Pharmacological interventions for heart failure in people with chronic kidney disease

Meaghan Lunney; Marinella Ruospo; Patrizia Natale; Robert R Quinn; Paul E Ronksley; Ioannis Konstantinidis; Suetonia C Palmer; Marcello Tonelli; Giovanni FM Strippoli; Pietro Ravani

doi:10.1002/14651858.CD012466.pub2

. 2020 Feb 27;2020(2):CD012466. doi: 10.1002/14651858.CD012466.pub2

Pharmacological interventions for heart failure in people with chronic kidney disease

Meaghan Lunney ¹, Marinella Ruospo ^2,³, Patrizia Natale ^2,³, Robert R Quinn ^1,⁴, Paul E Ronksley ¹, Ioannis Konstantinidis ⁵, Suetonia C Palmer ⁶, Marcello Tonelli ⁴, Giovanni FM Strippoli ^2,^3,⁷, Pietro Ravani ^1,^4,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC7044419 PMID: 32103487

Abstract

Background

Approximately half of people with heart failure have chronic kidney disease (CKD). Pharmacological interventions for heart failure in people with CKD have the potential to reduce death (any cause) or hospitalisations for decompensated heart failure. However, these interventions are of uncertain benefit and may increase the risk of harm, such as hypotension and electrolyte abnormalities, in those with CKD.

Objectives

This review aims to look at the benefits and harms of pharmacological interventions for HF (i.e., antihypertensive agents, inotropes, and agents that may improve the heart performance indirectly) in people with HF and CKD.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies through 12 September 2019 in consultation with an Information Specialist and using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

We included randomised controlled trials of any pharmacological intervention for acute or chronic heart failure, among people of any age with chronic kidney disease of at least three months duration.

Data collection and analysis

Two authors independently screened the records to identify eligible studies and extracted data on the following dichotomous outcomes: death, hospitalisations, worsening heart failure, worsening kidney function, hyperkalaemia, and hypotension. We used random effects meta‐analysis to estimate treatment effects, which we expressed as a risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias using the Cochrane tool. We applied the GRADE methodology to rate the certainty of evidence.

Main results

One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow‐up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta‐analyses.

In acute heart failure, the effects of adenosine A1‐receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported.

In chronic heart failure, the effects of angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I² = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta‐blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I² = 0%; moderate certainty evidence).

Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I² = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta‐blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I² = 87%; low certainty evidence).

Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I² = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I² = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta‐analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies.

The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported.

Effects of anti‐arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies.

Authors' conclusions

The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.

Plain language summary

Heart failure drugs in people with chronic kidney disease

What is the issue?

People with heart failure (when the heart doesn't pump blood properly) often need medicine to help with symptoms like fatigue, swelling, and breathing problems. Studies have looked at whether these medicines are harmful or helpful. However, but they do not clarify whether these treatments may help people with heart failure that also have kidney problems (when the kidneys don't remove waste and fluid from the body properly).

What did we do?

We searched for all research studies that assessed the different treatments for heart failure up to September 2019. We evaluated whether medicines prevent death or hospital admissions, or increase risk of harm, for people with kidney disease. We also measured how certain we could be about the effects of these medicines on the body using a system called "GRADE".

What did we find?

We found 31 studies involving 23,762 people with heart failure and chronic kidney disease. Patients were given either a heart failure medicine compared to standard care or a placebo. The treatment they received was decided by random chance. Although there were many different treatments studied, unfortunately, few of them looked at the same type of medicine. As well, there were many different ways that researchers measured what happened when patients took these medicines. As a result, we could not combine the studies together and clarify the benefits and harms of each treatment. Existing studies cannot really tell us whether medicines used to treat heart failure in the general population are effective or safe for people who have both heart failure and chronic kidney disease.

Conclusions

We are not able to recommend which heart failure medicines are best for people with heart failure and chronic kidney disease. We need more information from large clinical studies. Most of the heart failure studies did not report treatment effects separately based on levels of kidney function. Obtaining this information from existing studies may be helpful to learn more about how to treat heart failure in people with chronic kidney disease.

Summary of findings

Background

Description of the condition

Chronic kidney disease (CKD) is defined by structural (presence of albuminuria) or functional (persistently reduced kidney function) alterations of the kidney that persists for three or more months. CKD is classified according to estimated glomerular filtration rate (eGFR) and albumin:creatinine ratio (ACR), using 'G' to denote the GFR category (G1 to G5, with cut‐offs at 90, 60, 30 and 15 mL/min/1.73 m²) and 'A' for the ACR category (A1 to A3, with cut‐offs at 3 and 30 mg/mol) (Levey 2011). CKD is usually clinically silent until end‐stage kidney disease (ESKD) requiring dialysis or kidney transplantation, although complications including fluid retention, hypertension or anaemia are often identified in earlier CKD stages.

Heart failure (HF) results from any structural or functional cardiac disorder that impairs the ability of the heart to function as a pump to support the circulation of blood. People with HF have symptoms of fatigue and breathlessness and signs of fluid retention such as ankle swelling, elevated jugular venous pressure, and pulmonary crackles. Guidelines (McKelvie 2012; Ponikowski 2016; Yancy 2016) restrict HF definition and management recommendations to stages at which symptoms are apparent.

HF can be classified by symptoms or based on measurement of the left ventricular ejection fraction (EF) as below:

Based on symptoms (Yancy 2016)

Stage I: no limitation of physical activity; ordinary physical activity does not cause symptoms of HF
Stage II: slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in symptoms of HF
Stage III: marked limitation of physical activity; comfortable at rest, but less than ordinary activity causes symptoms of HF
Stage IV: unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.

Based on left ventricular EF (Ponikowski 2016)

HF with preserved EF (≥ 50%; HFpEF)
HF with reduced EF (< 40%; HFrEF or systolic HF)
HF with mid‐range EF (40% to 49%; HFmrEF).

According to current guidelines (McKelvie 2012; Ponikowski 2016; Yancy 2016) most studies of pharmacological interventions for HF included people with HFrEF, partly because HFrEF is felt to be more severe and possibly because HFpEF is more difficult to diagnose. Because most people with HFrEF also have diastolic dysfunction, and subtle systolic abnormalities are present in people with HFpEF, the terminology based on left ventricle EF (HFrEF/HFpEF) is preferred over the terminology of preserved or reduced ‘systolic function’ (Ponikowski 2016).

Based on time course and clinical presentation (Ponikowski 2016)

Chronic HF identifies HF for some time; unchanged symptoms and signs for at least one month define ‘stable HF’
Acute HF could present as decompensation of chronic stable HF, occurrence of de novo HF (e.g. due to a myocardial infarction (MI)), or progression of HF in a subacute (gradual) fashion (e.g. due to progressive dilated cardiomyopathy)
Congestive HF is a term sometimes used to describe acute or chronic HF with significant evidence of volume overload.

CKD and HF are highly prevalent in the general population. In population‐based studies, the prevalence of HF ranges from 0.2% in those aged 18 to 44 years, to 24% in patients 85 years and older (Hemmelgarn 2012). The prevalence of CKD ranges from 1% to 33% in individuals 18 to 44 years and over age 60, respectively (Hemmelgarn 2012). The two conditions often co‐exist and 40% to 60% of patients with HF will have evidence of CKD (Shiba 2011). Furthermore, people with both HF and CKD have a greater risk of cardiovascular morbidity and death than people with HF alone (Santoro 2014). As compared to people with either condition alone, those with both HF and CKD have worse quality of life (QoL), a higher risk of morbidity and death, and often require complex multidisciplinary management (Shiba 2011). Criteria to classify cardio‐renal syndromes, according to the direction of the organ damage or whether the clinical manifestations are acute or chronic, have been defined by the Acute Dialysis Quality Initiative consensus group (Ronco 2010).

The prevalence of HF and concomitant CKD is increasing. Additionally, CKD may increase the risk of harms associated with HF medication (e.g. spironolactone (Quach 2016)). Therefore, a better understanding of appropriate pharmacological management of HF in this patient population is particularly important.

Description of the intervention

Several pharmacological interventions are used to treat HF. These include:

Direct agents
- Those that reduce peripheral resistance, heart rate or blood volume (anti‐hypertensive agents)
- Those that increase the strength of the heart contraction (positive inotropes)
Indirect agents
- Those that may improve the heart performance indirectly (lipid lowering agents, antiplatelet agents and nutritional supplements)

Guidelines for the general population (Ponikowski 2016; Yancy 2016) make a distinction between:

Interventions that are recommended for HFrEF: angiotensin‐converting enzyme inhibitors (ACEi), beta‐blockers and mineralocorticoid receptor antagonists
Interventions that may be beneficial in HFrEF: diuretics, angiotensin receptor neprilysin inhibitor (a single molecule that combines the moieties of valsartan and sacubitril), sinus node I_f channel inhibitors (ivabradine), angiotensin receptor blockers (ARB), hydralazine and isosorbide dinitrate
Interventions with uncertain benefits in HFrEF: digoxin and other digitalis glycosides, and n‐3 polyunsaturated fatty acids
Interventions with unproven benefits in HFrEF: statins, oral anticoagulants and antiplatelet therapy, renin inhibitors
Interventions potentially harmful in HFrEF: calcium‐channel blockers.

The same guidelines specify that no treatment has yet been shown, convincingly, to reduce morbidity or death in patients with HFpEF (Ponikowski 2016).

Interventions for acute HF are supported by a lower level of evidence, according to these guidelines (McKelvie 2012; Ponikowski 2016; Yancy 2016). These interventions include diuretics for congestive HF (loop diuretics, thiazides and mineral‐corticoid antagonists), vasodilators for hypertensive HF (nitroglycerin, isosorbide dinitrate, nitroprusside, nesiritide), inotropic agents for hypotensive HF (dopamine, dobutamine, levosimendan, milrinone, enoximone), vasopressors for hypotensive HF (norepinephrine, epinephrine), and digoxin, beta‐blockers or amiodarone for atrial fibrillation with high ventricular rate.

How the intervention might work

Pharmacological interventions improve the heart performance by reducing how quickly the heart beats, reducing its workload, or by increasing the strength of the cardiac muscle directly or indirectly. In the general population, there is strong evidence to support the use of renin‐angiotensin‐aldosterone system (RAAS) blockers, beta‐blockers and their combination, and moderate levels of evidence for diuretics and inotropes. In the CKD population, these agents are thought to work in the same way. However, most studies of interventions for HF excluded people with CKD because it was felt that these interventions may not have the same benefits in a CKD population, and they may be potentially harmful (Coca 2006; Konstantinidis 2016). For example, RAAS blockers may increase the risk of hyperkalaemia, excessive volume depletion with diuretics may worsen kidney function, and some inotropes may accumulate in CKD and adversely affect cardiac rhythm.

Why it is important to do this review

People with CKD and HF require coordinated care from CKD and HF specialists. Individuals with CKD are at high risk of cardiovascular morbidity and death. A narrative review including 1,076,104 patients found a significantly higher risk of death among HF patients with comorbid CKD, compared to those without baseline CKD (Damman 2014a). They may have the potential for significant benefit more from interventions for HF, but they may also be more vulnerable to the potential harms of these interventions. We do not know if benefits and harms of interventions for HF vary with the severity of CKD. For example, people with more advanced stages of CKD benefit less from interventions for ischaemic heart disease (e.g. statins (Palmer 2012)), and complications from HF dominate as the leading cause of hospitalisation. A systematic review of studies addressing questions about pharmacological interventions for HF in people with CKD is not available. Given the increasing prevalence of HF as eGFR declines, the complex and costly management of people affected by both conditions, and the uncertain benefits and harms of available therapies to treat HF in people who also have CKD, this information is important for patients, healthcare providers and policy makers.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised controlled trials (RCTs) and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) evaluating the benefits and harms attributable to any pharmacological interventions for HF in people with CKD.

