Combination of diuretics for acute heart failure: a protocol for a systematic review of randomised clinical trials with network meta-analysis and trial sequential analysis

Abstract

Introduction

Acute heart failure (AHF) is a critical, costly condition with high mortality rates, affecting millions annually. Despite advances in cardiovascular care, AHF treatment lacks robust evidence. AHF commonly manifests with sudden heart failure symptoms such as pulmonary congestion, and the pathophysiology involves fluid overload. Initial treatment is based on intravenous diuretics typically, but the optimal combination of drugs remains uncertain.

Methods and analysis

We will systematically review randomised controlled trials enrolling patients with AHF and volume overload undergoing in-hospital diuretic treatment. We aim to investigate any diuretic intervention. Our search strategy includes the following databases: Embase, Medline, Latin American and Caribbean Health Sciences Literature, Web of Science and the Cochrane Central Register of Controlled Trials. The primary outcome is all-cause mortality. Secondary outcomes are serious adverse events, hospital readmission and kidney failure. Study results reported at the most extended follow-up will be used for all outcomes. If appropriate, we will conduct meta-analysis, trial sequential analysis and network meta-analysis.

Ethics and dissemination

No ethics approval is required for this study. The results will be published in a peer-reviewed journal in this field.

PROSPERO registration number

CRD42023463979.

Correspondence to Nihal Nahiz; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• The systematic review is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols checklist, and thus a predefined methodology will be accounting for the risk of random errors and systematic errors.

• Data from all trials regardless of acute heart failure phenotypes and specific diuretics will be pooled, thus theoretically giving rise to statistical and clinical heterogeneity.

• Several predefined sensitivity analyses and subgroup analyses will be performed to assess whether a given intervention effect will differ between conditions and trials.

• Evidence synthesis adjusted for bias, sparse data and multiple testing regarding the treatment with a combination of diuretics for acute heart failure will be providing reliable results.

Introduction

Acute heart failure (AHF)

Epidemiology

AHF is a life-threatening clinical syndrome. In-hospital mortality is reported to be 4%–10%. Nearly a third of hospitalised patients require rehospitalisation within 3 months, and post discharge, 1-year mortality is reported to be around 25%–30%.^1–3 With increasing age and comorbidities, heart failure contributes to significant costs to healthcare systems worldwide.^{4 5} In the USA, AHF is the primary admission diagnosis in approximately one million emergency department hospitalisations annually. Similar trends are reported in Europe.³ Despite the expanding management options in other cardiovascular fields, such as chronic heart failure and acute coronary syndrome, treatment options for AHF are still based on little to no evidence.^{2 3} Currently, the initial treatment for hospitalised patients with AHF is based on the achievement of decongestion with removal of excessive fluid.⁶

Definition and classification

AHF can be defined as an episode with acute symptoms of heart failure requiring hospitalisation. AHF is a result of decompensation in a patient with chronic heart failure or a de novo admission of heart failure in a patient without a prior heart failure diagnosis. The symptoms include dyspnoea, oedema and tiredness. Clinically, signs of systemic and pulmonary congestion are seen.⁶

The European Society of Cardiology (ESC) guidelines for heart failure (2021) highlights four clinical phenotypes of AHF: (1) acute decompensated heart failure (ADHF) occurring in 50%–70% of presentations, (2) acute pulmonary oedema representing 13%–25% of presentations, (3) isolated right ventricular failure or (4) cardiogenic shock accounting for the last <5% of presentations.^6–8 These can be separated based on signs of congestion (no congestion=dry; congestion=wet) and/or peripheral perfusion (normoperfusion=warm; hypoperfusion=cold).⁶ The academic purpose of dividing heart failure into more distinct phenotypes is to assess specific treatments, although guidelines underline the importance of considering the possibility of overlap.

Pathophysiology

More than 75% of AHF-patients present with congestion and volume overload (wet and warm).⁶

ADHF is dominated by systemic fluid overload in relation to fluid and salt retention. Forward failure of the left ventricle activates neuroendocrine compensatory mechanisms including the sympathetic nervous system and the renin–angiotensin–aldosterone system with stimulation of renal tubular sodium and water reabsorption.⁹ ADHF may also include an isolated right ventricle dysfunction, although rarely, which causes blood to accumulate in the central venous system, resulting in peripheral oedema, elevated jugular venous pressure and congestion of liver, kidneys and intestines.¹⁰

