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Clin Evid (Online). 2010; 2010: 0204.
Published online Feb 25, 2010.
PMCID: PMC2907608

Heart failure

Robert Samuel McKelvie, BSc MSc MD PhD FRCPC, Professor of Medicine

Abstract

Introduction

Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality. The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug treatments, and of drug and invasive treatments, for heart failure? What are the effects of angiotensin-converting enzyme inhibitors in people at high risk of heart failure? What are the effects of treatments for diastolic heart failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 85 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: aldosterone receptor antagonists, amiodarone, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, anticoagulation, antiplatelet agents, beta-blockers, calcium channel blockers, cardiac resynchronisation therapy, digoxin (in people already receiving diuretics and angiotensin-converting enzyme inhibitors), exercise, hydralazine plus isosorbide dinitrate, implantable cardiac defibrillators, multidisciplinary interventions, non-amiodarone antiarrhythmic drugs, and positive inotropes (other than digoxin).

Key Points

Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality.

  • The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.

Multidisciplinary interventions and exercise may reduce admissions to hospital and mortality in people with heart failure compared with usual care, although long-term benefits remain unclear.

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, and beta-blockers reduce mortality and hospital admissions from heart failure compared with placebo, with greater absolute benefits seen in people with more severe heart failure.

  • Combined treatment with angiotensin II receptor blockers and ACE inhibitors may lead to a greater reduction in admission for heart failure compared with ACE inhibitor treatment alone.

Aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) may reduce all-cause mortality in people with heart failure, but increase the risk of hyperkalaemia.

Digoxin slows the progression of heart failure compared with placebo, but may not reduce mortality.

Hydralazine plus isosorbide dinitrate may improve survival and quality-of-life scores compared with placebo in people with chronic congestive heart failure.

ACE inhibitors delay the onset of symptomatic heart failure, reduce cardiovascular events, and improve long-term survival in people with asymptomatic LVSD compared with placebo.

We don't know whether amiodarone, anticoagulants, or antiplatelets are effective at reducing mortality or hospital re-admission rates.

We don't know whether angiotensin II receptor blockers reduce mortality or rate of hospital admissions for cardiovascular events in people with diastolic heart failure.

CAUTION: Positive inotropic agents (other than digoxin), calcium channel blockers, and antiarrhythmic drugs (other than amiodarone and beta-blockers) may all increase mortality and should be used with caution, if at all, in people with systolic heart failure.

Implantable cardiac defibrillators and cardiac resynchronisation therapy can reduce mortality in people with heart failure who are at high risk of ventricular arrhythmias. However, studies evaluating cardiac resynchronisation therapy were performed in centres with considerable experience, which may have overestimated the benefits.

About this condition

Definition

Heart failure occurs when abnormal cardiac function causes failure of the heart to pump blood at a rate sufficient for metabolic requirements under normal filling pressure. It is characterised clinically by breathlessness, effort intolerance, fluid retention, and poor survival. Fluid retention and the congestion related to this can often be relieved with diuretic therapy. However, diuretic therapy should generally not be used alone and, if required, should be combined with the pharmacological therapies outlined in this review. Heart failure can be caused by systolic or diastolic dysfunction, and is associated with neurohormonal changes.[1] Left ventricular systolic dysfunction (LVSD) is defined as a left ventricular ejection fraction (LVEF) below 0.40. It may be symptomatic or asymptomatic. Defining and diagnosing diastolic heart failure can be difficult. Recently proposed criteria include: (1) clinical evidence of heart failure; (2) normal or mildly abnormal left ventricular systolic function; (3) evidence of abnormal left ventricular relaxation, filling, diastolic distensibility, or diastolic stiffness; and (4) evidence of elevated N-terminal-probrain natriuretic peptide.[2] However, assessment of some of these criteria is not standardised.

Incidence/ Prevalence

Both incidence and prevalence of heart failure increase with age. Studies of heart failure in the US and UK found annual incidence in people 45 years or over to be between 29 and 32 cases/1000 persons/year, and, in those over 85 years of age, incidence was considerably higher, at 45 to 90 cases/1000 persons/year.[3] [4] The study carried out in the US reported a decline in incidence of heart failure (all age groups) over a 10-year period, with incidence falling from 32.2 cases/1000 persons/year in 1994 to 29.1 cases/1000 persons/year in 2003.[4]However, analysis of those aged 65 years or over indicated an increase in prevalence of heart failure (from 89.9 cases/1000 people in 1994 to 121 cases/1000 people in 2003). Prevalence of heart failure was higher in men (130 cases/1000 men) compared with women (115 cases/1000 women).[4] In older people (65 years or over), incidence of heart failure after a myocardial infarction (MI) is on the rise, with one study finding an increase of 25.1% in in-hospital heart failure (from 31.4% to 39.3%, P = 0.001).[5] Furthermore, the study noted that 76% of people who survived MI had developed heart failure at 5 years' follow-up. Prevalence of asymptomatic LVSD is 3% in the general population, and the mean age of people with asymptomatic LVSD is lower than that of symptomatic individuals.[6] Both heart failure and asymptomatic LVSD are more common in men.[6] Prevalence of diastolic heart failure in the community is unknown. Prevalence of heart failure with preserved systolic function in people in hospital with clinical heart failure varies from 13% to 74%.[7] [8] Less than 15% of people with heart failure under65 years of age have normal systolic function, whereas prevalence is about 40% in people over 65 years of age.[7]

Aetiology/ Risk factors

Coronary artery disease is the most common cause of heart failure.[9] Other common causes include hypertension and idiopathic dilated congestive cardiomyopathy. After adjustment for hypertension, the presence of left ventricular hypertrophy remains a risk factor for the development of heart failure. Other risk factors include cigarette smoking, hyperlipidaemia, and diabetes mellitus.[6] The common causes of left ventricular diastolic dysfunction are coronary artery disease and systemic hypertension. Other causes are hypertrophic cardiomyopathy, restrictive or infiltrative cardiomyopathies, and valvular heart disease.[8]

Prognosis

The prognosis of heart failure is poor, with 5-year mortality ranging from 26% to 75%.[9] Up to 16% of people are re-admitted with heart failure within 6 months of first admission. In the US, heart failure is the leading cause of hospital admission among people over 65 years of age.[9] In people with heart failure, a new MI increases the risk of death (RR 7.8, 95% CI 6.9 to 8.8). About one third of all deaths in people with heart failure are preceded by a major ischaemic event.[10] Sudden death, mainly caused by ventricular arrhythmia, is responsible for 25% to 50% of all deaths, and is the most common cause of death in people with heart failure. Women with heart failure have a 15% to 20% lower risk of total and cardiovascular mortality compared with men with heart failure: risk after adjustment for demographic and social economic characteristics, comorbidities, cardiovascular treatments, and LVEF.[11] The presence of asymptomatic LVSD increases an individual's risk of having a cardiovascular event. One large prevention trial found that the risk of heart failure, admission for heart failure, and death increased linearly as ejection fraction fell (for each 5% reduction in ejection fraction: RR for mortality 1.20, 95% CI 1.13 to 1.29; RR for hospital admission 1.28, 95% CI 1.18 to 1.38; RR for heart failure 1.20, 95% CI 1.13 to 1.26).[12] The annual mortality for people with diastolic heart failure varies in observational studies (1-18%).[7] Reasons for this variation include age, presence of coronary artery disease, and variation in the partition value used to define abnormal ventricular systolic function. The annual mortality for left ventricular diastolic dysfunction is lower than that found in people with systolic dysfunction.[12]

Aims of intervention

To relieve symptoms; to improve quality of life; and to reduce morbidity and mortality with minimum adverse effects.

Outcomes

Functional capacity (assessed by the New York Heart Association functional classification or more objectively by using standardised exercise testing or the 6-minute walk test);[13] quality of life (assessed with questionnaires);[14] mortality; hospital re-admission rates; adverse effects of treatment. Effects of ACE inhibitors in people at high risk of heart failure: mortality; hospital admission rates; cardiovascular events (including non-fatal MI). Proxy measures of clinical outcome (e.g., LVEF) are used only when clinical outcomes are unavailable.

Methods

Clinical Evidence search and appraisal May 2009. The following databases were used to identify studies for this systematic review (SR): Medline 1966 to May 2009, Embase 1980 to May 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 2 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published SRs of RCTs and RCTs in any language, at least single blinded (unless blinding was impossible), and containing more than 100 individuals of whom more than 80% were followed up. Generally, RCTs with less than 500 people have been excluded because of the number of large RCTs available. If, for any comparison, large RCTs or SRs were found, then smaller RCTs have been excluded, even if they include more than 500 people. Size of follow-up was 80% or more. There was no minimum length of follow-up required to include studies. We included SRs of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table
GRADE evaluation of interventions for heart failure

Glossary

Beck Depression Inventory
Standardised scale to assess depression. This instrument consists of 21 items to assess the intensity of depression. Each item is a list of four statements (rated 0, 1, 2, or 3), arranged in increasing severity, about a particular symptom of depression. The range of scores possible are 0 = least severe depression to 63 = most severe depression. It is recommended for people aged 13–80 years. Scores of more than 12 or 13 indicate the presence of depression.
High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Minnesota Living with Heart Failure Questionnaire
scores range from 1 to 105, with higher scores reflecting a lower quality of life.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
New York Heart Association functional classification
Classification of severity by symptoms. Class I: no limitation of physical activity; ordinary physical activity does not cause undue fatigue or dyspnoea. Class II: slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue or dyspnoea. Class III: limitation of physical activity; comfortable at rest, but less than ordinary activity causes fatigue or dyspnoea. Class IV: unable to carry out any physical activity without symptoms; symptoms are present even at rest; if any physical activity is undertaken, symptoms are increased.
Usual or conventional care
describes the comparator arm of some controlled trials. It refers to appropriate drug and non-drug treatment, in the absence of the intervention being examined in the active treatment arm of the trial.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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74. Cleophas T, van Marum R. Meta-analysis of efficacy and safety of second-generation dihydropyridine calcium channel blockers in heart failure. Am J Cardiol2001;87:487–490. Search date not reported. [PubMed]
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77. Packer M, O'Connor CM, Ghali JK, et al, for the Prospective Randomized Amlodipine Survival Evaluation Study Group. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med1996;335:1107–1114. [PubMed]
78. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med1986;314:1547–1552. [PubMed]
79. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049–2057. [Erratum in: N Engl J Med2005;352:1276]. [PubMed]
80. Finks SW, Finks AL, Self TH, et al. Hydralazine-induced lupus: maintaining vigilance with increased use in patients with heart failure. South Med J2006;99:18–22. [PubMed]
81. Ezekowitz JA, Armstrong PW, McAlister FA. Implantable cardioverter defibrillators in primary and secondary prevention: a systematic review of randomised, controlled trials. Ann Intern Med2003;138:445–452. Search date 2002. [PubMed]
82. Desai AS, Fang JC, Maisel WH, et al. Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy. A meta-analysis of randomised controlled trials. JAMA2004;292:2874–2879. Search date 2004. [PubMed]
83. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators - The OPTIC study: a randomized trial. JAMA2006;295:165−171. [PubMed]
84. Lam SK, Owen A, Lam SimonKH, et al. Combined resynchronisation and implantable defibrillator therapy in left ventricular dysfunction: Bayesian network meta-analysis of randomised controlled trials. BMJ2007;335:925. [PMC free article] [PubMed]
85. McAlister FA, Ezekowitz JA, Wiebe N, et al. Systematic Review: Cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med2004;141:381–390. Search date 2003. [PubMed]
86. Freemantle N. Cardiac resynchronisation for patients with heart failure due to left ventricular systolic dysfunction: a systematic review and meta-analysis. Eur J Heart Failure2006;8:433−440. [PubMed]
87. Linde C, Abraham WT, Gold MR, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol2008;52:1834−1843. [PubMed]
88. Leon AR, Abraham WT, Curtis AB, et al. Safety of transvenous cardiac resynchronization system implantation in patients with chronic heart failure: combined results of over 2,000 patients from a multicenter study program. J Am Coll Cardiol2005;46:2348–2356. [PubMed]
89. Dagenais GR, Pogue J, Fox K, et al. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet2006;368:581–588. [PubMed]
90. Rutherford JD, Pfeffer MA, Moyé LA, et al. Effects of captopril on ischaemic events after myocardial infarction. Circulation1994;90:1731–1738. [PubMed]
91. Jong P, Yusuf S, Rousseau MF, et al. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet2003;361:1843–1848. [PubMed]
92. Buch P, Rasmussen S, Abildstrom SZ, et al. The long-term impact of the angiotensin-converting enzyme inhibitor trandolapril on mortality and hospital admissions in patients with left ventricular dysfunction after a myocardial infarction: follow-up to 12 years. Eur Heart J2005;26:145–152. [PubMed]
93. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med1992;327:685–691. [PubMed]
94. Yusuf S, Pfeffer MA, Swedberg K, et al. (CHARM Investigators and Committees). Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet2003;362:777–781. [PubMed]
95. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med2008;359:2456−2467. [PubMed]
96. Hogg K, McMurray J, Hogg Karen, et al. The treatment of heart failure with preserved ejection fraction ("diastolic heart failure"). Heart Failure Rev2006;11:141−146. [PubMed]
97. Heckman GA, McKelvie RS. Diagnosis and management of heart failure with preserved ejection fraction in older adults. Geriatr Aging2009;12:93-96.
98. Cleland JGF, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J2006:2338–2345. [PubMed]
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Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Multidisciplinary interventions

Summary

MORTALITY Compared with usual care: Multidisciplinary programmes are more effective at reducing all-cause mortality ( high-quality evidence ). ADMISSION TO HOSPITAL Compared with usual care: Multidisciplinary programmes are more effective at reducing all-cause hospital admissions, and hospital admissions for heart failure (high-quality evidence).

Benefits

We found six systematic reviews (search date 2004, 33 RCTs, 7387 people;[15] search date 2005, 36 RCTs, 8341 people;[16] search date 2004, 30 RCTs, 7532 people;[17] search date 2006, 26 RCTs, 4671 people;[18] search date 2006, 14 RCTs, 4264 people;[19]search date 2007, 12 RCTs, 2060 people)[20] and two subsequent RCTs.[21] [22] Between them, the reviews identified 62 RCTs assessing the effects of multidisciplinary programmes in people with heart failure. Although there was considerable overlap among the reviews in the RCTs identified, only two RCTs were identified by all six reviews. The reviews included different RCTs in their meta-analyses, and analysed different aspects of multidisciplinary programmes, and so we report data from all reviews.

The first systematic review found that disease-management programmes significantly reduced all-cause mortality compared with usual care (28 RCTs, 5308 people; 389/2587 [15%] with disease-management programme v 492/2721 [18%] with usual care; OR 0.80, 95% CI 0.69 to 0.93; P = 0.003).[15] The review also found significant reductions in all-cause hospital re-admission and heart failure-specific hospital re-admission (all-cause hospital re-admission; 32 RCTs, 7387 people: OR 0.76, 95% CI 0.69 to 0.94; P less than 0.00001; heart failure-specific hospital re-admission; 20 RCTs, 3817 people: OR 0.58, 95% CI 0.50 to 0.67; P less than 0.00001; absolute numbers not reported) with disease-management programmes compared with usual care. The different disease-management programmes seemed equally effective; therefore, the choice of a specific programme could depend on the local health service characteristics and the available resources. The RCTs of multidisciplinary treatment were generally small, involving highly selected patient populations. Many lasted less than 6 months and were usually carried out in academic centres, and so the results may not generalise to longer-term outcomes based in smaller community centres.

The second systematic review included RCTs lasting 3 months or over; the primary outcome was all-cause mortality.[16] The review found that disease-management programmes significantly reduced all-cause mortality compared with usual care (30 RCTs, ARR –3%, 95% CI –5% to –1%, P less than 0.01; absolute numbers not reported). The benefit of the intervention was dependent on age, severity of disease, guideline-based treatment at baseline, and disease-management programme modalities.