Types of participants

We included studies in people with HF as defined by the authors. For example, people with HF or people with symptoms of HF in case the term HF or the NYHA classification were not explicitly stated. These included breathlessness, ankle swelling and fatigue that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress (Ponikowski 2016). Eligible studies included those in any population age, sex, race, educational status or disease type/severity, and could be conducted in any setting (e.g. community, hospital, nursing home, chronic care institution, or outpatient setting). We included individuals with CKD of any stage (from persistent albuminuria without diminished eGFR to ESKD treated with dialysis or kidney transplantation).

Inclusion criteria

CKD is defined based on the presence of urinary albumin excretion of ≥ 30 mg/mol, or equivalent (marker of kidney damage), or as eGFR < 60 mL/min/1.73 m² (marker of decreased kidney function) for three months or longer regardless of the primary cause of kidney injury. We considered studies that included people with any CKD stage (including stage V treated with dialysis or transplantation); however, we considered definitions used by study authors. HF is a common clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with (diastolic dysfunction) or eject blood (systolic dysfunction). Therefore, we considered studies of HF due to left ventricular dysfunction (left‐sided HF), with reduced ejection fraction (EF≤ 40%; systolic left‐sided HF (HFrEF)) or preserved ejection fraction (EF > 40%; diastolic left‐sided HF (HFpEF or HFmrEF)); or due to right ventricular dysfunction (right‐sided HF). We considered studies including people with stable HF or acute HF as described above, similarly, as defined by study authors. We only included studies of at least three months in duration, without publication year or language restriction.

Exclusion criteria

We excluded studies shorter than three months.

Types of interventions

Based on existing recommendations (McKelvie 2012; Ponikowski 2016; Yancy 2016), we considered the following pharmacological intervention for either acute or chronic HF.

Interventions for acute HF

Diuretics for congestive HF: loop diuretics, thiazides and mineral‐corticoid antagonists
Vasodilators for hypertensive HF: nitroglycerin, isosorbide dinitrate, nitroprusside, nesiritide
Inotropic agents for hypotensive HF: dopamine, dobutamine, levosimendan, milrinone, enoximone
Vasopressors for hypotensive HF: norepinephrine, epinephrine
Digoxin, beta‐blockers or amiodarone for atrial fibrillation with high ventricular rate.

Interventions for chronic HF

The combination of ACEi and beta‐blockers with and without mineral‐corticoid receptor antagonists
Diuretics, angiotensin receptor neprilysin inhibitor, sinus node I_f channel inhibitors, ARB, hydralazine and isosorbide dinitrate
Digoxin and other digitalis glycosides, n‐3 polyunsaturated fatty acids, coenzyme Q10, creatine analogues, L‐carnitine, thiamine, vitamin D supplementation
Statins, fibrates, ezetimibe, oral anticoagulants and antiplatelet therapy (cyclooxygenase inhibitors, ADP receptor blockers, PDE inhibitors, PAR‐1 antagonists, thromboxane inhibitors, adenosine re‐uptake inhibitors, others), renin inhibitors
Calcium‐channel blockers.

For all interventions, we considered any preparation, route of administration, dose, duration, frequency, and combinations.

Given the large number of research questions that this review could potentially address, we focused on the following interventions that are recommended in the non‐CKD population.

Use of ACEi or ARB, and beta‐blockers
Mineralocorticoid receptor antagonists
Use of diuretics in congestive HF.

The primary focus of this review was to assess whether there is evidence that these treatments for HF are effective and safe in people with concomitant CKD when compared to an active control, placebo or no intervention.

Types of outcome measures

Primary outcomes

Death (any cause)
Hospitalisation for decompensated HF

Secondary outcomes

Cardiovascular death
Hospitalisation (any cause)
Worsening HF (reported as a dichotomous outcome by authors)
Worsening kidney function, including acute kidney injury (reported as a dichotomous outcome by authors)
Hyperkalaemia
Hypotension
Other adverse events due to treatment, worsening of the disease course (syncope/pre‐syncope, shortness of breath, and peripheral oedema), and measures of quality of life (QoL) as reported by authors

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources.

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Hand‐searching of kidney‐related journals and the proceedings of major kidney and transplant conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

We searched the reference lists of review articles, relevant studies and clinical practice guidelines.

Data collection and analysis

Selection of studies

We used the search strategy to identify studies relevant to this review. Two authors screened the titles and abstracts independently and selected studies based on whether they met the patient, intervention, comparator, and design criteria. When necessary, two authors (ML, PR) independently assessed full texts to determine which studies satisfied the full inclusion criteria.

Data extraction and management

Four authors extracted data independently using standard forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of a study existed, reports were grouped together and the publication with the most complete data was used in the analyses.

Assessment of risk of bias in included studies

Four authors independently assessed the following items using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)
Was knowledge of the allocated interventions adequately prevented during the study (blinding)?
- Participants and personnel (performance bias)
- Outcome assessors (detection bias)
Were incomplete outcome data adequately addressed (attrition bias)?
Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
Was the study apparently free of other problems that could put it at a risk of bias (registration, funding, etc.)?

Measures of treatment effect

We used risk ratios (RR) with 95% confidence intervals (CI) to summarize dichotomous outcomes (e.g. death, hospitalisation, kidney failure). Where continuous scales of measurement were reported (e.g. QoL, symptom burden), we assessed the effects of treatment using the mean difference (MD) or the standardised mean difference (SMD) for different scales. We referred to the Cochrane Handbook for Systematic Reviews of Interventions to deal with specific issues (e.g. change scores or time‐to‐event data) (Higgins 2011). Summary intervention effect measures were estimated in comparisons with at least two studies.

Unit of analysis issues

We referred to the Cochrane Handbook for Systematic Reviews of Interventions to deal with non‐standard designs (e.g. as cross‐over studies or cluster‐randomised studies) (Higgins 2011).

Dealing with missing data

We requested any further information required from the original author by written correspondence (e.g. emailing corresponding authors) and included any relevant information obtained in this manner in the review. We also investigated attrition rates, for example drop‐outs, losses to follow‐up and withdrawals and critically appraised issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) (Higgins 2011).

Assessment of heterogeneity

In analyses with at least two studies, we assessed heterogeneity by visual inspection of the forest plot. We then quantified statistical heterogeneity using the I² statistic, which described the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). We followed this guide to interpret I² values.

0% to 40%: might not be important
30% to 60%: may represent moderate heterogeneity
50% to 90%: may represent substantial heterogeneity
75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depended on both its magnitude and the strength of evidence for heterogeneity (e.g. P‐value from the chi‐squared test or a confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

In analyses with at least 10 studies, we planned to use funnel plots to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

We summarized data using random‐effects models.

Subgroup analysis and investigation of heterogeneity

In analyses with at least three studies, we investigated potential sources of heterogeneity. We considered participant factors, including demographics (age, sex, race), comorbidity (diabetes, coronary heart disease), type of HF, and stage of CKD. Where possible, we considered agent subclasses (ACEi versus ARB) and dose and duration of therapy, as well as the following pre‐specified indicators for subgroup analyses (defining different types of cardiac disease or stages of CKD).

The type of HF (right‐ versus left‐sided HF)
The nature of the functional impairment of the left ventricle (HFrEF versus HFmrEF or HFpEF)
Congestive versus non‐congestive acute HF
Cardio‐renal (acute versus chronic) versus reno‐cardiac (acute versus chronic) HF
The severity of CKD (defined by levels of urine albumin:creatinine ratio and eGFR; CKD stages 1‐5).

Sensitivity analysis

Where possible, we planned to perform sensitivity analyses to explore the influence of the following factors on effect size.

Repeating the analysis excluding unpublished studies
Repeating the analysis taking into account of the risk of bias, as specified
Repeating the analysis excluding studies of short duration or small studies (using the median as a cut‐off)
Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.

'Summary of findings' tables

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the quality of a body of evidence as the extent to which one can be confident that an estimate of effect is close to the true quantity of specific interest. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). Assumed risk was calculated by dividing the number of participants in the control group that experienced an event by the total number of participants in the control group. Corresponding risk was calculated by multiplying the assumed risk with the risk ratio estimate from the meta‐analysis. The 95% CI for the corresponding risk was calculated by multiplying the assumed risk with the lower and upper CI of the risk ratio estimate from the meta‐analysis.

We included the following outcomes in the 'Summary of findings' tables.

Death (any cause)
Cardiovascular death
Hospitalisation (any cause)
Hospitalisation for decompensated HF
Worsening HF
Worsening kidney function
Hyperkalaemia
Hypotension
Quality of Life

Results

Description of studies

Results of the search

Our search of the Cochrane Kidney and Transplant specialised register identified 869 records. We identified an additional 78 records using other sources (reference lists of review articles, relevant studies, and clinical practice guidelines) ‐ therefore a total of 947 records (176 studies) were identified. We excluded 61 studies (252 records), either due to a population other than HF (38 studies), a non‐pharmacological intervention (5), follow‐up shorter than three months (16), or a study design other than a RCT (2) (see Characteristics of excluded studies).

Overall, 115 studies were eligible. Of these, three are ongoing and awaiting publication of primary data (PARAGON‐HF 2018; RELAX‐AHF‐2 2017; TMAC 2007) and will be included in a future update of this review. As a result, 112 studies were included in this review (Figure 1) and are categorised as follows.

CKD population studies:

Reported data on CKD patients only (15): AQUAMARINE 2014; ARIANA‐CHF‐RD 2016; Cice 1999a; Cice 2001; Cice 2010; FUSION II 2008; Palazzuoli 2014; Pita‐Fernandez 2015; Pre‐RELAX‐AHF 2009; PROTECT 2008; RELAX‐AHF 2012; RENO‐DEFEND 1 2011; ROSE AHF 2013; Taheri HD 2009; Taheri CAPD 2012.

