# Pharmacological Treatment of Heart Failure with Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis

Bart J van Essen, Daan C.H. Ceelen, Wouter Ouwerkerk, Tiew-Hwa Teng, Ganash N Tharshana, Fook Ming Hew, Javed Butler, Faiez Zannad, Carolyn S Lam, Justin Ezekowitz, et al.

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## To cite this version:

Bart J van Essen, Daan C.H. Ceelen, Wouter Ouwerkerk, Tiew-Hwa Teng, Ganash N Tharshana, et al.. Pharmacological Treatment of Heart Failure with Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis. JACC. Advances, 2025, 10.1016/j.jacc.2025.08.054. hal-05240563

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Pharmacological Treatment of Heart Failure with Reduced Ejection Fraction: An
Updated Systematic Review and Network Meta-Analysis

Bart J. van Essen, MD, Daan C.H. Ceelen, BSc, Wouter Ouwerkerk, PhD, Tiew-Hwa K. Teng, MPH, PhD, Ganash N. Tharshana, Fook Ming Hew, Javed Butler, MD, MPH, MBA, Faiez Zannad, MD, PhD, Carolyn S. Lam, MD, PhD, Justin Ezekowitz, MD, PhD, Adriaan A. Voors, MD, PhD, Jasper Tromp, MD, PhD

PII: S0735-1097(25)07572-2

DOI: https://doi.org/10.1016/j.jacc.2025.08.054

Reference: JAC 32228

To appear in: JACC

Received Date: 29 July 2025

Revised Date: 21 August 2025

Accepted Date: 22 August 2025

Please cite this article as: van Essen BJ, Ceelen DCH, Ouwerkerk W, Teng T-HK, Tharshana GN, Hew FM, Butler J, Zannad F, Lam CS, Ezekowitz J, Voors AA, Tromp J, Pharmacological Treatment of Heart Failure with Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis, JACC (2025), doi: https://doi.org/10.1016/j.jacc.2025.08.054.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
# Pharmacological Treatment of Heart Failure with Reduced Ejection Fraction:
An Updated Systematic Review and Network Meta-Analysis

## Brief title: Pharmacological Treatment of HFrEF

Bart J. van Essen MD¹, Daan C.H. Ceelen BSc¹, Wouter Ouwerkerk PhD²,³, Tiew-Hwa K. Teng MPH, PhD³, Ganash N. Tharshana⁵, Fook Ming Hew⁵, Javed Butler MD, MPH, MBA⁶,

Faiez Zannad MD, PhD⁷, Carolyn S. Lam MD, PhD³,⁴,⁸, Justin Ezekowitz MD, PhD⁹, Adriaan A. Voors MD, PhD¹, Jasper Tromp MD, PhD¹,³,⁴,⁵

1. Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

2. Dept of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands

3. National Heart Centre Singapore, Singapore

4. Duke-NUS Medical School, Singapore

5. Saw Swee Hock School of Public Health, National University of Singapore & the National University Health System, Singapore

6. Baylor Scott and White Research Institute, Dallas, Texas, USA; University of Mississippi, Jackson, Mississippi, USA.

7. Université de Lorraine INSERM, Centre d'Investigations Cliniques Plurithématique 1433, CHRU Nancy, France.

8. Baim Institute of Clinical Research, Boston MA, USA

9. University of Alberta, Edmonton, Canada.
Disclosures

WO has received consulting or speaker fees from Us2.ai and owns a patent US-10702247-B2 unrelated to the present work.

JB is a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll.

FZ reports personal fees from Alnylam, Bayer, Bioeuetics, Boehringer, Cellprothera, Centrix, Cereno, Centrix Corteria, CVRx, Lilly, Lupin, Merck, NovoNordisk, Opalia Recordati, Owkin, Polygon, Ribocure, Roche, Viatris, having stock options or equities at Cereno Pharmaceutical, and being the founder of Cardiovascular Clinical Trialists (CVCT).

CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from NovoNordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Bioeuetics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc., Quidel Corporation, Radcliffe Group Ltd., Recardio Inc., ReCor Medical, Roche Diagnostics, Sanofi,
Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder & non-executive director of Us2.ai.

JE has received research grants from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics, and has received consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics.

The employer of AAV (UMCG) received consultancy fees and/or research grants from the following companies: Adrenomed, Anacardio, AstraZeneca, Bayer AG, Boehringer Ingelheim, BMS, Cardurion, Corteria, Moderna, Myokardia, Merck, Novo Nordisk, Novartis, Roche Diagnostics, and SalubrisBio.

JT is supported by the National University of Singapore Start-up grant, the tier 1 grant from the Ministry of Education, and the CS-IRG Grant from the National Medical Research Council; has received research support from AstraZeneca; has received consulting or speaker fees from Us2.ai and Roche diagnostics; owns a patent US-10702247-B2 unrelated to the present work.

All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

**Corresponding author:**

Jasper Tromp MD PhD MPH

Email: [Jasper_tromp@nus.edu.sg](mailto:Jasper_tromp@nus.edu.sg)

**Postal Address:**

Saw Swee Hock School Of Public Health
12 Science Drive 2, #10-01, Singapore 117549

**Acknowledgements**

We acknowledge the support from Aprajita Kaushik in the screening process.
**Abstract**

**Background.** In 2022, our network meta-analysis showed that a combination of β-blockers, angiotensin receptor-neprilysin inhibitors (ARNi), mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was most effective in reducing all-cause mortality in heart failure with reduced ejection fraction (HFrEF). This study updates the treatment benefit by including additional large randomized controlled trials (RCTs) since 2022, including the Vericiguat Global Study in Participants with Chronic Heart Failure (VICTOR) trial.

**Objectives.** To evaluate and compare regimens of pharmacotherapy in patients with HFrEF.

**Methods.** We searched MEDLINE, EMBASE, and Cochrane CENTRAL for RCTs in patients with HFrEF through April 2025. Using frequentist network meta-analysis, we estimated hazard ratios (HRs) for all-cause mortality (primary outcome), cardiovascular death, and the composite of cardiovascular death or heart failure hospitalization (secondary outcomes). Absolute benefits were quantified as life-years gained using BIOSTAT-CHF and ASIAN-HF cohort data.

**Results.** The analysis included 103,754 patients across 89 randomized controlled trials. Relative to placebo, quintuple therapy with ARNi, β-blockers, MRA, SGLT2i, and vericiguat most effectively reduced all-cause mortality (HR 0.35, 95% confidence interval [CI]: 0.27-0.45), followed by quadruple therapy with ARNi, β-blockers, MRA and SGLT2i (0.39, 95% CI: 0.32-0.49). For a representative 70-year-old patient, quadruple therapy (ARNi/β-blockers/MRA/SGLT2i) provided 5.3 additional life-years (95% CI: 2.8-7.7 years) versus no treatment, while quintuple therapy (ARNi/β-blockers/MRA/SGLT2i/vericiguat) provided 6.0 additional life-years (95% CI: 3.7-8.4).

**Conclusions.** This analysis reinforces the substantial mortality and morbidity benefit associated with the currently recommended quadruple therapy regimen—angiotensin receptor-neprilysin inhibitors (ARNi), β-blockers, mineralocorticoid receptor antagonists
(MRA), and sodium-glucose cotransporter-2 inhibitors (SGLT2i)—in patients with HFrEF. The addition of vericiguat may provide an incremental survival gain of approximately 0.7 years beyond that achieved with quadruple therapy. However, these results should be regarded as exploratory, as they are derived from a secondary endpoint of a single trial.

**Condensed Abstract**

This study updates the treatment benefit of pharmacotherapy in HFrEF by including additional large randomized controlled trials (RCTs) since 2022. Treatment regimens of pharmacotherapy in patients with HFrEF were evaluated and compared. Using a frequentist network meta-analysis, we estimated hazard ratios (HRs) for all-cause mortality (primary outcome) and other secondary outcomes. Quintuple therapy with ARNi, β-blockers, MRA, SGLT2i, and vericiguat most effectively reduced all-cause mortality (HR 0.35, 95% confidence interval [CI]: 0.27-0.45), followed by quadruple therapy with ARNi, β-blockers, MRA and SGLT2i (0.39, 95% CI: 0.32-0.49). This analysis confirms the mortality and morbidity benefit of the currently recommended quadruple therapy regimen including ARNi, β-blockers, MRA, and SGLT2i in patients with HFrEF. The addition of vericiguat may confer a modest incremental survival benefit.

**Keywords:** HFrEF, pharmacotherapy, drug therapy
## Introduction

Heart failure (HF) remains a significant source of mortality and morbidity globally.¹ Over the past three decades, landmark clinical trials have progressively expanded therapeutic options for patients with heart failure with reduced ejection fraction (HFrEF).²,³

The landscape of HFrEF treatment has undergone rapid evolution in recent years. Previous trials established angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), β-blockers, and mineralocorticoid receptor antagonists (MRA) as foundational therapies. The introduction of angiotensin receptor-neprilysin inhibitors (ARNi)⁴ and sodium-glucose cotransporter 2 inhibitors (SGLT2i)⁴⁻⁶ established the foundational four therapies for HFrEF. Concurrently, novel agents targeting distinct pathophysiological pathways have emerged, including vericiguat (a soluble guanylyl cyclase stimulator)⁷,⁸ and omecamtiv mecarbil (a cardiac myosin activator),⁹ both of which have demonstrated clinical efficacy in large-scale randomized controlled trials (RCTs).

Previous network meta-analyses have demonstrated that a combination of ARNi, β-blockers, MRA, and SGLT2i is most effective in reducing all-cause mortality, cardiovascular (CV) death, and heart failure (HF) hospitalization.¹⁰⁻¹⁶ However, additional large-scale RCTs have been published since these previous analyses, providing further evidence on the role of newer agents, such as vericiguat.

Therefore, this updated systematic review and network meta-analysis extends our previous work by incorporating the latest evidence published through April 2025 in patients with HFrEF. Our analysis seeks to quantify the comparative effectiveness of current therapeutic combinations and estimate their aggregate impact on clinical outcomes and life expectancy, thereby informing evidence-based treatment decisions in contemporary clinical practice.¹⁷

## Methods

### Protocol & Study Design
A prespecified protocol and analysis plan was registered on PROSPERO (PROSPERO ID: CRD420251054997). Data were analyzed using a frequentist statistical framework, and the results are reported following the PRISMA extension statement for network meta-analyses.<sup>17</sup>

<u>Search strategy, selection criteria, and data extraction</u>

We updated our previous systematic search of MEDLINE, EMBASE, and the Cochrane
Central Register of Controlled Trials to include RCTs published between January 2021 and
April 2025. The complete search strategy and protocol are available in the Supplementary
Material and on PROSPERO.

Eligible studies included adult patients (aged ≥18 years) with HFrEF, defined as a left ventricular ejection fraction (LVEF) ≤50%. We excluded studies where the entire population had comorbidities likely to significantly impact outcomes (e.g., post-myocardial infarction or studies exclusively enrolling patients with diabetes). Trials focused on acute heart failure or comparisons within a single drug class were also excluded.

Consistent with our previous review,¹¹ the pharmacological agents of interest included: digoxin, hydralazine-isosorbide dinitrate (H-ISDN), ACEi, ARBs, β-blockers, MRA, ivabradine, ARNi, SGLT2i, vericiguat, and omecamtiv mecarbil. We additionally included studies evaluating glucagon-like peptide-1 receptor agonists (GLP-1a) in patients with HFrEF. All studies published between 1987 and April 2025 were considered.

After removing duplicates, all titles and abstracts were independently screened by at
least two of the six investigators (BE, DC, GT, FH, TT, and AK) to identify potentially eligible
studies. Full-text articles of selected records were then reviewed independently by two
investigators (BE & DC). Any disagreements were resolved through consensus. The same two
investigators conducted data extraction (BE & DC), who cross-checked each other's entries to
ensure the robustness of the data extraction process. Data from the unpublished VICTOR trial
were provided by the trial sponsors prior to peer-reviewed publication. The sponsors had no
role in the design of this network meta-analysis, its funding, or in the generation, analysis, or
interpretation of the results presented herein.
## Outcomes

The primary outcome was all-cause mortality. Secondary outcomes included cardiovascular (CV) death, and a composite of CV death or hospitalizations for heart failure (HHF).

## Network meta-analysis

We performed the network meta-analysis using a frequentist statistical framework, which incorporates graph-theoretical approaches developed initially for electrical networks. ¹⁸⁻²¹ Both fixed-effect and random-effects models were constructed to assess treatment effects. Heterogeneity was assessed using the I² and the τ² statistic with random-effects models applied when I² exceeded 30%. As an important secondary analysis we explored potential temporal heterogeneity, by conducting era-stratified analyses, evaluating all studies separately across three periods: pre-2000, 2000–2010, and post-2010.

To evaluate the effect of treatments comprising multiple components (e.g., ARNi, BB, MRA), we used an additive component network meta-analysis model. This model assumes that the combined effect of a treatment regimen equals the sum of its individual components. To test whether treatments were additive, we performed an additive model assumptions test for all outcomes. Comparisons were based on background therapies used within individual trials; thus, only treatment combinations that formed part of a connected network were analyzed.

Many earlier trials did not include composite endpoints such as cardiovascular (CV) death or hospitalization for heart failure (HHF). The Cardiac Insufficiency Bisoprolol Study (CIBIS) III served as a reference for analyzing these composite outcomes. Patients were on background therapy if at least 50% of participants in the trial received the treatment.²² Background therapy variations between studies were addressed through sensitivity analyses examining treatment effects across different patterns of concomitant medication use.

We reported hazard ratios (HRs) for time-to-event outcomes. Treatments were ranked using P-scores.²³,²⁴
To assess confidence in the results, we applied the Confidence in Network Meta-
Analysis (CINEMA) framework, which evaluates six domains: within-study bias, reporting bias,
indirectness, imprecision, heterogeneity, and incoherence. Within-study bias was assessed
using a modified Cochrane risk-of-bias tool across six criteria (e.g., allocation concealment,
blinding, missing data). A study was classified as high risk if it had more than three domains
rated as high risk. Funnel plot symmetry and Egger's test were used to assess reporting bias.
Indirectness was considered low, in accordance with published guidelines.

Indirectness was considered low based on the similarity of study populations,
interventions, and outcome definitions across the included trials. All studies enrolled patients
with HFrEF, used comparable pharmacologic interventions, and reported standardized clinical
outcomes. Imprecision was assessed by comparing 95% confidence intervals with a
predefined equivalence range (OR = 2.0). This conservative threshold was selected to improve
the robustness of estimates, where advances in HF therapy have resulted in progressively
more modest treatment effects compared to the conventional GRADE recommendation of OR
= 2.5.²⁵ Incoherence, disagreement between direct and indirect evidence, was evaluated
using a global design-by-treatment interaction model.