The third systematic review found that multidisciplinary programmes significantly reduced all-cause mortality compared with control (not further defined) (27 RCTs, 7532 people: 613/3867 [16%] with multidisciplinary programme v 661/3580 [18%] with control; RR 0.79, 95% CI 0.69 to 0.92; P = 0.002). [17] However, there was significant heterogeneity among RCTs (P = 0.04); the review identified two RCTs that were outliers as potential sources of heterogeneity. Sensitivity analysis excluding one outlier removed heterogeneity with only a small reduction in results for effectiveness (26 RCTs, 7213 people; RR 0.83, 95% CI 0.73 to 0.95). The review carried out subgroup analyses based on type of intervention offered in the multidisciplinary programme (home visit; home physiological monitoring or televideo contact; telephone or mailing patient without home visit; or programme delivered exclusively in hospital, clinic, or general practice). The review found a significant reduction in all-cause mortality with programmes incorporating televideo or remote monitoring, or contact by telephone or mail compared with control (televideo or remote monitoring; 3 RCTs, 553 people: 35/316 [11%] with multidisciplinary programme v 51/237 [22%] with control; RR 0.49, 95% CI 0.33 to 0.73; P = 0.0004; contact by telephone or mail; 11 RCTs, 3384 people: 220/1679 [13%] with multidisciplinary programme v 279/1705 [16%] with control; RR 0.70, 95% CI 0.53 to 0.94; P = 0.02). However, there was no significant difference in all-cause mortality between control and programmes consisting of home visits or the programmes delivered in hospital, clinic, or general practice (programmes consisting of home visits; 11 RCTs, 1811 people: 149/890 [17%] with multidisciplinary programme v 183/921 [20%] with control; RR 0.87, 95% CI 0.72 to 1.06; P = 0.17; programmes delivered in hospital, clinic, or general practice; 3 RCTs, 1784 people: 209/982 [21.3%] with multidisciplinary programme v 170/802 [21.2%] with control; RR 1.00, 95% CI 0.84 to 1.20; P = 0.98). The review also found that, compared with control, multidisciplinary programmes significantly reduced all-cause hospital admissions (21 RCTs, 6569 people; 1332/3331 [40%] with multidisciplinary programme v 1442/3238 [45%] with control; RR 0.87, 95% CI 0.79 to 0.95; P = 0.002) and hospital admission for heart failure (16 RCTs, number of people in analysis not clear; RR 0.70, 95% CI 0.61 to 0.81; P less than 0.0001; absolute numbers not reported). There was significant heterogeneity among RCTs in the analyses of hospital admission rates (P = 0.04 for both analysis). Most RCTs identified by the review included people who were hospitalised or had been recently hospitalised with a diagnosis of heart failure (26 RCTs). The review defined a multidisciplinary intervention as one in which heart failure management was the responsibility of a team incorporating medical input and input from one or more other areas (specialist nurse, pharmacist, dietitian, or social worker).

The fourth systematic review found that multidisciplinary programmes significantly reduced all-cause mortality and heart failure-specific hospital admission (all-cause mortality; 22 RCTs, 3918 people: 0.69, 95% CI 0.56 to 0.85; heart failure-specific hospital admission; 21 RCTs, 3844 people: OR 0.41, 95% CI 0.30 to 0.56; absolute numbers not reported for either outcome) compared with control (predominantly usual care).[18] The review assessed mode of intervention offered: face-to-face; non face-to-face; and combined face-to-face plus non face-to face. Programmes involving face-to-face contact give the healthcare provider an opportunity to observe the patient. The review found that programmes involving face-to-face contact significantly reduced all-cause mortality (OR 0.63, 95% CI 0.44 to 0.91) and hospital admission for heart failure (OR 0.42, 95% CI 0.22 to 0.81) compared with control. Combination of face-to-face contact plus telephone contact significantly reduced hospital admission for heart failure (OR 0.37, 95% CI 0.21 to 0.64) compared with control, but there was no significant difference between groups in all-cause mortality (OR 0.68, 95% CI 0.44 to 1.06). The review found no significant difference between telephone (non face-to-face) management and control for either all-cause mortality (OR 0.82, 95% CI 0.48 to 1.40) or hospital admission for heart failure (OR 0.67, 95% CI 0.36 to 1.26; number of RCTs and people included in subgroup analysis not reported for any comparison; absolute numbers not reported).

The fifth systematic review assessed the effects of remote monitoring (structured telephone support or telemonitoring) without regular clinic or home visits on all-cause mortality, all-cause rate of readmission to hospital, and heart failure-specific rate of readmission.[19] The review found that, compared with control (not further defined), remote monitoring programmes significantly reduced all-cause mortality (5 RCTs, 4264 people: 286/2210 [13%] with remote monitoring v 295/2054 [14%] with control; RR 0.80, 95% CI 0.69 to 0.92) and rates of readmission to hospital for chronic heart failure (9 RCTs, 3374 people: 339/1718 [20%] with remote monitoring v 389/1656 [23%] with control; RR 0.79, 95% CI 0.69 to 0.89). However, the review found no significant difference between groups in all-cause hospital readmission rates (8 RCTs, 3586 people; 793/1822 [43.5%] with remote monitoring v 768/1764 [43.5%] with control; RR 0.95, 95% CI 0.89 to 1.02). The review carried out subgroup analysis of programmes focusing on telemonitoring and those involving structured telephone support. The review found that telemonitoring significantly reduced all-cause mortality compared with control (5 RCTs, 807 people; 59/445 [13%] with telemonitoring v 68/362 [19%] with control; RR 0.62, 95% CI 0.45 to 0.85). However, there was no significant difference between structured telephone-support programmes and control, although all-cause mortality was lower with structured telephone support (10 RCTs, 3542 people; 227/1765 [13%] with telephone support v 255/1777 [14%] with control; RR 0.85, 95% CI 0.72 to 1.01).

The sixth systematic review focused on the role of pharmacist care (both pharmacist-directed and pharmacist-assisted care) in the management of heart failure.[20] The review found that pharmacist care significantly reduced all-cause hospital admissions (11 RCTs, 2026 people: 363/984 [37%] with pharmacist care v 449/1042 [43%] with no pharmacist care; OR 0.71, 95% CI 0.54 to 0.94) and heart failure-specific hospital admissions (11 RCTs, 1977 people: 183/959 [19%] with pharmacist care v 238/1018 [23%] with no pharmacist care; OR 0.69, 95% CI 0.51 to 0.94) compared with no pharmacist care. The review found no significant difference between groups in all-cause mortality, although rate was lower with pharmacist care (12 RCTs, 2060 people: 117/1001 [12%] with pharmacist care v 136/1059 [13%] with no pharmacist care; OR 0.84, 95% CI 0.61 to 1.15).

The first subsequent RCT (1049 people hospitalised because of heart failure, New York Heart Association functional class II to IV) is a large multicentre three-arm RCT that compared an intensive disease management programme involving specialised nursing care together with consultation with a cardiologist (353 people) versus a basic support intervention (348 people; follow-up with specialised nurse and cardiologist) versus usual care (348 people; follow-up with cardiologist alone).[21] Here, we report data for only the comparison of the intensive-treatment programme versus usual care. The RCT found no significant difference between intensive disease management and usual care at 18 months in a composite outcome of all-cause mortality or hospital re-admission as a result of heart failure (132/344 [38%] with intensive disease management v 141/339 [42%] with usual care; HR 0.93, 95% CI 0.73 to 1.17). The results from this large RCT do not correlate with the results of the six SRs reported. One possible reason for the lack of observed benefit for the intensive disease-management programme is that, during the course of the study, people in the usual-care group had a closer follow-up by the cardiologist than was anticipated prior to starting the study. Also, for the individual components of the composite outcome, the RCT found that rate of all-cause mortality was lower (83/344 [24%] with intensive disease management v 99/339 [29%] with usual care) with intensive disease management, but heart failure hospital re-admission rates were higher (92/344 [27%] with intensive disease management v 84/339 [25%] with usual care; significance not assessed for either outcome). The RCT was not powered to assess mortality alone.

The second subsequent RCT (460 people hospitalised with confirmed diagnosis of congestive heart failure and left ventricular ejection fraction [LVEF] of less than 40%) compared a home-based telemanagement multidisciplinary approach versus usual care.[22] The RCT found that the home-based telemanagement programme significantly reduced all-cause and heart failure-specific hospital readmission rates at 1 year compared with usual care (all-cause readmission: 67/229 [29%] with telemanagement v 96/226 [42%] with usual care; RR 0.57, 95% CI 0.39 to 0.87: heart failure readmission: 43/229 [19%] with telemanagement v 73/226 [32%] with usual care; RR 0.49, 95% CI 0.31 to 0.76). The RCT found no significant difference between groups in all-cause mortality at 1 year (9% with telemanagement v 14% with usual care; reported as not significant; P value not reported; absolute numbers not reported).

Harms

The reviews and subsequent RCTs gave no information on adverse effects.[15] [16] [17] [18] [19] [20] [21] [22]

Comment

Clinical guide:

The multiple systematic reviews identified have suggested that disease-management programmes may reduce mortality, all-cause hospital admissions, and hospital admission for heart failure. It is reassuring that, despite the lack of specific analysis of adverse effects, all-cause mortality and all-cause hospital re-admissions were reduced, suggesting that multidisciplinary treatment overall is beneficial and not associated with any clinically important adverse effects.The data at this time are supportive of the use of disease-management programmes to treat people with heart failure, with the expectation that there will be a reduction in mortality and morbidity compared with usual care.

Substantive changes

Multidisciplinary interventions: Four systematic reviews[17] [18] [19] [20] and one subsequent RCT[22] added all found that multidisciplinary programmes reduced all-cause mortality and hospital re-admission rates compared with usual care/control, providing even stronger evidence on the beneficial effects of multidisciplinary interventions in heart failure. By contrast, one large subsequent RCT added found no significant difference between an intensive disease management programme and usual care in a composite outcome of all-cause mortality and hospital re-admission because of heart failure.[21] However, people in the usual-care group had a closer follow-up by the cardiologist than was anticipated prior to starting the study, which may bias the results against the intensive intervention. Categorisation unchanged (Beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Exercise

Summary

MORTALITY Compared with usual care: Exercise training may be more effective at reducing mortality ( low-quality evidence ). HOSPITAL ADMISSION Compared with usual care: We don't know whether exercise training is more effective at reducing hospital admissions or composite outcomes including all-cause hospital admission (other outcomes in composites include emergency department admission, urgent transplant, and death) (low-quality evidence). FUNCTIONAL IMPROVEMENT Compared with no exercise: Exercise training may be more effective at increasing exercise duration and distance on the 6-minute walk (low-quality evidence). QUALITY OF LIFE Compared with no exercise: Exercise training seems no more effective at improving quality of life ( moderate-quality evidence ).

Benefits

We found three systematic reviews (search date not reported, 9 RCTs, 801 people;[23] search date 2001, 29 parallel group or crossover RCTs, 1126 people;[24] and search date 2003, 30 parallel group RCTs plus nine crossover RCTs, 2387 people[25]), and three subsequent RCTs.[26] [27] [28] Between them, the reviews identified 50 RCTs (includes parallel group and crossover RCTs). The reviews reported different outcomes and so we report all three reviews here.

The first review found that exercise training (to 60–80% of peak heart rate or peak oxygen consumption) significantly reduced all-cause mortality and the combined outcome of death or hospital admission compared with usual care (mortality: 88/395 [22%] with exercise v 105/406 [26%] with usual care; HR 0.65, 95% CI 0.46 to 0.92; death or admission: 127/395 [32%] with exercise v 173/406 [43%] with usual care; HR 0.72, 95% CI 0.56 to 0.93).[23]

The second review found that exercise significantly increased exercise duration and distance on the 6-minute walk compared with no exercise (WMD for increase in exercise duration: 15 RCTs, 510 people, 2.38 minutes, 95% CI 1.92 minutes to 2.85 minutes; WMD for increase in distance: 8 RCTs, 282 people, 40.9 metres, 95% CI 17.1 metres to 64.7 metres).[24]

The third review found no significant difference between exercise and control in events (including hospital admission causing temporary or permanent withdrawal from exercise) or all-cause mortality at a mean 5.9 months of follow-up (events: 14 parallel group RCTs, 1197 people; 30/622 [5%] with exercise v 34/575 [6%] with control; OR 0.83, 95% CI 0.50 to 1.39; mortality: 26/622 [4%] with exercise v 41/575 [7%] with control; OR 0.71, 95% CI 0.37 to 1.02).[25] Follow-up among RCTs ranged from 4 weeks to 192 weeks; about half of the RCTs included in the review had a follow-up of 3 months or less.

The first subsequent RCT (173 people with heart failure and left ventricular ejection fraction [LVEF] 40% or less, New York Heart Association functional class II to IV) compared a home-based exercise programme that incorporated a combination of aerobic and resistance exercise training versus usual care.[26] The RCT found no significant difference between exercise and usual care at 12 months in the composite outcome of all-cause hospital admission, emergency department admission, urgent transplant, and death (38/87 [44%] with exercise v 37/86 [43%] with usual care; P = 0.88). The RCT also found no significant difference between groups at 6 months in improvement in 6-minute walk test (change from baseline: from 1350 m to 1422 m with exercise v from 1324 m to 1385 m with usual care; P = 0.275) or in quality of life (assessed using the Minnesota Living with Heart Failure Questionnaire [MLHFQ; higher score represents worse quality of life]: change in total score from baseline: from 46.7 to 35.7 with exercise v from 49.2 to 43.2 with usual care; P = 0.819). The method of randomisation of the RCT is unclear.

The second subsequent RCT (169 people with LVEF 40% or less and New York Heart Association functional class II or more) assessed the effect of adding home-based exercise training to specialist heart failure nurse care.[27] The RCT found no significant difference between exercise and usual care (specialist nurse care alone) in quality of life at 6 months (assessed using MLHFQ: mean difference –2.53, 95% CI –7.87 to +2.80; P = 0.3) or at 12 months' follow-up (mean difference –0.55, 95% CI –5.87 to +4.76; P = 0.8). The RCT also found no significant difference between groups in the incremental shuttle walking test at 6 months (mean difference: +14.98 m, 95% CI –11.89 m to +41.86 m; P = 0.1).

The third subsequent RCT (2331 people with medically stable heart failure and LVEF of 35% or less) compared exercise training versus usual care and had a median follow up of 30 months.[28] The RCT found no significant difference between exercise training and usual care in a composite outcome of all-cause mortality or all-cause hospital admission, although rate of outcome was lower with exercise (759/1159 [65%] with exercise training v 796/1171 [68%] with usual care; HR 0.93, 95% CI 0.84 to1.02; P = 0.13). Separate analysis of all-cause mortality alone showed no significant difference between groups for this outcome (189/1159 [16%] with exercise v 198/1171 [17%] with usual care; HR 0.96, 95% CI 0.79 to 1.17; P = 0.70). The RCT protocol prespecified an analysis to adjust for baseline characteristics that are strongly predictive (duration of cardiopulmonary exercise test, LVEF, Beck Depression Inventory II score, history of atrial fibrillation or flutter, and heart failure aetiology) of the clinical outcomes of interest. After adjustment for the prespecified covariates, the RCT found the difference between exercise training and usual care in the composite outcome of all-cause mortality or all-cause hospital admission to be significant, in favour of exercise (HR 0.89, 95% CI 0.81 to 0.99; P = 0.03).

Harms

The first and second systematic reviews gave no information on adverse effects of exercise training.[23] [24] The third review found no reports of deaths directly related to exercise during more than 60,000 people-hours of exercise training.[25] The first and second subsequent RCT gave no information on adverse effects.[26] [27] The third subsequent RCT found that the performance of exercise training was well tolerated and safe.[28] Although the usual-care group did not undergo a formal exercise programme, the RCT found that a similar proportion of people in each group had at least one hospital admission as a result of an event during or within 3 hours after exercise (37/1159 [3%] with exercise v 22/1171 [2%] with usual care; significance not assessed).

Comment

Clinical guide:

The specific form of exercise training varied among studies, and the relative merits of each strategy are unknown. Most studies identified have generally lasted less than 1 year, and adherence to home-based exercise programmes is typically low, which could result in underestimation of the beneficial effects of exercise training. The most recent RCT (HF-ACTION RCT) identified is the largest (2331 people) study identified to date.[28] Results from this multicentre, international study may more appropriately be generalised to smaller community centres. The findings from HF-ACTION support a prescribed exercise training programme for heart-failure patients in addition to other evidence-based therapies.