General population studies, including people with CKD:

Reported data on general population, including both people with and without CKD, and provided stratified data for CKD patients (16): ALOFT 2008; A‐HeFT 2002; CIBIS II 1997; DIAMOND 1999; DIG 1996; EMPHASIS‐HF 2010; EVEREST 2005; HEAAL 2008; MERIT‐HF 1997; PROMISE 1989; RALES 1995; SAVE 1991; SENIORS 2002; SHIFT 2010; SOLVD (Treatment) 1992; Val‐HeFT 1999

General population studies, potentially including people with CKD:

Reported data on general population, including both people with and without CKD, but did not provide stratified data for CKD patients (81): ABC‐HFT 2011; ACTIV in CHF 2003; AIRE 1991; ALIVE 1998; ANZ 1995; ARTS‐HF 2015; ASCEND‐HF 2009; ASTRONAUT 2011; ATLAS 1999; ATMOSPHERE 2011; Barr 1995; Barr 1997; BEAUTIFUL 2006; Berry 2007; BEST 1995; BETACAR 1999; BLAST‐AHF 2015; CAPRICORN 2001; CARMEN 2001; CASINO 2004; CHARM‐Added 2003; CHARM‐Alternative 2003; CHARM‐Preserved 2003; CIBIS I 1994; CIBIS III 2006; COMET 2003; CONSENSUS 1987; COPERNICUS 2001; CORONA 2005; DAD‐HF II 2014; de Graeff 1989; ELITE 1995; ELITE II 2000; Erb 2014; EXACT‐HF 2013; Fuchs 1995; FUSION I 2004; Giles 1989; GISSI‐HF 2004; HORIZON‐HF 2008; I‐PRESERVE 2008; Jia 2015; Kum 2008; MDC 1993; MMHFT 1992; MOXCON 2003; NAPA 2007; OPTIMAAL 2002; Ozdemir 2007; Pacher 1996; Packer 1986; PARADIGM‐HF 2013; PEP‐CHF 1999; PRAISE‐II 2003; PRIME‐II 1997; PROFILE 2002; REACH UP 2010; Risler 1991; SADKO‐CHF 2005; Skvortsov 2007; SOLVD (Prevention) 1992; SPICE 2000; Statsenko 2007; SWORD 1995; Toblli 2007; TOPCAT 2014; TRACE 1994; ULTIMATE‐HFrEF 2013; US‐Carvedilol 1996; VALIANT 2000; van den Broek 1995; VERITAS 1 2005; VERITAS 2 2005; V‐HEFT I 1986; V‐HEFT II 1991; V‐HEFT III 1996; Vizzardi 2014; Xamoterol in SHF 1990; Yamada 2013; Yang 2015a; Zhao 2010.

Detailed information on the design, participants, intervention, comparator and outcomes of these included studies are summarised in Characteristics of included studies.

Included studies

In total, 31 studies reported data for CKD patients and the characteristics of these 31 studies are reported here. Full details for all studies are summarised in the Characteristics of included studies table.

Study size, country and year

A total of 23,762 adult CKD participants were randomised; six studies (3892) were in the setting of acute HF and 25 (19,870) were in the setting of chronic HF. The number of CKD participants per group was not provided in two studies (A‐HeFT 2002; DIG 1996). Sample sizes ranged from 16 to 3157 participants and the reported follow‐up ranged from 12 weeks to five years.

Ten of 31 studies (32%) were conducted in single‐country settings. Three (10%) in Canada or the USA only, and 16 (52%) were in at least three countries. Two studies (6%) did not report this information. Study initiation ranged from 1986 to 2015.

Participants’ mean age was reported in 24 (77%) of the 31 studies. The proportion of men ranged between 64.9% and 82.1% and the proportion of people with diabetes ranged between 14.5% and 62.5%. Demographic data for CKD participants (age, sex, diabetes status) were not reported in seven studies (A‐HeFT 2002; ALOFT 2008; DIAMOND 1999; EMPHASIS‐HF 2010; EVEREST 2005; HEAAL 2008; PROMISE 1989).

Studies in acute HF (6) included patients who had been admitted for acute decompensated HF (Palazzuoli 2014; Pre‐RELAX‐AHF 2009; PROTECT 2008; RELAX‐AHF 2012; RENO‐DEFEND 1 2011; ROSE AHF 2013). Studies in chronic HF (25) included patients with HFrEF (A‐HeFT 2002; ARIANA‐CHF‐RD 2016; CIBIS II 1997; Cice 2001; Cice 2010; DIAMOND 1999; DIG 1996; EMPHASIS‐HF 2010; EVEREST 2005; FUSION II 2008; HEAAL 2008; MERIT‐HF 1997; PROMISE 1989; RALES 1995; SAVE 1991; SENIORS 2002; SHIFT 2010; SOLVD (Treatment) 1992; Taheri CAPD 2012; Taheri HD 2009; Val‐HeFT 1999), HFpEF (Cice 1999a), or with no prespecified ejection fraction criteria for inclusion (ALOFT 2008; AQUAMARINE 2014; Pita‐Fernandez 2015).

Interventions

Studies in acute HF evaluated adenosine A1‐receptor antagonists (PROTECT 2008; RENO‐DEFEND 1 2011), diuretics (Palazzuoli 2014), dopamine and nesiritide (ROSE AHF 2013), and serelaxin (Pre‐RELAX‐AHF 2009; RELAX‐AHF 2012).

In chronic settings, studies evaluated ARB (Cice 2010; HEAAL 2008; Pita‐Fernandez 2015; Val‐HeFT 1999), beta‐blockers (CIBIS II 1997; Cice 2001; MERIT‐HF 1997; SENIORS 2002), ACEi (Cice 2010; SAVE 1991; SOLVD (Treatment) 1992), aldosterone antagonists (EMPHASIS‐HF 2010; RALES 1995; Taheri CAPD 2012; Taheri HD 2009), nesiritide (FUSION II 2008), calcium‐channel blockers (Cice 1999a), renin inhibitors (ALOFT 2008; ARIANA‐CHF‐RD 2016), vasopressin receptor antagonists (AQUAMARINE 2014; EVEREST 2005), anti‐arrhythmics (DIAMOND 1999), digitalis glycoside (DIG 1996), phosphodiesterase inhibitors (PROMISE 1989), sinus node inhibitors (SHIFT 2010), and vasodilators (A‐HeFT 2002).

Of the 31 studies, 28 studies (90%) including a total of 22,893 CKD patients, the intervention was compared with placebo or standard care. Of the remaining studies, two compared different doses of the same drug (HEAAL 2008; Pita‐Fernandez 2015) and one compared different IV infusion strategies (continuous versus bolus) of furosemide (Palazzuoli 2014).

Outcomes

Study outcomes included death, hospitalisation, worsening HF, progression of kidney disease, quality of life, and adverse events such as hyperkalaemia and hypotension. Of the 31 studies, nine reported data in a form that could not be extracted for meta‐analysis. We contacted the authors of these nine studies and two (22%) were able to provide data (AQUAMARINE 2014; SHIFT 2010). One study investigating calcium‐channel blockers (Cice 1999a) did not report any outcomes of interest and was also not included the in meta‐analysis. At this time, we do not have extractable data for any outcomes for four studies (A‐HeFT 2002; DIG 1996; EMPHASIS‐HF 2010; HEAAL 2008) and did not include these studies in our meta‐analyses. Of the 81 studies in the general population, 39 had valid author contact information and the authors were emailed to request data on the subset of patients with CKD. No authors have responded to this request, to date.

Combining all intervention types:

29 (94%) studies reported on death (any cause), of which 21 provided extractable data and were meta‐analysed
25 (81%) on hospitalisations for HF, of which eight provided extractable data and were meta‐analysed
18 (58%) on cardiovascular death, of which ten provided extractable data and were meta‐analysed
10 (32%) on all‐cause hospitalisation, of which three provided extractable data and were meta‐analysed
11 (35%) reported a dichotomous measure of worsening HF, of which seven were extractable and meta‐analysed
17 (55%) reported a dichotomous measure of progression of kidney disease, of which eight were extractable and meta‐analysed
10 (31%) reported a dichotomous measure of hyperkalaemia, of which seven were extractable and meta‐analysed
15 (48%) reported a dichotomous measure of hypotension, of which eight were extractable and meta‐analysed
3 (10%) reported a quality of life score, of which one was extractable and analysed

Other secondary outcomes (e.g. dyspnoea, oedema) in CKD populations were not extractable and excluded from analysis.

In summary, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta‐analyses (ALOFT 2008; AQUAMARINE 2014; ARIANA‐CHF‐RD 2016; CIBIS II 1997; Cice 2001; Cice 2010; DIAMOND 1999; EVEREST 2005; FUSION II 2008; MERIT‐HF 1997; Palazzuoli 2014; Pita‐Fernandez 2015; Pre‐RELAX‐AHF 2009; PROMISE 1989; PROTECT 2008; RALES 1995; RELAX‐AHF 2012; RENO‐DEFEND 1 2011; ROSE AHF 2013; SAVE 1991; SENIORS 2002; SHIFT 2010; SOLVD (Treatment) 1992; Taheri HD 2009; Taheri CAPD 2012; Val‐HeFT 1999). Studies were either exclusively in patients with HF and CKD (14) or in the general HF population, but included patients with CKD and stratified results based on kidney function at baseline (12).

Excluded studies

Reasons for exclusion are summarised in the Characteristics of excluded studies table. In 38 studies, the populations studied had conditions other than HF, five evaluated a non‐pharmacological intervention, and 16 measured short‐term outcomes (less than three months follow‐up)

Risk of bias in included studies

Risk of bias for all 112 included studies is summarised in Figure 2 and Figure 3. In general, the risk of bias was unclear in most studies for many domains. Fifty‐four studies (48%) were published after 2005, the year when trial registration became mandatory. Of these, 37 had evidence of registration within a trial registry and 33 reported information on authorship and/or involvement of the study sponsor in data collection, analysis, and interpretation.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

Risk of bias was deemed low for 46 studies, high for one study, and unclear for 65 studies.

Allocation concealment

Risk of bias was deemed low for 28 studies and unclear for the remaining 84 studies.

Blinding

Participants and personnel (performance bias)

Eighty‐six studies were judged to be at low risk of bias, 13 did not blind participants or study personnel, and 13 were judged unclear.

Blinding of outcome assessment (detection bias)

Fifty‐four studies were judged to be at low risk of bias, either because outcome assessors were blinded or because the outcome measured was unlikely to be influenced by a lack of blinding. Seven studies were judged to be at high risk of bias, and the remaining 51 were judged to be at unclear risk of bias.

Incomplete outcome data

Seventy‐four studies were at low risk of attrition bias as < 10% of patients were lost to follow‐up and analysis followed an intention‐to‐treat design. Thirty‐four studies were at high risk of attrition bias and 14 studies were judged to be at unclear risk of bias.

Selective reporting

Ninety‐nine studies were at low risk of bias, either because a protocol was published or because it was clear that the published report included all expected outcomes. Three studies were at high risk of bias and 10 were judged to be at unclear risk of bias.

Other potential sources of bias

Twenty‐nine studies appeared to be free of other sources of bias. Forty‐three studies were at high risk of bias, as the study sponsor was involved in the design, data acquisition and/or analysis, or preparation of the manuscript. The remaining 40 studies were deemed to be at unclear risk of bias.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4

Summary of findings for the main comparison. ACUTE: Serelaxin versus placebo in patients with heart failure and chronic kidney disease.

