. 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;355:1582–7.
- Australian medicines handbook 2011. Adelaide: Australian Medicines Handbook Pty Ltd, 2011.
- Cardiovascular Writing Group. Therapeutic guidelines: cardiovascular, version 5 [eTG complete CD-ROM]. Melbourne: Therapeutic Guidelines Ltd, 2008.
- CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13.
- MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7.
- Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. New Engl J Med 2001;344:1651–8.
- Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215–25.
- Scottish Intercollegiate Guidelines Network. Management of chronic heart failure: a national clinical guideline. Edinburgh: SIGN, 2007. (accessed 4 July 2011).
- Clinical Knowledge Summaries. Heart failure - chronic - management. London: National Institute for Health and Clinical Excellence, 2010. (accessed 22 June 2011).
- Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005:CD003566.
- Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for reversible airway disease. Cochrane Database Syst Rev 2002:CD002992.
- Dimopoulos K, Salukhe TV, Coats AJ, et al. Meta-analyses of mortality and morbidity effects of an angiotensin receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a beta-blocker). Int J Cardiol 2004;93:105–11.
- Kuenzli A, Bucher HC, Anand I, et al. Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure. PLoS One 2010;5:e9946.
- Lee VC, Rhew DC, Dylan M, et al. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 2004;141:693–704.
- Lakhdar R, Al-Mallah MH, Lanfear DE. Safety and tolerability of angiotensin-converting enzyme inhibitor versus the combination of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in patients with left ventricular dysfunction: a systematic review and meta-analysis of randomized controlled trials. J Card Fail 2008;14:181–8.
- Phillips CO, Kashani A, Ko DK, et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Arch Intern Med 2007;167:1930–6.
- Armstrong PW. Aldosterone antagonists — last man standing? N Engl J Med 2011;364:79–80.
- MeReC. Does eplerenone have a role in mild heart failure? NPC Rapid review. Liverpool: National Prescibing Centre, 2011. (accessed 23 June 2011).
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17.
- Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21.
- Zannad F, McMurray JJ, Drexler H, et al. Rationale and design of the Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure (EMPHASIS-HF). Eur J Heart Fail 2010;12:617–22.
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