Description of the intervention

The ESC 2021 guidelines recommend using intravenous loop diuretics as the primary treatment of fluid overload and congestion as they increase renal excretion of salt and water. Intravenous loop diuretics are mainly used as initial treatment to alleviate symptoms of fluid overload in patients with ADHF due to their rapid onset of action and efficacy.⁶

Loop diuretics, such as furosemide, inhibit the Na–K–2Cl transporter in the ascending loop of Henle and have potent diuretic effect, promoting excretion of sodium and chloride and to a lesser extend potassium.¹¹ The elimination of salt and water results in a decreased overall intravascular volume, thus decreased preload of both ventricles. Furosemide also activates the sympathetic and the renin–angiotensin–aldosterone systems, increasing systemic vascular resistance, which may increase left ventricular afterload and decrease cardiac output.¹² However, there are still limitations regarding optimal dosing, timing and methods of administration, due to a lack of evidence. The Diuretic Optimization Strategies Evaluation (DOSE) trial did not show any significant difference in primary efficacy outcome between high-dose regimen compared with a low-dose regimen; yet, a higher relief of dyspnoea, change in weight and net fluid loss were observed in patients following a high-dose regimen.^13–15 Additionally, studies have highlighted the importance of starting intravenous diuretic treatment in low doses in patients with AHF, to assess the diuretic response and increase the dose when it becomes insufficient.¹⁶ Even though a cause-and-effect relation could not be proven, high diuretic doses have been associated with greater neurohormonal activation and electrolyte abnormalities when used as an initial treatment.^17–20 According to current guidelines, diuretic treatment involves an initial intravenous dose of loop diuretics (furosemide, bumetanide or torasemide) corresponding to 1–2 times the daily oral dose taken by the patient before admission. If the patient was not on oral diuretics, a starting dose of 20–40 mg of furosemide, or a bolus of 10–20 mg intravenous torasemide, can be used, while assessing the diuretic response (measuring spot urine sodium). A satisfactory response is indicated by >50–70 mEq/L at 2 hours and/or urine output>100–150 mL/hour during the first 6 hours. If the response is inadequate, the dose can be doubled. If still insufficient, a combination of other diuretics acting at different sites (thiazides, acetazolamide or metolazone) is recommended while monitoring serum electrolytes and renal function.^{14 21–24}

Acetazolamide, a carbonic anhydrase inhibitor, works in the proximal tubule in the kidneys, accounting for at least one-third of renal sodium reabsorption.²⁵ Combining this with loop diuretics, which work in the more distal part of the nephron, may improve diuresis by creating a physiological synergy, compared with increasing loop diuretics. In the Acetazolamide in Decompensated heart failure with Volume Overload (ADVOR) study by Mullens et al. (2022), a trial including 519 patients, it was investigated whether adding acetazolamide to standardised intravenous loop-diuretic therapy would improve the incidence of successful decongestion in patients with ADHF.²⁶ It was shown that adding acetazolamide resulted in a higher incidence of successful decongestion after 3 days and reduced the average hospital stay by 1 day. However, some limitations were noted, which make further testing of acetazolamide for AHF mandatory: (1) ADVOR was not powered for clinically relevant hard outcomes such as mortality or cardiovascular events, (2) loop-diuretic doses were kept similar between groups per protocol, raising the question of whether a larger loop-diuretic dose could have similar or better effects than a secondary diuretic, and (3) patients taking sodium–glucose cotransporter 2 (SGLT2) inhibitors were excluded, which since the initiation of ADVOR have been implemented as mandatory heart failure medication.

Metolazone, comparable to thiazides inhibiting sodium reabsorption in distal tubules, can in combination with furosemide produce significant diuresis in diuretic resistant oedematous patients in general.^27–30 In several countries, where acetazolamide is not available, thiazides and metolazone are used as add on to loop diuretics in cases of diuretic resistance. In AHF, metolazone has been compared with indapamide in 150 patients²⁸, chlorothiazide and tolvaptan in 60 patients²⁹ and bendroflumethiazide in 33 patients.³⁰ Altogether, metolazone use in AHF is based on a few studies containing less than 250 patients in total but is widely used in combination with a loop diuretic in the clinic.³¹