Substantive changes

Exercise Three RCTs added found no significant difference between exercise and usual care in various outcomes (quality-of-life and composite outcomes comprising all-cause mortality, all-cause hospital re-admission, and heart failure-specific hospital admission),[26] [27] [28] which is in contrast to evidence previously reported that showed a benefit with exercise. The largest RCT added (2331 people) carried out a prespecified analysis to adjust for baseline characteristics (duration of cardiopulmonary exercise test, left ventricular ejection fraction [LVEF], Beck Depression Inventory II score, history of atrial fibrillation or flutter, and heart failure aetiology) that are strongly predictive for all-cause mortality and other clinical outcomes.[28] After adjustment, the RCT found that exercise reduced a composite outcome of all-cause mortality or all-cause hospital admission. Categorisation unchanged (Likely to be beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

ACE inhibitors for treating heart failure

Summary

MORTALITY Compared with placebo: ACE inhibitors are more effective at reducing mortality ( high-quality evidence ). Different doses compared with each other: Low-dose and high-dose lisinopril seem equally effective at reducing mortality ( moderate-quality evidence ). Compared with angiotensin II receptor blockers: ACE inhibitors and angiotensin II receptor blockers are equally effective at reducing all-cause mortality at 4 weeks to 2.7 years (high-quality evidence). ACE inhibitors alone compared with angiotensin II receptor blockers plus ACE inhibitors: We don't know whether ACE inhibitors alone are more effective than angiotensin II receptor blockers plus ACE inhibitors at reducing mortality or a composite outcome of mortality plus morbidity independent of whether people are taking beta-blockers ( low-quality evidence ). Compared with beta-blockers: The ACE inhibitor enalapril and the beta-blocker bisoprolol may be equally effective at reducing the composite outcome of all-cause mortality or hospital admission in people with heart failure (low-quality evidence). HOSPITAL ADMISSION Compared with placebo: ACE inhibitors are more effective at reducing hospital admissions for heart failure (high-quality evidence). Different doses compared with each other: Low-dose lisinopril is less effective than high-dose lisinopril at reducing admissions for heart failure (moderate-quality evidence). Compared with angiotensin II receptor blockers: ACE inhibitors and angiotensin II receptor blockers are equally effective at 4 weeks to 2.7 years at reducing hospital admissions for heart failure (high-quality evidence). ACE inhibitors alone compared with angiotensin II receptor blockers plus ACE inhibitors: ACE inhibitors alone are less effective than adding angiotensin II receptor blockers to ACE inhibitors at reducing hospital admissions for heart failure (high-quality evidence).

Benefits

Angiotensin-converting enzyme (ACE) inhibitors versus placebo:

We found two systematic reviews (search dates 1994[29] and not reported)[30] of ACE inhibitors versus placebo in heart failure. The first review (32 RCTs, duration 3–42 months, 7105 people, New York Heart Association [NYHA] functional class III or IV) found that ACE inhibitors significantly reduced mortality compared with placebo (611/3870 [16%] with ACE inhibitors v 709/3235 [22%] with placebo; ARR 6%, 95% CI 4% to 8%; OR 0.77, 95% CI 0.67 to 0.88).[29] Relative reductions in mortality were similar in different subgroups (stratified by age, sex, cause of heart failure, and NYHA functional class). The second review (5 RCTs, 12,763 people with left ventricular dysfunction or heart failure of mean duration 35 months) analysed long-term results from large RCTs comparing ACE inhibitors versus placebo.[30] Three RCTs examined the effects of ACE inhibitors in people for 1 year after myocardial infarction (MI). In these three post-infarction trials (5966 people), ACE inhibitors significantly reduced mortality, re-admission for heart failure, and re-infarction compared with placebo (mortality: 702/2995 [23%] with ACE inhibitors v 866/2971 [29%] with placebo; OR 0.74, 95% CI 0.66 to 0.83; re-admission for heart failure: 355/2995 [12%] with ACE inhibitors v 460/2971 [16%] with placebo; OR 0.73, 95% CI 0.63 to 0.85; re-infarction: 324/2995 [11%] with ACE inhibitors v 391/2971 [13%] with placebo; OR 0.80, 95% CI 0.69 to 0.94). For all five trials, ACE inhibitors significantly reduced mortality and re-admission for heart failure compared with placebo (mortality: 1467/6391 [23%] with ACE inhibitors v 1710/6372 [27%] with placebo; OR 0.80, 95% CI 0.74 to 0.87; re-admission for heart failure: 876/6391 [14%] with ACE inhibitors v 1202/6372 [19%] with placebo; OR 0.67, 95% CI 0.61 to 0.74). The relative benefits began soon after the start of treatment, persisted in the long term, and were independent of age, sex, and baseline use of diuretics, aspirin, and beta-blockers. Although there was a trend toward greater relative reduction in mortality or re-admission for heart failure in people with lower ejection fraction, benefit was apparent over the range examined.

Dose:

We found one large RCT (3164 people with NYHA functional class II–IV heart failure), which compared low-dose lisinopril (2.5 or 5.0 mg/day) versus high-dose lisinopril (32.5 or 35.0 mg/day).[31] It found no significant difference in mortality (717/1596 [45%] with low dose v 666/1568 [43%] with high dose; ARR 2.4%, CI not reported; HR 0.92, 95% CI 0.80 to 1.03; P = 0.128), but it found that high-dose lisinopril reduced the combined outcome of death or hospital admission for any reason (events: 1338/1596 [84%] with low dose v 1250/1568 [80%] with high dose; ARR 4.1%, CI not reported; HR 0.88, 95% CI 0.82 to 0.96) and reduced admissions for heart failure (admissions: 1576/1596 [99%] with low dose v 1199/1568 [77%] with high dose; ARR 22.2%, CI not reported; P = 0.002).

Comparison of different ACE inhibitors:

The first systematic review found similar benefits with different ACE inhibitors.[29]

ACE inhibitors versus angiotensin II receptor blockers:

See benefits of angiotensin II receptor blockers.

ACE inhibitors alone versus ACE inhibitors plus angiotensin II receptor blockers:

See benefits of angiotensin II receptor blockers.

ACE inhibitors versus beta-blockers:

See benefits of beta-blockers.

Harms

The main adverse effects in large RCTs were cough, hypotension, hyperkalaemia, and renal dysfunction. We found one systematic review (search date 1999), which specifically examined the adverse effects of ACE inhibitors in people with heart failure.[32] It found that ACE inhibitors significantly increased withdrawal caused by adverse effects compared with control (placebo or non-ACE inhibitor treatments) after about 2 years (22 RCTs, 9668 people; AR 13.8% with ACE inhibitor v 9.4% with control; RR 1.54, 95% CI 1.30 to 1.83). ACE inhibitors significantly increased cough, hypotension, renal dysfunction, dizziness, and impotence compared with control treatments (cough: RR 3.19, 95% CI 2.22 to 4.57; hypotension: RR 1.95, 95% CI 1.39 to 2.74; renal dysfunction: RR 1.84, 95% CI 1.20 to 2.81; dizziness: RR 1.60, 95% CI 1.15 to 2.23; impotence: RR 6.46, 95% CI 1.14 to 36.58).

Angiotensin-converting enzyme (ACE) inhibitors versus placebo:

Compared with placebo, ACE inhibitors increased cough (37% with ACE inhibitor v 31% with placebo; ARI 7%, 95% CI 3% to 11%; RR 1.23, 95% CI 1.11 to 1.35), dizziness or fainting (57% with ACE inhibitor v 50% with placebo; ARI 7%, 95% CI 3% to 11%; RR 1.14, 95% CI 1.06 to 1.21), creatinine concentrations greater than 177 micromol/L (11% with ACE inhibitor v 8% with placebo; ARI 3.0%, 95% CI 0.6% to 6.0%; RR 1.38, 95% CI 1.09 to 1.67), and potassium concentrations greater than 5.5 mmol/L (AR: 6% with ACE inhibitor v 3% with placebo; ARI 4%, 95% CI 2% to 7%; RR 2.56, 95% CI 1.92 to 3.20).[33] The risk of angio-oedema was similar with ACE inhibitors and placebo (3.8% with enalapril v 4.1% with placebo; ARI +0.3%, 95% CI –1.4% to +1.5%).[33]

Dose:

The trial comparing low-dose versus high-dose lisinopril found that adverse effects were more common with high dose (dizziness: 12% with low dose v 19% with high dose; hypotension: 7% with low dose v 11% with high dose; worsening renal function: 7% with low dose v 10% with high dose; significant change in serum potassium concentration: 7% with low dose v 7% with high dose; P values not reported), although there was no difference in withdrawal rates between groups (18% discontinued with low dose v 17% discontinued with high dose).[31] The trial found that cough was less commonly experienced with high-dose than low-dose lisinopril (13% with low dose v 11% with high dose).

ACE inhibitors versus angiotensin II receptor blockers:

See harms of angiotensin II receptor blockers.

ACE inhibitors alone versus ACE inhibitors plus angiotensin II receptor blockers:

See harms of angiotensin II receptor blockers.

ACE inhibitors versus beta-blockers:

See harms of beta-blockers.

Comment

Clinical guide:

The relative benefits of ACE inhibitors were similar in different subgroups of people with heart failure. Most RCTs evaluated left ventricular function by assessing LVEF, but some studies defined heart failure clinically, without measurement of left ventricular function in people at high risk of developing heart failure (soon after MI). It is unclear whether there are additional benefits from adding an ACE inhibitor to antiplatelet treatment in people with heart failure (see antiplatelet agents).

Substantive changes

ACE inhibitors for treating heart failure One systematic review[34] added found no significant difference between angiotensin receptor blockers, either alone or in combination, and ACE inhibitors in all-cause mortality, which is in agreement with evidence already reported. Although RCTs identified by the review are included in existing reporting, the inclusion criteria of the review differ from reviews reported (minimum follow-up of 6 months and minimum size of RCT of 500 people). One systematic review added focusing on adverse effects of treatment with angiotensin II receptor blocker plus ACE inhibitor found that, compared with control (predominantly ACE inhibitor alone) combination treatment was associated with higher rates of discontinuation because of adverse effects, symptomatic hypertension, and worsening renal function.[35] Categorisation unchanged (Beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Angiotensin II receptor blockers

Summary

MORTALITY Compared with placebo: Angiotensin II receptor blockers are more effective at reducing all-cause mortality at 4 weeks to 2.7 years ( high-quality evidence ). Compared with ACE inhibitors: Angiotensin II receptor blockers and ACE inhibitors are equally effective at reducing all-cause mortality at 4 weeks to 2.7 years (high-quality evidence). Angiotensin II receptor blockers plus ACE inhibitors compared with ACE inhibitors alone: We don't know whether angiotensin II receptor blockers plus ACE inhibitors are more effective than ACE inhibitors alone at reducing mortality or a composite outcome of mortality plus morbidity independent of whether people are taking beta-blockers ( low-quality evidence ). HOSPITAL ADMISSION Compared with placebo: Angiotensin II receptor blockers are more effective at reducing hospital admissions for heart failure (high-quality evidence). Compared with ACE inhibitors: Angiotensin II receptor blockers and ACE inhibitors are equally effective at 4 weeks to 2.7 years at reducing hospital admissions for heart failure (high-quality evidence). Angiotensin II receptor blockers plus ACE inhibitors compared with ACE inhibitors: Angiotensin II receptor blockers plus ACE inhibitors are more effective at reducing hospital admissions for heart failure (high-quality evidence).

Benefits

Angiotensin II receptor blockers (ARBs) versus placebo:

We found one systematic review (search date 2003, 24 RCTs, 38,080 people with New York Heart Association [NYHA] functional class II–IV, follow-up 4 weeks to 2.7 years).[36] It found that, compared with placebo, ARBs significantly reduced all-cause mortality (9 RCTs, 4623 people; 299/2821 [11%] with ARBs v 319/1802 [18%] with placebo; OR 0.83, 95% CI 0.69 to 1.00) and hospital admission for heart failure (3 RCTs, 2590 people; 230/1340 [17%] with ARBs v 314/1250 [25%] with placebo; OR 0.64, 95% CI 0.53 to 0.78).

ARBs versus ACE inhibitors:

We found two systematic reviews (search date 2003, 10 RCTs, 25,739 people with NYHA functional class II–IV, follow-up 4 weeks to 2.7 years;[36] search date 2007, 5 RCTs [all of which were identified by the first review],[36] 24,822 people).[34] The reviews differed in their criteria for inclusion in minimum number of people enrolled and length of follow-up. The first review included RCTs of any size with a minimum length of follow-up of 4 weeks,[36] whereas the second review specified a minimum number of 500 people and at least 6 months' follow-up.[34] The reviews therefore included different RCTs in their analysis of all-cause mortality and so we report both reviews here.

Both reviews found no significant difference between ARBs and ACE inhibitors in all-cause mortality (first review:[36] 8 RCTs, 5201 people; 331/2889 [11%] with ARBs v 295/2312 [13%] with ACE inhibitors; OR 1.06, 95% CI 0.90 to 1.26; second review:[34]3 RCTs, 4310 people: 317/2257 [14.0%] with ARBs v 286/2053 [13.9%] with ACE inhibitors; RR 1.06, 95% CI 0.56 to 1.62).

The reviews included the same three RCTs in their meta-analyses of hospital admission for heart failure, with both reviews finding no significant difference between ARBs and ACE inhibitors in this outcome (meta-analysis from first review:[36] 3 RCTs, 4310 people; 333/2257 [15%] with ARBs v 321/2053 [16%] with ACE inhibitors; OR 0.95, 95% CI 0.80 to 1.13).

ARBs plus ACE inhibitors versus ACE inhibitors alone:

We found three systematic reviews (search date 2003, 7 RCTs, 8260 people with NYHA functional class II–IV heart failure;[36] search date 2003, 4 RCTs;[37] search date 2007, 3 RCTs, 7999 people[34]). All RCTs identified by the second and third reviews[37] [34] were identified by the first review.[36] However, there was variation among the reviews in their inclusion criteria and outcomes assessed and so we report all three reviews here. The first review included RCTs of any size with a minimum length of follow-up of 4 weeks,[36] whereas the second and third reviews specified at least 6 months' follow-up.[37] [34] The third review also specified a minimum number of 500 people.[34]

The first review found that, compared with ACE inhibitors alone, ARBs plus ACE inhibitors significantly reduced hospital admission for heart failure (4 RCTs, 8108 people; 688/4176 [16%] with ARB plus ACE inhibitor v 819/3932 [21%] with ACE inhibitor alone; OR 0.77, 95% CI 0.69 to 0.87). It found no significant difference between treatments in all-cause mortality (7 RCTs, 8260 people; 903/4265 [21%] with ARB plus ACE inhibitor v 901/3995 [23%] with ACE inhibitor alone; OR 0.97, 95% CI 0.87 to 1.08).[36]

The second review (4 RCTs identified by the first systematic review,[36] 7666 people) primarily assessed the effects of ARBs plus ACE inhibitors versus ACE inhibitors alone with and without beta-blockers.[37] The review found that ARBs plus ACE inhibitors (with or without beta-blockers) significantly reduced the composite outcome of mortality and morbidity compared with ACE inhibitor alone (4 RCTs, 7666 people: OR 0.89, 95% CI 0.81 to 0.98; absolute numbers not reported). The review carried out a meta-analysis comparing treatments for the outcome of mortality, which included the same four RCTs as the first review and found the same result. In a subgroup analysis of people not taking beta-blockers, the review found that ARBs plus ACE inhibitors significantly reduced the composite outcome of morbidity and mortality compared with ACE inhibitors alone (2 RCTs, OR 0.83, 95% CI 0.73 to 0.94), but found no significant difference between treatments in mortality (2 RCTs, OR 0.93, 95% CI 0.81 to 1.06; absolute numbers not reported for either outcome; no statistically significant heterogeneity in either analysis). Subgroup analysis of people also taking beta-blockers found no significant difference between treatments in mortality alone or in the composite outcome of morbidity and mortality; however, there was statistical heterogeneity among the RCTs (P less than 0.05), and direction of effect differed for the outcomes (morbidity or mortality: 2 RCTs, OR 0.94, 95% CI 0.80 to 1.10; mortality: 2 RCTs, OR 1.08, 95% CI 0.90 to 1.29; absolute numbers not reported for either analysis).

The third review specified inclusion criteria of 500 or more people and 6 months' or longer follow-up.[34] The review found the same results as the other two reviews.[36] [37] It found that ARBs plus ACE inhibitors significantly reduced hospital admission for heart failure compared with ACE inhibitor alone (3 RCTs [all of which were included in the meta-analysis of the first review for this outcome],[36] 7999 people: 686/4119 [17%] with ARB plus ACE inhibitor v 818/3980 [21%] with ACE inhibitor alone; RR 0.83, 95% CI 0.71 to 0.97). It found no significant difference between treatments in mortality (3 RCTs, 7999 people: 901/4119 [22%] with ARB plus ACE inhibitor v 900/3980 [23%] with ACE inhibitor alone; RR 0.98, 95% CI 0.84 to 1.15).