ACUTE: Serelaxin versus placebo in patients with heart failure and chronic kidney disease
Patient or population: heart failure with chronic kidney disease Settings: acute, inpatient Intervention: serelaxin Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Serelaxin
Death (any cause)	42 per 1000	25 per 1000 (14 to 43)	RR 0.59 (0.34 to 1.02)	1395 (2)	⊕⊕⊝⊝  low^2,3,4
Cardiovascular death	97 per 1000	46 per 1000 (20 to 105)	RR 0.47 (0.21 to 1.08)	1395 (2)	⊕⊕⊝⊝  low^2,3,4
Hospitalisation (any cause)	not reported	not reported	‐‐	‐‐	‐‐
Heart failure hospitalisation	not reported	not reported	‐‐	‐‐	‐‐
Worsening heart failure	162 per 1000	115 per 1000 (87 to 149)	RR 0.71 (0.54 to 0.92)	1395 (2)	⊕⊕⊝⊝  low^3,4
Worsening kidney function	86 per 1000	74 per 1000 (32 to 170)	RR 0.86 (0.37 to 1.98)	1395 (2)	⊕⊕⊝⊝  low^2,3,4
Hypotension	48 per 1000	60 per 1000 (39 to 94)	RR 1.26 (0.81 to 1.96)	1395 (2)	⊕⊕⊝⊝  low^2,3,4
Hyperkalaemia	48 per 1000	52 per 1000 (15 to 187)	RR 1.08 (0.30 to 3.87	234 (1)	⊕⊝⊝⊝  very low^2,3,4
Quality of life	not reported	not reported	‐‐	‐‐	‐‐
CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

CHRONIC: ACEi or ARB versus placebo in patients with heart failure and chronic kidney disease
Patient or population: heart failure with chronic kidney disease Settings: chronic, outpatient Intervention: ACEi or ARB Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Placebo	ACEi or ARB
Death (any cause) (follow‐up 2 to 3.5 years)	320 per 1000	272 per 1000  (224 to 326)	RR 0.85 (0.70 to 1.02)	5003 (4)	⊕⊕⊝⊝  low^2,3,4
Cardiovascular death (follow‐up 3 to 4 years)	411 per 1000	333 per 1000  (263 to 415)	RR 0.81 (0.64 to 1.01)	1368 (2)	⊕⊕⊝⊝  low^2,3,4
Hospitalisation (any cause)	not reported	not reported	‐‐	‐‐	‐‐
Heart failure hospitalisation (follow‐up 2 to 3.5 years)	546 per 1000	491 per 1000  (235 to 1037)	RR 0.90 (0.43 to 1.90)	1368 (2)	⊕⊝⊝⊝  very low²^,3,4
Worsening heart failure	not reported	not reported	‐‐	‐‐	‐‐
Worsening kidney function	not reported	not reported	‐‐	‐‐	‐‐
Hypotension (ARB; withdrawn from study)	42 per 1000	109 per 1000 (47 to 254	RR 2.60 (1.12 to 6.07)	332 (1)	⊕⊝⊝⊝  very low^3,4
Hyperkalaemia	not reported	not reported	‐‐	‐‐	‐‐
Quality of life	not reported	not reported	‐‐	‐‐	‐‐
The assumed risk* (e.g. the median control group risk across studies) was calculated by dividing the number of participants in the control group that experienced an event by the total number of participants in the control group. The corresponding risk was calculated by multiplying the assumed risk with the relative effect from the meta‐analysis. The 95% CI for the corresponding risk was calculated by multiplying the assumed risk with the lower and upper CI of the risk ratio estimate from the meta‐analysis. CI: Confidence interval; RR: Risk Ratio; ACEi: angiotensin‐converting enzyme inhibitor; ARB: angiotensin receptor blocker
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

CHRONIC: Beta‐blockers versus placebo in patients with heart failure and chronic kidney disease
Patient or population: heart failure with chronic kidney disease Settings: chronic, outpatient Intervention: beta‐blockers Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Beta‐blockers
Death (any cause) (follow‐up 1 to 2.5 years)	215 per 1000	148 per 1000  (129to 170)	RR 0.69 (0.60 to 0.79)	3136 (4)	⊕⊕⊝⊝  moderate^3,4
Cardiovascular death (follow‐up 1 to 2.5 years)	123 per 1000	65 per 1000  (43 to 100)	RR 0.53 (0.35 to 0.81)	2287 (3)	⊕⊕⊝⊝  low^3,4
Hospitalisation (any cause)	432 per 1000	324 per 1000  (225 to 467)	RR 0.75 (0.52 to 1.08)	1583 (2)	⊕⊕⊝⊝  low^2,3,4
Heart failure hospitalisation (follow‐up 1 to 2.5 years)	318 per 1000	213 per 1000  (137 to 334)	RR 0.67 (0.43 to 1.05)	2287 (3)	⊕⊕⊝⊝  low^2,3,4
Worsening heart failure	25 per 1000	34 per 1000	RR 1.36 (0.58 to 3.20)	704 (1)	⊕⊝⊝⊝  very low^2,3,4
Worsening kidney function	no events	no events	‐‐	704 (1)	⊕⊝⊝⊝  very low^3,4
Hypotension	no events	2/356**	RR 5.11 (0.25 to 106.15)	704 (1)	⊕⊝⊝⊝  very low^2,3,4
Hyperkalaemia	not reported	not reported	‐‐	‐‐	‐‐
Quality of life	not reported	not reported	‐‐	‐‐	‐‐
The assumed risk* (e.g. the median control group risk across studies) was calculated by dividing the number of participants in the control group that experienced an event by the total number of participants in the control group. The corresponding risk was calculated by multiplying the assumed risk with the relative effect from the meta‐analysis. The 95% CI for the corresponding risk was calculated by multiplying the assumed risk with the lower and upper CI of the risk ratio estimate from the meta‐analysis. Event rate derived from the raw data. A 'per thousand' rate is non‐informative in view of the scarcity of evidence and zero events in the control group CI: Confidence interval; RR:** Risk Ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

CHRONIC: Aldosterone antagonists versus placebo in patients with heart failure and chronic kidney disease
Patient or population: heart failure with chronic kidney disease Settings: chronic, outpatient Intervention: aldosterone antagonists Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Quality of the evidence  (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Anti‐aldosterone
Death (any cause) (follow‐up 6 to 21 months)	294 per 1000	179 per 1000  (17 to 1,938)	RR 0.61 (0.06 to 6.59)	34 (2)	⊕⊝⊝⊝  very low^1,2,3,4
Cardiovascular death	not reported	not reported	‐‐	‐‐	‐‐
Hospitalisation (any cause)	not reported	not reported	‐‐	‐‐	‐‐
Heart failure hospitalisation	not reported	not reported	‐‐	‐‐	‐‐
Worsening heart failure	not reported	not reported	‐‐	‐‐	‐‐
Worsening kidney function	not reported	not reported	‐‐	‐‐	‐‐
Hypotension	not reported	not reported	‐‐	‐‐	‐‐
Hyperkalaemia follow‐up 6‐24 months	84 per 1000	243 per 1000  (170 to 350)	RR 2.91 (2.03 to 4.17)	826 (3)	⊕⊕⊝⊝  Low^1,4
Quality of life	not reported	not reported	‐‐	‐‐	‐‐
The assumed risk* (e.g. the median control group risk across studies) was calculated by dividing the number of participants in the control group that experienced an event by the total number of participants in the control group. The corresponding risk was calculated by multiplying the assumed risk with the relative effect from the meta‐analysis. The 95% CI for the corresponding risk was calculated by multiplying the assumed risk with the lower and upper CI of the risk ratio estimate from the meta‐analysis. CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Comparison	Outcome	Relative effect (95% CI)	No. participants (studies)	Quality of the evidence  (GRADE)
Acute heart failure
Adenosine A1‐receptor antagonist versus placebo	Death (any cause)	RR 0.71 (0.39 to 1.26)	2078 (2)	⊕⊕⊝⊝ low^2,3,4
	Cardiovascular death	Not reported		‐‐
	Hospitalisation (any cause)	RR 0.85 (0.43 to 1.68)	45 (1)	⊕⊝⊝⊝  very low^2,3,4
	Heart failure hospitalisation	Not reported		‐‐
	Worsening heart failure	RR 0.93 (0.70 to 1.24)	2033 (1)	⊕⊝⊝⊝  very low^2,3,4
	Worsening kidney function	1.14 (0.89 to 1.48)	2033 (1)	⊕⊝⊝⊝  very low^2,3,4
	Hyperkalaemia	Not reported		‐‐
	Hypotension	Not reported		‐‐
	Quality of life	Not reported		‐‐

Diuretic bolus versus continuous infusion	Death (any cause)	Not reported		‐‐
	Cardiovascular death	RR 0.56 (0.15 to 2.01)	57 (1)	⊕⊝⊝⊝  very low^2,3,4
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	RR 0.83 (0.33 to 2.10)	57 (1)	⊕⊝⊝⊝  very low^2,3,4
	Worsening heart failure	Not reported		‐‐
	Worsening kidney function	Not reported		‐‐
	Hyperkalaemia	Not reported		‐‐
	Hypotension	Not reported		‐‐
	Quality of life	Not reported		‐‐

Dopamine versus placebo	Death (any cause)	RR 0.89 (0.41 to 1.95)	241 (1)	⊕⊝⊝⊝  very low^1,2,3,4
	Cardiovascular death	Not reported		‐‐
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	Not reported		‐‐
	Worsening heart failure	RR 2.15 (0.77 to 5.99)	241 (1)	⊕⊝⊝⊝  very low^1,2,3,4
	Worsening kidney function	Not reported		‐‐
	Hyperkalaemia	Not reported		‐‐
	Hypotension	RR 0.09 (0.01 to 0.65)	226 (1)	⊕⊝⊝⊝  very low^1,2,3,4
	Quality of life	Not reported		‐‐

Nesiritide versus placebo	Death (any cause)	RR 0.67 (0.28 to 1.57)	238 (1)	⊕⊝⊝⊝  very low^2,3,4
	Cardiovascular death	Not reported		‐‐
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	Not reported		‐‐
	Worsening heart failure	RR 0.83 (0.26 to 2.66)	238 (1)	⊕⊝⊝⊝  very low^2,3,4
	Worsening kidney function	Not reported		‐‐
	Hyperkalaemia	Not reported		‐‐
	Hypotension	RR 1.80 (0.94 to 3.47)	232 (1)	⊕⊝⊝⊝  very low^2,3,4
	Quality of life	Not reported		‐‐
Chronic heart failure
Anti‐arrhythmics versus placebo	Death (any cause)	RR 0.95 (0.83 to 1.09)	755 (1)	⊕⊝⊝⊝  very low^2,3,4
	Cardiovascular death	Not reported		‐‐
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	Not reported		‐‐
	Worsening heart failure	Not reported		‐‐
	Worsening kidney function	Not reported		‐‐
	Hyperkalaemia	Not reported		‐‐
	Hypotension	Not reported		‐‐
	Quality of life	Not reported		‐‐

Nesiritide versus placebo	Death (any cause)	RR 0.98 (0.64 to 1.50)	911 (1)	⊕⊝⊝⊝  very low^2,3,4
	Cardiovascular death	RR 0.88 (0.56 to 1.38)	911 (1)	⊕⊝⊝⊝  very low^2,3,4
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	Not reported		‐‐
	Worsening heart failure	Not reported		‐‐
	Worsening kidney function	Not reported		‐‐
	Hyperkalaemia	Not reported		‐‐
	Hypotension	RR 1.80 (1.38 to 2.35)	911 (1)	⊕⊝⊝⊝  very low^2,3,4
	Quality of Life	MD 1.20 (‐1.85 to 4.25)	911 (1)	⊕⊝⊝⊝  very low^2,3,4

Phosphodiesterase inhibitors versus placebo	Death (any cause)	RR 1.26 (0.98 to 1.61)	539 (1)	⊕⊝⊝⊝  very low^2,3,4
	Cardiovascular death	Not reported		‐‐
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	Not reported		‐‐
	Worsening heart failure	Not reported		‐‐
	Worsening kidney function	Not reported		‐‐
	Hyperkalaemia	Not reported		‐‐
	Hypotension	Not reported		‐‐
	Quality of life	Not reported		‐‐