In a recent randomised, placebo-controlled trial, 230 patients with AHF were randomised to receive chlorothiazide or placebo in addition to intravenous furosemide (Combination of Loop Diuretics with Hydrochlorothiazide in Acute Heart Failure (CLOROTIC) trial).³² Adding chlorothiazide to loop diuretic therapy improved diuretic response in patients with AHF, but CLOROTIC was underpowered for hard outcomes. Two retrospective studies have compared oral metolazone versus intravenous chlorothiazide as add-on therapy to loop diuretics in hospitalised patients.^{33 34} Both studies did find similar diuretic effects and similar adverse events, but a significant cost disparity existed between the two agents: metolazone costs US$1–2 per dose, whereas a single dose of intravenous chlorothiazide may exceed US$200.³⁴ Given the considerable cost difference, larger randomised studies are warranted. So far, no specific combination of diuretics is given a guideline recommendation for AHF other than a ‘may be considered’ combination of loop diuretics with thiazides in case of diuretic resistance. Meanwhile, other subgroups of diuretics with potential synergetic effects exist and have been studied in comparison to furosemide.^{2 6}

Why is it important to do this review?

The traditional use of various diuretics as an initial treatment strategy for AHF has been the main focus of several studies and reviews.^{1 2 4 5 35–44} Some reviews have focused on single diuretics or comparing two diuretics.^{1 2 4 5 35–44} However, none of the reviews have compared all combinations of diuretic therapies. Orso et al.² focused on a selected group of diuretics, which did not include acetazolamide and did not encompass recent major trials in this area.^{24 27 32} Furthermore, the review did not focus on clinically relevant hard outcomes. Additionally, the review did not include SGLT2 inhibitors (such as dapagliflozin and empagliflozin) as a subgroup of diuretics, while their diuretic efficacy in AHF patients with loop diuretic resistance has recently been discussed.²⁷ Finally, the review did not use trial sequential analysis (TSA) to minimise the risks of random errors. Thus, there is a need for a systematic review based on recent large trials assessing the harms and benefits of a double diuretic treatment for AHF, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, searching relevant databases, minimising the risk of random error by a TSA, assessing risk of bias in each trial and assessing the certainty of the evidence with Grading of Recommendations, Assessment, Development, and Evaluations (GRADE).^45–47

Review questions

The aim of this systematic review is to summarise the existing evidence of the effects of different combinations of diuretic therapy for AHF.

Methods and analysis

This protocol for a systematic review is reported according to the PRISMA Protocols (PRISMA-P).⁴⁶ The reporting checklist has been elaborated using PRISMA-P reporting guidelines.⁴⁸ Data will be published as a supplement to the meta-analysis.

Inclusion criteria

Types of studies

This review will include randomised clinical trials irrespective of setting, publication year, publication type and language. Quasi-randomised studies and observational studies will not be included.

Types of participants, interventions and outcome

The research questions were formulated using population, intervention, control and outcomes (PICO) framework.

The population will be adults (≥18 years) with AHF with volume overload (according to trialists definition) irrespective of age, sex and comorbidities. Trials focusing on AHF population presenting with cardiogenic shock will be excluded. The trial population should consist of at least 80% patients with AHF.

AHF may be defined as new onset or worsening of symptoms and signs of heart failure leading to hospitalisation in the presence of an underlying structural or functional cardiac dysfunction.⁴⁹ Other different definitions of AHF will also be included.

Interventions will be all diuretics, which can be defined as drugs increasing the excretion of water from the body through the kidneys by promoting diuresis, and whose effect is used for decongestion in the population. All types of diuretics will be included. Specifically, the following diuretics will be included in the search: furosemide, torsemide, acetazolamide, metolazone, chlorothiazide, bendroflumethiazide, indapamide, tolvaptan, dapagliflozin, empagliflozin, eplerenone and spironolactone.

Trials will be included if the intervention is compared against placebo, no intervention or alternatively against another active treatment. The results of diuretics will be reported versus placebo/no intervention and diuretics versus active comparators separately.

Outcomes

The primary outcome will be all-cause mortality. Secondary outcomes will be (1) all-cause hospital readmission (as defined by trialists), (2) serious adverse events, and (3) kidney failure (as defined by trialists).

Exploratory outcomes will be (1) body weight, (2) urinary output, (3) blood pressure, and (4) estimated glomerular filtration rate (eGFR).

For all outcomes, study results reported at the longest follow-up will be used.