Harms

Angiotensin II receptor blockers (ARBs) versus placebo:

The review gave no information on adverse effects.[36]

ARBs versus ACE inhibitors:

The reviews gave no information on adverse effects.[36] [34]

ARBs plus ACE inhibitors versus ACE inhibitors alone:

The reviews reported in the benefits section gave no information on adverse effects.[36] [37] [34]

We found one systematic review examining the adverse effects associated with treatment with ARB plus ACE inhibitor in heart failure (search date 2006, 4 RCTs [all of which were identified by the 3 reviews reported in the benefits section],[36] [37] [34] 17,337 people).[35] The review reported that two of the RCTs included in the analysis were described as placebo-controlled trials, but that people in the control groups received ACE inhibitors as usual care. The review identified statistical heterogeneity among studies and suggested clinical condition (chronic heart failure or MI with symptomatic left ventricular dysfunction) as a potential source of heterogeneity. When analysing results based on clinical condition, results were statistically homogeneous. It found that, compared with control (predominantly ACE inhibitor alone), ARB plus ACE inhibitor was associated with a significantly higher rate of discontinuation of medication caused by adverse effects in people with chronic heart failure (540/3602 [15%] with ARB plus ACE inhibitor v 391/3590 [11%] with control; RR 1.38, 95% CI 1.22 to 1.55) and in people with MI with symptomatic left ventricular dysfunction (438/4885 [9%] with ARB plus ACE inhibitor v 375/4909 [8%] with control; RR 1.17, 95% CI 1.03 to 1.34). Combination treatment was also associated with a significant increase in worsening of renal function, and in risk of symptomatic hypotension for both clinical conditions compared with control (renal function: chronic heart failure; 128/3934 [3%] with ARB plus ACE inhibitor v 55/3699 [2%] with control; RR 2.17, 95% CI 1.59 to 2.97; MI with symptomatic left ventricular dysfunction: 232/4885 [5%] with ARB plus ACE inhibitor v 148/4909 [3%] with control; RR 1.61, 95% CI 1.31 to 1.98: symptomatic hypotension: chronic heart failure; 94/3934 [2.4%] with ARB plus ACE inhibitor v 60/3699 [1.5%] with control; RR 1.50, 95% CI 1.09 to 2.07; MI with symptomatic left ventricular dysfunction; 884/4885 [18%] with ARB plus ACE inhibitor v 582/4909 [12%] with control; RR 1.48, 95% CI 1.33 to 3.18).[35] The review found that, in people with chronic heart failure, ARB plus ACE inhibitor was associated with a significant increase in hyperkalaemia compared with control (44/1276 [4%] with ARB plus ACE inhibitor v 9/1272 [1%] with control; RR 4.87, 95% CI 2.39 to 9.94), but there was no significant difference between groups in rate of hyperkalaemia in people with MI with symptomatic left ventricular dysfunction (57/4885 [1.2%] with ARB plus ACE inhibitor v 43/4909 [0.9%] with control; RR 1.33, 95% CI 0.90 to 1.98).[35]

Comment

Clinical guide:

Evidence suggests that, in people intolerant of ACE inhibitors, an ARB would be as effective at reducing mortality and morbidity. Furthermore, the evidence suggests that, for people with NYHA functional class II–IV, an ARB should be added to treatment after ACE inhibition and beta-blocker treatment have been optimised, to further reduce both mortality and morbidity.

Substantive changes

Angiotensin II receptor blockers for heart failure One systematic review[34] added found no significant difference between angiotensin receptor blockers, either alone or in combination, and ACE inhibitors in all-cause mortality, which is in agreement with evidence already reported. Although RCTs identified by the review are included in existing reporting, the inclusion criteria of the review differ from reviews reported (minimum follow-up of 6 months and minimum size of RCT of 500 people). One systematic review added focusing on adverse effects of treatment with angiotensin II receptor blocker plus ACE inhibitor found that, compared with control (predominantly ACE inhibitor alone) combination treatment was associated with higher rates of discontinuation because of adverse effects, symptomatic hypertension, and worsening renal function.[35] Categorisation unchanged (Beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Beta-blockers

Summary

MORTALITY Compared with placebo (in people with any severity of heart failure): Beta-blockers are more effective at reducing the risk of death in people with heart failure of any severity also receiving triple therapy, and in particular ACE inhibitors. However, when given to older people, the beta-blocker nebivolol seems no more effective than placebo at reducing all-cause mortality ( moderate-quality evidence ). Compared with placebo (in people with severe heart failure): Beta-blockers seem more effective at reducing mortality in people with severe heart failure who are also taking ACE inhibitors and diuretics with or without digitalis, and in those not taking ACE inhibitors or angiotensin II receptor blockers at baseline (moderate-quality evidence). Compared with ACE inhibitors: The beta-blocker bisoprolol and the ACE inhibitor enalapril may be equally effective at reducing the composite outcome of all-cause mortality or hospital admission in people with heart failure ( low-quality evidence ). HOSPITAL ADMISSION Compared with placebo (in people with any severity of heart failure): Beta-blockers may be more effective at reducing hospital admissions in people with heart failure of any severity also receiving triple therapy, and in particular ACE inhibitors, and may be more effective at reducing a composite outcome of mortality and hospital admissions in older people (low-quality evidence). Compared with placebo (in people with severe heart failure): Beta-blockers may be more effective at reducing the combined outcome of death and hospital admissions independent of whether people are taking ACE inhibitors or angiotensin II receptor blockers at baseline (low-quality evidence). FUNCTIONAL IMPROVEMENT Compared with placebo (in people with any severity of heart failure): Beta-blockers are more effective at increasing the proportion of people with an improvement in function (New York Heart Association functional classification) by at least one class, and at improving exercise time (moderate-quality evidence).

Benefits

Beta-blockers versus placebo:

In people with any severity of heart failure:

We found two systematic reviews in people with any severity of heart failure, which between them identified 35 RCTs.[38] [39] We also found one subsequent RCT.[40]

The first systematic review (search date 2000; 22 RCTs, 10,315 people with heart failure, most receiving triple therapy, and in particular ACE inhibitors) found that beta-blockers significantly reduced mortality and hospital admission compared with placebo (22 RCTs; mortality: 444/5273 [8%] with beta-blockers v 624/4862 [13%] with placebo; OR 0.65, 95% CI 0.53 to 0.80; hospital admissions: 540/5244 [10%] with beta-blockers v 754/4832 [16%] with placebo; OR 0.64, 95% CI 0.53 to 0.79).[38] This is equivalent to three fewer deaths and four fewer hospital admissions per 100 people treated for 1 year. The results were consistent for selective and non-selective beta-blockers. Sensitivity analysis and funnel plots found that publication bias was unlikely.

The second systematic review (search date 2004; 28 RCTs, 7637 people with heart failure) examined the effects of beta-blockers on functional status.[39] Of the people included, 95% had New York Heart Association (NYHA) class II or III heart failure and were randomised to receive either beta-blocker (4015 people) or placebo (3622 people). The review found that beta-blockers significantly increased the proportion of people who had improved NYHA class by at least one class and exercise time (NYHA class by at least one class; 25 RCTs, 7511 people: OR 1.80, 95% CI 1.33 to 2.43, P less than 0.0001; absolute numbers not reported; exercise time; 10 RCTs, 1120 people: mean difference 44.19 seconds, 95% CI 6.62 seconds to 81.75 seconds; P = 0.021).

The subsequent RCT (2128 older people with heart failure, mean age 76 years, mean left ventricular ejection fraction [LVEF] 36%, 35% of people had LVEF greater than 35%) assessed the effects of nebivolol in older people.[40] It found that nebivolol significantly reduced the composite end point of all-cause mortality or cardiovascular hospital admission compared with placebo (332/1067 [31%] with nebivolol v 375/1061 [35%] with placebo; HR 0.86, 95% CI 0.74 to 0.99). It found no significant difference between treatments in all-cause mortality, although mortality was lower with nebivolol (169/1067 [16%] with nebivolol v 192/1061 [18%] with placebo; HR 0.88, 95% CI 0.71 to 1.08). The absence of a significant effect of nebivolol on mortality may have been because of the inclusion of people with an LVEF greater than 35%.

In people with severe heart failure:

We found two systematic reviews (search dates not reported) assessing the effects of people with severe heart failure, which identified seven RCTs between them.[41] [42]

The first systematic review (4 RCTs, 635 people with NYHA functional class IV heart failure, on ACE and diuretic with or without digitalis) found that beta-blockers significantly reduced mortality compared with placebo in people with severe heart failure (56/313 [18%] with beta-blockers v 81/322 [25%] with placebo; RR 0.71, 95% CI 0.52 to 0.96).[41]

The second systematic review (6 RCTs, 13,370 people with chronic heart failure [people with NYHA functional class III or IV heart failure]) assessed the effects of beta-blockers in people with and without ACE inhibitors or angiotensin II receptor blockers (ARBs) at baseline.[42] Subgroup analysis of people taking ACE inhibitors or ARBs at baseline (95.2% of people in identified RCTs) found that beta-blockers significantly reduced all-cause mortality compared with placebo (6 RCTs, 12,728 people: 867/6496 [13%] with beta-blocker v 1120/6232 [18%] with placebo; RR 0.76, 95% CI 0.71 to 0.83). However, the review found no significant difference in all-cause mortality between beta-blockers and placebo in subgroup analysis of people not taking ACE inhibitors or ARBs at baseline, although the rate was lower with beta-blockers and the size of effect was similar to that of people taking beta-blockers plus ACE inhibitors or ARBs (50/347 [14%] with beta-blocker v 62/295 [21%] with placebo; RR 0.73, 95% CI 0.53 to 1.02). The review also assessed the effects of beta-blocker treatment on the composite outcome of death or hospital admission for heart failure in the absence or presence of ACE inhibitors (3 RCTs, 8988 people). The review found that beta-blockers significantly reduced rate of death or hospital admission for heart failure compared with placebo in people taking ACE inhibitors or ARBs at baseline (26% with beta-blocker v 33% with placebo; RR 0.78, 95% CI 0.74 to 0.83: absolute numbers not reported: number of people in analysis not clear). However, there was no significant difference between groups in this outcome in people not taking ACE inhibitors or ARBs, although rate was lower with beta-blocker and the size of effect was similar to that of people taking beta-blockers plus ACE inhibitors or ARBs (28% with beta-blocker v 35% with placebo: RR 0.81, 95% CI 0.61 to 1.08: absolute numbers not reported; number of people in analysis not clear).

Beta-blockers versus ACE inhibitors:

We found one RCT (1010 people with LVEF 35% or less and not receiving ACE inhibitors, beta-blockers, or ARBs).[43] People were randomised to receive either the beta-blocker bisoprolol (10 mg daily, 505 people) or the ACE inhibitor enalapril (10 mg twice daily, 505 people) for 6 months, followed by their combination for 6 to 24 months. The RCT found no significant difference between bisoprolol and enalapril in the composite outcome of all-cause mortality or hospital admission (178/505 [35%] with bisoprolol v 186/505 [37%] with enalapril; HR 0.94, 95% CI 0.77 to 1.16).[43] In the intention-to-treat analysis, bisoprolol was found to be non-inferior compared with enalapril. These data suggest that bisoprolol may be as safe and efficacious as enalapril for treating heart failure.

Harms

Beta-blockers versus placebo:

The reviews gave no information on adverse effects. [38] [39] [41] [42] The first subsequent RCT found that a similar proportion of people in the nebivolol group and placebo group experienced aggravated cardiac failure (256/1067 [24%] with nebivolol v 265/1061 [25%] with placebo; significance not assessed).[40]

We found one systematic review (search date 2002, 9 RCTs, 14,594 people followed up for 6 to 24 months), which assessed adverse effects of beta-blockers in people with heart failure.[44] It found that beta-blockers significantly reduced the risk of withdrawal from treatment, death, and worsening heart failure compared with placebo (withdrawal: 9 RCTs, 14,594 people: 1195/7458 [16%] with beta-blockers v 1287/7136 [18%] with placebo; RR 0.89, 95% CI 0.81 to 0.98; death: 9 RCTs, 14,594 people: 968/7458 [13%] with beta-blockers v 1244/7136 [17%] with placebo; RR 0.73, 95% CI 0.62 to 0.85; worsening heart failure: 4 RCTs, 4439 people: 625/2379 [26%] with beta-blockers v 691/2060 [34%] with placebo; RR 0.83, 95% CI 0.71 to 0.98). It found that beta-blockers significantly increased dizziness and bradycardia, but there was no significant difference between groups in hypotension and fatigue (dizziness: 4 RCTs, 10,082 people: 1117/5196 [22%] with beta-blockers v 810/4886 [17%] with placebo; RR 1.37, 95% CI 1.09 to 1.71; bradycardia: 7 RCTs, 13,796 people: 400/7057 [6%] with beta-blockers v 118/6739 [2%] with placebo; RR 3.62, 95% CI 2.48 to 5.28; hypotension: 7 RCTs, 13,796 people: 535/7057 [8%] with beta-blockers v 409/6739 [6%] with placebo; RR 1.41, 95% CI 0.96 to 2.06; fatigue: 3 RCTs, 7793 people: 953/4040 [24%] with beta-blockers v 840/3753 [22%] with placebo; RR 1.04, 95% CI 0.97 to 1.11).

Beta-blockers versus ACE inhibitors:

The RCT gave no information on adverse effects.[43]

Comment

Clinical guide

Fears that beta-blockers may cause excessive problems with worsening heart failure, bradyarrhythmia, or hypotension have not been confirmed. We found good evidence for beta-blockers in people with moderate symptoms (NYHA functional class II or III) receiving standard treatment, including ACE inhibitors. Data suggest that the magnitude of the prognostic benefit conferred by beta-blockers in the absence of ACE inhibitors or ARBs is similar to that of ACE inhibitors.[42]Therefore, evidence suggests that either ACE inhibitors or beta-blockers could be used as first-line treatment in systolic heart failure. The value of beta-blockers is uncertain in heart failure with preserved ejection fraction and in asymptomatic left ventricular systolic dysfunction. One RCT (1959 people) found that carvedilol reduced all-cause mortality compared with placebo (AR for death: 12% with carvedilol v 15% with placebo; HR 0.77, 95% CI 0.60 to 0.98) in people with MI and LVEF 40% or less.[45]

Effects of different beta-blockers:

The RCTs of beta-blockers have consistently found a mortality benefit, but it is not clear whether this is a class effect. One small RCT (150 people) comparing metoprolol versus carvedilol found some differences in surrogate outcomes, but both drugs produced similar improvements in symptoms, submaximal exercise tolerance, and quality of life.[46] Another RCT (3029 people) compared carvedilol versus metoprolol tartrate in people with heart failure.[47] It found that carvedilol significantly reduced all-cause mortality compared with metoprolol (512/1511 [34%] with carvedilol v 600/1518 [40%] with metoprolol; HR 0.83, 95% CI 0.74 to 0.93). It found no significant difference between groups for the composite outcome of mortality or all-cause admission to hospital (P = 0.122). The results of this RCT suggest that carvedilol extends survival compared with metoprolol. However, potential limitations to this RCT were that the target dose of metoprolol was lower than that usually suggested, and that the formulation of metoprolol used was not the long-acting formulation used in a previous RCT,[48] which had shown significant clinical benefit. The results for non-black people were consistent between bucindolol and carvedilol.

Effects in different populations:

The lack of observed benefit for black people in one RCT[48] raises the possibility that there may be race-specific responses to pharmacological treatment for cardiovascular disease. There may also be different responses in people with diabetes mellitus. A meta-analysis (6 RCTs, 13,129 people) examined whether beta-blockers in people with heart failure are as efficacious in those with as without diabetes mellitus.[49] It found that overall mortality was significantly increased in people with diabetes mellitus compared with people without diabetes mellitus, regardless of treatment (RR 1.25, 95% CI 1.15 to 1.36). Carvedilol has also been assessed in people with diabetes in a meta-analysis because it is believed that carvedilol has unique characteristics compared with other beta-blockers.[50] In this meta-analysis, seven RCTs were examined (5757 people, 25% with diabetes mellitus) to determine whether the effects of carvedilol were similar in people with and without diabetes mellitus. There was no significant difference in mortality or the number needed to treat (NNT) to prevent one death for 1 year for people with or without diabetes (mortality in people with diabetes: carvedilol v placebo: RRR 28%, 95% CI 3% to 46%, P = 0.03; people without diabetes: RRR 37%, 95% CI 22% to 48%, P less than 0.001; difference between 2 groups reported as not significant, P value not reported; NNT 25, 95% CI 14 to 118 for people with diabetes mellitus v NNT 23, 95% CI 17 to 37 for people without diabetes mellitus). Although beta-blockers significantly reduced mortality compared with placebo in people with diabetes mellitus (RR 0.84, 95% CI 0.73 to 0.96), the magnitude of benefit was significantly lower than that in people who did not have diabetes mellitus (P = 0.023).