We estimated the potential life-years gained in the BIOSTAT-CHF (BIOlogy Study to TTailored Treatment in Chronic Heart Failure) and ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) registries.²⁶⁻²⁸ We used actuarial (age-based) models to estimate life-years gained for different treatment combinations.²⁸ This method treats age as the time-to-event variable. We calculated nonparametric Kaplan-Meier estimates for overall life expectancy at each year of age using a life-table approach based on the area under the survival curve. Since none of the study medications demonstrated significant age interactions, the observed differences in survival curves represent predicted event-free survival and remaining life expectancy. We addressed variations in baseline pharmacotherapy by calculating treatment effects for each therapeutic combination relative to the patient's existing regimen. For instance, when evaluating a patient receiving ACEi and β-blockers, the projected life-years gained from adding ARNi MRA, and SGLT2i were calculated using ACEi and β-blockers as the reference
standard. Additionally, we quantified individual patient-level survival benefits by modeling the incremental advantage of various treatment combinations under the theoretical assumption of no prior therapy (i.e., placebo). Number-needed-to-treat (NNT) values were derived from estimated 2-year survival differences between each treatment regimen and placebo, with confidence intervals calculated using nonparametric bootstrap resampling. All statistical analyses were conducted using the netmeta package in R (version 4.0.2), with p-values < 0.05 considered statistically significant.

## Sensitivity analyses

We performed a meta-regression using all-cause mortality as the primary outcome to test the association between study year on treatment effect, as well as between age and treatment effect. In addition, we performed a leave-one-out analysis excluding the results of the VICTOR trial. We conducted a sensitivity analysis assuming 80% adherence after two years of treatment. In these analyses, treatment effects were adjusted for each patient's current therapy, with 20% of patients randomly assigned to remain on their existing treatment and not reach the target combination. We additionally performed a sensitivity analysis excluding the A-HeFT trial, given its influence on the estimated effect sizes of the individual drugs. Lastly, in sensitivity analysis, we varied the threshold for background therapy from 50% to 70% and 90%.

## Results

### Study Identification and Inclusion

The systematic search identified 5,065 additional entries. After screening titles and abstracts, 17 full-text articles met the eligibility criteria<sup>29-44</sup>[REF VICTOR]. We identified only three articles using GLP-1 agonists, involving a total of 619 patients with only 36 mortality events, which we considered too few to provide meaningful estimates and were therefore excluded. Additionally, we incorporated data from the VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial. Collectively, 89 studies were included for analysis (Figure 1), representing 103,754 patients with a cumulative follow-up of 199,724 patient-years.
In total, 17 studies had fewer than 100 participants, while 24 studies included over 1,000 participants. The median follow-up duration across studies was 9 months (interquartile range [IQR]: 5.5-18.4 months). Baseline age (Supplementary Figure 1) and left ventricular ejection fraction (LVEF) were largely consistent across studies (Supplementary Figure 2).

## Bias Assessment and Publication Bias

The overall risk of bias was low (Supplementary Figure 3). The primary source of bias was a lack of blinding and reporting bias (Supplementary Table 1). There was no significant evidence of reporting bias based on Egger's test: mortality (P = 0.072), CV death and HF hospitalization composite (P = 0.705), or CV death alone (P = 0.177) (Supplementary Figure 4). Indirectness was considered low. Most comparisons did not show imprecision. Heterogeneity estimates were low to moderate: I² = 0% (range 0.0%-27.4%; P = 0.688) for all-cause mortality, 10.5% (range from 0.0%-49.8%; P = 0.342) for the composite of CV death or HF hospitalization, and 3.1% (range from 0.0%-28.7%; P = 0.412) for CV mortality. τ² estimates were 0 for all-cause mortality, 0.0013 for cardiovascular mortality or heart failure hospitalization, and 0.0012 for cardiovascular mortality. No evidence of incoherence was found (P > 0.10). Confidence ratings were primarily high or moderate. The additive model assumptions test was non-significant for all outcomes (P>0.5 for all). Observed versus predicted effects and additive model assumptions tests for all outcomes can be found in Supplementary Table 5 – 10.

## Outcomes

All-cause mortality was reported in 84 studies with 102,489 patients and 18,520 deaths (Supplemental Table 3). The HR for all-cause mortality of the quintuple combination of ARNI, β-blockers, MRA, SGLT2i, and vericiguat versus placebo was 0.35; 95% CI: 0.27 - 0.45. For the quadruple combination of ARNI, β-blockers, MRA, and SGLT2i, this was 0.39; 95% CI: 0.32 - 0.49. (Figure 2A). Supplemental Table 4 ranks treatment regimens using SUCRA P values and the network is shown in Supplementary Figure 5 and 6. Comparisons between
combinations showed that the quintuple combination of ARNi, β-blockers, MRA, SGLT2i and vericiguat was associated with a significantly lower hazard for all-cause mortality compared to the quadruple combination of ARNI, β-blockers, MRA and SGLT2i (HR: 0.88, 95% CI: 0.79 - 0.98) (Supplementary Table 11). The association between individual treatments and all-cause mortality showed that H-ISDN was associated with the lowest risk of all-cause mortality (HR: 0.68, 95% CI: 0.54 - 0.86), followed by MRAs (HR: 0.76, 95% CI 0.67 - 0.85) and ARNI (HR: 0.76, 95% CI 0.67 - 0.87) (Figure 3A).

Among the included studies, 21 assessed the composite endpoint of CV death or HF hospitalization. The HR for the quintuple therapy of ARNi, β-blockers, MRA, SGLT2i and vericiguat for the composite outcome of CV mortality or HF hospitalization was 0.34; 95% CI: 0.26 - 0.43, followed by the combination of ARB, β-blockers and MRA (HR: 0.36; 95% CI: 0.22 - 0.59) and ARNi, β-blockers, MRA and SGLT2i (HR: 0.36; 95% CI 0.29 - 0.46) (Figure 2B). There was no significant difference between the combination of ARNi, β-blockers, MRA, SGLT2i and vericiguat versus ARNi, β-blockers, MRA and SGLT2i (HR: 0.93; 95% CI 0.85 - 1.02) (Supplementary Table 12).

Among the included studies, 55 reported CV death as a standalone outcome. The HR of the quintuple combination was HR: 0.30; 95% CI: 0.22 - 0.39. For the quadruple combination of ARNi, β-blockers, MRA and SGLT2i the HR was HR 0.34; 95% CI: 0.27 - 0.44, and for the quadruple combination of ARNi, β-blockers, MRA and vericiguat the HR was 0.34; 95% CI: 0.27 - 0.44. The quintuple combination of ARNi, β-blockers, MRA, SGLT2i and vericiguat was associated with a significantly lower hazard of CV mortality compared to the quadruple combination of both ARNi, β-blockers, MRA and SGLT2i (HR: 0.87; 95% CI: 0.77 - 0.98) and to the quadruple combination of ARNi, β-blockers, MRA and vericiguat (HR: 0.87; 95% CI: 0.76 - 0.99) (Supplementary Table 13). The association between individual treatments and CV mortality showed that ARNI was associated with the lowest risk of CV mortality (HR: 0.69, 95% CI: 0.60 - 0.79), followed by MRAs (HR: 0.74, 95% CI 0.64 - 0.84) and β-blockers (HR: 0.78,
95% CI 0.71 – 0.86) (Figure 3B). Network plots for all outcomes are provided in Supplementary
Figures 6-8.

Secondary analysis

Supplementary Figures 9-11 show era-stratified analyses. The heterogeneity among the eras was low (pre-2000 I2 2.9%, τ2 0.002, 2000-2010 max I2 22.2%, τ2 0.008, post-210 I2 0%, τ2 0). In the contemporary era the HR for all-cause mortality of treatment with quintuple therapy was 0.60 (95% CI 0.53, 0.41 – 0.69). For the quadruple therapy this was 0.60 (95% CI 0.47 – 0.77).

Estimated Life-Years Gained and Number Needed to Treat

Survival modeling was performed in 7,376 patients from the BIOSTAT-CHF and ASIAN-HF, which included patients treated with ACEi and BB. Median age was 63 years (IQR: 54-72 years), with 1,664 (23%) women and 2,904 (43%) in NYHA class III/IV. Over a median follow-up of 22 months (IQR: 12-25 months), 1,287 (19%) of participants died.

At baseline, 5,691 (77%) patients were on ACEi/ARB, 6,018 (82%) on BB, and 4,093 (55%) on MRA. Compared with no treatment, the quintuple regimen of ARNi, β-blockers, MRA, SGLT2i, and vericiguat increased life expectancy by 9.2 life-years (95% CI, 6.0 -12.4 life-years) in 50-year-olds and 6.0 life-years (95% CI, 3.7 - 8.4 life-years) in 70-year-olds (Supplemental Table 14). Compared with no treatment, the quadruple regimen of ARNi, β-blockers, MRA, and SGLT2i increased life expectancy by 7.8 life-years (95% CI 4.6 - 11.1 life-years) in 50-year-olds and 5.3 life-years (95% CI 2.8 - 7.7 life-years) in 70-year-olds. Similar trends were observed between the BIOSTAT-CHF and ASIAN-HF cohorts. When evaluating a scenario where drug adherence was 80% after 2 years, the quintuple combination of ARNi, β-blockers, MRA, SGLT2i, and vericiguat increased life-expectancy by 5.9 life-years (95% CI 2.54 – 9.19) for a 50-year-old and 2.67 life-years (95% CI 0.1 – 5.2) for a 70-year-old (Supplementary Table 15). The NNT for ARNI + β-blockers + MRA + SGLT2i
was 6.3 (95% CI 6.2-6.4), and for the quintuple combination adding vericiguat was 5.8 (95% CI 5.8-5.9). Complete NNT results are provided in Supplementary Table 16.

## Sensitivity analyses

When excluding VICTOR, the quadruple regimen of ARNI, β-blockers, MRA and SGLT2i was found to be associated with the lowest risk of all-cause mortality (HR: 0.36, 95% CI 0.29-0.46) (Figure 5 and Supplementary Figures 12 – 14).

In sensitivity analyses using higher background therapy thresholds, the 70% threshold, the quadruple combination of ARNI, β-blockers, MRA, and SGLT2i demonstrated the most significant mortality benefit (HR 0.39, 95% CI 0.32-0.49), followed closely by the combination of ARNI, β-blockers, MRA, and vericiguat (HR 0.42, 95% CI 0.33-0.54).

When the threshold was increased to 90%, two triple-drug combinations showed equivalent efficacy: ARNI, β-blockers, and MRA (HR 0.47, 95% CI 0.39-0.56) and ARNI, β-blockers, and vericiguat (HR 0.47, 95% CI 0.39-0.57, Supplementary Figures 15 – 20. A meta-regression did not find any association between study year and treatment effect (estimate = 0.0022 ± 0.0032; p = 0.487) or between age and treatment effect (estimate = 0.0006 ± 0.007 p-value 0.941).

Results for the individual drugs are presented in Supplementary Figure 21, which displays the estimated effect sizes after exclusion of the A-HeFT trial. H-ISDN remained the drug associated with the largest reduction in all-cause mortality (HR 0.72, 95% CI 0.55–0.95).

## Discussion

Results from this updated network meta-analysis (1) confirm the robust evidence for the mortality and morbidity benefit of the currently recommended quadruple therapy regimen —ARNI, β-blockers, MRA, and SGLT2i—in patients with HFrEF. The addition of vericiguat may confer a modest incremental survival benefit. (2) The addition of vericiguat has the
possibility of adding an additional 0.7 years beyond quadruple therapy; however, this finding
is exploratory and derived from a secondary endpoint of a single trial.

The present analysis represents the most comprehensive evaluation of contemporary
HFrEF pharmacotherapy to date, incorporating data from 89 randomized controlled trials and
over 103,000 patients. Importantly, our findings are consistent with and extend previous
network meta-analyses while adding substantial new evidence. ¹⁰⁻¹⁶ Previous analyses were
limited by the nascent adoption of SGLT2i therapy.¹⁰⁻¹⁶ Our updated network incorporates
new evidence from trials conducted during widespread SGLT2i use, enabling more precise
estimates of additive therapeutic benefits across contemporary treatment paradigms. These
findings further strengthen the evidence supporting the incorporation of SGLT2 inhibitors into
the currently recommended quadruple therapy regimen. The inclusion of the VICTOR trial
data, which enrolled the highest proportion of patients receiving comprehensive background
therapy including SGLT2i, provides important additional insights into the effects of vericiguat
in patients with HFrEF. In the previously published VICTORIA trial, vericiguat demonstrated a
modest reduction in the composite endpoint of cardiovascular death or hospitalization for
heart failure among patients with high-risk heart failure. The VICTOR trial randomized
approximately 6,000 stable ambulatory patients without a recent HF hospitalization or
intravenous diuretic use were randomized to vericiguat or placebo added to contemporary
guideline-directed therapy. Vericiguat did not significantly reduce the primary composite
endpoint of cardiovascular death or hospitalization for heart failure. However, both all-cause
mortality and cardiovascular mortality were lower in the vericiguat group. Accordingly, the
finding from the present network meta-analysis that the addition of vericiguat may confer a
modest incremental survival benefit on top of quadruple therapy is based on a secondary
endpoint from a single trial and should therefore be interpreted with caution. The pooled
analysis of VICTOR and VICTORIA trials (Zannad et al., 2025) suggests that the beneficial
effects of vericiguat may be most pronounced in patients with NT-proBNP ≤6000 pg/ml,
highlighting the importance of careful patient selection. Importantly, clinical implementation
might face significant challenges, including increased pill burden, potential adherence issues, and complex monitoring requirements that may limit real-world effectiveness. In addition, higher costs compared to most of the therapies from the quadruple treatment regimen that ran out of patent, might limit the availability in parts of the world. Further research is needed to assess the optimal sequence of up-titration and to evaluate clinical feasibility and the potential risk of discontinuation associated with the simultaneous use of multiple therapies.