We will use the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use-Good Clinical Practice (ICH-GCP) definition of a serious adverse event, which is any untoward medical occurrence that resulted in death, was life-threatening, required hospitalisation or prolonging of existing hospitalisation and resulted in persistent or significant disability or jeopardised the participant.⁵⁰ If the trialists do not use the ICH-GCP definition, we will include the data if the trialists use the term ‘serious adverse event’. If the trialists neither use the ICH-GCP definition nor use the term serious adverse event, then we will also include the data, if the event clearly fulfils the ICH-GCP definition for a serious adverse event. We will then assess each serious adverse event separately.⁵¹

Search methods

Information sources

The search (online supplemental material) will be based on the following electronic databases: Embase, Medline, Latin American and Caribbean Health Sciences Literature, Web of Science and the Cochrane Central Register of Controlled Trials. The bibliographies of included articles will be reviewed for potential additional articles. The search began in November 2023.

Searching other resources

The bibliographies of relevant publications will be checked for randomised trials. Authors of included studies will be asked (email) for unpublished randomised trials. Ongoing trials will be searched on the following websites:

• ClinicalTrials.gov (www.clinicaltrials.gov).

• Google Scholar (https://scholar.google.dk/).

• Turning Research into Practice Database (https://www.tripdatabase.com).

• European Medicines Agency (https://www.ema.europa.eu/ema/).

• US Food and Drug Administration (www.fda.gov).

• China Food and Drug Administration (http://eng.sfda.gov.cn/WS03/CL0755/).

• Medicines and Healthcare products Regulatory Agency (https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency).

• The WHO International Clinical trials Registry Platform search portal (http://apps.who.int/trialsearch).

• Clinical Trials Registry Platform (http://www.who.int/ictrp/en/).

Selection process

Screening of all titles and abstracts retrieved from the systematic searches in duplicate using dedicated software Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org) will be performed independently by at least two reviewers using predefined screening criteria. Any disagreement regarding inclusion or exclusion will be discussed between the reviewers, with a third reviewer eventually. The full-text reports of all potentially relevant publications passing the first screening level will be reviewed. Any disagreement regarding eligibility will be discussed and if pertinent, study authors will be contacted. The final report will include a PRISMA diagram illustrating the number of studies remaining after each stage of the selection process, including the exclusion reasons of full-text articles.

Data extraction and management

The meta-analysis of the study data and TSA will be performed using Stata V.17.⁴⁷ Two authors will in duplicate extract data from included trials, and disagreements will be discussed with a third author. Duplicate publications and publications from the same main trial will be excluded. Authors will be contacted by email to expand any additional data, which might not have been reported sufficiently or at all in the publication.

Trial characteristics

Data items

The following data will be extracted as relevant:

• General information

  • First author name

  • Year of publication

  • Geographical location of the study (country, continent)

  • Study design.

  • Inclusion and exclusion criteria.

  • Years of patient enrollment.

  • Number of patients screened and analyzed (sample size).

  • Intervention/exposure/comparator.

  • Length of follow-up.

• Participants

  • Summary demographics

    • Age (mean/median).

    • Sex (proportion of males).

  • Type of AHF (decompensated heart failure, pulmanary edema, mixed type of AHF).

  • Type of heart failure (HF): Heart failure with reduced Ejection Fraction(HfrEF), Heart failure with preserved Ejection Fraction (HfpEF).

  • Presence of diuretic resistance as defined by trialists.

  • Baseline blood pressure.

  • Baseline left ventricular ejection fraction.

  • Baseline comorbidities, including atrial fibrillation or flutter, baseline number of participants with heart failure, estimated glomerular filtration rate and N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP).

  • Baseline heart failure-medication (beta-blockers, intravenous nitrates, intravenous loop-diuretics, angiotensin converting enzyme inhibitors, angiotensin II-receptor antagonists, and/or mineralocorticoid receptor antagonists).

• Relevant results.

Diuretic strategy characteristics

Diuretic strategy characteristics are dose of intervention, timing of intervention, mode of administration and duration of administration.

Co-intervention characteristics

Co-intervention characteristics are type of co-intervention, timing of co-intervention, dose of co-intervention, duration of co-intervention and mode of administration.

Risk of bias in individual studies

At least two investigators will independently assess risk of bias in the included studies, based on the Cochrane risk of bias tool for randomised trials V.2 outlined in the Cochrane Handbook of Systematic Reviews of Interventions.⁵² For controlled trials, the assessment tool for individually randomised parallel-group trials and the supplement for cluster-randomised parallel-group trials will be used as appropriate. The risk of bias in the included studies will be assessed according to the following domains of bias:

• Bias arising from randomisation process.

• Bias due to deviations from intended interventions.

• Bias due to missing outcome data.

• Bias in measurement of the outcome.

• Bias in selection of the reported results.