One systematic review (search date 2007) identified assessed whether the magnitude of the benefit of beta-blockers differs in ischaemic and non-ischaemic heart failure.[51]The review searched for RCTs that reported mortality data for people with ischaemic or non-ischaemic heart failure separately. In the RCTs identified by the review (4 RCTs, 7250 people), heart failure was associated with ischaemic aetiology in 4746 (65%) people included in the analysis and with non-ischaemic aetiology in 2504 (35%) people. The review found the risk reduction in mortality for non-ischaemic heart failure (75/1335 [6%] with beta-blocker v 108/1169 [9%] with placebo; RR 0.62, 95% CI 0.45 to 0.84; P = 0.002) to be similar to that of ischaemic heart failure (226/2457 [9%] with beta-blocker v 324/2289 [14%] with placebo; RR 0.62, 95% CI 0.52 to 0.75; P less than 0.00001).

We found one systematic review (search date not reported, 5 RCTs, 17,346 people) investigating whether beta-blockers are as effective in older people as in the non-elderly for chronic heart failure.[52] The cut-off points for elderly age ranges varied across trials (59–71 years). The review found that beta-blocker treatment significantly reduced all-cause mortality for the non-elderly (RR 0.66, 95% CI 0.52 to 0.85; P = 0.001; absolute numbers not reported) and for older people (RR 0.76, 95% CI 0.64 to 0.90; P = 0.002; absolute numbers not reported), without a statistically significant difference in mortality reduction between the two groups (P = 0.38).[52]

Substantive changes

Beta-blockers One RCT, conducted in older people, added found that, compared with placebo, the beta-blocker nebivolol reduced the composite end point of all-cause mortality or cardiovascular hospital admission.[40] However, the RCT found no significant difference between treatments in all-cause mortality, although mortality was lower with nebivolol. Categorisation unchanged (Beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Digoxin

Summary

MORTALITY Compared with placebo: Digoxin is no more effective at reducing mortality in people in sinus rhythm ( moderate-quality evidence ). HOSPITAL ADMISSION Compared with placebo: Digoxin is more effective at 37 months at reducing all-cause hospital admissions and hospital admissions for heart failure in people in sinus rhythm receiving ACE inhibitors and diuretics (moderate-quality evidence).

Benefits

We found one systematic review (search date 2003, 13 RCTs with greater than 7 weeks' follow-up, 7896 people in sinus rhythm).[53] It found that digoxin significantly reduced hospital admissions compared with placebo but found no significant difference between treatments for mortality (hospital admissions: 4 RCTs, 7262 people, OR 0.68, 95% CI 0.61 to 0.75; mortality: 8 RCTs, 7756 people, OR 0.98, 95% CI 0.89 to 1.09). All but one of the RCTs included in the review followed up people for 6 months or less. The largest RCT in the review, which dominated the meta-analysis (6800 people, 88% male, mean age 64 years, New York Heart Association [NYHA] functional class I–III, 94% already taking ACE inhibitors, 82% taking diuretics), compared blinded additional treatment with either digoxin or placebo for a mean of 37 months.[54] It found no significant difference between digoxin and placebo in all-cause mortality (1181/3397 [34.8%] with digoxin v 1194/3403 [35.1%] with placebo; ARR +0.3%, 95% CI –2.0% to +2.6%; RR 0.99, 95% CI 0.93 to 1.06). It found that digoxin significantly reduced admission rates for heart failure over 37 months compared with placebo and reduced the combined outcome of death or hospital admission caused by worsening heart failure (heart failure admissions: 910/3397 [27%] with digoxin v 1180/3403 [35%] with placebo; ARR 8%, 95% CI 6% to 10%; RR 0.77, 95% CI 0.72 to 0.83; NNT 13, 95% CI 10 to 17; death or hospital admission: 1041/3397 [31%] with digoxin v 1291/3403 [38%] for placebo; ARR 7%, 95% CI 5% to 9%; RR 0.81, 95% CI 0.75 to 0.87).

Harms

The systematic review gave no information on adverse effects.[53] The largest RCT in the systematic review (6800 people) found that significantly more people had suspected digoxin toxicity in the digoxin group compared with placebo (12% with digoxin v 8% with placebo; ARI 4%, 95% CI 2% to 6%; RR 1.50, 95% CI 1.30 to 1.73).[54] The RCT found no significant difference between digoxin and placebo in the risk of ventricular fibrillation or tachycardia (37/3397 [1.1%] with digoxin v 27/3403 [0.8%] with placebo; ARI +0.3%, 95% CI –0.1% to +1.0%; RR 1.37, 95% CI 0.84 to 2.24). It found that, compared with placebo, digoxin significantly increased rates of supraventricular arrhythmia (3% with digoxin v 1% with placebo; ARI 1.3%, 95% CI 0.5% to 2.4%; RR 2.08, 95% CI 1.44 to 2.99) and second- or third-degree atrioventricular block (1.2% with digoxin v 0.4% with placebo; ARI 0.8%, 95% CI 0.2% to 1.8%; RR 2.93, 95% CI 1.61 to 5.34).

Comment

None.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Positive inotropes other than digoxin

Summary

MORTALITY Positive inotropes other than digoxin compared with placebo: Positive inotropic drugs other than digoxin (including intravenous inotropes acting through the adrenergic pathway, and phosphodiesterase III inhibitors) are less effective at reducing mortality at 6 to 11 months ( moderate-quality evidence ).

Benefits

We found two systematic reviews[55] [56] and two additional RCTs[57] [58]on inotropic agents.

The first systematic review (search date 2000, 21 RCTs, 632 people) assessed the effects of intravenous inotropic agents that act through the adrenergic pathway (beta-agonists and phosphodiesterase inhibitors [PDIs]) in people with heart failure.[55] The review identified 11 RCTs comparing inotropic agents (including dobutamine, dopexamine, toborinone, and milrinone) versus placebo or control. The review found that, compared with placebo or control, intravenous inotropes that act through the adrenergic pathway tended to increase mortality, although this did not reach significance (11 RCTs; OR 1.50, 95% CI 0.51 to 3.92; absolute numbers not reported). The authors of this review concluded that "intravenous inotropic agents acting through the adrenergic pathway are often used in people with worsening heart failure to achieve arbitrary haemodynamic targets. Our analyses show that there is very little evidence that such treatment improves symptoms or patient outcomes, and may not be safe". Of the 21 RCTs identified, 16 RCTs (474 people) were acute invasive haemodynamic studies of symptomatically severe heart failure, and five RCTs (158 people) were based on intermittent inotropic treatment in an outpatient setting. Included RCTs were often small.

The second systematic review (search date 2004, 21 RCTs, 8408 people) found that phosphodiesterase III inhibitors (PDIs) significantly increased mortality compared with placebo (897/5138 [17%] with PDI v 478/3270 [15%] with placebo; RR 1.17, 95% CI 1.06 to 1.30).[56] Considering mortality from all causes, the deleterious effects of PDIs were consistent, regardless of the severity of heart failure, use of background treatment, or type of PDI.[56]

The first additional RCT (3833 people with heart failure) found that vesnarinone (a PDI) 60 mg daily significantly increased mortality compared with placebo over 9 months (292/1275 [23%] with vesnarinone v 242/1280 [19%] with placebo; ARI 4%, 95% CI 1% to 8%; RR 1.21, 95% CI 1.04 to 1.40).[57]

The second additional RCT (1906 people with heart failure) compared ibopamine versus placebo over 11 months.[58] It found that ibopamine significantly increased mortality compared with placebo (232/953 [24%] with ibopamine v 193/953 [20%] with placebo; RR 1.26, 95% CI 1.04 to 1.53). The review found that some RCTs reported improved functional capacity and quality of life, but this was not consistent across all RCTs.

Harms

Most RCTs found that inotropic agents other than digoxin increased risk of death (see benefits above).[56] [55] [57] [58]

Comment

None.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Aldosterone receptor antagonists

Summary

MORTALITY Compared with placebo: Aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) seem more effective at reducing all-cause mortality in people with heart failure and in people with heart failure after an MI ( moderate-quality evidence ). HOSPITAL ADMISSION Compared with placebo: Aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) seem more effective at reducing rate of hospital admission in people with heart failure (moderate-quality evidence).

Benefits

We found one systematic review (search date 2008, 19 RCTs, 10,807 people) assessing the effectiveness of aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) in people with symptomatic and asymptomatic left ventricular dysfunction, including heart failure and post MI with heart failure.[59] The review did not specify left ventricular ejection fraction (LVEF) for inclusion: two identified RCTs (58 people) recruited people with an LVEF of greater than 45%, and 5 RCTs (883 people) did not report LVEF of people included. Of the 19 RCTs identified, 15 RCTs included people with chronic heart failure (3395 people), and four RCTs included people who had previous MI and had heart failure (7412 people). Two RCTs (134 people) compared aldosterone receptor antagonists versus usual care rather than versus placebo and one RCT (105 people) assessed an active comparator (metoprolol) plus usual care.

The review found that aldosterone receptor antagonists significantly reduced all-cause mortality compared with control (19 RCTs: 804/5565 [14%] with aldosterone receptor antagonist v 994/5200 [19%] with control; RR 0.80, 95% CI 0.74 to 0.87).[59] Subgroup analysis based on clinical condition found similar results. Aldosterone receptor antagonists significantly reduced all-cause mortality compared with control in people with heart failure (15 RCTs, 3353 people: 303/1858 [16%] with aldosterone receptor antagonist v 404/1495 [27%] with control; RR 0.75, 95% CI 0.67 to 0.84) and in people with heart failure after an MI (4 RCTs, 7412 people: 501/3707 [14%] with aldosterone receptor antagonist v 590/3705 [16%] with control; RR 0.85, 95% CI 0.76 to 0.95). The review also found that rate of all-cause hospital re-admission was significantly lower with aldosterone receptor antagonists compared with placebo (9 RCTs, 8699 people: RR 0.77, 95% CI 0.68 to 0.87; absolute numbers not reported). The two largest studies identified by the review (one assessing spironolactone including 1663 people[60] and one assessing eplerenone including 6632 people[61]) included people with only New York Heart Association (NYHA) functional class III or IV; therefore, these results cannot necessarily be generalised to people with milder heart failure. The RCT of eplerenone was limited to people who were post-MI with heart failure and therefore these results cannot necessarily be generalised to people with stable heart failure — that is, those without a recent MI and who have milder symptoms of heart failure. The contribution of these two large RCTs, which represent 76% (8295 people) of the people included in the analysis carried out by the review, should be considered when interpreting the results of the review.

Harms

The review found that aldosterone receptor antagonists were associated with higher rates of hyperkalaemia, worsening renal failure, and gynaecomastia (hyperkalaemia; 17 RCTs, 10,261 people: 315/5314 [6%] with aldosterone receptor antagonist v 148/4947 [3%] with control; worsening renal failure; 11 RCTs, 1613 people: 86/959 [9%] with aldosterone receptor antagonist v 11/654 [2%] with control; gynaecomastia; 16 RCTs, 10,213 people: 88/5291 [2%] with aldosterone receptor antagonist v 26/4922 [1%] with control: significance not assessed for any outcome).[59]

Comment

A population-based time series analysis[62] examined the trends in the rate of spironolactone prescriptions and the rate of hospital admissions for hyperkalaemia in ambulatory patients before and after the publication of an RCT that demonstrated the benefits of spironolactone.[60] The spironolactone prescription rate significantly increased after publication of the RCT (rising from 34/1000 people to 149/1000 people; P less than 0.001). There was also a significant increase in the rate of hospital admission for hyperkalaemia (from 2.4/1000 people to 11.0/1000 people; P less than 0.001) and associated mortality (from 0.3/1000 people to 2.0/1000 people; P less than 0.001). The results of the study are important because they emphasise the need for appropriate monitoring of people treated with spironolactone.

Substantive changes

Aldosterone receptor antagonists One systematic review added found that aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) reduced all-cause mortality and all-cause hospital admission rates compared with control.[59] Categorisation unchanged (Likely to be beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Amiodarone

Summary

MORTALITY Compared with placebo or conventional treatment: Amiodarone may be more effective at 3 to 24 months at reducing all-cause mortality (in people with a wide range of heart conditions such as symptomatic and asymptomatic heart failure, ventricular arrhythmia, recent MI, and recent cardiac arrest) and at reducing arrhythmic death or sudden death ( very low-quality evidence ).

Benefits

We found two systematic reviews comparing amiodarone versus placebo in heart failure.[63] [64] The most recent review (search date 1997, 10 RCTs, 4766 people) included people with a wide range of conditions (symptomatic and asymptomatic heart failure, ventricular arrhythmia, recent MI, and recent cardiac arrest).[63] Eight of these RCTs reported the number of deaths. The review found that treatment with amiodarone over 3 to 24 months significantly reduced the risk of all-cause mortality compared with placebo or conventional treatment (436/2262 [19%] with amiodarone v 507/2263 [22%] with control; ARR 3.0%, 95% CI 0.8% to 5.3%; RR 0.86, 95% CI 0.76 to 0.96). This review did not perform any subgroup analyses in people with heart failure. The earlier systematic review (search date not reported) found eight RCTs (5101 people after MI) comparing prophylactic amiodarone versus placebo or usual care, and five RCTs (1452 people) in people with heart failure.[64] Mean follow-up was 16 months. Analysis of results from all 13 RCTs found a lower total mortality with amiodarone than with control (annual mortality: 11% with amiodarone v 12% with control). The effect was significant with some methods of calculation (fixed effects model: OR 0.87, 95% CI 0.78 to 0.99) but not with others (random effects model: OR 0.85, 95% CI 0.71 to 1.02). The effect of amiodarone was significantly greater in RCTs comparing amiodarone versus usual care than in placebo-controlled RCTs. It found that amiodarone significantly reduced arrhythmic death, or sudden death, compared with placebo (OR 0.71, 95% CI 0.59 to 0.85). Subgroup analysis found that amiodarone significantly reduced mortality in the five heart failure RCTs compared with placebo (annual mortality: 20% with amiodarone v 24% with placebo; OR 0.83, 95% CI 0.70 to 0.99).

Harms

Amiodarone did not significantly increase non-arrhythmic mortality (OR 1.02, 95% CI 0.87 to 1.19).[64] In placebo-controlled RCTs, after 2 years, 41% of people in the amiodarone group and 27% in the placebo group had permanently discontinued study medication.[64] In 10 RCTs comparing amiodarone versus placebo, amiodarone increased the odds of reporting adverse drug reactions compared with placebo (OR 2.22, 95% CI 1.83 to 2.68). Nausea was the most common adverse effect. Hypothyroidism was the most common serious adverse effect (7% with amiodarone v 1% with placebo). Hyperthyroidism, peripheral neuropathy, lung infiltrates, bradycardia, and liver dysfunction were all more common in the amiodarone group (hyperthyroidism: 1.4% with amiodarone v 0.5% with placebo; peripheral neuropathy: 0.5% with amiodarone v 0.2% with placebo; lung infiltrates: 2% with amiodarone v 1% with placebo; bradycardia: 2% with amiodarone v 1% with placebo; liver dysfunction: 1% with amiodarone v 0.4% with placebo).[64]

Comment

Clinical guide:

RCTs of amiodarone versus usual treatment found larger effects than placebo-controlled trials.[64] These findings suggest bias; unblinded follow-up may be associated with reduced usual care or improved adherence with amiodarone. Further studies are required to assess the effects of amiodarone treatment on mortality and morbidity in people with heart failure.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Antiarrhythmics other than amiodarone

Summary

Evidence extrapolated from studies in people treated after an MI suggest that other antiarrhythmic drugs (apart from beta-blockers) may be associated with increased mortality in people with heart failure.

Benefits

Apart from beta-blockers, other antiarrhythmic drugs increase mortality in people at high risk (see class I antiarrhythmic agents [quinidine, procainamide, disopyrimide, encainide, flecainide, moracizine] in review on secondary prevention of ischaemic cardiac events).

Harms

These agents (particularly class I antiarrhythmics) may increase mortality (see class I antiarrhythmic agents [quinidine, procainamide, disopyrimide, encainide, flecainide, moracizine] under secondary prevention of ischaemic cardiac events).

Comment

None.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Anticoagulation

Summary

MORTALITY Compared with placebo: We don't know whether warfarin is more effective at 27 months than no antithrombotic treatment at reducing a combined outcome of death, MI, and stroke ( very-low quality evidence ). Compared with antiplatelets: We don't know whether warfarin is more effective than aspirin or clopidogrel at reducing mortality at 21 months or a composite outcome of death, MI, and stroke at 27 months (very low-quality evidence). HOSPITAL ADMISSION Compared with antiplatelets: Warfarin may be more effective than aspirin at reducing all-cause hospital readmission rates at 21–27 months, but we don't know whether warfarin is more effective than clopidogrel at reducing all-cause hospital readmission rates at 21 months (very low-quality evidence).