Our analyses showed that quadruple therapy was associated with 5.3 life years gained, compared to no therapy in a 70-year-old patient. New evidence from trials conducted during widespread SGLT2i use resulted in an even more robust estimation compared to the previous network meta-analysis. These findings extend prior cross-trial analyses, which have demonstrated substantial survival benefits from comprehensive disease-modifying therapy.¹¹,⁴⁵ Vaduganathan et al. used indirect comparisons across EMPHASIS-HF, PARADIGM-HF, and DAPA-HF to estimate that quadruple therapy could extend survival by 1.4 to 6.3 years relative to conventional treatment with ACEi/ARB and β-blockers, depending on patient age.⁴⁵ The addition of vericiguat may provide an incremental survival gain of approximately 0.7 years beyond that achieved with quadruple therapy. However, these results should be regarded as exploratory, as they are derived from a secondary endpoint of a single trial. The differential benefit by age strata, with attenuated effects in older patients, likely reflects competing non-cardiovascular mortality and highlights the importance of considering life expectancy when implementing intensive multi-drug regimens. Patient-centered outcomes such as event-free survival years may provide valuable complementary information for clinical decision-making. Similarly, our previous network meta-analysis of 75 trials found that ARNi, β-blockers, MRA, and SGLT2i provided 5.0 life-years gained in a 70-year-old patient compared to no treatment.¹¹

## Limitations

The current study has several limitations that should be acknowledged. First, some degree of disagreement between direct and indirect evidence may remain undetected, particularly in less well-connected parts of the network where fewer trials provide comparisons
between specific treatment combinations. While our global inconsistency tests did not reveal
significant incoherence, localized inconsistencies may still exist that could affect the precision
of estimates for specific comparisons. Second, the exclusion of three small GLP-1RA trials due
to network connectivity constraints and imprecise estimates represents a limitation, though
these emerging therapies may warrant separate systematic evaluation as the evidence base
expands. Third, real-world applicability and generalizability may differ substantially from trial-
based estimates. Trial populations often include highly selected populations and may vary from
broader clinical populations in terms of comorbidities, medication adherence, healthcare
access, and concurrent treatments. Fourth, our life-years gained calculations assume
sustained adherence to treatment over time, which may not fully reflect real-world patterns.
Treatment discontinuation rates vary considerably across drug classes and patient
populations, and declining adherence over time could diminish the projected survival benefits.
To account for this, we also modelled a reduced-adherence scenario, which yielded consistent
conclusions regarding the relative treatment effects. Fifth, the substantial period over which
trials were conducted (1987-2025) may have introduced temporal bias. Changes in
background medical therapy, diagnostic criteria, clinical care standards, and patient
populations over nearly four decades could affect the consistency of treatment effects across
studies. However, temporal analyses did not identify substantial heterogeneity. Finally, the
quintuple therapy node is based on a single RCT (VICTOR), which limits the robustness of
these conclusions despite favorable effect estimates and narrow confidence intervals.
Consequently, the evidence supporting the quintuple therapy node is derived from a single
RCT, which may limit the robustness of the conclusion and stress the need for additional trials
with high rates of background therapy.

Conclusion

In patients with HFrEF, treatment with the quadruple combination of ARNi, β-blockers, MRA and SGLT2i is associated with mortality and morbidity benefit. The addition of vericiguat may confer a modest incremental survival benefit. The addition of vericiguat may provide an
incremental survival gain of approximately 0.7 years beyond that achieved with quadruple
therapy. However, these results should be regarded as exploratory, as they are derived from a
secondary endpoint of a single trial.
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**Figure 1 – Study selection flowchart**

Flow diagram showing the identification, screening, eligibility assessment, and inclusion of randomized controlled trials evaluating pharmacological therapies in heart failure with reduced ejection fraction (HFrEF). The diagram outlines the number of records retrieved from databases, reasons for exclusion at each stage, and the final set of studies included in the network meta-analysis.

**Figure 2 – Forest plot of hazard ratios for treatment regimens**

Forest plots summarizing the estimated hazard ratios for (A) all-cause mortality, (B) cardiovascular (CV) mortality, and (C) the composite of CV death or heart failure (HF) hospitalization for all evaluated drug combinations in HFrEF. Results are derived from the network meta-analysis, with placebo as the reference, and abbreviations are provided for each drug class. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; CV: cardiovascular; Dig: digoxin; HR: hazard ratio; H-ISDN: hydralazine-isosorbide dinitrate; HF: heart failure; IVA: ivabradine; MRA: mineralocorticoid receptor antagonist; PLBO: placebo; SGLT2: sodium glucose cotransporter-2 inhibitors. * The incremental benefit of quintuple therapy is exploratory and based on a single trial's secondary endpoint.

**Figure 3 – Effects of individual drug classes on mortality**

Forest plots showing the association between each pharmacological class and (A) all-cause mortality and (B) CV mortality in HFrEF patients, based on pooled hazard ratios from the network meta-analysis. Placebo is used as the reference category, and abbreviations for drug classes are provided. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; CV: cardiovascular; Dig: digoxin; HR: hazard ratio; H-ISDN: hydralazine-isosorbide dinitrate; IVA: ivabradine; MRA: mineralocorticoid receptor antagonist; PLBO: placebo; SGLT2: sodium glucose cotransporter-2 inhibitors.

**Figure 4A – Survival benefit at age 50**

Estimated life-years gained for a 50-year-old patient with HFrEF receiving different pharmacological regimens, compared with placebo. Estimates are derived from the network meta-analysis and survival modelling, illustrating the potential magnitude of benefit in a younger patient population. ACEI: angiotensin-converting enzyme inhibitor; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; MRA:
mineralocorticoid receptor antagonist, PLBO: placebo, SGLT2: sodium glucose cotransporter-2 inhibitors.

The incremental benefit of quintuple therapy is exploratory and based on a single trial's secondary endpoint.

## Figure 4B – Survival benefit at age 70

Estimated life-years gained for a 70-year-old patient with HFrEF receiving different pharmacological regimens, compared with placebo. Estimates are derived from the network meta-analysis and survival modelling, illustrating the potential but comparatively smaller benefit in an older patient population. ACEI: angiotensin-converting enzyme inhibitor; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; PLBO: placebo; SGLT2: sodium glucose cotransporter-2 inhibitors. The incremental benefit of quintuple therapy is exploratory and based on a single trial's secondary endpoint.

## Figure 5. Panel figure of the leave-one-out sensitivity analysis excluding the VICTOR trial

Panel figure displaying the results of the leave-one-out sensitivity analysis excluding the VICTOR trial. Shown are the estimated hazard ratios (HRs) and 95% confidence intervals for (A) all-cause mortality, (B) cardiovascular mortality, and (C) the composite of cardiovascular mortality and heart failure hospitalization.
<figure><img src="image_4.png" /></figure>
<figure><img src="image_5.png" /><figcaption>**Figure 1.** Flowchart of screened and included studies.</figcaption></figure>
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A

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B

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<figure><img src="image_11.png" /><figcaption>**Figure 4A:** Figure 4A - Survival benefit at age 50 Estimated life-years gained for a 50-year-old patient with HFrEF receiving different pharmacological regimens, compared with placebo. Estimates are derived from the network meta-analysis and survival modelling, illustrating the potential magnitude of benefit in a younger patient population.</figcaption></figure>
<figure><img src="image_12.png" /><figcaption>**Figure 4B:** Estimated life-years gained for a 70-year-old patient with HFrEF receiving different pharmacological regimens, compared with placebo. Estimates are derived from the network meta-analysis and survival modelling, illustrating the potential but comparatively smaller benefit in an older patient population.</figcaption></figure>
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## Supplementary Material

### Index

<table><tr><td><strong>Supplementary Tables</strong></td><td><strong>4</strong></td></tr><tr><td>Supplementary Table 1: Risk of Bias</td><td>4</td></tr><tr><td>Supplementary Table 2: CINEMA Framework</td><td>9</td></tr><tr><td>Supplementary Table 3: Outcomes and follow-up of included studies</td><td>29</td></tr><tr><td>Supplementary Table 4: SUCRA p-values</td><td>38</td></tr><tr><td>Supplementary Table 5: Additive model assumptions test – summary for all-cause mortality</td><td>40</td></tr><tr><td>Supplementary Table 6: Predicted versus observed effects for all-cause mortality</td><td>41</td></tr><tr><td>Supplementary Table 7: Additive model assumptions test – summary for cardiovascular mortality</td><td>42</td></tr><tr><td>Supplementary Table 8: Predicted versus observed effects for cardiovascular mortality</td><td>43</td></tr><tr><td>Supplementary Table 9: Additive model assumptions test – summary for cardiovascular mortality or heart failure hospitalization</td><td>44</td></tr><tr><td>Supplementary Table 10: Predicted versus observed effects for cardiovascular mortality or heart failure hospitalization</td><td>45</td></tr><tr><td>Supplementary Table 11: Relative differences in all-cause death for different treatment combinations. The estimates presented are for the treatment combination in the column versus the treatment combination in the respective row</td><td>46</td></tr><tr><td>Supplementary Table 12: Relative differences in cardiovascular mortality and heart failure hospitalizations for different treatment combinations. The estimates presented are for the treatment combination in the column versus the treatment combination in the respective row</td><td>47</td></tr><tr><td>Supplementary Table 13: Relative differences in cardiovascular mortality for different treatment combinations. The estimates presented are for the treatment combination in the column versus the treatment combination in the respective row</td><td>48</td></tr><tr><td>Supplementary Table 14: Number of life years saved in the combined cohort compared to no treatment, ASIAN-HF and BIOSTAT-CHF</td><td>50</td></tr><tr><td>Supplementary Table 15: Number of life years saved in the combined cohort compared to no treatment, ASIAN-HF and BIOSTAT-CHF when adherence after 2 years is 80%</td><td>51</td></tr><tr><td>Supplementary Table 16: Number needed to treat (NNT) for different treatment regimens to prevent one case of all-cause mortality</td><td>53</td></tr><tr><td><strong>Supplementary Figures</strong></td><td><strong>55</strong></td></tr><tr><td>Supplementary Figure 1: Mean or median age per study with 95% confidence intervals</td><td>55</td></tr><tr><td>Supplementary Figure 2: Mean or median left ventricular ejection fraction per study with 95% confidence intervals</td><td>57</td></tr><tr><td>Supplementary Figure 3: Risk of Bias</td><td>59</td></tr></table>
<table><tr><td>Supplementary Figure 4: Funnel Plots for (A) all-cause mortality, (B) cardiovascular mortality, (C) cardiovascular mortality and heart failure hospitalization.</td><td>60</td></tr><tr><td>Supplementary Figure 5: Network for all-cause mortality.</td><td>62</td></tr><tr><td>Supplementary Figure 6: Network plot of available direct treatment comparisons for all-cause mortality.</td><td>63</td></tr><tr><td>Supplementary Figure 7: Network plot of available direct treatment comparisons for cardiovascular mortality or heart failure hospitalization.</td><td>64</td></tr><tr><td>Supplementary Figure 8: Network plot of available direct treatment comparisons for cardiovascular mortality.</td><td>65</td></tr><tr><td>Supplementary Figure 9: Era-stratified analyses for all-cause mortality. Pre-2000 era.</td><td>66</td></tr><tr><td>Supplementary Figure 10: Era-stratified analyses for all-cause mortality. Era between 2000-2010.</td><td>67</td></tr><tr><td>Supplementary Figure 11: Era-stratified analyses for all-cause mortality. Post-2010 era.</td><td>68</td></tr><tr><td>Supplementary Figure 12: Sensitivity analysis leave-one-out analysis excluding VICTOR trial results for all-cause mortality.</td><td>69</td></tr><tr><td>Supplementary Figure 13: Sensitivity analysis leave-one-out analysis excluding VICTOR trial results for cardiovascular mortality or heart failure hospitalization.</td><td>70</td></tr><tr><td>Supplementary Figure 14: Sensitivity analysis leave-one-out analysis excluding VICTOR trial results for cardiovascular mortality.</td><td>71</td></tr><tr><td>Supplementary Figure 15: Sensitivity analysis with background therapy cut-off of 70%. Forest plot for treatment effects of treatment regimens for all-cause mortality.</td><td>72</td></tr><tr><td>Supplementary Figure 16: Sensitivity analysis with background therapy cut-off of 70%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality or heart failure hospitalization.</td><td>73</td></tr><tr><td>Supplementary Figure 17: Sensitivity analysis with background therapy cut-off of 70%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality.</td><td>74</td></tr><tr><td>Supplementary Figure 18: Sensitivity analysis with background therapy cut-off of 90%. Forest plot for treatment effects of treatment regimens for all-cause mortality.</td><td>75</td></tr><tr><td>Supplementary Figure 19: Sensitivity analysis with background therapy cut-off of 90%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality or heart failure hospitalization.</td><td>76</td></tr><tr><td>Supplementary Figure 20: Sensitivity analysis with background therapy cut-off of 90%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality.</td><td>77</td></tr><tr><td>Supplementary Figure 21: Forest plots displaying the estimated effect sizes for individual drugs after exclusion of the A-HeFT trial.</td><td>78</td></tr><tr><td>Protocol and Search Strategy</td><td>79</td></tr><tr><td>References</td><td>85</td></tr></table>
<figure><img src="image_17.png" /></figure>
Supplementary Tables

<table><caption>Supplementary Table 1: Risk of Bias.</caption><thead><tr><th>Study ID</th><th>D1</th><th>D2</th><th>D3</th><th>D4</th><th>D5</th><th>Overall</th><th></th></tr></thead><tbody><tr><td>Dogheim 2022</td><td>+</td><td>+</td><td>+</td><td>+</td><td>!</td><td>!</td><td>Low risk</td></tr><tr><td>Bano 2021</td><td>+</td><td>-</td><td>+</td><td>-</td><td>!</td><td>-</td><td>Some concerns</td></tr><tr><td>Halle 2021</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>High risk</td></tr><tr><td>Jorsal 2017</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td></td></tr><tr><td>Lewis 2022</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td></td></tr><tr><td>Lin 2024</td><td>+</td><td>+</td><td>+</td><td>+</td><td>!</td><td>!</td><td>Randomisation process</td></tr><tr><td>Mann 2021</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>Deviations from the intended interventions</td></tr><tr><td>Margulies 2016</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>Missing outcome data</td></tr><tr><td>Palau 2022</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>Measurement of the outcome</td></tr><tr><td>Pastore 2024</td><td>+</td><td>+</td><td>+</td><td>-</td><td>+</td><td>-</td><td></td></tr><tr><td>Reis 2022</td><td>+</td><td>+</td><td>+</td><td>+</td><td>!</td><td>!</td><td></td></tr><tr><td>Santos 2021</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td></td></tr><tr><td>Santos-Gallego 2021</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td></td></tr><tr><td>Tsutsui 2021</td><td>!</td><td>+</td><td>+</td><td>+</td><td>+</td><td>!</td><td></td></tr><tr><td>Ye 2022</td><td>-</td><td>+</td><td>+</td><td>+</td><td>+</td><td>-</td><td></td></tr><tr><td>Zhang 2017</td><td>+</td><td>+</td><td>+</td><td>!</td><td>+</td><td>!</td><td></td></tr></tbody></table>
Cohn 1986

