New European guidelines1 place beta-blockers firmly at the centre of heart failure management, but it hasn’t always been this way. In this article we go on a journey by looking at the history of beta-blockers over the last three decades. We also speak to heart failure expert Professor John Amerena about their role in current clinical practice.
The history and the journey
Beta-blockers are a cornerstone of heart failure treatment, but just 20 years ago they were avoided because of concerns about a lack of benefit and unacceptable side effects.2
In an article published in Australian Prescriber in 20003 Australian cardiologist Professor Peter Fletcher said the rationale at the time was that the sympathetic nervous system was overactive and provided a crucial level of compensation for the failing heart.
“To remove this by using a beta-blocker would risk precipitating or exacerbating heart failure,” he said. However, trials published from the mid-1990s had “seriously challenged” this conventional wisdom.
In 1996 the US Carvedilol Heart Failure Study showed that adding carvedilol to standard care reduced overall mortality from 7.8% to 3.2%, a relative risk reduction of 65%.4 Subsequent trials established the survival benefits of metoprolol XL and bisoprolol, in 1999,5,6 and most recently nebivolol, in 2005.7
A recent commentary in the New England Journal of Medicine reviewed the key papers published in the journal over three decades to document progress in heart failure management.2
Discussing the role of beta-blockers, it said that understanding the role of adrenergic activation in the pathophysiology of heart failure “underscored a novel, transformative approach to therapy”.
At the timeline’s beginning in 1986, digoxin and diuretics were the first-line treatment for heart failure but neither improved survival.
“By the timeline’s last entry [2014], ACE inhibitors, beta blockers, aldosterone antagonists, cardiac devices, and now angiotensin receptor-neprilysin inhibitors have strong evidence bases demonstrating a reduction in mortality,” it said.
Mortality reductions with beta-blockers
A recent meta-analysis of individual data on 13,833 patients, by the Beta-Blockers in Heart Failure Collaborative Group, concluded that irrespective of age or sex, patients with heart failure with reduced ejection fraction in sinus rhythm should receive beta-blockers to reduce the risk of death and admission to hospital.8
It identified mortality reductions in every age group, including a 23% reduction in the oldest quartile (median age 75), and equivalent benefits in men and women. Reductions in hospital admission for heart failure remained significant, but were attenuated, as age increased.
“Older patients and women often receive less evidence-based treatment and often at lower doses than shown to be effective in clinical trials,” the study group said.
Among the patients in these clinical trials, “…treatment with beta-blockers reduced all-cause mortality and hospital admissions for heart failure, regardless of age or sex, and the tolerability of treatment was the same with beta-blockers and placebo”.
Nebivolol: SENIORS study
The SENIORS study compared the beta-blocker nebivolol with placebo in patients aged 70 years or more with heart failure, regardless of ejection fraction.7 Although earlier trials showed that beta-blockers reduced mortality and hospital admissions, their effects in elderly patients with a broad range of left ventricular ejection fraction were uncertain.
The mean age of participants was 76 years, 37% were female, their mean ejection fraction was 36%, and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and the mean follow-up was 21 months.
The primary outcome, a composite of all-cause mortality or cardiovascular hospital admission, occurred in 31.1% of patients on nebivolol compared with 35.3% on placebo (hazard ratio [HR] 0.86, 95% CI 0.74–0.99; p=0.039).
There was no significant influence of age, gender or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 18.1% of patients on placebo and 15.8% of patients on nebivolol (HR 0.88, 95% CI 0.71-1.08; p=0.21).
“Nebivolol is a beta-1-selective blocker with vasodilating properties related to nitric oxide modulation,” the study noted. “This effect may improve tolerability in elderly patients with heart failure, where endothelial vasodilator reserve may be limited”.7
Guidelines confirm central role of beta-blockers
Guidelines on the management of heart failure from the European Society of Cardiology, updated in May this year, confirm the central role of beta-blockers in heart failure with reduced ejection fraction (HFrEF).1
“The goals of treatment in patients with heart failure are to improve their clinical status, functional capacity and quality of life, prevent hospital admission and reduce mortality,” they state.
“Neuro-hormonal antagonists [ACE inhibitors, mineralocorticoid receptor antagonists and beta-blockers] have been shown to improve survival in patients with HFrEF and are recommended for the treatment of every patient with HFrEF, unless contraindicated or not tolerated.”
Practical guidance published as web addenda note that a beta-blocker should be started as first-line treatment in patients with stabilised heart failure as early as possible in the course of disease.
Contraindications include second- or third-degree AV block (in the absence of a permanent pacemaker) and critical limb ischaemia.
The guidelines state that asthma is a relative rather than absolute contraindication if cardioselective beta-blockers are indicated, but the medications should only be used under close medical supervision by a specialist, with consideration of the risks and benefits. “COPD is not a contraindication,” the authors state.
The practical guidance also discusses dose titration and approaches to problem-solving, for example the appropriate response to worsening symptoms or signs, low heart rate, and asymptomatic or symptomatic hypotension.
Recommended advice to patients includes discussing possible symptomatic deterioration during initiation and dose titration, as well as a clear explanation of the benefits of beta-blocker therapy.
The role of beta-blockers in clinical practice
Associate Professor John Amerena, Director of the Heart Failure Program at Barwon Health in Geelong, agrees that patients with heart failure, and their GPs, need to be aware that their symptoms may worsen rather than improve for a week or two after starting treatment or increasing the dose.