Benefits

Anticoagulation versus placebo:

We found one systematic review (search date 2001, 1 RCT, 279 people, 70% with New York Heart Association [NYHA] functional class III),[65]and one subsequent RCT.[66]The RCT identified by the systematic review [65]compared warfarin (international normalised ratio [INR] 2.5) or aspirin versus no antithrombotic treatment.[67]It found no significant difference between warfarin and no antithrombotic treatment in the combined outcome of death, MI, and stroke after a mean follow-up of 27 months (combined outcome: 26% with warfarin v 27% with no antithrombotic treatment; P value not reported).[67]The subsequent RCT recruited 197 people aged 20 to 75 years with NYHA class II to IV caused by either previous MI or idiopathic dilated cardiomyopathy.[66] Those with cardiomyopathy (82 people) were randomised to warfarin or placebo. The RCT found that both treatments were associated with similar increases in the time to the primary combined outcome of non-fatal stroke, peripheral or pulmonary embolism, MI, hospital admission, exacerbation of heart failure, or death from any cause (8.9/100 patient-years with warfarin v 14.8/100 patient-years with placebo; significance not assessed).

Anticoagulation versus antiplatelet agents:

See benefits of antiplatelet agents.

Harms

Anticoagulation versus placebo:

The RCT identified by the systematic review found four haemorrhagic events with warfarin and none with no antithrombotic treatment (total number of people in each group not reported).[67]The subsequent RCT found a haemorrhagic-event rate of 4.6/100 patient-years with warfarin and no haemorrhagic events with no antithrombotic treatment.[66]

Anticoagulation versus antiplatelet agents:

See harms of antiplatelet agents.

Comment

The systematic review (search date 2001)[65] found three additional non-randomised trials. Meta-analysis of these trials and the RCT[67] found that anticoagulant significantly reduced death from all causes and cardiovascular event rates compared with control (death from all causes: 1087 people, OR 0.64, 95% CI 0.45 to 0.90; cardiovascular event rates: 1130 people, OR 0.26, 95% CI 0.16 to 0.43).[65] Meta-analysis of two non-randomised trials (645 people) found no significant difference in bleeding complications between warfarin and no warfarin (OR 1.52, 95% CI 0.56 to 4.10). The non-randomised controlled studies were performed in the early 1950s in hospitalised people with a high prevalence of rheumatic heart disease and atrial fibrillation, and the methods used may be considered unreliable today. One retrospective analysis assessed the effect of anticoagulants used at the discretion of individual investigators in RCTs on the incidence of stroke, peripheral arterial embolism, and pulmonary embolism.[68] The first cohort was from one RCT (642 men with chronic heart failure) comparing hydralazine plus isosorbide dinitrate versus prazosin versus placebo. The second cohort was from another RCT (804 men with chronic heart failure) comparing enalapril versus hydralazine plus isosorbide dinitrate. All people were given digoxin and diuretics. The retrospective analysis found that, without treatment, the incidence of all thromboembolic events was low (2.7/100 patient-years in the first RCT; 2.1/100 patient-years in the second RCT) and that anticoagulation did not reduce the incidence of thromboembolic events (2.9/100 patient-years in the first RCT; 4.8/100 patient-years in the second RCT). In this group, atrial fibrillation was not associated with a higher risk of thromboembolic events. A second retrospective analysis was from two large RCTs (2569 people with symptomatic and asymptomatic left ventricular dysfunction), which compared enalapril versus placebo.[69] The analysis found that people treated with warfarin at baseline had a significantly lower risk of death during follow-up (HR adjusted for baseline differences 0.76, 95% CI 0.65 to 0.89). Warfarin use was associated with a reduction in the combined outcome of death plus hospital admission for heart failure (adjusted HR 0.82, 95% CI 0.72 to 0.93). The benefit with warfarin use was not significantly influenced by the presence of symptoms, randomisation to enalapril or placebo, sex, presence of atrial fibrillation, age, ejection fraction, NYHA functional class, or cause of heart failure. Warfarin reduced cardiac mortality, specifically deaths that were sudden or associated with either heart failure or MI. Neither of the retrospective studies was designed to determine the incidence of thromboembolic events in heart failure or the effects of treatment. Neither study included information about the intensity of anticoagulation or warfarin use. We found several additional cohort studies showing a reduction in thromboembolic events with anticoagulation, but they all reported on too few people to provide useful results. The two RCTs are of inadequate size to definitively conclude whether anticoagulation is of benefit in people with heart failure who are in sinus rhythm.[67] [66] An RCT is still needed to compare anticoagulation versus no anticoagulation in people with heart failure.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Antiplatelet agents

Summary

MORTALITY Compared with no treatment: We don't know whether aspirin is more effective at 27 months than no antithrombotic treatment at reducing the combined outcome of death, MI, and stroke ( very low-quality evidence ). Compared with warfarin: We don't know whether antiplatelet agents (aspirin and clopidogrel) are more effective than warfarin at reducing mortality at 21 months or composite outcomes that include mortality (other outcomes in composite include MI, stroke, exacerbation of heart failure, and peripheral or pulmonary embolism) (very low-quality evidence). HOSPITAL ADMISSION Compared with no treatment: Aspirin may be less effective at reducing all-cause hospital readmission rates at 27 months ( low-quality evidence ). Compared with warfarin: Aspirin may be less effective at reducing all-cause hospital readmission rates at 21 to 27 months, but we don't know whether clopidogrel is more effective than warfarin at reducing all-cause hospital readmission rates at 21 months (very low-quality evidence).

Benefits

Antiplatelet agents versus no treatment:

We found two systematic reviews (search dates 2005),[65] [70] both of which identified the same three-arm RCT (279 people, 70% with New York Heart Association [NYHA] functional class III).[67] The RCT identified by the reviews compared warfarin or aspirin (300 mg/day) versus no antithrombotic treatment.[67] It found no significant difference between aspirin and no antithrombotic treatment for the combined outcome of death, MI, and stroke at a mean follow-up of 27 months (combined outcome: 29/91 [32%] with aspirin v 26/99 [27%] with no antithrombotic treatment; reported as not significant; P value not reported). It found that aspirin significantly increased all-cause hospital admission compared with placebo (P less than 0.05; absolute numbers not reported).

Antiplatelet agents versus warfarin:

We found two RCTs comparing aspirin versus warfarin,[67] [66] and one RCT comparing aspirin versus clopidogrel versus warfarin.[71]

The first RCT (3-arm RCT: see antiplatelets versus no treatment, above, for full details) found no significant difference between aspirin and warfarin for the composite outcome of death, MI, and stroke at a mean follow-up of 27 months (combined outcome: 29/91 [32%] with aspirin v 23/89 [26%] with warfarin; reported as not significant; P value not reported).[67] It found that all-cause hospital admissions were significantly higher with aspirin compared with warfarin (P = 0.05; absolute numbers not reported).

The second RCT recruited 197 people age 20 to 75 years with NYHA class II to IV caused by either previous MI or idiopathic dilated cardiomyopathy.[66] Those with previous MI (115 people) were randomised to either aspirin or warfarin. The RCT found that both treatments were associated with similar increases in the time to the primary combined outcome of non-fatal stroke, peripheral or pulmonary embolism, MI, hospital admission, exacerbation of heart failure, or death from any cause (MI group: primary end point in 14.9/100 patient-years with aspirin v 15.7/100 patient-years with warfarin; significance not assessed).

The third RCT (1587 people with NYHA class II to IV) is a three-arm RCT comparing aspirin (523 people) versus clopidogrel (524 people) versus warfarin (540 people).[71] The RCT found no significant difference between aspirin and warfarin or between clopidogrel and warfarin in all-cause mortality at a median follow-up of 21 months (92/540 [17%] with warfarin v 94/523 [19%] with aspirin v 96/524 [18%] with clopidogrel; warfarin v aspirin: HR 0.98, 95% CI 0.85 to 1.13; P = 0.75; warfarin v clopidogrel: HR 0.92, 95% CI 0.69 to 1.23; P = 0.58). Rate of hospital admission for worsening heart failure was significantly higher with aspirin compared with warfarin, but there was no significant difference between clopidogrel and warfarin for this outcome (89/540 [16%] with warfarin v 116/523 [22%] with aspirin v 97/524 [19%] with clopidogrel; aspirin v warfarin; P less than 0.02: clopidogrel v warfarin; P = 0.38). All-cause mortality and rate of hospital admission for worsening heart failure are secondary outcomes. The primary outcome assessed was a composite of death, non-fatal MI, or non-fatal stroke: the RCT found no significant difference between aspirin and warfarin (106/540 [20%] with warfarin v 108/523 [21%] with aspirin v 113/524 [22%] with clopidogrel; warfarin v aspirin; HR 0.98, 95% CI 0.86 to 1.12; P = 0.77) or between clopidogrel and warfarin (warfarin v clopidogrel: HR 0.89, 95% CI 0.68 to 1.16; P = 0.39) for this composite outcome. The RCT was terminated early because of slow enrolment (1587 people randomised rather than planned 4500 people) and may have been underpowered to detect a clinically important difference. Results should be interpreted with caution.

Harms

Antiplatelet agents versus no treatment:

The RCT identified by the review reported five haemorrhagic events with aspirin and none with no antithrombotic treatment (total number of people in each group not reported; significance not assessed).[67]One of the reviews reported no significant difference among groups in the total number of serious adverse effects (198 with aspirin v 163 with warfarin v 178 with no antithrombotic treatment; P = 0.08).[70]The other review gave no information on adverse effects.[65]

Antiplatelet agents versus warfarin:

The first RCT reported five haemorrhagic events with aspirin compared with four with warfarin (total number of people in each group not reported; significance not assessed).[67]

The second RCT found a haemorrhagic event rate of 4.6/100 patient-years with warfarin and no haemorrhagic events associated with aspirin.[66]

The third RCT found that clopidogrel was associated with significantly lower rates of major haemorrhage and rate of minor bleed compared with warfarin (major haemorrhage: 11/524 [2%] with clopidogrel v 28/540 [5%] with warfarin; P less than 0.01; minor bleeds: 119/524 [23%] with clopidogrel v 155/540 [29%] with warfarin; P = 0.0254).[71] However, the RCT found no significant difference between aspirin and warfarin in rate of major haemorrhage or in rate of minor bleeds, although rate of both adverse effects was higher with warfarin (major haemorrhage: 19/523 [4%] with aspirin v 28/540 [5%] with warfarin; P = 0.2184; minor bleeds: 123/523 [24%] with aspirin v 155/540 [29%] with warfarin; P = 0.0544).

Comment

In people not taking ACE inhibitors:

We found no systematic review and no RCTs. We found one retrospective cohort analysis within one RCT in 642 men with heart failure.[68] The RCT compared hydralazine plus isosorbide dinitrate versus prazosin versus placebo in men receiving digoxin and diuretics. Aspirin or dipyridamole, or both, were used at the discretion of the investigators. The number of thromboembolic events was low in both groups (1 stroke, and 0 peripheral and 0 pulmonary emboli in 184 person-years of treatment with antiplatelet agents v 21 strokes, and 4 peripheral and 4 pulmonary emboli in 1068 person-years of treatment without antiplatelet agents; 0.5 events/100 person-years with antiplatelet agents v 2.0 events/100 person-years without antiplatelet agents; P = 0.07).

In people taking ACE inhibitors:

We found no RCTs. We found two large retrospective cohort studies.[68] [72] The first retrospective analysis assessed the effect of antiplatelet agents used at the discretion of individual investigators on the incidence of stroke, peripheral arterial embolism, and pulmonary embolism within one RCT.[68] The RCT (804 men with chronic heart failure) compared enalapril versus hydralazine plus isosorbide dinitrate. It found that the incidence of all thromboembolic events was low without antiplatelet treatment and found no significant difference between groups (1.6 events/100 person-years with antiplatelet treatment v 2.1 events/100 person-years with no antiplatelet treatment; P = 0.48).

The second cohort analysis was from two large RCTs, which compared enalapril versus placebo (2569 people with symptomatic and asymptomatic left ventricular dysfunction). It found that people treated with antiplatelet agents at baseline had a significantly lower risk of death (HR adjusted for baseline differences 0.82, 95% CI 0.73 to 0.92).[72] Subgroup analysis suggested that antiplatelet agents might have an effect in people randomised to placebo (mortality HR [for antiplatelet treatment at baseline v no antiplatelet treatment at baseline] 0.68, 95% CI 0.58 to 0.80), but not in people randomised to enalapril (mortality HR [for antiplatelet treatment v no antiplatelet treatment] 1.00, 95% CI 0.85 to 1.17). Both retrospective studies have important limitations common to studies with a retrospective cohort design. One study did not report on the proportions of people taking aspirin and other antiplatelet agents.[68] The other study noted that more than 95% of people took aspirin, but the dosage and consistency of antiplatelet use was not recorded.[72] One retrospective non-systematic review (4 RCTs, 96,712 people) provided additional evidence about the effect of aspirin on the benefits of early ACE inhibitors in heart failure.[73] It found a similar reduction in 30-day mortality with ACE inhibitors versus control for those people not taking aspirin compared with those taking aspirin (aspirin: OR 0.94, 95% CI 0.89 to 0.99; no aspirin: OR 0.90, 95% CI 0.81 to 1.01). However, the analysis may not be valid because the people who did not receive aspirin were older and had a worse baseline prognosis than those taking aspirin. The effects of antiplatelet treatment in combination with ACE inhibitors in people with heart failure require further research.

Substantive changes

Antiplatelet agents One three-arm RCT added comparing aspirin versus clopidogrel versus warfarin found no significant difference between aspirin and warfarin or between clopidogrel and warfarin in all-cause mortality at a median follow-up of 21 months.[71] Rate of hospital admission for worsening heart failure was higher with aspirin compared with warfarin; but there was no significant difference between clopidogrel and warfarin for this outcome. The RCT may have been underpowered to detect a clinically important difference and results should be interpreted with caution. Categorisation unchanged (Unknown effectiveness).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Calcium channel blockers

Summary

MORTALITY Compared with placebo: Calcium channel blockers may be no more effective at reducing mortality or the composite outcome of all-cause mortality and hospital admission for cardiovascular events ( very low-quality evidence ). ADVERSE EFFECTS Calcium channel blockers have been found to exacerbate symptoms of heart failure and increase mortality after MI in people who also have pulmonary congestion or left ventricular dysfunction.

Benefits

Calcium channel blockers after myocardial infarction:

See calcium channel blockers in review on myocardial infarction (ST-elevation).

Calcium channel blockers for other heart failure:

We found one systematic review (search date not reported, 18 RCTs, 3128 people with moderate to advanced heart failure for greater than 2 months) of second-generation dihydropyridine calcium channel blockers,[74] one non-systematic review of all calcium channel blockers (3 RCTs, 1790 people with heart failure),[75] and one subsequent RCT.[76] The systematic review found no significant difference in mortality (2 RCTs, 1603 people; OR 0.94, 95% CI 0.79 to 1.12; significant heterogeneity was found; P = 0.48).[74]

The largest RCT in the non-systematic review[75] (1153 people with New York Heart Association [NYHA] functional class III or IV, left ventricular ejection fraction [LVEF] less than 0.30, using diuretics, digoxin, and ACE inhibitors) found no significant difference between amlodipine and placebo in the primary combined end point of all-cause mortality and hospital admission for cardiovascular events over 14 months (222/571 [39%] with amlodipine v 246/582 [42%] with placebo; ARR +3.4%, 95% CI –2.3% to +8.8%; RR 0.92, 95% CI 0.79 to 1.06).[77] Subgroup analysis of people with primary cardiomyopathy found a significant reduction in mortality with amlodipine (45/209 [22%] with amlodipine v 74/212 [35%] with placebo; ARR 13%, 95% CI 5% to 20%; RR 0.62, 95% CI 0.43 to 0.85). There was no significant difference in the group with heart failure caused by coronary artery disease.

The second RCT (186 people, idiopathic dilated cardiomyopathy, NYHA functional class I–III) compared diltiazem versus placebo.[75] It found no evidence of a difference in survival between diltiazem and placebo in people who did not have a heart transplant, although people on diltiazem had improved cardiac function, exercise capacity, and subjective quality of life.

The third RCT (451 people with mild heart failure, NYHA functional class II or III) compared felodipine versus placebo.[75] It found no significant effect.