Chalmers 1987

CONSENSUS

Captopril-Digoxin Group

Lewis 1989

SOLVD-treat 1991

SOLVD-prevent 1992

Colfer 1992

Hy-C 1992

MHFT 1993

Veldhuisen 1993

CIBIS I 1994

Dickstein 1995

CASSIS 1995

Krum 1995

Brown 1995

FEST 1995

Beller 1995

Colucci 1996

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MOCHA 1996

PRECISE 1996

Packer 1996

Losartan Pilot Exercise 1997

ELITE I 1997

Cohn 1997

Digitalis Investigation Group
1997

Veldhuisen 1998

Hamroff 1999

STRETCH 1999

MERIT-HF (pilot) 1999

CIBIS II 1999

RALES 1999

ELITE II 2000

RESOLVD (pilot) 2000

MERIT-HF 1999

MIC 2000

Spice 2000

CELICARD 2000

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Sturm 2000

Val-HeFT 2001

BEST 2001

COPERNICUS 2001

REPLACE 2001

deMilliano 2002

Dubach 2002

Cicoira 2002

HEAVEN 2002

Mitrovic 2003

RESOLVD 2003

CHARM-Alternative

CHARM-Added

SYMPOXYDEX 2004

A-HeFT 2004

MUCHA

CARMEN 2004

CIBIS III 2005

ENECA 2005

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Palazzuoli 2005

Palazzuoli 2005b

AREA IN-CHF

SENIORS 2009

SHIFT 2010

EMPHASIS-HF 2011

PARADIGM-HF 2014

Vizzardi 2014

SOCRATES reduced 2015

COSMIC HF 2016

J-EMPHASIS-HF 2017

PIONEER-HF

DAPA-HF 2019(70)

J-SHIFT 2019

EMPEROR-REDUCED 2020

GALACTIC-HF 2020

VICTORIA 2020

Shettigar 1999

VICTOR 2025

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<table><caption>Supplementary Table 2: CINEMA Framework</caption><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI:ACEI + BB</td><td>7</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARB</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:BB</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI:Dig</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:PLBO</td><td>6</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + ARB + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ARB + BB + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ARB + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + Dig:ACEI + Dig</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARB + BB + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARB + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB:ACEI + BB + MRA</td><td>5</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB:ARB + BB</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB:ARNI + BB</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB:BB</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ACEI + BB + Dig + H-ISDN</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ACEI + Dig</td><td>16</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ACEI + BB + MRA + IVA</td><td>4</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ACEI + BB + MRA + Omecamtiv</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA:ACEI + BB + MRA + SGLT2</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA:ACEI + BB + MRA + Vericiguat</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA:ARNI + BB + MRA</td><td>3</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ACEI + MRA + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARB + Dig</td><td>3</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + Dig:Dig</td><td>7</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:Dig + H-ISDN</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB:PLBO</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB:BB</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + Dig:ARB + Dig</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + MRA:ARNI + BB + MRA</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + Dig:Dig</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB:ARNI + BB + SGLT2</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + MRA:ARNI + BB + MRA + Omecamtiv</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ARNI + BB + MRA:ARNI + BB + MRA + SGLT2</td><td>3</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA:ARNI + BB + MRA + Vericiguat</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>Dig:Dig + H-ISDN</td><td>1</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>Some concerns</td><td>Moderate</td></tr><tr><td>Dig:PLBO</td><td>2</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + BB + Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + BB + MRA + IVA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ACEI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB + Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB + MRA + IVA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + BB + Dig:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + BB + Dig:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + ARB + BB + Dig:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + BB + Dig:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + BB + Dig:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + BB + Dig:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + BB + Dig:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB + Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB + MRA + IVA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + Dig:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + Dig:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + Dig:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + ARB + Dig:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + ARB + Dig:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + ARB + Dig:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + ARB + Dig:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ACEI + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ACEI + BB + Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ACEI + BB + MRA + IVA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ACEI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ACEI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ACEI + BB + MRA + IVA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ACEI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB + Dig:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ACEI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ACEI + BB + MRA + IVA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ACEI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB + Dig + H-ISDN:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + Dig + H-ISDN:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB + MRA:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ACEI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + IVA:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + IVA:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + IVA:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + IVA:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + IVA:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + IVA:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + IVA:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB + MRA + IVA:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + IVA:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + IVA:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + IVA:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ACEI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>Some concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB + MRA + Omecamtiv:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ACEI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB + MRA + SGLT2:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>Some concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + SGLT2:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + SGLT2:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + SGLT2:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ACEI + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ACEI + MRA + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + BB + MRA + Vericiguat:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + BB + MRA + Vericiguat:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + Dig:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + Dig:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + Dig:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + Dig:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + Dig:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + Dig:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + MRA + Dig:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ACEI + MRA + Dig:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + MRA + Dig:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ACEI + MRA + Dig:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ACEI + MRA + Dig:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ACEI + MRA + Dig:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARB + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ARB:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB:ARB + BB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB + BB:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB + BB:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + Dig:ARB + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB + BB + Dig:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + Dig:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + Dig:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ARB + BB + Dig:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + Dig:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + Dig:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + Dig:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB + BB + Dig:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + Dig:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + Dig:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + Dig:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + MRA:ARB + Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + MRA:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + MRA:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + MRA:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + MRA:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB + BB + MRA:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + MRA:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB + BB + MRA:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + BB + MRA:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + MRA:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + BB + MRA:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + Dig:ARNI + BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + Dig:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ARB + Dig:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + Dig:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + Dig:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + Dig:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + Dig:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARB + Dig:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARB + Dig:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARB + Dig:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB:ARNI + BB + MRA</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB:ARNI + BB + MRA + Omecamtiv</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB + MRA:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + MRA:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB + MRA:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ARNI + BB + MRA:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:ARNI + BB + MRA + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + MRA + SGLT2:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB + MRA + SGLT2:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat:ARNI + BB + MRA + Vericiguat</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>
<table><thead><tr><th>Comparison</th><th>Number of studies</th><th>Within-study bias</th><th>Reporting bias</th><th>Indirectness</th><th>Imprecision</th><th>Heterogeneity</th><th>Incoherence</th><th>Confidence rating</th></tr></thead><tbody><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Vericiguat:ARNI + BB + SGLT2</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + MRA + Vericiguat:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>ARNI + BB + MRA + Vericiguat:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Vericiguat:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + MRA + Vericiguat:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>ARNI + BB + SGLT2:BB</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + SGLT2:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + SGLT2:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>ARNI + BB + SGLT2:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Major concerns</td><td>No concerns</td><td>No concerns</td><td>Low</td></tr><tr><td>BB:Dig</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr><tr><td>BB:Dig + H-ISDN</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>BB:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>Some concerns</td><td>No concerns</td><td>No concerns</td><td>Moderate</td></tr><tr><td>Dig + H-ISDN:PLBO</td><td>0</td><td>No concerns</td><td>Low risk</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>No concerns</td><td>High</td></tr></tbody></table>