These domains will be encompassed into ‘overall risk of bias’. Furthermore, this procedure enables classification of trials into being at overall ‘low risk of bias’, if all of the domains are classified as ‘low risk of bias’. Meanwhile, a trial will be classified as overall ‘high risk of bias’, if at least one of the bias components are classified as ‘unclear’ or ‘high risk of bias’. It will also be evaluated for ‘profit bias’.

We will for each outcome result separately bias risk assess ‘blinding of outcome assessment’, ‘incomplete outcome data’ and ‘selective outcome reporting’, so the bias risk for each outcome result can be assessed. The main conclusions will be based on the results of outcomes at an overall low risk of bias.

Measures of treatment effect

Risk ratios (RRs) with 95% CI will be calculated for dichotomous outcomes, while for continuous outcomes, the mean differences (MDs) with 95% CI will be calculated. In the primary analysis, mean changes from baseline between treatment arms will be compared, and if SDs are not reported, they will be calculated using trial data, if possible.

Missing data

Intention-to-treat data will be used if such data are available. Contacting trial authors to acquire relevant missing data (ie, for data extraction and for assessment of risk of bias) will be considered. No missing data for outcomes will be imputed in the primary analysis.

Sensitivity analysis

Potential impact of missing data will be assessed by the two following sensitivity analyses on both the primary and secondary outcomes: (1) ‘best–worst case’ scenario, in which all participants lost to follow-up in the diuretic groups will be assumed to having survived without any adverse events and the opposite for all participants lost to follow-up in the control group, and (2) ‘worst–base case’ scenario, in which all participants lost to follow-up in the diuretic group will be assumed to having not survived with all adverse events and the opposite for all participants lost to follow-up in the control group.

Also, the influence of variations in follow-up duration on the results will be addressed in terms of potential source of bias through sensitivity analysis.

Heterogeneity

Studies will be assessed for clinical (ie, participants, interventions and outcomes), methodological (ie, study design or risk of bias) and potentially statistical heterogeneity.⁵³ If there is no substantial clinical or methodological heterogeneity, statistical heterogeneity will primarily be assessed via visual inspection of forest plots. A p value<0.10 or I² statistic of >50% will indicate considerable statistical heterogeneity.⁵³ Possible heterogeneity will be investigated via sensitivity analyses and subgroup analyses. Ultimately, it may be decided that a meta-analysis should be avoided because of unexpected high heterogeneity (clinical, methodological or statistical). A narrative synthesis will be performed if heterogeneity is deemed too substantial between studies to allow for meaningful meta-analyses.

Assessment of reporting biases

A funnel plot for a visual evaluation of reporting bias will be used, but only if 10 or more trials are included, while being aware of the limitations of a funnel plot (a funnel plot evaluates bias from trials with small sample sizes). From this information, possible reporting bias will be quantified. Asymmetry will be tested with the Harbord et al.’s test⁵⁴ if τ2 is less than 0.1 and with the Rücker test if τ2 is greater than 0.1, for dichotomous outcomes, while the regression asymmetry test and the adjusted rank correlation test will be used for continuous outcomes.^{55 56}

Units

For trials using a crossover design, only data from the first period will be included.⁵⁷ Cluster-randomised trials will also be included after adjusting the original sample size to the effective sample size using the intracluster correlation coefficient from the ‘design effect’.⁴⁵ Therefore, in any unit of analysis issues are expected.

Data synthesis

Meta-analysis

Meta-analyses according to the international recommendations⁴⁵ and the eight-step assessment by Jakobsen et al.⁵⁸ will be carried out. The intervention effects will be evaluated with both fixed effects meta-analyses⁵⁹ and random effects meta-analyses.⁶⁰ The most conservative results (highest p value) will be reported, and the less conservative result will be considered in a sensitivity analysis. One primary outcome will be used, and the primary conclusions will be based on this outcome; therefore, a p value of 0.05 as the threshold for statistical significance for all outcomes will be considered. Our main conclusion will be based on the results from the primary outcomes at low risk of bias.

Trial sequential analysis

Traditional meta-analyses have a risk of random errors owing to sparse data and repeat testing of accumulative data when updating reviews. Control of the risks of type I and II errors will be pursued, thus a TSA (a detailed description is found in the trial sequential analysis manual⁴⁷) on the outcomes will be performed to estimate the required information size (the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) and cumulative Z-curve’s breach of trial sequential monitoring boundaries.⁶¹

Regarding dichotomous outcomes, an estimation of the needed data size based on the observed proportion of patients with an outcome in the control group, a relative risk reduction of 25%, an alpha of 5% and a beta of 10% will be performed. While the observed SD, an MD of the observed SD/2 an alpha of 5% and a beta of 10% in the TSA will be used.