The subsequent RCT (2590 people with NYHA functional class II–IV heart failure, mean follow-up of 1.5 years with mibefradil and 1.6 years with placebo) found no significant difference in mortality between mibefradil and placebo (350/1295 [27%] with mibefradil v 319/1295 [25%] with placebo; RR 1.10, 95% CI 0.96 to 1.25).[76]

Harms

The review found that second-generation dihydropyridine calcium channel blockers did not cause significant adverse effects.[74] Calcium channel blockers have been found to exacerbate symptoms of heart failure or increase mortality after MI in people who also have pulmonary congestion or left ventricular dysfunction (see calcium channel blockers in review on myocardial infarction [ST-elevation]).[75] The subsequent RCT found that mibefradil increased risk of death in people taking digoxin, class I or II antiarrhythmics, amiodarone, or drugs associated with torsade de pointes compared with placebo.[76]

Comment

Many of the RCTs were underpowered and had wide confidence intervals. One RCT of amlodipine in people with primary dilated cardiomyopathy is in progress.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Hydralazine

Summary

MORTALITY Hydralazine plus isosorbide dinitrate compared with placebo: Hydralazine plus isosorbide dinitrate may be more effective at reducing cumulative mortality at 2 years and at reducing a composite outcome (mortality from any cause, a first hospital admission for heart failure within 18 months, and change in quality of life at 6 months) in people with heart failure also receiving standard treatment ( very-low quality evidence ). QUALITY OF LIFE Hydralazine plus isosorbide dinitrate compared with placebo: Hydralazine plus isosorbide dinitrate may be more effective at 6 months at improving quality of life in people with heart failure also receiving standard treatment ( low-quality evidence ). NOTE We found no direct information from RCTs about the effects of hydralazine alone in the treatment of people with heart failure.

Benefits

Hydralazine plus isosorbide dinitrate versus placebo:

We found no systematic review but found two RCTs.[78] [79]The first RCT (642 men aged 18–75 years with stable chronic congestive heart failure) compared three interventions: hydralazine plus isosorbide dinitrate, prazosin, and placebo.[78] The RCT found that hydralazine plus isosorbide dinitrate significantly reduced the cumulative mortality at 2 years compared with placebo (78/186 [42%] with hydralazine plus isosorbide dinitrate v 139/273 [51%] with placebo; estimated cumulative reduction in mortality risk 34%, 95% CI 4% to 54%, P less than 0.03).

The second RCT (1050 African-Americans with New York Heart Association [NYHA] class III or IV heart failure with dilated ventricles) also compared hydralazine plus isosorbide dinitrate versus placebo.[79] The primary end point was a composite score made up of weighted values for mortality from any cause, a first hospital admission for heart failure within 18 months, and change in quality of life at 6 months. The score could range from –6 to +2 with higher scores indicating improved outcomes. The RCT found that hydralazine plus isosorbide dinitrate significantly improved the composite end point compared with placebo (–0.1 with hydralazine-isosorbide dinitrate v –0.5 with placebo; P = 0.01). The trial was terminated early (after 10 months instead of 18 months) because mortality was higher with placebo (6% with hydralazine-isosorbide v 10% with placebo; P = 0.02). The RCT also found that hydralazine plus isosorbide dinitrate significantly improved quality of life at 6 months compared with placebo (measured on a scale where lower scores indicate better quality of life: –5.6 with hydralazine-isosorbide v –2.7 with placebo; P = 0.02).

Harms

Hydralazine plus isosorbide dinitrate versus placebo:

The first RCT found that headache and dizziness were the most common adverse effects leading to discontinuation of treatment, but it did not assess the significance of the difference between groups (headache: 23/186 [12%] with hydralazine plus isosorbide dinitrate v 1/273 [0.4%] with placebo; dizziness: 12/186 [6%] with hydralazine plus isosorbide dinitrate v 5/273 [2%] with placebo; significance assessment not reported).[78] The second RCT found that headache and dizziness occurred significantly more often with hydralazine plus isosorbide dinitrate than with placebo (headache: 48% with hydralazine plus isosorbide dinitrate v 19% with placebo; P less than 0.001; dizziness: 29% with hydralazine plus isosorbide dinitrate v 12% with placebo; P less than 0.001).[79] One systematic review has highlighted the potential risk of developing hydralazine-induced systemic lupus erythematous (SLE).[80] Although the risk is small because of lower doses used, people taking hydralazine should be monitored at each visit for signs and symptoms of SLE. A baseline antinuclear antibody (ANA) level should be determined prior to initiating hydralazine. However, it is not recommended to regularly check ANA levels. If any symptoms or signs of SLE develop, hydralazine treatment should be discontinued immediately because complications from the syndrome can be potentially fatal.[80]

Comment

In the first RCT, all participants were already receiving diuretics and digoxin.[78] In the second RCT, participants were required to have been receiving standard treatment, as determined to be appropriate by their physician, prior to the start of the trial.[79] This included diuretics, ACE inhibitors, angiotensin receptor blockers, beta-blockers, digoxin, and spironolactone.

Clinical guide:

This treatment could be used in combination with other medications for heart failure and in people intolerant to ACE inhibitors or angiotensin receptor blockers. The combination of hydralazine and isosorbide dinitrate would not be considered first-line treatment for heart failure.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Implantable cardiac defibrillators

Summary

MORTALITY Compared with usual care: Implantable cardiac defibrillators seem more effective at reducing all-cause mortality and sudden cardiac death ( moderate-quality evidence ). Implantable cardiac defibrillator plus cardiac resynchronisation therapy compared with usual care: Implantable cardiac defibrillator plus cardiac resynchronisation therapy is more effective than medical therapy at reducing all-cause mortality ( high-quality evidence ). Implantable cardiac defibrillator plus cardiac resynchronisation therapy compared with cardiac resynchronisation therapy or implantable cardiac defibrillator alone: Implantable cardiac defibrillator plus cardiac resynchronisation therapy is no more effective than either cardiac resynchronisation therapy or implantable cardiac defibrillator alone at reducing all-cause mortality (high-quality evidence). NOTE People with an implantable cardiac defibrillator are at risk of shocks from the device.

Benefits

Implantable cardiac defibrillators (ICDs) versus usual care:

We found two systematic reviews.[81] [82] The first systematic review (search date 2002, 8 RCTs, 4909 people at risk for sudden cardiac death or ventricular arrhythmia) compared ICD versus usual care in the primary prevention (people at risk for sudden cardiac death or ventricular arrhythmia who had evidence of heart failure or CAD [coronary artery disease]) or secondary prevention population (people who had survived sudden cardiac death or had unstable ventricular rhythm) of life-threatening arrhythmias and sudden cardiac death.[81] Over all trials (for primary and secondary prevention combined), the review found that ICD significantly reduced sudden cardiac death and all-cause mortality compared with usual care (cardiac death: 124/2428 [5%] with ICD v 339/2481 [14%] with control; RR 0.43, 95% CI 0.35 to 0.53; all-cause mortality: 459/2428 [19%] with ICD v 695/2481 [28%] with control; RR 0.74, 95% CI 0.67 to 0.82). In people who had survived sudden cardiac death or had unstable ventricular rhythm (secondary prevention), it found that ICD significantly reduced sudden cardiac death and all-cause death (3 RCTs, 1963 people; cardiac death: 67/934 [7%] with ICD v 162/1029 [16%] with control; RR 0.50, 95% CI 0.38 to 0.66; all-cause mortality: 199/934 [21%] with ICD v 304/1029 [30%] with control; RR 0.76, 95% CI 0.65 to 0.89). In people with evidence of heart failure or CAD (primary prevention), the review found that ICD significantly reduced sudden cardiac death and all-cause mortality (5 RCTs, 2946 people; cardiac death: 57/1494 [4%] with ICD v 177/1452 [12%] with control; RR 0.37, 95% CI 0.27 to 0.50; all-cause mortality: 260/1494 [17%] with ICD v 391/1452 [27%] with control; RR 0.72, 95% CI 0.63 to 0.84). In primary prevention RCTs, the magnitude of absolute-mortality benefit increased with increasing baseline risk of sudden cardiac death. There was significant heterogeneity among the primary prevention RCTs because three RCTs were in people at high risk of heart failure and two RCTs were in people at moderate risk of heart failure.

The second systematic review (search date 2004, 7 RCTs, 2110 people) compared ICD treatment versus usual care in people with heart failure caused by non-ischaemic cardiomyopathy, and analysed results separately for primary and secondary prevention RCTs.[82] For all studies, it found that ICD treatment significantly reduced mortality compared with usual care (RR 0.69, 95% CI 0.56 to 0.86; absolute numbers not reported). For primary prevention, it found that ICD treatment significantly reduced all-cause mortality compared with usual care (4 RCTs, 1457 people; RR 0.74, 95% CI 0.58 to 0.96; absolute numbers not reported). In people with previous resuscitated cardiac arrest or symptomatic ventricular tachycardia (secondary prevention), it found that ICD treatment reduced all-cause mortality compared with usual care, but the difference was not significant (2 RCTs, 256 people; RR 0.69, 95% CI 0.39 to 1.24; absolute numbers not reported). The number analysed may have been too small to detect a significant difference.

ICDs plus cardiac resynchronisation therapy versus usual care:

See benefits of cardiac resynchronisation therapy.

ICDs plus cardiac resynchronisation therapy versus either device alone:

See benefits of cardiac resynchronisation therapy.

Harms

Implantable cardiac defibrillators (ICDs) versus usual care:

The first systematic review found that complications associated with ICD treatment included perioperative infection (range 0.7–12.3%), lead fracture or device malfunction (range 0.8–14%), serious bleeding (range 1–6%), and pneumothorax (less than 1%).[81] The second systematic review did not report harms.[82]

ICDs plus cardiac resynchronisation therapy versus usual care:

See harms of cardiac resynchronisation therapy.

ICDs plus cardiac resynchronisation therapy versus either device alone:

See harms of cardiac resynchronisation therapy.

Comment

Clinical guide:

The systematic reviews suggest that ICDs are more beneficial than drug treatment for secondary prevention of sudden cardiac death, and for primary prevention in certain high-risk groups.[81] [82] However, the treatment is expensive and must be used appropriately in people in whom indications for treatment clearly exist. Further research is required to develop accurate risk-stratification tools, to determine the impact of ICD treatment in different subgroups of people, and to evaluate quality-of-life issues. People with ICDs are at risk of shocks from the device and this can adversely affect quality of life. An RCT has demonstrated that a combination of amiodarone plus a beta-blocker may be better to reduce the risk of shock compared with either sotalol (HR 0.43, 95% CI 0.22 to 0.85, P = 0.02) or beta-blocker alone (HR 0.27, 95% CI 0.14 to 0.52, P less than 0.001). [83]There was a trend for sotalol to reduce shocks compared with beta-blockers alone (HR 0.61, 95% CI 0.37 to 1.01, P = 0.05). There was a slightly greater incidence of adverse pulmonary and thyroid events, and of symptomatic bradycardia in people receiving amiodarone. As people with an ICD require some form of treatment to reduce the potential for shocks, therapeutic decisions should be individualised. The type of treatment used must take into consideration the possible improvements in quality of life, and small but increased risks of drug-related adverse effects.

Substantive changes

Implantable cardiac defibrillators One systematic review added found that a combination of cardiac resynchronisation therapy plus implantable cardiac defibrillation reduced all-cause mortality compared with usual care.[84] However, it found no significant difference in all-cause mortality between combination of devices and implantable cardiac defibrillator alone. Categorisation unchanged (Beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Cardiac resynchronisation therapy

Summary

MORTALITY Cardiac resynchronisation therapy alone compared with usual care: Cardiac resynchronisation therapy may be more effective at reducing all-cause mortality and death from progressive heart failure and reducing the proportion of people classed as "worsened" on the heart failure clinical composite response ( low-quality evidence ). Cardiac resynchronisation therapy plus implantable cardiac defibrillator compared with usual care: Cardiac resynchronisation therapy plus implantable cardiac defibrillator is more effective than medical therapy at reducing all-cause mortality ( high-quality evidence ). Cardiac resynchronisation therapy plus implantable cardiac defibrillator compared with cardiac resynchronisation therapy or implantable cardiac defibrillator alone: Cardiac resynchronisation therapy plus implantable cardiac defibrillator is no more effective than either cardiac resynchronisation therapy or implantable cardiac defibrillator alone at reducing all-cause mortality (high-quality evidence). HOSPITAL ADMISSION Compared with usual care: Cardiac resynchronisation therapy may be more effective at reducing hospital admissions for heart failure or major cardiovascular events (low-quality evidence). FUNCTIONAL IMPROVEMENT Compared with usual care: Cardiac resynchronisation therapy may be more effective at improving function (New York Heart Association functional classification) by at least one functional class but we don't know whether cardiac resynchronisation therapy is more effective at improving distance walked in the 6-minute walking test at 12 months (low-quality evidence). QUALITY OF LIFE Compared with standard care/usual care: Cardiac resynchronisation therapy seems more effective at improving quality-of-life scores as assessed by Minnesota Living with Heart Failure Questionnaire ( moderate-quality evidence ).

Benefits

We found three systematic reviews (search date 2003, 9 RCTs, 3216 people, 85% with New York Heart Association [NYHA] functional class III or IV symptoms;[85] search date 2005, 8 RCTs, 3380 people;[86] search date 2006, 7 RCTs, 3889 people),[84] which between them identified 10 RCTs. We also found one subsequent RCT.[87] The reviews included different RCTs in their meta-analyses and so we report data from all three reviews.

Cardiac resynchronisation therapy (CRT) alone versus usual care/control:

The first review found that CRT significantly improved quality of life and function compared with usual care (7 RCTs, 2472 people: weighted mean reduction in quality of life score on the Minnesota Living with Heart Failure Questionnaire [MLHFQ]: 7.6 points, 95% CI 3.8 points to 11.5 points; function improved by at least one NYHA functional class: 4 RCTs [number of people included in analysis not reported], 58% with CRT v 37% with usual care; RR 1.6, 95% CI 1.3 to 1.9).[85] It found no significant difference between CRT and usual care in hospital admission for heart failure, although the rate was lower with CRT (all hospital admission for heart failure: 6 RCTs, 1642 people: RR 0.68, 95% CI 0.41 to 1.12). However, CRT significantly reduced hospital admission for heart failure in people with NYHA class III or IV symptoms at baseline (RR 0.65, 95% CI 0.48 to 0.88; number of people in analysis not reported). It found that CRT significantly reduced all-cause mortality (8 RCTs, 3203 people: RR 0.79, 95% CI 0.66 to 0.96). However, there was no significant difference between groups in death from progressive heart failure, although the rate was lower with CRD (7 RCTs, 1647 people: RR 0.60, 95% CI 0.36 to 1.01; absolute numbers not reported for any outcome). Some RCTs included in the analysis compared CRT plus implantable cardiac defibrillators (ICDs) versus ICDs alone.

The second review found that CRT significantly reduced all-cause mortality compared with control (not further defined) (8 RCTs, 3380 people: 264/1847 [14%] with CRT v 260/1533 [17%] with control; OR 0.72, 95% CI 0.59 to 0.88).[86] The review also found that CRT significantly reduced hospital admissions for worsening heart failure (7 RCTs, 2455 people: 174/1230 [14%] with CRT v 282/1225 [23%] with control; OR 0.55, 95% CI 0.44 to 0.68) and significantly improved quality of life (assessed by the MLHFQ; 8 RCTs, 3380 people: WMD –7.1, 95% CI –11.4 to –2.9). The review included RCTs in which ICDs were used in all people randomised.

The third review found that CRT significantly reduced all-cause mortality compared with usual care (medical treatment) (4 RCTs, 2249 people: 245/1283 [19%] with CRT v 247/966 [26%] with medical treatment; OR 0.67, 95% CI 0.50 to 0.90).[84] This analysis included those RCTs in which neither arm was treated with an ICD.

The subsequent RCT (610 people with NYHA class I to II, left ventricular ejection fraction [LVEF] less than or equal to 40%, and with a QRS 120 ms or more) found no significant difference between CRT (with or without ICD) and control (CRT device not activated) in the proportion of people classed as "worsened" based on the heart failure clinical composite response at 12 months, although the proportion of people meeting criteria for "worsened" was smaller with CRT (67/419 [16%] with CRT activated v 41/191 [21%] with CRT inactivated; P = 0.10).[87] People were classed as "worsened" if they died, were hospitalised because of worsening heart failure, crossed over or permanently discontinued treatment because of worsening heart failure, had worsening NYHA functional class, or reported moderately or markedly worse symptoms than before implant (assessed using Patient Global Assessment). The RCT also found no significant difference between groups at 12 months in change in 6-minute walking test (12.7 metres with CRT activated v 18.7 metres with CRT inactivated; P = 0.52) or change in quality of life (assessed using MLHFQ; higher score represents worse quality of life: –8.4 with CRT activated v –6.7 with CRT inactivated; P = 0.26).