**Abbreviations:** ACEI, ACE-inhibitor; ARB, angiotensin-receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blocker; Dig, digoxin; H-ISDN, hydralazine-isosorbide dinitrate; MRA, mineralocorticoid receptor antagonist; PLBO, placebo; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
<table><caption>Supplementary Table 3: Outcomes and follow-up of included studies</caption><thead><tr><th>Study</th><th>Drug classes</th><th>Treatment duration (mean/median) months</th><th>Patients randomized</th><th>Number of males</th><th>mean/median LVEF</th><th>SD/IQR LVEF</th><th>mean/median age</th><th>SD/IQR age</th><th>Ischaemic HF</th><th>All-cause mortality</th><th>CV mortality</th><th>Composit CV/HFhosp</th><th>Number of discontinuating patients</th></tr></thead><tbody><tr><td>Cohn 1986</td><td>Dig</td><td>27.6</td><td>273.00</td><td>273</td><td>30.4</td><td>NR</td><td>58.50</td><td>NR</td><td>NR</td><td>120</td><td>NR</td><td>NR</td><td>47</td></tr><tr><td>Cohn 1986</td><td>Dig + IDH</td><td>27.6</td><td>186.00</td><td>186</td><td>30.3</td><td>NR</td><td>58.30</td><td>NR</td><td>NR</td><td>72</td><td>NR</td><td>NR</td><td>60</td></tr><tr><td>Chalmers 1987</td><td>ACEI</td><td>3</td><td>87</td><td>62</td><td>NR</td><td>NR</td><td>56.70</td><td>18-79</td><td>41</td><td>4</td><td>NR</td><td>NR</td><td>7.00</td></tr><tr><td>Chalmers 1987</td><td>Dig</td><td>3</td><td>43</td><td>28</td><td>NR</td><td>NR</td><td>60.30</td><td>29-79</td><td>21</td><td>3</td><td>NR</td><td>NR</td><td>4.00</td></tr><tr><td>CONSENSUS 1987</td><td>ACEI + Dig</td><td>12</td><td>127</td><td>89</td><td>NR</td><td>NR</td><td>71</td><td>NR</td><td>NR</td><td>46</td><td>44</td><td>NR</td><td>17.00</td></tr><tr><td>CONSENSUS 1987</td><td>Dig</td><td>12</td><td>126</td><td>89</td><td>NR</td><td>NR</td><td>70</td><td>NR</td><td>NR</td><td>66</td><td>64</td><td>NR</td><td>12.00</td></tr><tr><td>Captopril-Digoxin group 1988</td><td>ACEI</td><td>6</td><td>104</td><td>88</td><td>24.5</td><td>NR</td><td>54.80</td><td>NR</td><td>67</td><td>8</td><td>NR</td><td>NR</td><td>3</td></tr><tr><td>Captopril-Digoxin group 1988</td><td>PLBO</td><td>6</td><td>100</td><td>78</td><td>25.1</td><td>NR</td><td>57.30</td><td>NR</td><td>62</td><td>6</td><td>NR</td><td>NR</td><td>0</td></tr><tr><td>Captopril-Digoxin group 1988</td><td>Dig</td><td>6</td><td>96</td><td>84</td><td>25.40</td><td>NR</td><td>58.30</td><td>NR</td><td>57</td><td>7</td><td>NR</td><td>NR</td><td>4</td></tr><tr><td>Lewis 1989</td><td>ACEI + Dig</td><td>3</td><td>87</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>4</td><td>NR</td><td>NR</td><td>9</td></tr><tr><td>Lewis 1989</td><td>Dig</td><td>3</td><td>43</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>3</td><td>NR</td><td>NR</td><td>3</td></tr><tr><td>SOLVD-treat 1991</td><td>ACEI + Dig</td><td>55</td><td>1285</td><td>1040</td><td>24.8</td><td>NR</td><td>60.70</td><td>NR</td><td>902</td><td>452</td><td>399</td><td>NR</td><td>182</td></tr><tr><td>SOLVD-treat 1991</td><td>Dig</td><td>55</td><td>1284</td><td>1025</td><td>24.9</td><td>NR</td><td>61.00</td><td>NR</td><td>926</td><td>510</td><td>461</td><td>NR</td><td>320</td></tr><tr><td>SOLVD-prevent 1992</td><td>ACEI</td><td>48</td><td>2111</td><td>1868</td><td>28.0</td><td>NR</td><td>59.10</td><td>NR</td><td>1763</td><td>313</td><td>265</td><td>NR</td><td>507</td></tr><tr><td>SOLVD-prevent 1992</td><td>PLBO</td><td>48</td><td>2117</td><td>1876</td><td>28.0</td><td>NR</td><td>59.10</td><td>NR</td><td>1755</td><td>334</td><td>298</td><td>NR</td><td>571</td></tr><tr><td>Colfer 1992</td><td>ACEI + Dig</td><td>3</td><td>114</td><td>94.00</td><td>25.0</td><td>7.0</td><td>62.00</td><td>39-87</td><td>64.00</td><td>3</td><td>2.00</td><td>NR</td><td>12</td></tr><tr><td>Colfer 1992</td><td>Dig</td><td>3</td><td>58</td><td>49.00</td><td>25.0</td><td>1.0</td><td>61.00</td><td>29-79</td><td>32.00</td><td>0</td><td>0.00</td><td>NR</td><td>5</td></tr></tbody></table>
<table><tr><td>Hy-C 1992</td><td>ACEI + Dig</td><td>8</td><td>59</td><td>40</td><td>21.0</td><td>7.0</td><td>53</td><td>12</td><td>30</td><td>10</td><td>9</td><td>NR</td><td>1</td></tr><tr><td>Hy-C 1992</td><td>Dig + IDH</td><td>8</td><td>58</td><td>49</td><td>19.0</td><td>6.0</td><td>51</td><td>15</td><td>31</td><td>26</td><td>26</td><td>NR</td><td>3</td></tr><tr><td>MHFT 1993</td><td>ACEI + Dig</td><td>40.4</td><td>83</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>26</td><td>18</td><td>NR</td><td>24</td></tr><tr><td>MHFT 1993</td><td>Dig</td><td>36.5</td><td>87</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>32</td><td>30</td><td>NR</td><td>13</td></tr><tr><td>Veldhuisen 1993</td><td>Dig</td><td>6</td><td>55</td><td>89</td><td>28</td><td>8</td><td>61</td><td>9</td><td>38</td><td>2</td><td>2</td><td>NR</td><td>6</td></tr><tr><td>Veldhuisen 1993</td><td>PLBO</td><td>6</td><td>53</td><td>83</td><td>30</td><td>8</td><td>61</td><td>8</td><td>37</td><td>3</td><td>2</td><td>NR</td><td>2</td></tr><tr><td>CIBIS I 1994</td><td>ACEI + BB + Dig</td><td>26</td><td>320</td><td>264</td><td>25.0</td><td>0.9</td><td>60.1</td><td>1.2</td><td>180</td><td>53</td><td>40</td><td>NR</td><td>75</td></tr><tr><td>CIBIS I 1994</td><td>ACEI + Dig</td><td>26</td><td>321</td><td>265</td><td>25.8</td><td>0.9</td><td>59.2</td><td>1.1</td><td>170</td><td>67</td><td>59</td><td>NR</td><td>82</td></tr><tr><td>Dickstein 1995</td><td>ACEI + Dig</td><td>2</td><td>58</td><td>49</td><td>23</td><td>6</td><td>64</td><td>9</td><td>37</td><td>2</td><td>NR</td><td>NR</td><td>0</td></tr><tr><td>Dickstein 1995</td><td>ARB + Dig</td><td>2</td><td>56</td><td>42</td><td>24</td><td>7</td><td>64</td><td>11</td><td>38</td><td>2</td><td>NR</td><td>NR</td><td>0</td></tr><tr><td>CASSIS 1995</td><td>ACEI + Dig</td><td>3</td><td>51</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>3</td><td>NR</td><td>NR</td><td>4.00</td></tr><tr><td>CASSIS 1995</td><td>ACEI + Dig</td><td>3</td><td>48</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>2</td><td>NR</td><td>NR</td><td>6.00</td></tr><tr><td>CASSIS 1995</td><td>Dig</td><td>3</td><td>48</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>6</td><td>NR</td><td>NR</td><td>6.00</td></tr><tr><td>Krum 1995</td><td>ACEI + Dig</td><td>3.5</td><td>16</td><td>12.00</td><td>15</td><td>2</td><td>53.30</td><td>4</td><td>3</td><td>2</td><td>0</td><td>NR</td><td>2</td></tr><tr><td>Krum 1995</td><td>ACEI + BB + Dig</td><td>3.5</td><td>33</td><td>26.00</td><td>17.00</td><td>1.00</td><td>56.50</td><td>2</td><td>10</td><td>3</td><td>0</td><td>NR</td><td>4</td></tr><tr><td>Brown 1995</td><td>ACEI</td><td>6</td><td>116</td><td>89</td><td>25</td><td>7</td><td>62</td><td>10</td><td>NR</td><td>3</td><td>NR</td><td>NR</td><td>28</td></tr><tr><td>Brown 1995</td><td>PLBO</td><td>6</td><td>125</td><td>103</td><td>25</td><td>7</td><td>62</td><td>9</td><td>NR</td><td>4</td><td>NR</td><td>NR</td><td>47</td></tr><tr><td>FEST 1995</td><td>ACEI</td><td>3</td><td>155</td><td>118</td><td>26</td><td>7</td><td>63</td><td>9</td><td>NR</td><td>5</td><td>NR</td><td>NR</td><td>3</td></tr><tr><td>FEST 1995</td><td>PLBO</td><td>3</td><td>153</td><td>111</td><td>27</td><td>7</td><td>64</td><td>8</td><td>NR</td><td>3</td><td>NR</td><td>NR</td><td>19</td></tr><tr><td>Beller 1995</td><td>ACEI + Dig</td><td>3</td><td>130</td><td>99</td><td>28</td><td>NR</td><td>58.8</td><td>NR</td><td>60</td><td>4</td><td>NR</td><td>NR</td><td>25</td></tr><tr><td>Beller 1995</td><td>Dig</td><td>3</td><td>63</td><td>46</td><td>28</td><td>NR</td><td>61.2</td><td>NR</td><td>25</td><td>5</td><td>NR</td><td>NR</td><td>17</td></tr><tr><td>Colucci 1996</td><td>ACEI + Dig</td><td>12</td><td>134</td><td>111</td><td>23.0</td><td>7.0</td><td>53.0</td><td>12.0</td><td>50</td><td>5</td><td>4</td><td>NR</td><td>7</td></tr><tr><td>Colucci 1996</td><td>ACEI + BB + Dig</td><td>12</td><td>232</td><td>200</td><td>23.0</td><td>7.0</td><td>55.0</td><td>11.0</td><td>102</td><td>2</td><td>0</td><td>NR</td><td>12</td></tr><tr><td>MOCHA 1996</td><td>ACEI + Dig</td><td>6</td><td>84</td><td>64</td><td>23</td><td>7</td><td>60.0</td><td>11.0</td><td>46</td><td>7</td><td>NR</td><td>NR</td><td>11</td></tr><tr><td>MOCHA 1996</td><td>ACEI + BB + Dig</td><td>6</td><td>89</td><td>70</td><td>23</td><td>8</td><td>70.0</td><td>13.0</td><td>48</td><td>1</td><td>NR</td><td>NR</td><td>5</td></tr><tr><td>PRECISE 1996</td><td>ACEI + Dig</td><td>6</td><td>145</td><td>106</td><td>22</td><td>7</td><td>61.2</td><td>11.8</td><td>NR</td><td>11</td><td>NR</td><td>NR</td><td>30</td></tr><tr><td>PRECISE 1996</td><td>ACEI + BB + Dig</td><td>6</td><td>133</td><td>98</td><td>22</td><td>7</td><td>59.3</td><td>11.8</td><td>NR</td><td>6</td><td>NR</td><td>NR</td><td>19</td></tr></table>
<table><tr><td>Packer 1996</td><td>ACEI + Dig</td><td>6</td><td>398</td><td>304</td><td>22</td><td>7</td><td>58.1</td><td>12.3</td><td>189</td><td>32</td><td>32</td><td>NR</td><td>25</td></tr><tr><td>Packer 1996</td><td>ACEI + BB + Dig</td><td>6</td><td>696</td><td>534</td><td>23</td><td>7</td><td>57.9</td><td>12.2</td><td>332</td><td>22</td><td>20</td><td>NR</td><td>43</td></tr><tr><td>Losartan Pilot Exercise 1997</td><td>ACEI + Dig</td><td>3</td><td>38</td><td>29</td><td>25</td><td>7.9</td><td>59.7</td><td>11.5</td><td>18.00</td><td>0</td><td>0</td><td>NR</td><td>NR</td></tr><tr><td>Losartan Pilot Exercise 1997</td><td>ARB + Dig</td><td>3</td><td>40</td><td>29</td><td>25</td><td>10.7</td><td>56.3</td><td>16.2</td><td>19.00</td><td>5</td><td>2</td><td>NR</td><td>NR</td></tr><tr><td>ELITE I 1997</td><td>ACEI + Dig</td><td>11</td><td>370</td><td>248</td><td>30</td><td>7.6</td><td>73.0</td><td>6.1</td><td>250</td><td>32</td><td>24</td><td>NR</td><td>77</td></tr><tr><td>ELITE I 1997</td><td>ARB + Dig</td><td>11</td><td>352</td><td>234</td><td>31</td><td>7.2</td><td>74.0</td><td>5.8</td><td>242</td><td>17</td><td>12</td><td>NR</td><td>43</td></tr><tr><td>Cohn 1997</td><td>ACEI + Dig</td><td>6</td><td>35</td><td>23</td><td>21</td><td>7.0</td><td>60.60</td><td>1.6</td><td>16</td><td>2</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Cohn 1997</td><td>ACEI + BB + Dig</td><td>6</td><td>70</td><td>38</td><td>22</td><td>8.0</td><td>59.70</td><td>13.9</td><td>31</td><td>2</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Digitalis Investigation Group 1997</td><td>ACEI + Dig</td><td>37</td><td>3397</td><td>2643</td><td>28.60</td><td>8.9</td><td>63.40</td><td>11.00</td><td>2405</td><td>1181</td><td>1016</td><td>NR</td><td>NR</td></tr><tr><td>Digitalis Investigation Group 1997</td><td>ACEI</td><td>37</td><td>3403</td><td>2637</td><td>28.40</td><td>8.9</td><td>63.50</td><td>10.80</td><td>2396</td><td>1194</td><td>1004</td><td>NR</td><td>NR</td></tr><tr><td>Veldhuisen 1998</td><td>ACEI</td><td>3</td><td>60</td><td>45</td><td>34</td><td>8.0</td><td>62</td><td>9</td><td>37</td><td>0</td><td>NR</td><td>NR</td><td>4</td></tr><tr><td>Veldhuisen 1998</td><td>PLBO</td><td>3</td><td>62</td><td>44</td><td>33</td><td>7.0</td><td>61</td><td>9</td><td>43</td><td>1</td><td>NR</td><td>NR</td><td>7</td></tr><tr><td>Hamroff 1999</td><td>ACEI + Dig</td><td>6</td><td>17</td><td>11</td><td>26</td><td>2.0</td><td>60.0</td><td>10.0</td><td>5</td><td>1</td><td>NR</td><td>NR</td><td>2.00</td></tr><tr><td>Hamroff 1999</td><td>ACEI + ARB + Dig</td><td>6</td><td>16</td><td>5</td><td>27</td><td>2.0</td><td>61.7</td><td>13.0</td><td>5</td><td>0</td><td>NR</td><td>NR</td><td>3.00</td></tr><tr><td>STRETCH 1999</td><td>ARB</td><td>3</td><td>213</td><td>145</td><td>38.8</td><td>4.60</td><td>61.60</td><td>9.4</td><td>144.00</td><td>3</td><td>1</td><td>NR</td><td>11</td></tr><tr><td>STRETCH 1999</td><td>PLBO</td><td>3</td><td>211</td><td>153</td><td>39.0</td><td>4.80</td><td>62.10</td><td>9.3</td><td>155.00</td><td>1</td><td>1</td><td>NR</td><td>9</td></tr><tr><td>MERIT-HF (pilot) 1999</td><td>ACEI + Dig</td><td>6</td><td>19</td><td>16</td><td>27</td><td>9.0</td><td>NR</td><td>NR</td><td>9</td><td>0</td><td>NR</td><td>NR</td><td>6</td></tr><tr><td>MERIT-HF (pilot) 1999</td><td>ACEI + BB + Dig</td><td>6</td><td>42</td><td>30</td><td>27</td><td>8.0</td><td>NR</td><td>NR</td><td>13</td><td>1</td><td>NR</td><td>NR</td><td>9</td></tr><tr><td>RALES 1999</td><td>ACEI + Dig</td><td>24</td><td>841</td><td>614</td><td>25.2</td><td>6.8</td><td>65</td><td>12</td><td>453</td><td>386</td><td>314</td><td>NR</td><td>1</td></tr><tr><td>RALES 1999</td><td>ACEI + MRA + Dig</td><td>24</td><td>822</td><td>603</td><td>25.6</td><td>6.7</td><td>65</td><td>12</td><td>454</td><td>284</td><td>226</td><td>NR</td><td>10</td></tr><tr><td>ELITE II 2000</td><td>ACEI</td><td>18.2</td><td>1574</td><td>1083</td><td>31</td><td>7</td><td>71.5</td><td>6.9</td><td>1243</td><td>250</td><td>199</td><td>NR</td><td>NR</td></tr><tr><td>ELITE II 2000</td><td>ARB</td><td>18.2</td><td>1578</td><td>1102</td><td>31</td><td>7</td><td>71.4</td><td>6.7</td><td>1247</td><td>280</td><td>230</td><td>NR</td><td>NR</td></tr><tr><td>RESOLVD 2000</td><td>ACEI + ARB + Dig</td><td>9</td><td>212</td><td>212</td><td>180.00</td><td>29.00</td><td>11.00</td><td>61.00</td><td>50</td><td></td><td>17</td><td>NR</td><td>NR</td></tr><tr><td>RESOLVD 2000</td><td>ACEI + ARB + BB + Dig</td><td>2.8</td><td>214</td><td>214</td><td>170.00</td><td>28</td><td>11</td><td>62.00</td><td>58</td><td></td><td>8</td><td>NR</td><td>NR</td></tr></table>