Network meta-analysis

The synthesis comparator will encompass all diuretic interventions identified in the systematic review, along with placebo, standard care, no intervention or trials involving an 'active placebo’. Each intervention will be examined in one of the following groups: (1) loop diuretics, (2) thiazides including metolazone, (3) acetazolamide, (4) tolvaptan and (5) mineralocorticoid-receptor antagonists. We will generate descriptive statistics for each treatment comparison, highlighting essential clinical and methodological characteristics. A dedicated network diagram will be created for each outcome dataset, with node size representing the total number of participants and line width indicating the number of studies comparing linked treatments. Moreover, connecting lines will be colour coded based on the average risk of bias for each treatment comparison, with green indicating low risk, yellow indicating moderate risk and red indicating high risk of bias. We assume that any eligible participant is equally likely to be assigned to any intervention within the comparator set. These analyses will be conducted using Stata within a frequentist framework (using the ‘mvmeta’ command).

Network meta-analysis will be undertaken if a network of connected trials can be established. Should this occur, we will first evaluate the assumptions of transitivity and consistency before proceeding with the analysis. These assumptions will undergo a five-step assessment process. First, we will construct a network geometry to review the relationships within the network. Second, we will assess the transitivity assumption across treatment comparisons using boxplots. The assumption of consistency will be examined through the design-by-treatment interaction model as a global test. Third, we will create a network forest or interval plot to visualise the summary effect size of the interventions' comparative effectiveness. Fourth, we will compute cumulative rankings to identify any superiority among the interventions. Lastly, we will assess publication bias or effect modifiers to ensure the validity of our findings. Effect estimates will be presented with the relevant effect size (RR, MD or standardised MD), accompanied by a 95% CI and a 95% prediction interval.

Subgroup analysis

Subgroup analyses will be performed as per the following:

• Specific drug administered.

• Trials at high risk of bias compared with trials at low risk of bias.

• Presence of diuretic resistance.

‘Summary of findings’ table

A ‘summary of findings’ table will be created using the primary and secondary outcomes. First, the results in the table will be presented based on the results from the trials with low risk of bias. Second, the results will be presented based on all trials. The five GRADE considerations (consistency of effect, bias risk of the trials, imprecision (assessed by TSA), indirectness and publication bias) will be used to assess the certainty of evidence.

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Discussion

AHF contributes to worldwide significant costs to healthcare systems in admission, readmissions and prolonged hospitalisations, and it constitutes the primary diagnosis for approximately one million emergency department hospitalisations per year.³ Currently, 2021 European guidelines recommend loop diuretics as the primary treatment for decongesting systemic and pulmonary fluid overload.⁶ Diuretic resistance in patients with AHF is a major problem, and there is a need for additional decongestant therapies beyond the traditional diuretic strategies for improving outcomes. Furthermore, there is a need to determine optimal dosing, timing and methods of administration based on additional and stronger evidence. During the last year, large trials have compared acetazolamide versus placebo²⁶ and thiazides versus placebo.³² However, no studies have investigated these strategies against each other, and since numerous other potent diuretics exist, the optimal diuretic on top of loop diuretics is so far unknown. This review with network meta-analysis will analyse these trial data to potentially improve the care of AHF with diuretic resistance.

Several reviews have assessed this area, but no previous systematic reviews have included the recent large trials and have not assessed combinations of diuretic therapy to the traditional use of single diuretics, while adhering to PRISMA guidelines, using TSA.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

X @JohannesGrand

Contributors NN, JG, ES and JJ: primary investigators, conceptualisation, designed the research methodology and were instrumental in defining the intellectual content and the scope of the study. NN and JDL: data acquisition and collection. JG: data collection. NN, JDL and JG: developed the data collection tools, trained data collectors and oversaw the entire data acquisition phase to ensure the integrity and accuracy of the data. NN: took the lead in drafting the manuscript and synthesised the research findings, literature and analysis into a coherent document, ensuring that the study’s significance and conclusions were clearly communicated. All authors: participated in the critical revision of the manuscript, reviewed the draft for important intellectual content, provided feedback, contributed to revisions that enhanced the clarity, accuracy and impact of the work, reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding JG was supported by a research grant from the Danish Cardiovascular Academy, funded by the Novo Nordisk Foundation, grant number NNF20SA0067242, and the Danish Heart Foundation.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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