Renin inhibitors versus placebo	Death (any cause)	Not reported		‐‐
	Cardiovascular death	Not reported		‐‐
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	Not reported		‐‐
	Worsening heart failure	RR 0.26 (0.08 to 0.88)	41 (1)	⊕⊝⊝⊝  very low^2,3,4
	Worsening kidney function	RR 1.52 (0.22 to 10.33)	142 (2)	⊕⊝⊝⊝  very low^2,3,4
	Hyperkalaemia	RR 0.86 (0.49 to 1.49)	142 (2)	⊕⊝⊝⊝  very low^2,3,4
	Hypotension	RR 1.44 (0.62 to 3.31)	142 (2)	⊕⊝⊝⊝  very low^2,3,4
	Quality of life	Not reported		‐‐

Sinus node inhibitors versus placebo	Death (any cause)	Not reported
	Cardiovascular death	RR 0.96 (0.48 to 1.93)	1576 (1)	⊕⊝⊝⊝  very low^2,3,4
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	RR 0.83 (0.48 to 1.45)	1576 (1)	⊕⊝⊝⊝  very low^2,3,4
	Worsening heart failure	Not reported		‐‐
	Worsening kidney function	RR 0.95 (0.71 to 1.27)	1576 (1)	⊕⊝⊝⊝  very low^2,3,4
	Hyperkalaemia	RR 0.53 (0.28 to 1.01)	1576 (1)	⊕⊝⊝⊝  very low^2,3,4
	Hypotension	Not reported		‐‐
	Quality of life	Not reported		‐‐

Vasopressin receptor antagonists versus placebo	Death (any cause)	RR 1.26 (0.55 to 2.89)	1840 (2)	⊕⊝⊝⊝  low^2,3,4
	Cardiovascular death	Not reported		‐‐
	Hospitalisation (any cause)	Not reported		‐‐
	Heart failure hospitalisation	RR 0.82 (0.37 to 1.81)	208 (1)	⊕⊝⊝⊝  very low^2,3,4
	Worsening heart failure	Not reported		‐‐
	Worsening kidney function	RR 0.87 (0.56 to 1.38)	217 (1)	⊕⊝⊝⊝  very low^2,3,4
	Hyperkalaemia	Not reported		‐‐
	Hypotension	Not reported		‐‐
	Quality of life	Not reported		‐‐
CI: Confidence interval; RR: Risk Ratio; MD: Mean difference
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: 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.  Very low quality: We are very uncertain about the estimate.

Database	Search terms
CENTRAL	MeSH descriptor: [Heart Failure] explode all trees MeSH descriptor: [Ventricular Dysfunction, Left] this term only MeSH descriptor: [Ventricular Dysfunction] explode all trees ventricular dysfunction:ti,ab,kw (Word variations have been searched) ventricular hypertrophy:ti,ab,kw (Word variations have been searched) heart failure or heart disease:ti,ab,kw (Word variations have been searched) or #1‐#6} MeSH descriptor: [Kidney Diseases] explode all trees MeSH descriptor: [Renal Replacement Therapy] explode all trees MeSH descriptor: [Renal Insufficiency] explode all trees MeSH descriptor: [Renal Insufficiency, Chronic] explode all trees dialysis:ti,ab,kw (Word variations have been searched) hemodialysis or haemodialysis:ti,ab,kw (Word variations have been searched) hemofiltration or haemofiltration:ti,ab,kw (Word variations have been searched) hemodiafiltration or haemodiafiltration:ti,ab,kw (Word variations have been searched) kidney disease* or renal disease* or kidney failure or renal failure:ti,ab,kw (Word variations have been searched) ESRF or ESKF or ESRD or ESKD:ti,ab,kw (Word variations have been searched) CKF or CKD or CRF or CRD:ti,ab,kw (Word variations have been searched) CAPD or CCPD or APD:ti,ab,kw (Word variations have been searched) predialysis or pre‐dialysis:ti,ab,kw (Word variations have been searched) {or #8‐#20} {and #7, #21} MeSH descriptor: [Antihypertensive Agents] explode all trees MeSH descriptor: [Angiotensin‐Converting Enzyme Inhibitors] 1 tree(s) exploded MeSH descriptor: [Angiotensin II Type 1 Receptor Blockers] 1 tree(s) exploded aliskiren:ti,ab,kw (Word variations have been searched) MeSH descriptor: [Adrenergic alpha‐Antagonists] 2 tree(s) exploded MeSH descriptor: [Calcium Channel Blockers] 2 tree(s) exploded MeSH descriptor: [Vasodilator Agents] explode all trees MeSH descriptor: [Endothelin Receptor Antagonists] 1 tree(s) exploded MeSH descriptor: [Diuretics] 1 tree(s) exploded MeSH descriptor: [Hypolipidemic Agents] explode all trees ezetimibe:ti,ab,kw (Word variations have been searched) MeSH descriptor: [Fibric Acids] 3 tree(s) exploded MeSH descriptor: [Cardiotonic Agents] 2 tree(s) exploded MeSH descriptor: [Phosphodiesterase Inhibitors] explode all trees MeSH descriptor: [Cardiovascular Agents] 1 tree(s) exploded MeSH descriptor: [Cyclooxygenase Inhibitors] explode all trees MeSH descriptor: [Purinergic P2Y Receptor Antagonists] explode all trees MeSH descriptor: [Receptors, Thrombin] 5 tree(s) exploded MeSH descriptor: [Thromboxanes] 3 tree(s) exploded MeSH descriptor: [Dipyridamole] this term only MeSH descriptor: [Dietary Supplements] 1 tree(s) exploded MeSH descriptor: [Fatty Acids, Omega‐3] 3 tree(s) exploded MeSH descriptor: [Ubiquinone] this term only Ubiquinone:ti,ab,kw (Word variations have been searched) carnitine:ti,ab,kw (Word variations have been searched) "coenzyme q10":ti,ab,kw (Word variations have been searched) MeSH descriptor: [Thiamine] 4 tree(s) exploded MeSH descriptor: [Vitamin D] 4 tree(s) exploded MeSH descriptor: [Guanidines] 1 tree(s) exploded creatine or "creatine analog":ti,ab,kw (Word variations have been searched) antihypertensive agent:ti,ab,kw (Word variations have been searched) statin:ti,ab,kw (Word variations have been searched) neprilysin inhibitor:ti,ab,kw (Word variations have been searched) {or #23‐#55} {and #22, #56}
MEDLINE	exp Heart Failure/ exp Ventricular Dysfunction, Left/ Ventricular Dysfunction, Right/ exp ventricular outflow obstruction/ ventricular dysfunction.tw. ventricular hypertrophy.tw. heart failure.tw. or/1‐7 Kidney Diseases/ exp Renal Replacement Therapy/ Renal Insufficiency/ exp Renal Insufficiency, Chronic/ dialysis.tw. (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. (kidney disease* or renal disease* or kidney failure or renal failure).tw. (ESRF or ESKF or ESRD or ESKD).tw. (CKF or CKD or CRF or CRD).tw. (CAPD or CCPD or APD).tw. (predialysis or pre‐dialysis).tw. or/9‐21 exp Angiotensin‐Converting Enzyme Inhibitors/ exp Angiotensin II Type 1 Receptor Blockers/ exp Antihypertensive Agents/ aliskiren.tw. exp Adrenergic alpha‐Antagonists/ exp Calcium Channel Blockers/ exp Vasodilator Agents/ exp Endothelin Receptor Antagonists/ exp Diuretics/ or/23‐31 exp Hypolipidemic Agents/ exp Ezetimibe/ exp Fibric Acids/ or/33‐35 exp Cardiotonic Agents/ exp Phosphodiesterase Inhibitors/ exp Cardiovascular Agents/ or/37‐39 exp Platelet Aggregation Inhibitors/ exp Cyclooxygenase Inhibitors/ exp Purinergic P2Y Receptor Antagonists/ exp Receptors, Thrombin/ exp Thromboxanes/ exp Dipyridamole/ or/41‐46 exp Dietary Supplements/ exp Fatty Acids, Omega‐3/ Ubiquinone/ "coenzyme q10".tw. exp Carnitine/ l‐carnitine.tw. exp Thiamine/ exp Vitamin D/ exp Guanidines/ (creatine or creatine analog$).tw. or/48‐57 neprilysin inhibitor$.tw sacubitril valsartan.tw LCZ696.tw or/59‐61 or/32,36,40,47,58,62 and/8,22,63
EMBASE	exp heart failure/ heart ventricle function/ exp heart left ventricle failure/ heart right ventricle failure/ ventricular dysfunction.tw. ventricular hypertrophy.tw. heart failure.tw. or/1‐7 exp renal replacement therapy/ kidney disease/ chronic kidney disease/ kidney failure/ chronic kidney failure/ mild renal impairment/ stage 1 kidney disease/ moderate renal impairment/ severe renal impairment/ end stage renal disease/ renal replacement therapy‐dependent renal disease/ kidney transplantation/ (hemodialysis or haemodialysis).tw. (hemofiltration or haemofiltration).tw. (hemodiafiltration or haemodiafiltration).tw. dialysis.tw. (CAPD or CCPD or APD).tw. (kidney disease* or renal disease* or kidney failure or renal failure).tw. (CKF or CKD or CRF or CRD).tw. (ESRF or ESKF or ESRD or ESKD).tw. (predialysis or pre‐dialysis).tw. ((kidney or renal) adj (transplant* or graft* or allograft*)).tw. or/9‐30 exp antihypertensive agent/ exp adrenergic receptor blocking agent/ exp angiotensin receptor antagonist/ exp dipeptidyl carboxypeptidase inhibitor/ exp calcium channel blocking agent/ exp diuretic agent/ exp vasodilator agent/ exp endothelin receptor antagonist/ or/32‐39 inotropic agent/ digoxin/ exp phosphodiesterase inhibitor/ or/41‐43 exp antilipemic agent/ exp hypocholesterolemic agent/ exp fibric acid derivative/ or/45‐47 exp antithrombocytic agent/ exp prostaglandin synthase inhibitor/ exp anticoagulant agent/ exp thromboxane receptor affecting agent/ or/49‐52 diet supplementation/ omega 3 fatty acid/ ubidecarenone/ creatine kinase/ creatine analog$.tw. carnitine/ exp vitamin b group/ exp vitamin D/ or/54‐61 exp enkephalinase inhibitor/ neprilysin inhibitor$.tw. or/63‐64 or/40,44,48,53,62,65 and/8,31,66