<table><tr><td>MERIT-HF 1999</td><td>ACEI + Dig</td><td>12</td><td>2001</td><td>1554</td><td>28</td><td>7</td><td>63.7</td><td>9.7</td><td>1312</td><td>217</td><td>203</td><td>NR</td><td>306</td></tr><tr><td>MERIT-HF 1999</td><td>ACEI + BB + Dig</td><td>12</td><td>1990</td><td>1539</td><td>28</td><td>7</td><td>63.9</td><td>9.6</td><td>1294</td><td>145</td><td>128</td><td>NR</td><td>277</td></tr><tr><td>MIC 2000</td><td>ACEI + Dig</td><td>6</td><td>26</td><td>19</td><td>29.2</td><td>9.9</td><td>55.0</td><td>39-68</td><td>NR</td><td>2</td><td>NR</td><td>NR</td><td>0</td></tr><tr><td>MIC 2000</td><td>ACEI + BB + Dig</td><td>6</td><td>26</td><td>18</td><td>26.6</td><td>6.3</td><td>53.0</td><td>32-60</td><td>NR</td><td>1</td><td>NR</td><td>NR</td><td>0</td></tr><tr><td>SPICE 2000</td><td>ARB + Dig</td><td>3</td><td>179</td><td>31</td><td>26</td><td>22-30</td><td>66.0</td><td>58-71</td><td>128.00</td><td>6</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>SPICE 2000</td><td>Dig</td><td>3</td><td>91</td><td>23</td><td>29</td><td>23-32</td><td>65.0</td><td>58-73</td><td>65.00</td><td>3</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>CELICARD 2000</td><td>ACEI + Dig</td><td>12</td><td>66</td><td>56</td><td>26</td><td>7.00</td><td>56</td><td>11</td><td>NR</td><td>4</td><td>2</td><td>NR</td><td>24</td></tr><tr><td>CELICARD 2000</td><td>ACEI + BB + Dig</td><td>12</td><td>66</td><td>55</td><td>26</td><td>8.00</td><td>57</td><td>10</td><td>NR</td><td>2</td><td>2</td><td>NR</td><td>18</td></tr><tr><td>Sturm 2000</td><td>ACEI + Dig</td><td>12</td><td>49</td><td>44</td><td>17</td><td>6</td><td>52</td><td>10</td><td>12</td><td>8</td><td></td><td>NR</td><td>3</td></tr><tr><td>Sturm 2000</td><td>ACEI + BB + Dig</td><td>12</td><td>51</td><td>44</td><td>17</td><td>5</td><td>51</td><td>11</td><td>16</td><td>5</td><td></td><td>NR</td><td>10</td></tr><tr><td>Val-HeFT 2001</td><td>ACEI + Dig</td><td>27</td><td>2499</td><td>1999.00</td><td>26.9</td><td>7</td><td>63.0</td><td>11</td><td>NR</td><td>484</td><td>NR</td><td>NR</td><td>181.00</td></tr><tr><td>Val-HeFT 2001</td><td>ACEI + ARB + Dig</td><td>27</td><td>2511</td><td>2006.00</td><td>26.6</td><td>7.30</td><td>62.4</td><td>11.1</td><td>NR</td><td>495</td><td>NR</td><td>NR</td><td>249.00</td></tr><tr><td>BEST 2001</td><td>ACEI + Dig</td><td>24</td><td>1354</td><td>1047</td><td>23.0</td><td>7.2</td><td>60.0</td><td>12.3</td><td>791</td><td>449</td><td>389.00</td><td>NR</td><td>338.5</td></tr><tr><td>BEST 2001</td><td>ACEI + BB + Dig</td><td>24</td><td>1354</td><td>1068</td><td>23.0</td><td>7.4</td><td>60.0</td><td>12.6</td><td>796</td><td>411</td><td>342.00</td><td>NR</td><td>311.4</td></tr><tr><td>COPERNICUS 2001</td><td>ACEI + Dig</td><td>10.4</td><td>1133</td><td>906</td><td>19.8</td><td>4.0</td><td>63.4</td><td>11.5</td><td>759</td><td>190</td><td>NR</td><td>NR</td><td>210.00</td></tr><tr><td>COPERNICUS 2001</td><td>ACEI + BB + Dig</td><td>10.4</td><td>1156</td><td>913</td><td>19.9</td><td>4.0</td><td>63.4</td><td>11.4</td><td>775</td><td>130</td><td>NR</td><td>NR</td><td>171.00</td></tr><tr><td>REPLACE 2001</td><td>ACEI</td><td>3</td><td>75</td><td>68.00</td><td>27.10</td><td>7.6</td><td>63.00</td><td>10</td><td>NR</td><td>2</td><td>NR</td><td>NR</td><td>0.00</td></tr><tr><td>REPLACE 2001</td><td>ARB</td><td>3</td><td>77</td><td>68.00</td><td>25.9</td><td>6.30</td><td>64.00</td><td>9</td><td>NR</td><td>1</td><td>NR</td><td>NR</td><td>3.00</td></tr><tr><td>de Milliano 2002</td><td>ACEI</td><td>6</td><td>11</td><td>7</td><td>24.8</td><td>3.8</td><td>64.00</td><td>9</td><td>9.00</td><td>1</td><td>0.00</td><td>NR</td><td>NR</td></tr><tr><td>de Milliano 2002</td><td>ACEI + BB</td><td>6</td><td>43</td><td>29</td><td>25.3</td><td>7.40</td><td>65.00</td><td>10</td><td>21.00</td><td>4</td><td>1.00</td><td>NR</td><td>NR</td></tr><tr><td>Dubach 2002</td><td>ACEI</td><td>12</td><td>15</td><td>NR</td><td>25.1</td><td>5.1</td><td>59.40</td><td>10</td><td>NR</td><td>0</td><td>0.00</td><td>NR</td><td>NR</td></tr><tr><td>Dubach 2002</td><td>ACEI + BB</td><td>12</td><td>13</td><td>NR</td><td>26.70</td><td>0.20</td><td>55.40</td><td>12.00</td><td>NR</td><td>1</td><td>1.00</td><td>NR</td><td>NR</td></tr><tr><td>Cicoira 2002</td><td>ACEI + BB</td><td>12</td><td>52</td><td>46.00</td><td>34</td><td>7.00</td><td>61.70</td><td>9.8</td><td>33</td><td>4</td><td>NR</td><td>NR</td><td>0.0</td></tr></table>
<table><tr><td>Cicoira 2002</td><td>ACEI + BB + MRA</td><td>12</td><td>54</td><td>46.00</td><td>33</td><td>7.00</td><td>62.50</td><td>7.9</td><td>35</td><td>3</td><td>NR</td><td>NR</td><td>0.0</td></tr><tr><td>HEAVEN 2002</td><td>ACEI + BB</td><td>3</td><td>71</td><td>56.00</td><td>NR</td><td>NR</td><td>67.00</td><td>46-89</td><td>39.00</td><td>5</td><td>2.00</td><td>NR</td><td>3</td></tr><tr><td>HEAVEN 2002</td><td>ARB + BB</td><td>3</td><td>70</td><td>49.00</td><td>NR</td><td>NR</td><td>68.00</td><td>51-90</td><td>47.00</td><td>1</td><td>1.00</td><td>NR</td><td>2</td></tr><tr><td>Mitrovic 2003</td><td>ARB + Dig</td><td>3</td><td>44</td><td>40.00</td><td>29.1</td><td>6.10</td><td>55.70</td><td>11.8</td><td>NR</td><td>1</td><td>1.00</td><td>NR</td><td>NR</td></tr><tr><td>Mitrovic 2003</td><td>Dig</td><td>3</td><td>44</td><td>35.00</td><td>29.7</td><td>5.80</td><td>58.00</td><td>11.8</td><td>NR</td><td>2</td><td>2.00</td><td>NR</td><td>NR</td></tr><tr><td>RESOLVD 2003</td><td>ACEI + ARB + Dig</td><td>9</td><td>86</td><td>71</td><td>28</td><td>7</td><td>63.00</td><td>10</td><td>60.00</td><td>8</td><td>NR</td><td>NR</td><td>4</td></tr><tr><td>RESOLVD 2003</td><td>ACEI + ARB + BB + Dig</td><td>9</td><td>89</td><td>73</td><td>27</td><td>8.00</td><td>64.00</td><td>12</td><td>55.00</td><td>6</td><td>NR</td><td>NR</td><td>12</td></tr><tr><td>RESOLVD 2003</td><td>ARB + Dig</td><td>9</td><td>126</td><td>110.00</td><td>28.00</td><td>7.00</td><td>61.00</td><td>11.00</td><td>79.00</td><td>12</td><td></td><td>NR</td><td>4.00</td></tr><tr><td>RESOLVD 2003</td><td>ARB + BB + Dig</td><td>9</td><td>125</td><td>96.00</td><td>28.00</td><td>7.00</td><td>61.00</td><td>12.00</td><td>89.00</td><td>2</td><td></td><td>NR</td><td>17.00</td></tr><tr><td>CHARM-alternative 2003</td><td>ARB + BB</td><td>33.7</td><td>1013</td><td>691.00</td><td>29.8</td><td>7.60</td><td>66.30</td><td>11</td><td>706.00</td><td>265</td><td>219.00</td><td>334</td><td>218</td></tr><tr><td>CHARM-alternative 2003</td><td>BB</td><td>33.7</td><td>1015</td><td>691.00</td><td>30</td><td>7.20</td><td>66.80</td><td>10.5</td><td>679.00</td><td>296</td><td>252.00</td><td>406</td><td>196</td></tr><tr><td>CHARM-added 2003</td><td>ACEI + ARB + BB + Dig</td><td>42</td><td>1276</td><td>1006.00</td><td>28</td><td>7.50</td><td>64.00</td><td>10.7</td><td>794.00</td><td>377</td><td>302.00</td><td>483</td><td>309.00</td></tr><tr><td>CHARM-added 2003</td><td>ACEI + BB + Dig</td><td>42</td><td>1272</td><td>1000.00</td><td>28</td><td>7.50</td><td>64.10</td><td>11.3</td><td>796.00</td><td>412</td><td>347.00</td><td>538</td><td>233.00</td></tr><tr><td>SYMPOXYDEX 2004</td><td>ACEI + BB</td><td>6</td><td>28</td><td>24.00</td><td>25.00</td><td>11.00</td><td>59.00</td><td>12</td><td>11.00</td><td>1</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>SYMPOXYDEX 2004</td><td>ACEI</td><td>6</td><td>22</td><td>18.00</td><td>27</td><td>12</td><td>60.00</td><td>8</td><td>9.00</td><td>1</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>A-HeFT 2004</td><td>ACEI + BB + Dig</td><td>10</td><td>532</td><td>340</td><td>24.00</td><td>7.50</td><td>57</td><td>13</td><td>121</td><td>54</td><td>45</td><td>NR</td><td>NR</td></tr><tr><td>A-HeFT 2004</td><td>ACEI + BB + Dig + IDH</td><td>10</td><td>518</td><td>289</td><td>24.00</td><td>7.30</td><td>57</td><td>13</td><td>121</td><td>32</td><td>26</td><td>NR</td><td>NR</td></tr><tr><td>MUCHA 2004</td><td>ACEI + Dig</td><td>6</td><td>49</td><td>40</td><td>29</td><td>7</td><td>62</td><td>12</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>MUCHA 2004</td><td>ACEI + BB + Dig</td><td>6</td><td>77</td><td>57</td><td>30</td><td>7</td><td>60</td><td>12</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>CARMEN 2004</td><td>ACEI</td><td>18</td><td>190</td><td>160.00</td><td>NR</td><td>NR</td><td>62.90</td><td>36-86</td><td>137.00</td><td>14</td><td>14</td><td>NR</td><td>40</td></tr><tr><td>CARMEN 2004</td><td>ACEI + BB</td><td>18</td><td>191</td><td>155.00</td><td>NR</td><td>NR</td><td>62.10</td><td>29-83</td><td>117.00</td><td>14</td><td>9</td><td>NR</td><td>38</td></tr><tr><td>CARMEN 2004</td><td>BB</td><td>18</td><td>191</td><td>147.00</td><td></td><td></td><td>61.90</td><td>18-84</td><td>137.00</td><td>14</td><td>13.00</td><td></td><td>36.00</td></tr><tr><td>CIBIS II 1999</td><td>ACEI + Dig</td><td>46</td><td>1320</td><td>1062.00</td><td>27.6</td><td>5.5</td><td>61.00</td><td>22-80</td><td>654.00</td><td>228</td><td>161.00</td><td>463</td><td>192.00</td></tr></table>
<table><tr><td>CIBIS II 1999</td><td>ACEI + BB + Dig</td><td>46</td><td>1327</td><td>1106.00</td><td>27.50</td><td>6.00</td><td>61.00</td><td>26-80</td><td>662.00</td><td>156</td><td>119.00</td><td>388</td><td>194.00</td></tr><tr><td>ENECA 2005</td><td>ACEI + Dig</td><td>11</td><td>126</td><td>97.00</td><td>26.41</td><td>5.55</td><td>72.19</td><td>5.2</td><td></td><td>7</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>ENECA 2005</td><td>ACEI + BB + Dig</td><td>12</td><td>134</td><td>94.00</td><td>25.41</td><td>7.09</td><td>71.97</td><td>5.02</td><td></td><td>7</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Palazzuoli 2005</td><td>ACEI</td><td>12</td><td>25</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>1</td><td>NR</td><td>NR</td><td>3</td></tr><tr><td>Palazzuoli 2005</td><td>ACEI + BB</td><td>12</td><td>33</td><td>NR</td><td>32.00</td><td>5.00</td><td>NR</td><td>NR</td><td>NR</td><td>1</td><td>NR</td><td>NR</td><td>2</td></tr><tr><td>Palazzuoli 2005b</td><td>ACEI</td><td>12</td><td>27</td><td>NR</td><td>31.5</td><td>5</td><td>NR</td><td>NR</td><td>NR</td><td>2</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Palazzuoli 2005b</td><td>ACEI + BB</td><td>12</td><td>32</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>1</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>CIBIS III 2008</td><td>ACEI</td><td>6</td><td>505</td><td>359.00</td><td>28.80</td><td>5.2</td><td>72.50</td><td>5.7</td><td>323.00</td><td>32</td><td>16.00</td><td>NR</td><td>57.00</td></tr><tr><td>CIBIS III 2008</td><td>BB</td><td>6</td><td>505</td><td>333.00</td><td>28.8</td><td>4.80</td><td>72.40</td><td>5.8</td><td>308.00</td><td>23</td><td>8.00</td><td>NR</td><td>42.00</td></tr><tr><td>AREA-IN CHF 2009</td><td>ACEI + BB</td><td>12</td><td>236</td><td>201.00</td><td>39.7</td><td>8.60</td><td>62.70</td><td>9.5</td><td>123.00</td><td>12</td><td>8.00</td><td>34</td><td>16.00</td></tr><tr><td>AREA-IN CHF 2009</td><td>ACEI + BB + MRA</td><td>12</td><td>231</td><td>189.00</td><td>39.9</td><td>8.60</td><td>62.30</td><td>9.5</td><td>118.00</td><td>6</td><td>5.00</td><td>17</td><td>26.00</td></tr><tr><td>SENIORS 2009</td><td>ACEI</td><td>21</td><td>681</td><td>490</td><td>29.00</td><td>6.00</td><td>76</td><td>5</td><td>NR</td><td>135</td><td>104</td><td>NR</td><td>NR</td></tr><tr><td>SENIORS 2009</td><td>ACEI + BB</td><td>21</td><td>678</td><td>464</td><td>29.00</td><td>5.00</td><td>76</td><td>5</td><td>NR</td><td>115</td><td>88</td><td>NR</td><td>NR</td></tr><tr><td>SHIFT 2010</td><td>ACEI + BB + MRA</td><td>22.9</td><td>3290</td><td>2508.00</td><td>29.00</td><td>5.10</td><td>60.10</td><td>11.20</td><td>2203.00</td><td>552</td><td>491</td><td>937</td><td>416</td></tr><tr><td>SHIFT 2010</td><td>ACEI + BB + MRA + IVA</td><td>22.9</td><td>3268</td><td>2462.00</td><td>29.00</td><td>5.20</td><td>60.70</td><td>11.50</td><td>2215.00</td><td>503</td><td>449</td><td>793</td><td>467</td></tr><tr><td>EMPHASIS-HF 2011</td><td>ACEI + BB</td><td>21</td><td>1373</td><td>1061</td><td>26.1</td><td>4.70</td><td>68.60</td><td>7.6</td><td>935.00</td><td>213</td><td>185.00</td><td>356</td><td>222</td></tr><tr><td>EMPHASIS-HF 2011</td><td>ACEI + BB + MRA</td><td>21</td><td>1364</td><td>1055</td><td>26.2</td><td>4.60</td><td>68.70</td><td>7.7</td><td>951.00</td><td>171</td><td>147.00</td><td>249</td><td>188</td></tr><tr><td>PARADIGM-HF 2014</td><td>ACEI + BB + MRA</td><td>27</td><td>4212</td><td>3259.00</td><td>29.4</td><td>6.30</td><td>63.80</td><td>11.3</td><td>2530.00</td><td>835</td><td>693.00</td><td>1117</td><td>103.00</td></tr><tr><td>PARADIGM-HF 2014</td><td>ARNI + BB + MRA</td><td>27</td><td>4187</td><td>3308.00</td><td>29.6</td><td>6.10</td><td>63.80</td><td>11.5</td><td>2506.00</td><td>711</td><td>558.00</td><td>914</td><td>76.00</td></tr><tr><td>Vizzardi 2014</td><td>ACEI + BB</td><td>44</td><td>65</td><td></td><td>37.7</td><td>11.00</td><td>65.00</td><td>17.40</td><td>NR</td><td>8</td><td>8.00</td><td>28</td><td>1.00</td></tr></table>