“They might feel ‘flat’, tired and more short of breath, but this is normally a transient effect before they start to experience an improvement,” he says.
Titrating treatment to the evidence-based target dose (bisoprolol 10 mg o.d., carvedilol 25 mg b.d., metoprolol XL 200 mg o.d., nebivolol 10 mg o.d.), or the maximum tolerated dose if it is lower, is an essential part of the treatment strategy.
“GPs are very hesitant to increase doses. In the real world most dose titration is usually performed by cardiologists and in heart failure clinics,” Professor Amerena says.
“Bradycardia is usually the limiting symptom, and if the heart rate is lower than 60 bpm we are generally hesitant to push the dose any higher. There can also be issues with lowering blood pressure to the point where hypotension is symptomatic”.
Beta-blockers and airways disease
While cardiologists are generally confident about prescribing beta-blockers in heart failure patients with COPD, unless they have a history of bronchospasm, respiratory physicians are sometimes more cautious in their approach.
“Bisoprolol and nebivolol are more beta-1-selective than metoprolol and carvedilol so they tend to have less effect on the airways, but we sometimes need to reach a compromise with the patient’s respiratory physician on the optimal dose,” Professor Amerena says.
“However, there are studies showing that beta-blockers do not worsen airways obstruction.”9
A clear history of asthma is a contraindication to initiating beta-blocker treatment. “It’s usually evident from a lifelong history of asthma,” he says.
“If there is some doubt – for example a heavy smoker who has occasionally used a bronchodilator in the past – we would consider a cautious trial of a beta-blocker”.
*Healthcare professionals should review the relevant Product Information before prescribing β-blockers for patients with CHF and co-existent COPD.
Co-existing heart problems
A perceived but inaccurate contraindication is the presence of peripheral vascular disease. “Exercise tolerance in patients with claudication is not worsened by a beta-blocker,” Professor Amerena says.
Co-existing atrial fibrillation can complicate the management of heart failure. “In these patients beta-blockers are beneficial for both rate control and heart failure symptoms,” he says.
“Although it has been suggested that mortality benefits in heart failure patients are reduced in the presence of atrial fibrillation (AF),10 we would still use beta-blockers to control heart rate, reduce symptoms and hopefully reduce hospitalisations, even if there were no mortality benefit.
We often take a more aggressive approach to trying to restore sinus rhythm in patients who have both AF and heart failure to improve symptoms, although this has not been shown to improve mortality”.
Individualise treatment
The choice of a beta-blocker should be individualised in patients with heart failure, Professor Amerena says.
“If hypertension is a problem, then carvedilol probably achieves the best blood pressure control. Bisoprolol or nebivolol are preferred in patients with COPD, and the evidence supports nebivolol in older patients.
Other factors such as renal failure, gender, weight or diabetes usually have little impact on the choice.
In summary, we should make every attempt to treat a patient with heart failure with a beta-blocker because of the magnitude of the benefit.
If there are problems with titrating the dose to target due to bradycardia or hypotension, it’s preferable to have a patient on a smaller dose of both a beta-blocker and an ACE inhibitor rather than stopping one drug and increasing the dose of the other”.
Other heart failure medications
Other heart failure treatments include the angiotensin receptor-neprilysin inhibitor (ARNI) valsartan/sacubitril, and ivabradine.
In the PARADIGM study the ARNI valsartan/sacubitril reduced all-cause and CV death compared with enalapril, and reduced hospital admissions.11
The 2016 ESC heart failure guidelines include recommendations on ARNI therapy for the first time, recommending that it replace ACE inhibitors in ambulatory HFrEF patients who remain symptomatic despite optimal therapy and who fit the clinical trial criteria.
Valsartan/sacubitril is registered with the TGA for this indication but is not funded by the PBS. It is only available on a private prescription.
“Its use will have little effect on the role of beta-blockers in treating patients with HFrEF,” Professor Amerena says.
The guidelines note that ivabradine reduces the elevated heart rate often seen in HFrEF and improves outcomes, and should be considered when appropriate.
Ivabradine has a role in patients who have a high heart rate despite maximal tolerated dose beta-blockers, or cannot tolerate them, but the criteria for use in Australia are very restrictive,” Professor Amerena says.
“If beta-blockers are tolerated, they should be continued when ivabradine is commenced, but patients need to be monitored carefully for excessive bradycardia”.
The approved indication for PBS reimbursement of ivabradine is treatment of symptomatic chronic heart failure with a documented left ventricular ejection fraction ≤ 35% in patients in sinus rhythm and with heart rate at or above 77 bpm, in combination with optimal chronic heart failure treatment.
PBS prescription requires use of the maximum tolerated dose of a beta-blocker, unless contraindicated or not tolerated.
References
- Ponikowski P et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016; 37: 2129-200.
- Sacks CA et al. Paradigm shifts in heart-failure therapy – a timeline. N Engl J Med 2014; 371: 989-91.
- Fletcher P. Beta blockers in heart failure. Australian Prescriber 2000; 23: 120-3.
- Packer M et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349-55.
- [No author] 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.
- CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9-13.
- Flather MD 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.
- Kotecha D et al. Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis. BMJ 2016 Apr 20;353:i1855.
- Du Q et al. Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a meta-analysis of observational studies. PLoS One 2014; 9: e113048.
- Kotecha D et al. Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384: 2235-43.
- McMurray JJ et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993-1004.