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Cardiovascular death	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Hospitalisation for heart failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (any cause)	2	1395	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.34, 1.02]
2 Cardiovascular death	2	1395	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.21, 1.08]
3 Worsening heart failure	2	1395	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.54, 0.92]
4 Worsening kidney function	2	1395	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.37, 1.98]
5 Hyperkalaemia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6 Hypotension	2	1395	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.81, 1.96]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (any cause)	2	2078	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.39, 1.26]
2 Hospitalisation (any cause)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Worsening heart failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Worsening kidney function	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (any cause)	4	5003	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.70, 1.02]
1.1 ACEi versus placebo	2	1755	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.70, 1.03]
1.2 ARB versus placebo	2	3248	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.52, 1.32]
2 Cardiovascular death	2	1368	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.64, 1.01]
2.1 ACEi versus placebo	1	1036	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.75, 1.03]
2.2 ARB versus placebo	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.52, 0.92]
3 Hospitalisation for heart failure	2	1368	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.43, 1.90]
3.1 ACEi versus placebo	1	1036	Risk Ratio (M‐H, Random, 95% CI)	1.30 [1.18, 1.43]
3.2 ARB versus placebo	1	332	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.48, 0.79]
4 Hypotension	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1 ARB versus placebo	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (any cause)	4	3136	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.60, 0.79]
2 Cardiovascular death	3	2287	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.35, 0.81]
3 Hospitalisation (any cause)	2	1583	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.52, 1.08]
4 Hospitalisation for heart failure	3	2287	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.05]
5 Worsening heart failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6 Worsening kidney function	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7 Hypotension	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (any cause)	2	34	Risk Ratio (M‐H, Random, 95% CI)	0.61 [0.06, 6.59]
2 Hyperkalaemia	3	826	Risk Ratio (M‐H, Random, 95% CI)	2.91 [2.03, 4.17]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Worsening heart failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Worsening kidney function	2	142	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.22, 10.33]
3 Hyperkalaemia	2	142	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.49, 1.49]
4 Hypotension	2	142	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.62, 3.31]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Death (any cause)	2	1840	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.55, 2.89]
2 Hospitalisation for heart failure	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Worsening kidney function	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Methods	Study design: double‐blind, placebo‐controlled RCT Study duration: June 2001 to July 2004 Duration of follow‐up: 18 months
Participants	Country: USA Setting: multicentre (161 sites); outpatient Inclusion criteria: HF (NYHA class III or IV, LVEF ≤ 35%); on HF therapy (ACEi, ARB, beta‐blockers, digoxin, spironolactone, and diuretics for at least 3 months); and African American Total number of study participants (CKD cohort): 181 (17.2% of total cohort); numbers per group not reported Mean age ± SD (years) (CKD cohort): not reported Sex (M/F) (CKD cohort): not reported CKD stage (CKD cohort): chronic renal insufficiency (not defined) DM (CKD cohort): not reported Exclusion criteria: females who were pregnant, nursing, or of childbearing age who were not practicing effective contraception; acute MI, acute coronary syndrome, or stroke within the previous 3 months; cardiac surgery or PCI within 3 months or the likelihood of a requirement for such procedures during the study; significant valvular heart disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension; cardiac arrest or life‐threatening arrhythmias within the previous 3 months (unless they had been treated with an implantable defibrillator); treatment with parenteral inotropes within 1 month before randomisation; likely need to undergo cardiac transplantation during the study period; symptomatic hypotension; presence of an illness other than HF that was likely to result in death within the study period; inability to comprehend or complete the QoL assessment instrument; contraindications to nitrate or hydralazine therapy
Interventions	Treatment group Fixed‐dose combination of 37.5 mg of hydralazine HCl and 20 mg of isosorbide dinitrate 3 times/day (dose adjustment as per protocol) Control group Placebo
Outcomes	Composite score that weighted all‐cause death (18 months), first hospitalisation for HF (18 months) and change in QoL (6 months) Individual components of the primary composite score Cause‐specific death Total number of HF hospitalisations Total number of all hospitalisations Total days in‐hospital Overall QoL throughout the study Number of unscheduled emergency room and office/clinical visits Changes in LV ejection fraction, LV internal diastolic diameter LV wall thickness at 6 months Change in BNP level at 6 months Newly recognized need for cardiac transplantation
Notes	Secondary analysis Funding: sponsor was NitroMed, Inc (Lexington, Mass) Authors did not report screening information.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stratified randomisation
Allocation concealment (selection bias)	Low risk	Randomisation method described that would not allow investigator to know intervention group before eligible participant entered the study
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% patients lost to follow‐up; all patients randomised were included in the final analysis
Selective reporting (reporting bias)	Low risk	Rationale, design, and methodology paper published
Other bias	High risk	Sponsor involved in preparation of manuscript

Methods	Study design: RCT Study duration: July 2006 to July 2008 Duration of follow‐up: 24 months
Participants	Country: USA Setting: single centre Inclusion criteria: ADHF and admission BNP levels > 500 pg/mL Number: treatment group (44); control group (45) Mean age ± SD (years): treatment group (66.8 ± 17.2); control group (68.6 ± 14.1) Sex (M/F): treatment group (23/21); control group (25/20) CKD stage: SCr > 2.5 mg/dL at admission was an exclusion criterion DM: treatment group (30%); control group (36%) Exclusion criteria: women who were pregnant or lactating at the time of enrolment; < 18 years; symptomatic hypotension (SBP < 90 mm Hg) or cardiogenic shock; asymptomatic patients; BNP < 500 pg/mL; known allergy to E. coli‐derived products, or any history of anaphylactic reactions to nesiritide or nitroglycerin; history of dialysis, SCr > 2.5 mg/dL at admission; current participant in a clinical study
Interventions	Treatment group Nitroglycerin: 10 to 200 µg/min, IV for 48 hours Standard treatment Control group Nesiritide: 2 µg/kg optional bolus followed by 0.01 µg/kg/min infusion, IV for 48 hours Standard treatment.
Outcomes	Changes in renal and neurohormonal markers Relationship between vasodilator infusion duration and nephrotoxicity (change in SCr, BUN, and CrCl at 24 and 48 hours of infusion) Median length of stay, need for dialysis, and symptomatic hypotension Acute changes observed during vasodilator therapy were correlated with death and rehospitalisation at 3 and 6 months
Notes	Funding: Scios Speakers Bureau Authors report the number of patients screened, but no further details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10 % of lost to follow‐up; all patients randomised were included in the final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	Study design: placebo‐controlled, double‐blind RCT Study duration: not reported Duration of follow‐up: 12 months
Participants	Countries: 26 Setting: multicentre (483 sites) Inclusion criteria: documented MI within the previous 5 to 21 days, and had an LVEF of 15% to 35%, determined at least 1 day after the MI; NYHA I‐III Number: treatment group (1691), control group (1690) Mean age ± SD (years): treatment group (60 ± 10); control group (61 ± 11) Sex (M/F): treatment group (1318/373), control group (1318/372) CKD stage: not reported DM: treatment group (26%); control group (25%) Exclusion criteria: history of torsade de pointes; unstable angina pectoris or a high‐degree heart block; QTc interval of 450 ms; resting heart rate 50 BPM; NYHA class IV congestive HF; implantable cardioverter‐defibrillator; serum potassium of 4 mEq/L; amiodarone use within 1 month before enrolment, current use of class I or III anti‐arrhythmic drugs
Interventions	Treatment group Azimilide: 100 mg Control group Placebo
Outcomes	Death (any cause)
Notes	Funding: Health Care Research Center, Procter & Gamble Pharmaceuticals Inc, Cincinnati, Ohio Authors did not report screening information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	> 10 % of lost to follow up with differences between groups; all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: double‐blind, parallel‐group, placebo‐controlled RCT Study duration: May 2005 to February 2007 Duration of follow‐up: 12 weeks
Participants	Countries: 9 Setting: multicentre (75 sites); outpatient Inclusion criteria: HF (NYHA class II ‐ IV); essential hypertension; on ACEi or ARB, and beta‐blocker; BNP > 100 pg/mL Total number of study participants (CKD cohort): 99 (32.8% of total cohort; treatment group (50); control group (49) Mean age ± SD (years) (CKD cohort): not reported Sex (M/F) (CKD cohort): not reported CKD stage (CKD cohort): eGFR < 60 (but SCr > 2.0 mg/dL or on dialysis excluded) DM (CKD cohort): not reported Exclusion criteria: treatment with both an ACEi and an ARB; HF related to obstructive valve disease or hypertrophic, restrictive, or infective cardiomyopathy; pregnancy; lung disease; SBP > 90 mm Hg; serum potassium > 5.1 mmol/L; SCr > 2.0 mg/dL (or on dialysis); MI; cerebrovascular accident, transient ischaemic attack, or coronary revascularization within 6 months; cardiac resynchronization device or implantable cardioverter defibrillator; malignancy or other disease likely to greatly limit life expectancy, adherence to protocol, or absorption to study drug
Interventions	Treatment group Aliskiren: 150 mg once/day for 12 weeks Control group Placebo
Outcomes	Incidence of kidney dysfunction Symptomatic hypotension Hyperkalaemia Cardiac function (pro‐BNP, NYHA class, aldosterone, echocardiographic measures, BP, heart rate, neurohumoral and inflammatory biomarkers, LVEF, dyspnoea) Death (any cause) QoL
Notes	Funding: This study was funded by Novartis, which also funded the core echocardiography laboratory at the Brigham and Women’s Hospital Authors report the number of patients screened, but no further details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Treatment was randomised using a validated, automated system
Allocation concealment (selection bias)	Low risk	Randomisation method described that would not allow investigator to know intervention group before eligible participant entered the study
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	< 10% patients lost to follow up. Only reported outcomes on those that completed study
Selective reporting (reporting bias)	Low risk	Protocol available, all prespecified outcomes presented
Other bias	High risk	Sponsor involved in data analysis and manuscript preparation

Methods	Study design: open‐label, parallel‐group RCT Study duration: December 2011 to January 2015 (enrolment) Duration of follow‐up: 90 days
Participants	Country: Japan Setting: multicentre (14 sites); outpatient Inclusion criteria: admitted to hospital with acute HF and CKD (eGFR 15 to 60 mL/min/1.73 m²) Number: treatment group (108); control group (109) Mean age ± SD (years): treatment group (72.99 ± 8.90); control group (72.95 ± 10.24) Sex (M/F): 141/76 CKD stage: eGFR 15 to 60 mL/min/1.73 m²(not on dialysis) DM: 44.2% Exclusion criteria: requiring mechanical circulatory support; consciousness disturbance; hypernatraemia (serum Na at admission > 147 mEq/L); volume depletion; cardiac shock; allergy or contraindication for tolvaptan; acute coronary syndrome; Chronic HD
Interventions	Treatment group Tolvaptan: 15 mg once/day for 2 days Conventional therapy (continued as per physician decision) Control group Conventional therapy
Outcomes	Urine Output (48 hours) Worsening of kidney function (%) Dose of diuretics use within 48 hours Net fluid loss (48 h) Change in BNP from baseline to 48 h Change in body weight from baseline to 48 h Length of hospital stay Changes in dyspnoea and oedematous symptoms* Adverse events In‐hospital death Death (any cause) Readmission for HF
Notes	Funding: The AQUAMARINE study was funded by the Japan Heart Foundation of Multicentre Grant Authors did not report screening information *Unable to estimate relative rate of improvement of dyspnoea, oedema, or rales as number at risk not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were randomised using a web‐based randomisation system
Allocation concealment (selection bias)	Unclear risk	Randomisation stated but no information on method used is available
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% patients lost to follow‐up; not all patients randomised were included in final analysis for death (any cause) or heart‐failure hospitalisation, but this was a secondary outcome of the study
Selective reporting (reporting bias)	Low risk	Design and rationale paper published
Other bias	Unclear risk	The study appears to be free of other sources of bias