<table><tr><td>Vizzardi 2014</td><td>ACEI + BB + MRA</td><td>33</td><td>65</td><td>34.5</td><td>8.00</td><td>61.00</td><td>14.70</td><td>NR</td><td>8</td><td>3.00</td><td>9</td><td>5.00</td></tr><tr><td>SOCRATES reduced 2015</td><td>ACEI + BB + MRA</td><td>2.8</td><td>92</td><td>73.00</td><td>28.60</td><td>8.50</td><td>69.00</td><td>12.00</td><td>51.00</td><td>2</td><td>2</td><td>10</td><td>7</td></tr><tr><td>SOCRATES reduced 2015</td><td>ACEI + BB + MRA + VERICIGUAT</td><td>2.8</td><td>91</td><td>77.00</td><td>29.60</td><td>8.30</td><td>67.00</td><td>13.00</td><td>46.00</td><td>3</td><td>3</td><td>18</td><td>8</td></tr><tr><td>COSMIC HF 2016</td><td>ACEI + BB + MRA</td><td>5.5</td><td>149</td><td>119.0</td><td>29.3</td><td>7.40</td><td>64.00</td><td>10.00</td><td>89.00</td><td>4</td><td>2</td><td>NR</td><td>16</td></tr><tr><td>COSMIC HF 2016</td><td>ACEI + BB + MRA + Omecamtiv</td><td>5.5</td><td>149</td><td>125.0</td><td>29.0</td><td>7.30</td><td>63.00</td><td>12.00</td><td>101.00</td><td>3</td><td>2</td><td>NR</td><td>19</td></tr><tr><td>J-EMPHASIS-HF 2017</td><td>ACEI + BB</td><td>24.6</td><td>110</td><td>91.00</td><td>27.00</td><td>4.00</td><td>68.00</td><td>8.00</td><td>43</td><td>17</td><td>14</td><td>36</td><td>36</td></tr><tr><td>J-EMPHASIS-HF 2017</td><td>ACEI + BB + MRA</td><td>24.4</td><td>111</td><td>85.00</td><td>26.00</td><td>5.00</td><td>69.00</td><td>9.00</td><td>31</td><td>10</td><td>6</td><td>33</td><td>36</td></tr><tr><td>PIONEER-HF 2019</td><td>ACEI + BB</td><td>2</td><td>441</td><td>308</td><td>25</td><td>20-30</td><td>63</td><td>54-72</td><td>NR</td><td>15</td><td>NR</td><td>67</td><td>90</td></tr><tr><td>PIONEER-HF 2019</td><td>ARNI + BB</td><td>2</td><td>440</td><td>327</td><td>24</td><td>18-30</td><td>61</td><td>51-71</td><td>NR</td><td>10</td><td>NR</td><td>40</td><td>87</td></tr><tr><td>DAPA-HF 2019</td><td>ARNI + BB + MRA</td><td>18.2</td><td>2371</td><td>1826</td><td>31.00</td><td>7.00</td><td>67</td><td>11</td><td>1358</td><td>329</td><td>273</td><td>495</td><td>116</td></tr><tr><td>DAPA-HF 2019</td><td>ARNI + BB + MRA + SGLT2</td><td>18.2</td><td>2373</td><td>1809</td><td>31.00</td><td>7.00</td><td>66</td><td>11</td><td>1316</td><td>276</td><td>227</td><td>382</td><td>111</td></tr><tr><td>J-SHIFT 2019</td><td>ACEI + BB + MRA</td><td>18.4</td><td>127</td><td>102.00</td><td>27.00</td><td>6.10</td><td>60.00</td><td>13.30</td><td>50</td><td>9</td><td>8</td><td>37</td><td>10</td></tr><tr><td>J-SHIFT 2019</td><td>ACEI + BB + MRA + IVA</td><td>18.4</td><td>127</td><td>107.00</td><td>28.00</td><td>5.30</td><td>61.00</td><td>13.70</td><td>49</td><td>9</td><td>7</td><td>26</td><td>11</td></tr><tr><td>EMPEROR-REDUCED 2020</td><td>ARNI + BB + MRA</td><td>16</td><td>1867</td><td>1411</td><td>27.00</td><td>6.00</td><td>67</td><td>11</td><td>946</td><td>266</td><td>202</td><td>462</td><td>335</td></tr><tr><td>EMPEROR-REDUCED 2020</td><td>ARNI + BB + MRA + SGLT2</td><td>16</td><td>1863</td><td>1426</td><td>28.00</td><td>6.00</td><td>67</td><td>11</td><td>983</td><td>249</td><td>187</td><td>361</td><td>303</td></tr></table>
<table><tr><td>GALACTIC-HF 2020</td><td>ARNI + BB + MRA</td><td>21.8</td><td>4112</td><td>3238.00</td><td>26.50</td><td>6.30</td><td>64.50</td><td>11.40</td><td>2222.00</td><td>1065</td><td>371</td><td>1607</td><td>382</td></tr><tr><td>GALACTIC-HF 2020</td><td>ARNI + BB + MRA + Omecamtiv</td><td>21.8</td><td>4120</td><td>3246.00</td><td>26.60</td><td>6.30</td><td>64.50</td><td>11.30</td><td>2193.00</td><td>1067</td><td>346</td><td>1532</td><td>371</td></tr><tr><td>VICTORIA 2020</td><td>ARNI + BB + MRA</td><td>10.8</td><td>2524</td><td>1921.00</td><td>29.00</td><td>8.00</td><td>67.00</td><td>12.00</td><td>NR</td><td>285</td><td>225</td><td>972</td><td>190</td></tr><tr><td>VICTORIA 2020</td><td>ARNI + BB + MRA + VERICIGUAT</td><td>10.8</td><td>2526</td><td>1921.00</td><td>29.00</td><td>8.00</td><td>68.00</td><td>12.00</td><td>NR</td><td>266</td><td>206</td><td>897</td><td>195</td></tr><tr><td>Shettigar 1999</td><td>ACEI</td><td>3</td><td>102</td><td></td><td></td><td></td><td></td><td></td><td></td><td>2</td><td></td><td></td><td></td></tr><tr><td>Shettigar 1999</td><td>PLBO</td><td>3</td><td>104</td><td></td><td></td><td></td><td></td><td></td><td></td><td>3</td><td></td><td></td><td></td></tr><tr><td>Bano 2021</td><td>ACEI</td><td>12</td><td>200.00</td><td>90</td><td>31.8</td><td>4.02</td><td>55.00</td><td>12.00</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Bano 2021</td><td>ARNI</td><td>12</td><td>200.00</td><td>88</td><td>31.2</td><td>4.12</td><td>53.00</td><td>12.00</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Dogheim 2022</td><td>ACEI + BB + MRA</td><td>3</td><td>34.00</td><td>23</td><td>25.8</td><td>4.38</td><td>59.60</td><td>10.00</td><td>26.00</td><td>0</td><td>0</td><td>0</td><td>4</td></tr><tr><td>Dogheim 2022</td><td>ACEI + BB + MRA + IVA</td><td>3</td><td>34.00</td><td>22</td><td>25.6</td><td>4.34</td><td>55.63</td><td>10.05</td><td>28.00</td><td>0</td><td>0</td><td>0</td><td>4</td></tr><tr><td>Halle 2021</td><td>ACEI + BB + MRA</td><td>2.76</td><td>98.00</td><td>77</td><td>32.0</td><td>5.70</td><td>67.60</td><td>10.00</td><td>64</td><td>1</td><td>1</td><td>NR</td><td>7</td></tr><tr><td>Halle 2021</td><td>ARNI + BB + MRA</td><td>2.76</td><td>103.00</td><td>86</td><td>31.9</td><td>6.10</td><td>66.10</td><td>10.80</td><td>61</td><td>2</td><td>2</td><td>NR</td><td>4</td></tr><tr><td>Lewis 2022</td><td>ARNI + BB + MRA</td><td>4.6</td><td>91.00</td><td>76</td><td>26.0</td><td>22-32</td><td>67.00</td><td>57-73</td><td>48</td><td>1</td><td>NR</td><td>NR</td><td>6</td></tr><tr><td>Lewis 2022</td><td>ARNI + BB + MRA + Omecamtiv</td><td>4.6</td><td>185.00</td><td>158</td><td>28.0</td><td>20-33</td><td>63.00</td><td>56-70</td><td>117.00</td><td>3</td><td>NR</td><td>NR</td><td>21</td></tr><tr><td>Lin 2024</td><td>ACEI + BB + MRA</td><td>24</td><td>100.00</td><td>66</td><td>33.2</td><td>7.10</td><td>63.10</td><td>10.20</td><td>NR</td><td>10</td><td>NR</td><td>28</td><td>NR</td></tr><tr><td>Lin 2024</td><td>ACEI + BB + MRA + SGLT2</td><td>24</td><td>100.00</td><td>68</td><td>32.5</td><td>6.70</td><td>62.30</td><td>9.80</td><td>NR</td><td>8</td><td>NR</td><td>18</td><td>NR</td></tr><tr><td>Mann 2021</td><td>ARB + BB + MRA</td><td>5.52</td><td>168.00</td><td>125</td><td>20.9</td><td>6.80</td><td>58.30</td><td>13.1</td><td>121</td><td>8</td><td>7</td><td>37</td><td>36</td></tr><tr><td>Mann 2021</td><td>ARNI + BB + MRA</td><td>5.52</td><td>167.00</td><td>120</td><td>19.9</td><td>6.20</td><td>60.20</td><td>13.40</td><td>140.00</td><td>13</td><td>11</td><td>48</td><td>49</td></tr></table>
<table><tr><td>Palau 2022</td><td>ARNI + BB + MRA</td><td>3</td><td>45.00</td><td>34</td><td>34.0</td><td>5.30</td><td>67.30</td><td>60.8-75.1</td><td>NR</td><td>1</td><td>0</td><td>NR</td><td>NR</td></tr><tr><td>Palau 2022</td><td>ARNI + BB + MRA + SGLT2</td><td>3</td><td>45.00</td><td>35</td><td>33.7</td><td>5.30</td><td>69.80</td><td>62.4-74</td><td>NR</td><td>1</td><td>0</td><td>NR</td><td>NR</td></tr><tr><td>Pastore 2024</td><td>ARNI + BB + MRA</td><td>6</td><td>44.00</td><td>37</td><td>37.0</td><td>9.00</td><td>68.00</td><td>12</td><td>NR</td><td>NR</td><td>0</td><td>NR</td><td>NR</td></tr><tr><td>Pastore 2024</td><td>ARNI + BB + MRA + SGLT2</td><td>6</td><td>44.00</td><td>36</td><td>38.0</td><td>11.00</td><td>68.00</td><td>15.00</td><td>NR</td><td>NR</td><td>0</td><td>NR</td><td>NR</td></tr><tr><td>Reis 2022</td><td>ACEI + BB + MRA</td><td>6</td><td>20.00</td><td>16</td><td>33.5</td><td>7.80</td><td>61.70</td><td>14.80</td><td>12</td><td>0</td><td>0</td><td>NR</td><td>0</td></tr><tr><td>Reis 2022</td><td>ACEI + BB + MRA + SGLT2</td><td>6</td><td>20.00</td><td>17</td><td>34.5</td><td>8.9</td><td>60.3</td><td>11.6</td><td>16.00</td><td>0</td><td>0</td><td>NR</td><td>0</td></tr><tr><td>Santos 2021</td><td>ACEI + BB + MRA</td><td>5.52</td><td>23</td><td>14</td><td>25</td><td>19-34</td><td>61</td><td>55-67</td><td>NR</td><td>1</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Santos 2021</td><td>ARNI + BB + MRA</td><td>5.52</td><td>29</td><td>18</td><td>26</td><td>23-32</td><td>56</td><td>50-63</td><td>NR</td><td>1</td><td>NR</td><td>NR</td><td>NR</td></tr><tr><td>Santos-Gallego 2021</td><td>ARNI + BB</td><td>6</td><td>42.00</td><td>27</td><td>36.5</td><td>8.00</td><td>59.90</td><td>13.10</td><td>19</td><td>1</td><td>1</td><td>NR</td><td>2</td></tr><tr><td>Santos-Gallego 2021</td><td>ARNI + BB + SGLT2</td><td>6</td><td>42.00</td><td>27</td><td>36.2</td><td>8.20</td><td>64.20</td><td>10.90</td><td>23</td><td>0</td><td>0</td><td>NR</td><td>2</td></tr><tr><td>Tsutsui 2021</td><td>ACEI + BB + MRA</td><td>33.9</td><td>113.00</td><td>96</td><td>27.7</td><td>5.50</td><td>66.70</td><td>10.90</td><td>49</td><td>NR</td><td>11</td><td>28</td><td>13</td></tr><tr><td>Tsutsui 2021</td><td>ARNI + BB + MRA</td><td>33.9</td><td>112.00</td><td>96</td><td>28.6</td><td>5.10</td><td>69.00</td><td>9.70</td><td>57</td><td>NR</td><td>13</td><td>30</td><td>11</td></tr><tr><td>Ye 2022</td><td>ACEI + BB + MRA</td><td>7.36</td><td>181.00</td><td>128</td><td>28.8</td><td>7.60</td><td>54.00</td><td>12.00</td><td>42</td><td>6</td><td>6</td><td>NR</td><td>14</td></tr><tr><td>Ye 2022</td><td>ACEI + BB + MRA + IVA</td><td>7.36</td><td>179.00</td><td>138</td><td>27.2</td><td>7.9</td><td>51</td><td>12</td><td>39.00</td><td>4</td><td>4</td><td>NR</td><td>9</td></tr><tr><td>VICTOR 2025</td><td>ARNI + BB + MRA + SGLT2</td><td>20.0</td><td>3052</td><td>2339.00</td><td>30.40</td><td>7.01</td><td>67.00</td><td>11.00</td><td>NR</td><td>440</td><td>346.00</td><td>584</td><td>877.00</td></tr><tr><td>VICTOR 2025</td><td>ARNI + BB + MRA + SGLT2 + VERICIGUAT</td><td>20.3</td><td>3053.00</td><td>2326.00</td><td>30.50</td><td>7.01</td><td>67.10</td><td>11.00</td><td>NR</td><td>377</td><td>292.00</td><td>549</td><td>822.00</td></tr></table>
<table><caption>Supplementary Table 4: SUCRA p-values</caption><thead><tr><th colspan="2">All-cause death</th></tr></thead><tbody><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0.997</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>0.937</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>0.937</td></tr><tr><td>ARNI + BB + MRA</td><td>0.827</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>0.822</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>0.799</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>0.796</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td>0.779</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>0.759</td></tr><tr><td>ARNI + BB + SGLT2</td><td>0.657</td></tr><tr><td>ACEI + BB + MRA</td><td>0.647</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td>0.643</td></tr><tr><td>ARB + BB + MRA</td><td>0.582</td></tr><tr><td>ARNI + BB</td><td>0.536</td></tr><tr><td>ACEI + ARB + BB + Dig</td><td>0.473</td></tr><tr><td>ACEI + MRA + Dig</td><td>0.43</td></tr><tr><td>Dig + H-ISDN</td><td>0.415</td></tr><tr><td>ACEI + BB + Dig</td><td>0.405</td></tr><tr><td>ACEI + BB</td><td>0.39</td></tr><tr><td>ARB + BB + Dig</td><td>0.331</td></tr><tr><td>ARB + BB</td><td>0.317</td></tr><tr><td>BB</td><td>0.255</td></tr><tr><td>ACEI + ARB + Dig</td><td>0.218</td></tr><tr><td>ACEI + Dig</td><td>0.162</td></tr><tr><td>ACEI</td><td>0.149</td></tr><tr><td>ARB + Dig</td><td>0.099</td></tr><tr><td>ARB</td><td>0.082</td></tr><tr><td>Dig</td><td>0.035</td></tr><tr><td>PLBO</td><td>0.021</td></tr></tbody></table>
<table><thead><tr><th colspan="2">CV-mortality</th></tr></thead><tbody><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0.997</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>0.935</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>0.932</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>0.887</td></tr><tr><td>ARNI + BB + MRA</td><td>0.831</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>0.783</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>0.781</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>0.733</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td>0.707</td></tr><tr><td>ARNI + BB + SGLT2</td><td>0.671</td></tr><tr><td>ACEI + BB + MRA</td><td>0.634</td></tr><tr><td>ARB + BB + MRA</td><td>0.596</td></tr><tr><td>ARNI + BB</td><td>0.55</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td>0.502</td></tr><tr><td>ACEI + ARB + BB + Dig</td><td>0.501</td></tr><tr><td>ACEI + MRA + Dig</td><td>0.438</td></tr><tr><td>ACEI + BB</td><td>0.402</td></tr><tr><td>ACEI + BB + Dig</td><td>0.386</td></tr><tr><td>ARB + BB</td><td>0.36</td></tr><tr><td>ACEI + ARB + Dig</td><td>0.29</td></tr><tr><td>BB</td><td>0.25</td></tr><tr><td>ACEI</td><td>0.184</td></tr><tr><td>ACEI + Dig</td><td>0.17</td></tr><tr><td>Dig + H-ISDN</td><td>0.155</td></tr><tr><td>ARB</td><td>0.139</td></tr><tr><td>ARB + Dig</td><td>0.126</td></tr><tr><td>PLBO</td><td>0.035</td></tr><tr><td>Dig</td><td>0.025</td></tr></tbody></table>

