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 multidisciplinary interventions for heart failure? What are the effects of exercise in people with heart failure? What are the effects of drug treatments for heart failure? What are the effects of devices for treatment of heart failure? What are the effects of coronary revascularisation for treatment of heart failure? What are the effects of drug treatments 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 August 2010 (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 80 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, coronary revascularisation, 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 may reduce admissions to hospital and mortality in people with heart failure compared with usual care. Exercise may reduce admissions to hospital due to heart failure compared with usual care. However, long-term benefits of these interventions remain unclear.
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 hospital 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.
We don't know whether amiodarone, anticoagulants, or antiplatelets are effective at reducing mortality or hospital re-admission rates.
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.
We don't know how coronary revascularisation and drug treatment compare for reducing mortality in people with heart failure and left ventricular dysfunction because all the trials assessing this comparison were conducted before ACE inhibitors, aspirin, beta-blockers, and statins were in routine use, thus limiting their applicability to current clinical practice.
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.
Angiotensin II receptor blockers and ACE inhibitors seem equally effective at reducing all-cause mortality and cardiovascular mortality in people at high risk of heart failure.
The combination of angiotensin II receptor blockers and ACE inhibitors seems no more effective than ACE inhibitors alone and causes more adverse effects.
ACE inhibitors or angiotensin II receptor blockers seem no more effective at reducing mortality or rate of hospital admissions for cardiovascular events in people with diastolic heart failure compared with placebo.
We don't know whether treatments other than angiotensin II receptor blockers are beneficial in reducing mortality in people with diastolic heart failure as we found only one trial.
Clinical context
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 treatments 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) <0.40. It may be symptomatic or asymptomatic. Defining and diagnosing diastolic heart failure can be difficult. 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 people/year, and, in those over 85 years of age, incidence was considerably higher, at 45 to 90 cases/1000 people/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 people/year in 1994 to 29.1 cases/1000 people/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 1994 through to 2000 (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 under 65 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
Effects of treatments in people with heart failure: mortality; 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] hospital admission rates; quality of life (assessed with questionnaires);[14] adverse effects of treatment. Effects of treatments in people at high risk of heart failure: mortality; cardiovascular events (including non-fatal MI and the composite outcomes of cardiovascular mortality, MI, stroke, or hospital admission); hospital admission rates; adverse effects of treatment. Proxy measures of clinical outcome (e.g., LVEF) are used only when clinical outcomes are unavailable. Where a study reported only the composite outcome of death or hospital admission, we have reported this under hospital admission.
Methods
Clinical Evidence search and appraisal August 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to August 2010, Embase 1980 to August 2010, and The Cochrane Database of Systematic Reviews, August 2010 (online; 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 systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >100 individuals of whom >80% were followed up. Generally, RCTs with <500 people have been excluded because of the number of large RCTs available. If, for any comparison, large RCTs or systematic reviews were found, then smaller RCTs have been excluded, even if they include >500 people. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the 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 (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.
| Important outcomes | Admission to hospital, Cardiovascular events, Functional improvement, Mortality, Quality of life | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of multidisciplinary interventions for heart failure? | |||||||||
| at least 32 (at least 9733) | Mortality | Multidisciplinary interventions versus usual care | 4 | 0 | 0 | 0 | 0 | High | |
| at least 34 (at least 9588) | Admission to hospital | Multidisciplinary interventions versus usual care | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of exercise in people with heart failure? | |||||||||
| at least 14 (at least 1197) | Mortality | Exercise versus usual care | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for uncertainty about relative merits of the various exercise strategies assessed |
| at least 14 (at least 1197) | Admission to hospital | Exercise versus usual care | 4 | 0 | 0 | −2 | 0 | Low | Directness points deducted for use of composite outcome and uncertainty about the relative merits of the various exercise strategies assessed |
| 3 (2256) | Functional improvement | Exercise versus usual care | 4 | 0 | −1 | −1 | 0 | Low | Consistency point deducted for different results at different times. Directness point deducted for uncertainty about relative merits of the various exercise strategies assessed |