Methods	Study design: double‐blind, phase 2b RCT Study duration: June 2013 to August 2014 Duration of follow‐up: 3 months
Participants	Countries: 25 (Europe, North America, Asia, other countries) Setting: multicentre (173 sites) Inclusion criteria: worsening CHF requiring hospitalisation and treatment with IV diuretics; T2DM and/or CKD (i.e. an eGFR of > 30 mL/min/1.73 m² in patients with T2DM and 30 to 60 mL/min/1.73 m² in patients without T2DM); have been receiving treatment with evidence‐based therapy for HF for at least the previous 3 months; have a medical history of a left ventricular ejection fraction of ≤ 40% within the previous 12 months. Number: treatment group 1 (173); treatment group 2 (165); treatment group 3 (169); treatment group 4 (170); treatment group 5 (165); control group (224) Mean age ± SD (years): treatment group 1 (72.5 ± 9.7); treatment group 2 (71.8 ± 10.6); treatment group 3 (69.3 ± 9.8); treatment group 4 (71.3 ± 10.23); treatment group 5 (69.2 ± 10.2); control group (72.4 ± 9.9) Sex (M/F): treatment group 1 (135/37); treatment group 2 (126/37); treatment group 3 (124/43); treatment group 4 (128/41); treatment group 5 (132/31); control group (170/51) CKD stage (eGFR): treatment group 1 (52 ± 16); treatment group 2 (52 ± 16); treatment group 3 (55 ± 20); treatment group 4 (53 ± 17); treatment group 5 (55 ± 19); control group (52 ± 18) DM: not reported Exclusion criteria: acute de novo HF or acute inflammatory heart disease; acute coronary syndromes in the last 30 days before the screening visit; cardiogenic shock or valvular heart disease requiring surgical intervention; left ventricular assist device or awaiting heart transplantation; stroke or transient ischaemic attack within 3 months before screening
Interventions	Treatment group 1 Finerenone: 2.5 to 5 mg Treatment group 2 Finerenone: 5 to 10 mg Treatment group 3 Finerenone: 7.5 to 15 mg Treatment group 4 Finerenone: 10 to 20 mg Treatment group 5 Finerenone: 15 to 20 mg Control group Eplerone: 25 to 50 mg, once/day
Outcomes	Efficacy (percentage of responders; i.e. the number of patients with a decrease in plasma N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) level of > 30% from baseline to day 90) and safety of different oral doses of finerenone given once/day A composite endpoint of death from any cause, CV hospitalisation, or emergency presentation for worsening CHF until day 90 Change in efficacy biomarker (B‐type natriuretic peptide, NT‐proBNP, galectin 3, and N‐terminal procollagen III propeptide) Change in scores on HRQoL questionnaires (the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the five‐dimension European Quality of Life Questionnaire (EuroQoL)) Effects on the following safety parameters were assessed: (i) biomarker of organ injury (troponin T and cystatin C); (ii) vital signs; (iii) laboratory parameters (including potassium and SCr concentrations, and eGFR; (iv) incidence of adverse events including those of special interest (i.e. an increase in serum potassium concentration to at least 5.6 mmol/L leading to discontinuation or emergency presentation for worsening CHF after starting treatment with the study drug)
Notes	Funding: Bayer Pharma AG Authors report the number of patients screened and some other information pertaining to eligibility, but details on screen failures were not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was carried out centrally by an interactive voice/web response system
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Clinical endpoints have been adjudicated by the event committee
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10 % of lost to follow‐up; not all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	High risk	Sponsor involved in writing the manuscript

PERMALINK

Pharmacological interventions for heart failure in people with chronic kidney disease

Meaghan Lunney

Marinella Ruospo

Patrizia Natale

Robert R Quinn

Paul E Ronksley

Ioannis Konstantinidis

Suetonia C Palmer

Marcello Tonelli

Giovanni FM Strippoli

Pietro Ravani

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Based on symptoms (Yancy 2016)

Based on left ventricular EF (Ponikowski 2016)

Based on time course and clinical presentation (Ponikowski 2016)

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

Study size, country and year

Interventions

Outcomes

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Random sequence generation

Allocation concealment

Blinding

Participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. ACUTE: Serelaxin versus placebo in patients with heart failure and chronic kidney disease.

Methods	Study design: prospective, multicentre, double‐blind, placebo‐controlled RCT Study duration: May 2009 to December 2011 Duration of follow‐up: 11.3 months (median)
Participants	Countries: North and South America, Europe, Asia Setting: multicentre (316 sites) Inclusion criteria: history of CHF defined as requiring standard therapy for 30 days or longer prior to the index hospitalisation, LVEF ≤ 40%, elevated levels of natriuretic peptides (BNP > 400 pg/mL or NT‐proBNP > 600 pg/mL), signs and symptoms of fluid overload that required hospitalisation Number: treatment group (821); control group (818) Mean age ± SD (years): treatment group (64.7 ± 12.4); control group (64.5 ± 11.9) Sex (M/F): treatment group (637/171); control group (610/197) CKD stage (eGFR): treatment group (67.3 ± 20); control group (66.1 ± 19.9) DM: treatment group (39.5%); control group (42.5%) Exclusion criteria: MI, cardiac surgery, or stroke within 3 months prior to enrolment; presence of ventricular assist devices or any type of mechanical support; history of a cardiac transplant or listed for transplant at time of enrolment; haemodynamically significant uncorrected primary cardiac valvular disease; right HF due to pulmonary disease; eGFR < 40 mL/min/ 1.73 m²; serum sodium < 130 mEq/L; serum potassium > 5.0 mEq/L; comorbid conditions with an expected survival of < 3 years
Interventions	Treatment group Aliskiren: 150 or 300 mg/day Control group Placebo
Outcomes	The first occurrence of CV death or rehospitalisation for HF at 6 months (i.e. 190 days) after randomisation. The first occurrence of CV death or rehospitalisation for HF within 12 months of randomisation. The first CV event (defined as CV death, HF hospitalisation, nonfatal MI, nonfatal stroke, and resuscitated sudden death) within 12 months; death (any cause) within 6 and 12 months; changes from baseline in NT‐proBNP level (at months 1, 6, and 12); and QoL (activities of daily living, assessed by the Kansas City Cardiomyopathy Questionnaire at months 1, 6, and 12)
Notes	Funding: Novartis Pharma Authors report the number of patients screened and reasons for screen failure
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	All potential study end points were adjudicated by a blinded clinical event committee (Brigham and Women’s Hospital, Harvard Medical School)
Incomplete outcome data (attrition bias)   All outcomes	High risk	< 10 % of lost to follow‐up; not all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	High risk	Sponsor involved in the design, conduct, and management of the study

Methods	Study design: RCT Study duration: October 1992 to September 1997 Duration of follow‐up: ranged from 39 to 58 months (median 45.7)
Participants	Countries: 19 Setting: multicentre (287 sites) Inclusion criteria: NYHA class II, III, or IV symptoms of HF associated with a LVEF ≤ 30% despite treatment with diuretics for ≥ 2 months; patients with class II symptoms were required to have received treatment for HF in an emergency room or hospital within 6 months Number: treatment group (1596); control group (1568) Mean age ± SD (years): treatment group (63.6 ± 10.3); control group (63.6 ± 10.5) Sex (M/F): treatment group (1265/331); control group (1251/317) CKD stage: not reported but SCr > 2.5 mg/dL was an exclusion criterion DM: not reported Exclusion criteria: acute coronary Ischaemic event or revascularization procedure within 2 months; history of sustained or symptomatic ventricular tachycardia; known to be intolerant of ACEi; SCr > 2.5 mg/dL; any noncardiac disorder that could limit survival
Interventions	Treatment group Lisinopril: 20 mg/day (low dose lisinopril) Control group Lisinopril: 40 mg/day (high dose lisinopril)
Outcomes	Death (any cause) CV death, CV hospitalisations, death (any cause combined with CV hospitalisations, and CV death combined with CV hospitalisations)
Notes	Funding: Zeneca Pharmaceuticals Authors did not report screening information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	All end points were adjudicated according to prespecified criteria by an End Points Committee blinded to the treatment assignment
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Insufficient information regarding lost‐to‐follow‐up to permit judgement; all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All pre‐specified outcomes presented
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: double‐blind, double‐dummy treatment RCT Study duration: March 2009 to December 2013 Duration of follow‐up: 36.6 months (median)
Participants	Countries: 43 (North America, Latin America, Western Europe, Central Europe, Asia and Pacific region) Setting: multicentre (789 sites) Inclusion criteria: CHF with NYHA class II to IV symptoms and an LVEF ≤ 35%; BNP ≥ 150 pg/mL (or NT‐proBNP ≥ 600 pg/mL) or, if they had been hospitalised for HF within the previous 12 months, a BNP ≥ 100 pg/mL (or NT‐proBNP ≥ 400 pg/mL); must have been receiving stable doses of an ACEi (equivalent to at least 10 mg of enalapril/day) and of a beta‐blocker at the time of enrolment Number: treatment group 1 (2340); treatment group 2 (2336); control group (2340) Mean age ± SD (years): treatment group 1 (63.3 ± 12.06); treatment group 2 (63.3 ± 11.71); control group (63.2 ± 11.65) Sex (M/F): treatment group 1 (1808/532); treatment group 2 (1837/499); control group (1846/494) CKD stage (eGFR): treatment group 1 (74 ± 23); treatment group 2 (74 ± 22); control group (74 ± 27) DM: treatment group 1 (26.8%); treatment group 2 (27.9%); control group (28.4%) Exclusion criteria: symptomatic hypotension; SBP < 95 mm Hg at screening (or < 90 mm Hg at randomisation); eGFR < 40 mL/min/1.73 m² (or < 35 mL/min/1.73 m² at randomisation or a decline of > 25% in the eGFR between screening and randomisation); serum potassium ≥ 5.0 mmol/L at screening (or ≥ 5.2 mmol/L at randomisation); history of inability to take ACEi
Interventions	Treatment group 1 Aliskiren: 300 mg once/day Treatment group 2 Enalapril: 5 or 10 mg twice/day Control group Combination therapy
Outcomes	Composite of death from CV causes or a first hospitalisation for HF Change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score and the change in the NT‐proBNP concentration from baseline to 4 months (this outcome was removed after the protocol was amended)
Notes	Funding: Novartis Authors did not report screening information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Voice‐based computerized randomisation system
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	A clinical‐event committee adjudicated deaths and major CV outcomes in a blinded fashion, using prespecified criteria
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% of lost to follow‐up; all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	High risk	Sponsor involved in the analysis