CRT plus implantable cardiac defibrillator (ICD) versus usual care:

The third review found the combination of CRT plus ICD significantly reduced all-cause mortality compared with usual care (medical treatment) (1 RCT, 903 people: 105/595 [18%] with CRT plus ICD v 77/308 [25%] with medical treatment; OR 0.64, 95% CI 0.46 to 0.90).[84]

CRT plus ICD versus ICD alone:

The third review found no significant difference in all-cause mortality between a combination of CRT plus ICD and ICD alone (3 RCTs, 1045 people: 27/517 [5%] with CRT plus ICD v 33/528 [6%] with ICD alone; OR 0.81, 95% CI 0.48 to 1.37).[84]

CRT plus ICD versus CRT alone:

The third review found no significant difference in all-cause mortality between a combination of CRT plus ICD and CRT alone (one RCT, 1212 people: 105/595 [18%] with CRT plus ICD v 131/617 [21%] with CRT alone; OR 0.79, 95% CI 0.60 to 1.06).[84]

Harms

We found one non-systematic review that combined the results from the three studies in the MIRACLE implantable cardioverter-defibrillator (ICD) programme (2078 people) to evaluate the safety of CRT implantation.[88] The implant attempt succeeded in 1903/2078 (92%) of people overall. The perioperative complication rate ranged from 9% for CRT implantation alone to 21% for the combined ICD/CRT implantation. The postoperative complication rate ranged from 8.6% to 11.9%. A total of 8% of people required re-operation to treat lead dislodgement, extracardiac stimulation, or infection over 6 months' follow-up. There was 0.3% procedure-related mortality.

Cardiac resynchronisation therapy (CRT) alone versus usual care/control:

The first systematic review found that 0.4% of people died during implantation (95% CI 0.2% to 0.7%).[85] It found that, over a median of 6 months' follow-up, leads dislodged in 9% of recipients (95% CI 7% to 10%) and mechanical malfunctions occurred in 7% (95% CI 5% to 8%). The second and third reviews gave no information on adverse effects.[86] [84]

The subsequent RCT reported that there was no significant difference between the CRT group and control group in rate of complications (P = 0.64; no further comparative data reported).[87]

CRT plus implantable cardiac defibrillator (ICD) versus usual care/control/either device alone:

The third review gave no information on adverse effects.[84]

Comment

Clinical guide:

The results presented in the systematic reviews indicate beneficial effects with CRT.[85] [86] [84] People deriving benefit are those with the more severe symptoms of heart failure. Most people included in the studies were well selected, and procedures were performed in centres with experience. However, because in almost all RCTs people were randomly assigned to different modes of operation after placement of the pacemaker, the results may over-estimate the potential benefits of CRT. Furthermore, meta-analysis of RCTs comparing combination of CRT plus ICD versus either device alone found that the combination does not seem more effective than either ICD or CRT therapy alone in reducing mortality or hospital admission for heart failure.[84]

Substantive changes

Cardiac resynchronisation therapyTwo systematic reviews added support existing evidence that cardiac resynchronisation therapy (CRT) reduces all-cause mortality[84] [86] and hospital admissions for heart failure compared with usual care.[84]One review found that a combination of CRT plus implantable cardiac defibrillation (ICD) reduced all-cause mortality compared with usual care.[84] However, it found no significant difference in all-cause mortality between combination of devices and CRT alone. One subsequent RCT found no significant difference between CRT (with or without ICD) and control (CRT device not activated) in the proportion of people classed as "worsened" based on the heart failure clinical composite response at 12 months, although the proportion of people meeting criteria for "worsened" was smaller with CRT.[87] Categorisation unchanged (Likely to be beneficial).

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

ACE inhibitors in people at high risk of heart failure

Summary

MORTALITY Compared with placebo: ACE inhibitors seem more effective at reducing all-cause mortality and cardiovascular mortality in people with asymptomatic left ventricular systolic dysfunction, and in people with vascular disease without known evidence of left ventricular dysfunction or heart failure, and at reducing fatal MI in people with left ventricular systolic dysfunction ( moderate-quality evidence ). HOSPITAL ADMISSION Compared with placebo: ACE inhibitors are more effective at reducing all-cause hospital admissions, cardiovascular hospital admissions and heart-failure hospital admissions in people with heart failure, asymptomatic left ventricular dysfunction, or other risk factors for heart failure (moderate-quality evidence). CARDIOVASCULAR EVENTS Compared with placebo: ACE inhibitors are more effective at reducing non-fatal MIs in people at high risk of heart failure (people with asymptomatic left ventricular systolic dysfunction, and people with vascular disease without known evidence of left ventricular dysfunction or heart failure) (moderate-quality evidence).

Benefits

ACE inhibitors in people with asymptomatic left ventricular systolic dysfunction (LVSD):

We found one systematic review[89] and three additional RCTs, [90] [91] [92] one of which [91]reported the 12-year follow-up of one of the RCTs identified by the review.[93]

The systematic review identified three RCTs of people with vascular disease, but no heart failure or LVSD (29,805 people) and five RCTs of people with LVSD or heart failure (12,763 people).[89] In people with vascular disease, ACE inhibitors significantly reduced all-cause mortality and hospital admission for heart failure compared with placebo (all-cause mortality: 8% with ACE inhibitor v 9% with control; OR 0.86, 95% CI 0.79 to 0.94; P = 0.0004; hospital admission for heart failure: 2% with ACE inhibitor v 3% with control; OR 0.77, 95% CI 0.67 to 0.90; P = 0.0007). In people with LVSD or heart failure, ACE inhibitors also significantly reduced all-cause mortality and hospital admission for heart failure compared with placebo (all-cause mortality: 23% with ACE inhibitor v 27% with control; OR 0.80, 95% CI 0.74 to 0.87; P less than 0.0001; hospital admission for heart failure: 14% with ACE inhibitor v 19% with control; OR 0.66, 95% CI 0.60 to 0.74; P less than 0.0001). In the combined analysis (8 RCTs, 42,568 people), ACE inhibitors also significantly reduced all-cause mortality, non-fatal MI, and hospital admission for heart failure compared with placebo (all-cause mortality: 12% with ACE inhibitor v 14% with control; OR 0.83, 95% CI 0.79 to 0.88; P less than 0.0001; non-fatal MI: 6% with ACE inhibitor v 7% with control; OR 0.80, 95% CI 0.74 to 0.87; P less than 0.0001; hospital admission for heart failure: 5% with ACE inhibitor v 7% with control; OR 0.70, 95% CI 0.64 to 0.76; P less than 0.0001; absolute numbers not reported for any outcome). There was no heterogeneity among RCTs.

The first additional RCT (in 2231 asymptomatic people after MI with documented LVSD) found that an ACE inhibitor (captopril) significantly reduced the risk of fatal MI compared with placebo (56/1115 [5%] with captopril v 80/1116 [7%] with placebo; RR 0.68, 95% CI 0.49 to 0.96).[90]

The second additional RCT (5165 people followed up)[91] was a 12-year follow-up of one of the RCTs identified by the review.[93] It found that enalapril given for 3 to 4 years significantly reduced all-cause mortality and cardiac deaths compared with placebo (all-cause mortality: 1074/2111 [51%] with enalapril v 1195/2117 [56%] with placebo; HR 0.86, 95% CI 0.79 to 0.93; cardiac death: 736/2111 [35%] with enalapril v 826/2117 [39%] with placebo; HR 0.85, 95% CI 0.77 to 0.94).[91]

The third additional RCT (1749 people with MI and LVSD, ejection fraction 35% or less) compared trandolapril versus placebo given 3 to 7 days after MI.[92] The RCT found that, over 12 years, trandolapril significantly reduced the risk of all-cause mortality, all-cause hospital admissions, cardiovascular hospital admissions, and hospital admission for heart failure compared with placebo (all-cause mortality: RR 0.89, 95% CI 0.80 to 0.99; P = 0.03; all-cause hospital admissions: RR 0.92, 95% CI 0.88 to 0.96; P less than 0.001; cardiovascular hospital admissions: RR 0.95, 95% CI 0.91 to 1.00; P = 0.047; hospital admission for heart failure: RR 0.85, 95% CI 0.77 to 0.93; P less than 0.001; absolute numbers not reported for any outcome).[92]

Harms

ACE inhibitors in people with asymptomatic left ventricular systolic dysfunction:

The review[89] and two of the additional RCTs[90] [92] gave no information on adverse effects.

The second additional RCT found that a high proportion of people in both groups reported adverse effects over 40 months (76% with enalapril v 72% with placebo; absolute numbers not reported; significance not assessed).[91] Dizziness or fainting (46% with enalapril v 33% with placebo) and cough (34% with enalapril v 27% with placebo) were reported more often in the enalapril group (absolute numbers not reported for any outcome; significance not assessed for any outcome). The incidence of angio-oedema was the same in both groups (1%). Study medication was permanently discontinued by 8% of the people in the enalapril group compared with 5% in the placebo group (significance not assessed).

Comment

Asymptomatic LVSD is prognostically important, but we found no prospective studies that evaluated screening to detect its presence.

Substantive changes

No new evidence

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Angiotensin II receptor blockers for diastolic heart failure

Summary

MORTALITY Compared with placebo: Candesartan seems no more effective at reducing cardiovascular death at 36.6 months, and irbesartan seems no more effective at reducing all-cause mortality at 49.5 months ( moderate-quality evidence ). HOSPITAL ADMISSIONS Compared with placebo: Candesartan seems more effective at reducing hospital admissions for heart failure at 36.6 months, but irbesartan seems no more effective at reducing hospital admission for heart failure at 49.5 months (moderate-quality evidence).

Benefits

We found two RCTs assessing the effects of angiotensin II receptor blockers in people with diastolic heart failure.[94] [95] The first RCT (3023 people with New York Heart Association [NYHA] functional class II–IV heart failure and left ventricular ejection fraction [LVEF] greater than 40%) compared candesartan versus placebo.[94] The RCT found no significant difference between candesartan and placebo in cardiovascular mortality at a median follow-up of 36.6 months (170/1514 [11.2%] with candesartan v 170/1509 [11.3%] with placebo; adjusted HR 0.95, 95% CI 0.76 to 1.18). However, the RCT found that, compared with placebo, candesartan significantly reduced hospital admission for heart failure at a median follow-up of 36.6 months (241/1514 [16%] with candesartan v 276/1509 [18%] with placebo; adjusted HR 0.84, 95% CI 0.70 to 1.00; P = 0.047). Reported outcomes are secondary outcomes. The primary outcome assessed was a composite of cardiovascular mortality and hospital admission for heart failure: there was no significant difference between groups in this outcome (333/1514 [22%] with candesartan v 366/1509 [24%] with placebo; adjusted HR 0.86, 95% CI 0.74 to 1.00; P = 0.051).

The second RCT (4128 people with NYHA II to IV heart failure symptoms and LVEF 45% or greater) compared irbesartan versus placebo.[95] At a mean follow-up of 49.5 months, the RCT found no significant difference between irbesartan and placebo in all-cause mortality (445/2067 [22%] with irbesartan v 436/2061 [21%] with placebo; HR 1.00, 95% CI 0.88 to 1.14; P = 0.98) or in hospital admission for cardiovascular causes (heart failure, MI, unstable angina, arrhythmia, or stroke) (521/2067 [25%] with irbesartan v 537/2061 [26%] with placebo; HR 0.95, 95% CI 0.85 to 1.08; P = 0.44). Reported outcomes are secondary outcomes. The primary outcome assessed was a composite of all-cause mortality or hospital admission for a cardiovascular cause (heart failure, MI, unstable angina, arrhythmia, or stroke): there was no significant difference between groups for this outcome (742/2067 [36%] with irbesartan v 763/2061 [37%] with placebo; HR 0.95, 95% CI 0.86 to 1.05; P = 0.35).

Harms

The first RCT found that candesartan significantly increased permanent discontinuation of treatment caused by an adverse effect or an abnormal laboratory value compared with placebo (adverse events were hypotension, hyperkalaemia, and increase in plasma creatinine; 270/1514 [18%] with candesartan v 204/1509 [14%] with placebo; P = 0.001).[94]

The second RCT found no significant difference between irbesartan and placebo in rate of withdrawal caused by an adverse effects, although rate of withdrawal was higher with irbesartan (331/2067 [16%] with irbesartan v 288/2061 [14%] with placebo; P = 0.07).[95] There was also no significant difference between groups in rates of hypotension, renal dysfunction, and hyperkalaemia compared with placebo (hypotension: 60/2067 [2.9%] with irbesartan v 62/2061 [3.0%] with placebo; P = 0.84; renal dysfunction: 69/2067 [3.3%] with irbesartan v 57/2061 [2.8%] with placebo; P = 0.29; hyperkalaemia: 12/2067 [0.6%] with irbesartan v 9/2061 [0.4%] with placebo; P = 0.34).

Comment

Clinical guide:

The causes of diastolic dysfunction vary among people with diastolic heart failure. Current treatment is largely based on the results of small clinical studies and consists of treating the underlying cause and coexistent conditions with interventions optimised for individuals.[96] [97] Further RCTs with clinically relevant outcome measures are needed to determine the benefits and harms of treatments in diastolic heart failure.

Substantive changes

Angiotensin II receptor blockers for diastolic heart failure One RCT added comparing irbesartan versus placebo found no significant difference between irbesartan and placebo in all-cause mortality or in hospital admission for cardiovascular causes at a mean follow-up of 49.5 months.[95] Evidence for effect of irbesartan on hospital admission for cardiovascular disease differs from evidence previously reported for candesartan for this outcome. Effects of angiotensin II receptor blockers as a class in treatment of diastolic heart failure is unclear. Categorisation changed from Likely to be beneficial to Unknown effectiveness.

Clin Evid (Online) 2010; 2010: 0204.
Published online Feb 25, 2010.

Treatments other than angiotensin II receptor blockers for diastolic heart failure

Summary

MORTALITY Treatments other than angiotensin II receptor blockers compared with placebo: We don't know whether perindopril, an ACE inhibitor, and digoxin, are more effective at reducing the combined outcome of all-cause mortality and unplanned heart failure-related hospital admissions ( very low-quality evidence ).

Benefits

We found no systematic review but found two RCTs.[98] [99]The first RCT (850 people with New York Heart Association [NYHA] functional class I–IV heart failure and left ventricular ejection fraction [LVEF] greater than 40%) compared perindopril 4 mg daily versus placebo.[98]During a mean follow-up of 26.2 months it found no significant difference in the combined primary outcome of all-cause mortality or unplanned heart failure-related hospital admission (HR 0.92, 95% CI 0.70 to 1.21; P = 0.54). However, after a 1-year follow-up there was a trend to reduction in the combined primary outcome (HR 0.69, 95% CI 0.47 to 1.01; P = 0.055). Many of the participants withdrew after 1 year from perindopril (28%) or placebo (26%), and, by the end of the study, 35% of the those randomised to perindopril and 37% of those randomised to placebo were taking open-label ACE inhibitors, which may have considerably altered the results of the trial. The second RCT reported a post hoc subgroup analysis of people with heart failure with preserved ejection fraction from the DIG Study (988 people with NYHA functional class I–IV heart failure and LVEF greater than 45%), which compared digoxin versus placebo.[99]The subgroup analysis found no significant difference between digoxin and placebo in the combined primary outcome of hospital admission for heart failure, or heart failure mortality, over a mean follow-up of 37 months (HR 0.82, 95% CI 0.63 to 1.07; P = 0.136). Digoxin also had no effect on all-cause mortality or cardiovascular mortality over a mean follow-up of 37 months (all-cause mortality: HR 0.99, 95% CI 0.76 to 1.28; P = 0.92; cardiovascular mortality: HR 1.00, 95% CI 0.73 to 1.36; P = 0.98).

Harms

The first RCT reported serious adverse effects, including oedema and hypotension, in 9/424 (2%) people taking perindopril and 4/426 (1%) people in the placebo group, but it did not assess the significance of the difference in adverse effects between groups.[98] The second RCT found that 10% of people taking digoxin had suspected digoxin toxicity compared with 4% of people taking placebo (P less than 0.001). The RCT also found that digoxin was associated with more hospital admissions for unstable angina than placebo, although the difference between groups did not quite reach significance (HR 1.37, 95% CI 0.99 to 1.91; P = 0.06).

Comment

Clinical guide:

The causes of diastolic dysfunction vary among people with diastolic heart failure. Current treatment is largely based on the results of small clinical studies and consists of treating the underlying cause and coexistent conditions with interventions optimised for individuals.[96] [97] Further RCTs with clinically relevant outcome measures are needed to determine the benefits and harms of treatments in diastolic heart failure.

Substantive changes

No new evidence


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