| 11 (3278) | Quality of life | Exercise versus usual care | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for incomplete reporting. Directness point deducted for uncertainty about benefits of each strategy |
| What are the effects of drug treatments for heart failure? | |||||||||
| 37 (19,868) | Mortality | ACE inhibitors versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 5 (12,763) | Admission to hospital | ACE inhibitors versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (3164) | Mortality | Difference doses of ACE inhibitors versus each other | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for composite outcome in 1 RCT |
| 1 (3164) | Admission to hospital | Difference doses of ACE inhibitors versus each other | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for composite outcome in 1 RCT |
| 9 (4623) | Mortality | Angiotensin II receptor blockers versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (2590) | Admission to hospital | Angiotensin II receptor blockers versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 8 (5201) | Mortality | Angiotensin II receptor blockers versus ACE inhibitors | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (4310) | Admission to hospital | Angiotensin II receptor blockers versus ACE inhibitors | 4 | 0 | 0 | 0 | 0 | High | |
| at least 7 (8260) | Mortality | Angiotensin II receptor blockers plus ACE inhibitors versus ACE inhibitors alone | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for use of composite outcome in some assessments |
| 4 (8108) | Admission to hospital | Angiotensin II receptor blockers plus ACE inhibitors versus ACE inhibitors alone | 4 | 0 | 0 | 0 | 0 | High | |
| at least 23 (at least 19,209) | Mortality | Beta-blockers versus placebo | 4 | 0 | −1 | 0 | 0 | Moderate | Consistency point deducted for heterogeneity between studies |
| 23 (12,263) | Admission to hospital | Beta-blockers versus placebo | 4 | 0 | 0 | −2 | 0 | Low | Directness points deducted for uncertainty of benefit in older people and use of composite outcome |
| 28 (7637) | Functional improvement | Beta-blockers versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 6 (at least 12,278) | Mortality | Beta-blockers versus placebo (in people with severe heart failure) | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for inclusion of various co-interventions |
| 3 (8988) | Admission to hospital | Beta-blockers versus placebo (in people with severe heart failure) | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for composite outcome |
| 1 (1010) | Admission to hospital | Beta-blockers versus ACE inhibitors | 4 | 0 | 0 | −2 | 0 | Low | Directness points deducted for composite outcome and low number of comparators |
| 7 (7756) | Mortality | Digoxin versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 4 (7262) | Admission to hospital | Digoxin versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 24 (at least 13,957) | Mortality | Positive inotropes (other than digoxin) versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 19 (10,807) | Mortality | Aldosterone receptor antagonists versus placebo | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for non-generalisability of results (inclusion of people with ejection fraction >40%) |
| 9 (8699) | Admission to hospital | Aldosterone receptor antagonists versus placebo | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for non-generalisability of results (inclusion of people with ejection fraction >40%) |
| 13 (9626) | Mortality | Amiodarone versus placebo or conventional care | 4 | −1 | 0 | −2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for including people with a wide range of conditions and for bias |
| 2 (361) | Mortality | Anticoagulation versus placebo or no antithrombotic treatment | 4 | −1 | 0 | −2 | 0 | Very low | Quality point deducted for incomplete reporting of results. Directness points deducted for combined outcome and for not exclusively including people with heart failure |
| 1 (190) | Mortality | Antiplatelet agents versus no treatment | 4 | −2 | 0 | −1 | 0 | Very low | Quality points deducted for sparse data and for incomplete reporting of results. Directness point deducted for composite outcome |
| 1 (190) | Admission to hospital | Antiplatelet agents versus no treatment | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and for incomplete reporting of results |
| 3 (1882) | Mortality | Antiplatelet agents versus warfarin | 4 | −2 | 0 | −1 | 0 | Very low | Quality points deducted for incomplete reporting of results and for largest RCT being underpowered to detect a clinically important difference. Directness point deducted for composite outcomes |
| 2 (1767) | Admission to hospital | Antiplatelet agents versus warfarin | 4 | −2 | 0 | −1 | 0 | Very low | Quality points deducted for incomplete reporting of results and for largest RCT being underpowered to detect a clinically important difference. Directness point deducted for composite outcome |
| 5 (4614) | Mortality | Calcium channel blockers (for heart failure other than MI) versus placebo | 4 | −1 | −1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for different results for subgroup analysis |
| 3 (1790) | Admission to hospital | Calcium channel blockers (for heart failure other than MI) versus placebo | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for composite outcome |
| 2 (1509) | Mortality | Hydralazine plus isosorbide dinitrate versus placebo | 4 | −1 | 0 | −2 | 0 | Very low | Quality point deducted for short follow-up. Directness points deducted for mortality measured as secondary outcome in largest RCT and for differences in disease severity |
| 1 (1050) | Quality of life | Hydralazine plus isosorbide dinitrate versus placebo | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for short follow-up. Directness point deducted for quality of life measured as secondary outcome |