**Abbreviations:** ACEI, ACE-inhibitor; ARB, angiotensin-receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blocker; Dig, digoxin; H-ISDN, hydralazine-isosorbide dinitrate; MRA, mineralocorticoid receptor antagonist; PLBO, placebo; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
<table><caption>Supplementary Table 5: Additive model assumptions test – summary for all-cause mortality</caption><thead><tr><th>Metric</th><th>Value</th></tr></thead><tbody><tr><td>Total Treatments</td><td>29</td></tr><tr><td>Single Treatments</td><td>5</td></tr><tr><td>Combination Treatments</td><td>24</td></tr><tr><td>Total Studies</td><td>83</td></tr><tr><td>Reference Treatment</td><td>ACEI</td></tr><tr><td>Network Heterogeneity (τ²)</td><td>0</td></tr><tr><td>Network I² (%)</td><td>0 (0-0.3)</td></tr><tr><td>Combinations Tested for Additivity</td><td>24</td></tr></tbody></table>

## INCONSISTENCY TEST RESULTS

<table><thead><tr><th>Test</th><th>Q</th><th></th><th></th></tr></thead><tbody><tr><td>Overall (standard) Inconsistency Q-statistic</td><td>69.48391141</td><td>76</td><td>0.6879081</td></tr><tr><td>Additive model Inconsistency</td><td>54.26108321</td><td>59</td><td>0.6505004</td></tr><tr><td>Difference Inconsistency</td><td>15.2228282</td><td>17</td><td>0.5794352</td></tr></tbody></table>
<table><caption>Supplementary Table 6: Predicted versus observed effects for all-cause mortality.</caption><thead><tr><th>Combination</th><th>Observed Effect</th><th>Components</th><th>ComponentEffects</th><th>Predicted Additive</th><th>Difference</th><th>SE Observed</th></tr></thead><tbody><tr><td>ACEI + ARB + BB + Dig</td><td>-0.32</td><td>ACEI + ARB + BB + Dig</td><td>0, 0.063, -0.136, 0.103</td><td>0.03</td><td>-0.349</td><td>0.06</td></tr><tr><td>ACEI + ARB + Dig</td><td>-0.067</td><td>ACEI + ARB + Dig</td><td>0, 0.063, 0.103</td><td>0.166</td><td>-0.233</td><td>0.05</td></tr><tr><td>ACEI + BB</td><td>-0.252</td><td>ACEI + BB</td><td>0, -0.136</td><td>-0.136</td><td>-0.116</td><td>0.0</td></tr><tr><td>ACEI + BB + Dig</td><td>-0.266</td><td>ACEI + BB + Dig</td><td>0, -0.136, 0.103</td><td>-0.033</td><td>-0.233</td><td>0.05</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td>-0.645</td><td>ACEI + BB + Dig + H-ISDN</td><td>0, -0.136, 0.103, -0.379</td><td>-0.412</td><td>-0.233</td><td>0.13</td></tr><tr><td>ACEI + BB + MRA</td><td>-0.531</td><td>ACEI + BB + MRA</td><td>0, -0.136, -0.279</td><td>-0.414</td><td>-0.116</td><td>0.07</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>-0.625</td><td>ACEI + BB + MRA + IVA</td><td>0, -0.136, -0.279, -0.094</td><td>-0.509</td><td>-0.116</td><td>0.09</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td>-0.528</td><td>ACEI + BB + MRA + Omecamtiv</td><td>0, -0.136, -0.279, 0.002</td><td>-0.412</td><td>-0.116</td><td>0.08</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>-0.658</td><td>ACEI + BB + MRA + SGLT2</td><td>0, -0.136, -0.279, -0.128</td><td>-0.542</td><td>-0.116</td><td>0.09</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>-0.658</td><td>ACEI + BB + MRA + Vericiguat</td><td>0, -0.136, -0.279, -0.127</td><td>-0.541</td><td>-0.116</td><td>0.0</td></tr><tr><td>ACEI + Dig</td><td>-0.013</td><td>ACEI + Dig</td><td>0, 0.103</td><td>0.103</td><td>-0.116</td><td>0.04</td></tr><tr><td>ACEI + MRA + Dig</td><td>-0.292</td><td>ACEI + MRA + Dig</td><td>0, -0.279, 0.103</td><td>-0.175</td><td>-0.116</td><td>0.07</td></tr><tr><td>ARB + BB</td><td>-0.19</td><td>ARB + BB</td><td>0.063, -0.136</td><td>-0.073</td><td>-0.116</td><td>0.06</td></tr><tr><td>ARB + BB + Dig</td><td>-0.203</td><td>ARB + BB + Dig</td><td>0.063, -0.136, 0.103</td><td>0.03</td><td>-0.233</td><td>0.07</td></tr><tr><td>ARB + BB + MRA</td><td>-0.468</td><td>ARB + BB + MRA</td><td>0.063, -0.136, -0.279</td><td>-0.352</td><td>-0.116</td><td>0.08</td></tr><tr><td>ARB + Dig</td><td>0.049</td><td>ARB + Dig</td><td>0.063, 0.103</td><td>0.166</td><td>-0.116</td><td>0.06</td></tr><tr><td>ARNI + BB</td><td>-0.406</td><td>ARNI + BB</td><td>-0.27, -0.136</td><td>-0.406</td><td>0</td><td>0.06</td></tr><tr><td>ARNI + BB + MRA</td><td>-0.685</td><td>ARNI + BB + MRA</td><td>-0.27, -0.136, -0.279</td><td>-0.685</td><td>0</td><td>0.08</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>-0.682</td><td>ARNI + BB + MRA + Omecamtiv</td><td>-0.27, -0.136, -0.279, 0.002</td><td>-0.682</td><td>0</td><td>0.09</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>-0.812</td><td>ARNI + BB + MRA + SGLT2</td><td>-0.27, -0.136, -0.279, -0.128</td><td>-0.812</td><td>0</td><td>0.10</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>-0.939</td><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>-0.27, -0.136, -0.279, -0.128, -0.127</td><td>-0.939</td><td>0</td><td>0.11</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>-0.812</td><td>ARNI + BB + MRA + Vericiguat</td><td>-0.27, -0.136, -0.279, -0.127</td><td>-0.812</td><td>0</td><td>0.10</td></tr><tr><td>ARNI + BB + SGLT2</td><td>-0.534</td><td>ARNI + BB + SGLT2</td><td>-0.27, -0.136, -0.128</td><td>-0.534</td><td>0</td><td>0.08</td></tr><tr><td>Dig + H-ISDN</td><td>-0.276</td><td>Dig + H-ISDN</td><td>0.103, -0.379</td><td>-0.276</td><td>0</td><td>0.1</td></tr></tbody></table>
<table><caption>Supplementary Table 7: Additive model assumptions test – summary for cardiovascular mortality</caption><thead><tr><th>Metric</th><th>Value</th></tr></thead><tbody><tr><td>Total Treatments</td><td>28</td></tr><tr><td>Single Treatments</td><td>5</td></tr><tr><td>Combination Treatments</td><td>23</td></tr><tr><td>Total Studies</td><td>54</td></tr><tr><td>Reference Treatment</td><td>ACEI</td></tr><tr><td>Network Heterogeneity (τ²)</td><td>0</td></tr><tr><td>Network I² (%)</td><td>0 (0-0.3)</td></tr><tr><td>Combinations Tested for Additivity</td><td>23</td></tr></tbody></table>

INCONSISTENCY TEST RESULTS

<table><thead><tr><th>Test</th><th>Q</th><th></th><th></th></tr></thead><tbody><tr><td>Overall (standard) Inconsistency Q-statistic</td><td>45.428638</td><td>44</td><td>0.4123013</td></tr><tr><td>Additive model Inconsistency</td><td></td><td></td><td></td></tr><tr><td>Difference Inconsistency</td><td></td><td></td><td></td></tr></tbody></table>
<table><caption>Supplementary Table 8: Predicted versus observed effects for cardiovascular mortality</caption><thead><tr><th>Combination</th><th>Observed Effect</th><th>Components</th><th>Component Effects</th><th>Predicted Additive</th><th>Difference</th><th>SE Observ</th></tr></thead><tbody><tr><td>ACEI + ARB + BB + Dig</td><td>-0.372</td><td>ACEI + ARB + BB + Dig</td><td>0, 0.044, -0.073, 0.189</td><td>0.16</td><td>-0.532</td><td>0.084</td></tr><tr><td>ACEI + ARB + Dig</td><td>-0.121</td><td>ACEI + ARB + Dig</td><td>0, 0.044, 0.189</td><td>0.233</td><td>-0.355</td><td>0.068</td></tr><tr><td>ACEI + BB</td><td>-0.25</td><td>ACEI + BB</td><td>0, -0.073</td><td>-0.073</td><td>-0.177</td><td>0.048</td></tr><tr><td>ACEI + BB + Dig</td><td>-0.238</td><td>ACEI + BB + Dig</td><td>0, -0.073, 0.189</td><td>0.116</td><td>-0.355</td><td>0.065</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td>-0.374</td><td>ACEI + BB + Dig + H-ISDN</td><td>0, -0.073, 0.189, -0.135</td><td>-0.019</td><td>-0.355</td><td>0.218</td></tr><tr><td>ACEI + BB + MRA</td><td>-0.558</td><td>ACEI + BB + MRA</td><td>0, -0.073, -0.308</td><td>-0.38</td><td>-0.177</td><td>0.082</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>-0.651</td><td>ACEI + BB + MRA + IVA</td><td>0, -0.073, -0.308, -0.093</td><td>-0.474</td><td>-0.177</td><td>0.105</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td>-0.627</td><td>ACEI + BB + MRA + Omecamtiv</td><td>0, -0.073, -0.308, -0.069</td><td>-0.45</td><td>-0.177</td><td>0.111</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>-0.696</td><td>ACEI + BB + MRA + SGLT2</td><td>0, -0.073, -0.308, -0.139</td><td>-0.519</td><td>-0.177</td><td>0.106</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>-0.701</td><td>ACEI + BB + MRA + Vericiguat</td><td>0, -0.073, -0.308, -0.143</td><td>-0.524</td><td>-0.177</td><td>0.103</td></tr><tr><td>ACEI + Dig</td><td>0.012</td><td>ACEI + Dig</td><td>0, 0.189</td><td>0.189</td><td>-0.177</td><td>0.044</td></tr><tr><td>ACEI + MRA + Dig</td><td>-0.296</td><td>ACEI + MRA + Dig</td><td>0, -0.308, 0.189</td><td>-0.118</td><td>-0.177</td><td>0.08</td></tr><tr><td>ARB + BB</td><td>-0.206</td><td>ARB + BB</td><td>0.044, -0.073</td><td>-0.029</td><td>-0.177</td><td>0.076</td></tr><tr><td>ARB + BB + MRA</td><td>-0.514</td><td>ARB + BB + MRA</td><td>0.044, -0.073, -0.308</td><td>-0.336</td><td>-0.177</td><td>0.101</td></tr><tr><td>ARB + Dig</td><td>0.056</td><td>ARB + Dig</td><td>0.044, 0.189</td><td>0.233</td><td>-0.177</td><td>0.074</td></tr><tr><td>ARNI + BB</td><td>-0.448</td><td>ARNI + BB</td><td>-0.375, -0.073</td><td>-0.448</td><td>0</td><td>0.074</td></tr><tr><td>ARNI + BB + MRA</td><td>-0.756</td><td>ARNI + BB + MRA</td><td>-0.375, -0.073, -0.308</td><td>-0.756</td><td>0</td><td>0.1</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>-0.825</td><td>ARNI + BB + MRA + Omecamtiv</td><td>-0.375, -0.073, -0.308, -0.069</td><td>-0.825</td><td>0</td><td>0.124</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>-0.894</td><td>ARNI + BB + MRA + SGLT2</td><td>-0.375, -0.073, -0.308, -0.139</td><td>-0.894</td><td>0</td><td>0.12</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>-1.038</td><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>-0.375, -0.073, -0.308, -0.139, -0.143</td><td>-1.038</td><td>0</td><td>0.135</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>-0.899</td><td>ARNI + BB + MRA + Vericiguat</td><td>-0.375, -0.073, -0.308, -0.143</td><td>-0.899</td><td>0</td><td>0.117</td></tr><tr><td>ARNI + BB + SGLT2</td><td>-0.587</td><td>ARNI + BB + SGLT2</td><td>-0.375, -0.073, -0.139</td><td>-0.587</td><td>0</td><td>0.1</td></tr><tr><td>Dig + H-ISDN</td><td>0.054</td><td>Dig + H-ISDN</td><td>0.189, -0.135</td><td>0.054</td><td>0</td><td>0.215</td></tr></tbody></table>