Methods	Study design: prospective double‐blind RCT Study duration: not reported Duration of follow‐up: 2 months
Participants	Country: UK Setting: single centre Inclusion criteria: NYHA II to Ill congestive HF Number: treatment group (28); control group (14) Mean age ± SD (years): treatment group (68 ± 3); control group (70 ± 2) Sex (M/F): treatment group (22/6); control group (10/4) CKD stage (eGFR): treatment group (74 ± 11); control group (75 ± 15) DM: not reported Exclusion criteria: not reported
Interventions	Treatment group Spironolactone: 50 to100 mg/day Control group Placebo
Outcomes	Death in CHF
Notes	Funding: not reported Authors did not report screening information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blind assessment of all end points
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% of lost to follow‐up; all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: prospective triple‐blind RCT Study duration: not reported Duration of follow‐up: 12 months
Participants	Country: UK Setting: single centre Inclusion criteria: NYHA class I to II CHF (few or no symptoms), and with ECG evidence of left ventricular systolic dysfunction and LVEF > 35%; all patients had evidence of coronary artery disease Number: treatment group (21); control group (20) Mean age ± SD (years): treatment group (66 ± 8); control group (66 ± 8) Sex (M/F): treatment group (19/2); control group (19/1) CKD stage (eGFR): treatment group (85 ± 21); control group (79 ± 20) DM: not reported Exclusion criteria: not reported
Interventions	Treatment group Enalapril: 2.5 to 20 mg/day Control group Placebo
Outcomes	Death in CHF
Notes	Funding: This study was supported by Merck, Sharp & Dohme Hoddesdon Authors did not report screening information.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Triple‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% of lost to follow‐up; all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: multicentre, international, double‐blind placebo‐controlled RCT Study duration: December 2004 to December 2006 (screening) Duration of follow‐up: 17 to 36 months
Participants	Countries: 33 Setting: multicentre (781 sites) Inclusion criteria: ≥ 55 years for nondiabetic patients or ≥18 years for diabetic patients (type 1 or 2); evidence of coronary artery disease, in sinus rhythm with a resting heart rate of ≥ 60 BPM, with a LVEF < 40%, and with left ventricular dilation Number: treatment group (5479); control group (5438) Mean age ± SD (years): treatment group (65.3 ± 8.5); control group (65.0 ± 8.4) Sex (M/F): treatment group (4540/939); control group (4507/931) CKD stage: not reported (patients ineligible if known severe kidney disease) DM: treatment group (37%); control group (37%) Exclusion criteria: (1) unlikely to cooperate in the study or with inability or unwillingness to give informed consent; (2) pregnant or breast‐feeding women or women of childbearing potential; (3) recent (< 6 months) MI or coronary revascularization or with a history of stroke or cerebral transient ischaemic attack within the preceding 3 months or scheduled for revascularization (PCI and coronary artery bypass graft); (4) at least 1 of the following criteria: (a) implanted pacemaker or implantable cardioverter defibrillator; (b) valvular disease likely to require surgery within the next 3 years; (c) sick sinus syndrome, sinoatrial block, congenital long QT, complete atrioventricular block; (d) severe or uncontrolled hypertension (SBP > 180 mm Hg or DBP > 110 mm Hg); (e) current severe symptoms of HF (NYHA class IV); (f) expectation of death from other illness during the course of the study; (g) with known severe liver disease or kidney disease; (h) requiring or likely to require the following medications: macrolide antibiotics, cyclosporin, gestodene, antiretroviral drugs or azole antifungals such as ketoconazole or with known hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose‐galactose malabsorption
Interventions	Treatment group Ivabradine: target dose 7.5 mg twice/day Control group Matched placebo
Outcomes	Composite of CV death and hospital admission for acute MI or new onset or worsening of HF Death (any cause) Cardiac death (death from MI or HF, or death related to a cardiac procedure) CV death (defined as cardiac death, death from a vascular procedure, presumed arrhythmic death, stroke death, other vascular death, or sudden death of unknown cause) or admission to hospital for new‐onset or worsening HF Composite of admission to hospital for fatal and non‐fatal acute MI or unstable angina Coronary revascularization CV death Admission to hospital for HF Admission to hospital for MI
Notes	Funding: Servier, France. All authors have received fees, research grants, or both from Servier Authors report the number of patients screened and reasons for screen failure
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random‐allocation schedule was computer‐generated by non‐adaptive balanced randomisation
Allocation concealment (selection bias)	Low risk	An independent organization supervised randomisation. A central interactive voice‐response system and an interactive web‐response system was used to ensure investigators were unaware of treatment allocation
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	An endpoint validation committee, blinded to the allocation of randomised study medication, will review outcomes
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients randomised included in analysis; < 10% lost to follow‐up
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way
Other bias	High risk	All authors have received fees, research grants, or both from Servier

Methods	Study design: randomised, parallel‐group, double‐blind RCT Study duration: not reported Duration of follow‐up: 12 weeks
Participants	Country: UK Setting: single centre Inclusion criteria: NYHA class I to III and LVEF < 40% and taking an optimal maintenance dose of both a beta‐blocker and either an ACEi or an ARB for at least 30 days Number: treatment group (20), control group (20) Mean age ± SD (years): treatment group (65 ± 7.4); control group (59 ± 9.5) Sex (M/F): 31/9 CKD stage: not reported (included patients with SCr ≤ 220 μmol/L) DM: 10% Exclusion criteria: use of potassium‐sparing diuretics; SCr > 220 μmol/L; serum potassium >5 mmol/L before randomisation
Interventions	Treatment group Spironolactone 25 mg/day for 3 months Control group Placebo
Outcomes	Blood and urine assays Heart rate QT interval dispersion Cardiopulmonary exercise testing HRQoL Safety
Notes	Funding: not reported Authors did not report screening information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information to permit judgement
Allocation concealment (selection bias)	Low risk	Randomisation procedure performed by the hospital pharmacy clinical trials unit
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Investigators and patients were blinded to the allocated treatment
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	< 10% of patients withdrew from study; insufficient information to permit judgement regarding intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: double‐blind, multicentre RCT Study duration: May 1995 to December 1998 (patients randomised) Duration of follow‐up: 12 months
Participants	Countries: Canada, USA Setting: multicentre (90 sites) Inclusion criteria: compensated congestive HF due to idiopathic dilated cardiomyopathy or coronary disease with ejection fraction 10.35, are in NYHA class III or IV, and are taking an ACEi, digitalis, and if needed, a diuretic Number: treatment group (1354); control group (1354) Mean age ± SD (years): treatment group (60 ± 12.6); control group (60 ± 12.3) Sex (M/F): treatment group (1068/286); control group (1047/307) CKD stage: not reported (patients were ineligible if SCr ≥ 3.0 mg/dL) DM: treatment group (37%); control group (34%) Exclusion criteria: reversible cause of HF; uncorrected primary valvular disease; untreated thyroid disease; obstructive or hypertrophic cardiomyopathy; pericardial disease; amyloidosis; active myocarditis; a malfunctioning artificial heart valve; history of MI within the previous 6 months; candidates for heart transplantation; undergone a revascularization procedure (a percutaneous transluminal intervention or a coronary‐artery bypass procedure) within the previous 60 days; unstable angina (requiring treatment with more than 6 nitroglycerin tablets/week); heart rate slower than 50 BPM; undergoing treatment with other investigational agents; life expectancy of less than 3 years; active liver disease or if they had haematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease that could adversely affect the safety or the efficacy of the study drug; decompensated HF; active abusers of alcohol or illicit drugs; taken any of the following: calcium‐channel–blocking agents (including amlodipine), theophylline, tricyclic antidepressants, monoamine oxidase inhibitors, or beta‐agonists within 1 week before the base‐line evaluation; beta‐adrenergic–blocking agents within 30 days before the base‐line evaluation; flecainide, encainide, propafenone, or disopyramide within 2 weeks before randomisation; or amiodarone within 8 weeks before the baseline evaluation
Interventions	Treatment group Bucindolol: 6.25mg, 12.5 mg, 25mg, 50mg, or 100mg twice/day Control group Matched placebo
Outcomes	Death (any cause) CV death, death due to worsening HF, sudden death QoL, hospitalisation and cost, LVEF after 3 and 12 months of therapy, MI
Notes	Funding: National Heart, Lung, and Blood institute and the Department of Veterans Affairs Cooperative Studies Program; Incara Pharmaceuticals supplied bucindolol and placebo Authors do not report the number of patients screened or reasons for screen failure
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Treatment was assigned by an adaptive balancing scheme ("biased coin" randomisation)
Allocation concealment (selection bias)	Low risk	A central coordinating centre randomly assigned patients to treatment
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	The cause of death was adjudicated by a central end‐points committee whose members were blinded to the treatment‐group assignments
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% lost to follow‐up; all patients randomised included in final analysis
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study's pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way
Other bias	Low risk	The study appears to be free of other sources of bias

Methods	Study design: double‐blind RCT Study duration: March 1999 to June 2001 Duration of follow‐up: 21 months
Participants	Countries: 4 Setting: multicentre (29 sites) Inclusion criteria: stable CHF of NYHA class II and III for at least 3 months using ACEi or AT1‐blockers as mandatory therapy; had to have a satisfactory ECG reading with an LVEF ≤ 0.35 or LVEDD ≥ 60 mm in combination with a fractional shorting of ≤ 20% Number: treatment group (131); control group (124) Mean age ± SD (years): treatment group (56.1 ± 10.7); control group (57.7 ± 10.2) Sex (M/F): treatment group (114/17); control group (105/19) CKD stage: not reported DM: treatment group (18%); control group (25%) Exclusion criteria: myocarditis, hypertrophic or restrictive cardiomyopathy; valvular disorders, AV‐block II or III; inability to perform walk testing; major events within the last three months before recruitment, such as MI, PTCA, NSTEMI or CABG; sinus bradycardia < 60 BPM; supine SBP < 110/mm Hg; heart transplant, pacemakers or implantable cardioverter‐defibrillator implants
Interventions	Treatment group Carvedilol: 25 mg orally Control group Betaxolol: 20 mg orally
Outcomes	ECG assessments of LVEF Evaluation of the incidence of major CV adverse events Combined risk of hospitalisation and/or death for CV reason Exercise performance (6‐min walk test). NYHA class QoL using MLW Heart Failure questionnaire
Notes	Funding: Sanofi‐Synthelabo Authors did not report screening information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was described as randomised, method of randomisation was not reported
Allocation concealment (selection bias)	Unclear risk	Study was described as randomised, allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind study
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias)   All outcomes	High risk	> 10% of lost to follow‐up; not all participants randomised included in final analysis
Selective reporting (reporting bias)	Low risk	All prespecified outcomes presented
Other bias	High risk	Sponsor involved in data management

Methods	Study design: investigator‐initiated, multicentre, prospective, open‐label, 2‐parallel, blinded end point evaluation RCT Study duration: October 2002 and May 2005 Duration of follow‐up: 18 months
Participants	Countries: 18 Europe countries Setting: multicentre (number of sites not reported); outpatient Inclusion criteria: ≥ 65 years with mild to moderate CHF (NYHA class II or III, LVEF ≤ 35%), not taking ACEi, beta‐blockers, or ARB Number: treatment group 1 (505); treatment group 2 (505) Mean age ± SD (years): treatment group 1 (72.4 ± 5.8); treatment group (2 72.5 ± 5.7) Sex (M/F): 689/321 CKD: 18.0% Baseline SCr: treatment group 1 (99.6 ± 26.1); treatment group 2 (101.9 ± 26.9) DM: 20.6% Exclusion criteria: treatment with an ACEi, ARB, or a beta‐blocker for > 7 days during the 3 months before randomisation; acute coronary syndrome within 3 months before randomisation; PCI or coronary bypass surgery planned or performed within 3 months before randomisation; stroke within 1 month or with permanent neurological sequelae within 6 months before randomisation; heart rate at rest < 60 BPM without a functioning pacemaker; supine SBP < 100 mm Hg at rest; important electrolyte disturbances; SCr ≥ 220 mol/L; atrioventricular block greater than first degree without a functioning pacemaker; and obstructive lung disease contraindicating bisoprolol treatment
Interventions	Treatment group 1 Bisoprolol first Bisoprolol: 10 mg once/day for 6 months followed by combination of bisoprolol and enalapril for 6 to 24 months Treatment group 2 Enalapril first Enalapril: 10 mg twice/day for 6 months followed by combination of bisoprolol and enalapril for 6 to 24 months
Outcomes	Combined primary end point of death (any cause) or hospitalisation CV death CV hospitalisation Safety
Notes	Funding: supported by Merck KGaA, Darmstadt, Germany Authors did not report screening information
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers produced by a dynamic balancing algorithm
Allocation concealment (selection bias)	Low risk	Treatment was allocated by telephone from the statistical centre
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinded end point evaluation
Incomplete outcome data (attrition bias)   All outcomes	High risk	> 10% withdrew from study
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way
Other bias	High risk	Sponsor involved in study conduct