| What are the effects of devices for treatment of heart failure? | |||||||||
| at least 8 (at least 2110) | Mortality | Implantable cardiac defibrillators versus usual care | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 14 (at least 7154) | Mortality | Cardiac resynchronisation therapy (CRT) alone versus usual care/control | 4 | 0 | 0 | −2 | 0 | Low | Directness points deducted for inclusion of co-intervention in some analyses (implantable cardiac defibrillator) and for composite outcome |
| at least 12 (at least 4349) | Admission to hospital | Cardiac resynchronisation therapy (CRT) alone versus usual care/control | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of co-intervention in some analyses (implantable cardiac defibrillator) |
| 4 (number of people not reported) | Functional improvement | Cardiac resynchronisation therapy (CRT) alone versus usual care/control | 4 | −1 | 0 | −1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of co-intervention in some analyses (implantable cardiac defibrillator) |
| 7 (2472) | Quality of life | Cardiac resynchronisation therapy (CRT) alone versus usual care/control | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for uncertainty about generalisability of results |
| 1 (903) | Mortality | CRT plus implantable cardiac defibrillator (ICD) versus usual care | 4 | 0 | 0 | 0 | 0 | High | |
| 5 (3475) | Mortality | CRT plus ICD versus ICD alone | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for different conclusions from different studies |
| 2 (2430) | Admission to hospital | CRT plus ICD versus ICD alone | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for composite outcome |
| 1 (1212) | Mortality | CRT plus ICD versus CRT alone | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of coronary revascularisation for treatment of heart failure? | |||||||||
| 7 (549) | Mortality | Coronary revascularisation versus drug treatment | 4 | –2 | 0 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results and for subgroup analyses. Directness point deducted for inclusion of older trials that were completed before ACE inhibitors, aspirin, beta-blockers, and statins were in routine use |
| What are the effects of drug treatments in people at high risk of heart failure? | |||||||||
| 8 (46,548) | Mortality | ACE inhibitors versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (14,512) | Admission to hospital | ACE inhibitors versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| at least 8 (at least 42,568) | Cardiovascular events | ACE inhibitors versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (5926) | Mortality | Angiotensin II receptor blockers versus placebo | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for only including people intolerant of ACE inhibitors and because data only available for 1 angiotensin II receptor blocker |
| 1 (5926) | Admission to hospital | Angiotensin II receptor blockers versus placebo | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for only including people intolerant of ACE inhibitors and because data only available for 1 angiotensin II receptor blocker |
| 2 (26,258) | Cardiovascular events | Angiotensin II receptor blockers versus placebo | 4 | 0 | −1 | −2 | 0 | Very low | Consistency point deducted for different results at different time points. Directness points deducted for composite outcome and because data only available for 1 angiotensin II receptor blocker |
| 2 (26,936) | Mortality | Angiotensin II receptor blockers versus ACE inhibitors | 4 | 0 | 0 | −1 | 0 | Moderate | Directness point deducted for inclusion of people with diagnosed heart failure |
| 1 (17,118) | Admission to hospital | Angiotensin II receptor blockers versus ACE inhibitors | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for only 1 drug of each class in the analysis |
| 2 (26,936) | Cardiovascular events | Angiotensin II receptor blockers versus ACE inhibitors | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of people with clinical evidence of heart failure |
| 2 (26,872) | Mortality | Angiotensin II receptor blockers plus ACE inhibitors versus ACE inhibitors alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of people with clinically evident heart failure |
| 1 (17,118) | Admission to hospital | Angiotensin II receptor blockers plus ACE inhibitors versus ACE inhibitors alone | 4 | 0 | 0 | –2 | 0 | Low | Directness points deducted for inclusion of people with clinically evident heart failure and for only 1 drug of each class in the analysis |
| 2 (26, 872) | Cardiovascular events | Angiotensin II receptor blockers plus ACE inhibitors versus ACE inhibitors alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of all people with clinically evident heart disease |
| What are the effects of treatments for diastolic heart failure? | |||||||||
| 3 (8021) | Mortality | ACE inhibitors or angiotensin II receptor blockers versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (8021) | Admission to hospital | ACE inhibitors or angiotensin II receptor blockers versus placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting |
| 1 (988) | Mortality | Treatments other than angiotensin II receptor blockers versus placebo | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and for subgroup analysis |
| 1 (988) | Admission to hospital | Treatments other than angiotensin II receptor blockers versus placebo | 4 | −2 | 0 | −1 | 0 | Very low | Quality points deducted for incomplete reporting of results and for subgroup analysis. Directness point deducted for composite outcome |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- 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.
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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