# Sacubitril/valsartan and Quality of Life Assessed Using the EuroQol 5-Dimension 3-Level Questionnaire Level Sum Score (EQ-5D-3L-LSS) in Patients with HFrEF and HFmrEF/HFpEF

Mingming Yang, Alasdair D Henderson, Inder S Anand, Akshay S Desai, Carolyn Sp Lam, Aldo P Maggioni, Felipe A Martinez, Jean L Rouleau, Karl Swedberg, Muthiah Vaduganathan, et al.

► To cite this version:

Mingming Yang, Alasdair D Henderson, Inder S Anand, Akshay S Desai, Carolyn Sp Lam, et al. Sacubitril/valsartan and Quality of Life Assessed Using the EuroQol 5-Dimension 3-Level Questionnaire Level Sum Score (EQ-5D-3L-LSS) in Patients with HFrEF and HFmrEF/HFpEF. European Heart Journal - Cardiovascular Pharmacotherapy, 2025, 10.1093/ehjcvp/pvaf064. hal-05219761

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1 Full title: Sacubitril/valsartan and Quality of Life Assessed Using the EuroQol 5-Dimension 3-Level Questionnaire Level Sum Score (EQ-5D-3L-LSS) in Patients with HFrEF and -HFmrEF/HFpEF

4 Short title: Sacubitril/valsartan and EQ-5D-3L in heart failure

5 Authors: Mingming Yang MD, PhD¹,²

6 Alasdair D. Henderson, PhD¹

7 Inder S. Anand, MD, DPhil³

8 Akshay S. Desai, MD, MPH⁴

9 Carolyn SP. Lam, MD, PhD⁵

10 Aldo P. Maggioni, MD⁶

11 Felipe A. Martinez, MD⁷

12 Jean L. Rouleau, MD⁸

13 Karl Swedberg, MD, PhD⁹

14 Muthiah Vaduganathan, MD, MPH⁴

15 Dirk J. van Veldhuisen, MD¹⁰

16 Faiez Zannad, MD, PhD¹¹

17 Michael R. Zile, MD¹²

18 Milton Packer, MD¹³

19 Adel Rizkala, PharmD¹⁴

20 Eldrin F. Lewis, MD, MPH¹⁵

21 Pardeep S. Jhund, MBChB, MSc, PhD²

22 Scott D. Solomon, MD⁴

23 John J.V. McMurray MD²
1 Affiliations:
2 British Heart Foundation Cardiovascular Research Centre,
University of Glasgow, Glasgow, UK

3 Department of Cardiology, Zhongda Hospital, School of
4 Medicine, Southeast University, Nanjing, China

5 Department of Cardiovascular Medicine, University of Minnesota,
Minneapolis, MN, USA

7 Cardiovascular Division, Brigham and Women's Hospital,
Harvard Medical School, Boston, Massachusetts, USA

9 National Heart Centre Singapore & Duke-National University of
Singapore, Singapore

11 ANMCO Research Center, Heart Care Foundation, Florence, Italy

12 Universidad Nacional de Córdoba, Córdoba, Argentina

13 Institut de Cardiologie de Montréal, Université de Montréal,
Montréal, Canada

15 Department of Emergency and Cardiovascular Medicine,
Sahlgrenska Academy, University of Gothenburg, Gothenburg,
Sweden

18 Department of Cardiology, Thorax Center, University Medical
Center, Groningen, the Netherlands

20 Université de Lorraine, Inserm Clinical Investigation Centre,
CHU, Nancy, France

22 RHJ Department of Veterans Affairs Medical Center, Medical
University of South Carolina, Charleston, SC, USA

24 Baylor Heart and Vascular Institute, Baylor University Medical
Center, Dallas, Texas

26 Novartis Pharmaceuticals Corporation, East Hanover, NJ

27 Division of Cardiovascular Medicine, Stanford University School
of Medicine, Stanford University, Palo Alto, California, USA

30 JJVM and PSJ are supported by a British Heart Foundation Centre
of Research Excellence Grant RE/18/6/34217 and the Vera Melrose
Heart Failure Research Fund.
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Disclosures:

Both PARADIGM-HF and PARAGON-HF trials were funded by Novartis.

**Dr. Yang** has received Global CardioVascular Clinical Trialists (CVCT) Young Trialist Grant and travel grants from AstraZeneca and Bayer.

**Dr. Henderson** has reported receiving personal fees from Bayer outside the submitted work.

**Dr. Anand** reports receiving fees for serving on a steering committee from AstraZeneca, ARCA biopharma, Amgen, and LivaNova; fees for serving as chair of a data and safety monitoring board from Boston Scientific; and fees for serving on an end point committee from Boehringer Ingelheim.

**Dr. Desai** has received institutional research grants (to Brigham and Women's Hospital) from Abbott, Alnylam, AstraZeneca, Bayer, Novartis, and Pfizer as well as personal consulting fees from Abbott, Alnylam, AstraZeneca, Bayer, Biofourmis, Boston Scientific, Medpace, Medtronic, Merck, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, Veristat, Verily, Zydus.

**Dr. Lam** has received research support from NovoNordisk and Roche Diagnostics; has received consulting fees from Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Bioeutics, 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 is a co-founder & non-executive director of Us2.ai.

**Dr. Maggioni** has received fees for serving on a study committee from Bayer, Novartis, AstraZeneca and Sanofi.

**Dr. Martinez** has received personal fees from AstraZeneca, Novartis, Gador, Baliarda, Pfizer, Bayer, Bago.

**Dr. Rouleau** has received grants and consulting fees from DMC membership in trials funded by Alexion and Intellia, Bayer, AstraZeneca, BMS and Novartis.
**Dr. Swedberg** reports honoraria from AstraZeneca, Boehringer Ingelheim and Novartis.

**Dr. Vaduganathan** has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, BMS, Boehringer Ingelheim, Chiesi, Cytokinetics, Fresenius Medical Care, Idorsia Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Milestone Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health, and participates on clinical trial committees for studies sponsored by Amgen, AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics.

**Dr. van Veldhuisen** has no relevant disclosures.

**Dr. Zannad** reports personal fees from 89Bio, Abbott, Acceleron, Applied Therapeutics, Bayer, Betagenon, Boehringer, BMS, CVRx, Cambrian, Cardior, Cereno pharmaceutical, Cellprothera, CEVA, Inventiva, KBP, Merck, NovoNordisk, Owkin, Otsuka, Roche Diagnostics, Northsea, USa2, having stock options at G3Pharmaceutical and equities at Cereno, Cardiorenal, Eshmoun Clinical research and being the founder of Cardiovascular Clinical Trialists.

**Dr. Zile** has received research funding from Novartis; and has been a consultant for Novartis, Abbott, CVRx, Merck, Medtronic, V Wave, Edwards, and Lilly.

**Dr. Packer** reports consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance.

**Dr. Lewis** reports consulting fees from Astra Zeneca, Akebia, Merck, Dal-Cor, and Intellia; he reports institutional research support from Merck, Idorsia, the American Heart Association and the NIH.

**Dr. Jhund** has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals, and Intas Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; his employer the University of Glasgow has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk; and is the
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Director of Global Clinical Trial Partners (GCTP).

**Dr. Solomon** has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and S2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellPro-Thera, Moderna, American Regent, and Sarepta.

**Dr. McMurray** reports payments to Glasgow University for clinical trials and other research projects from the British Heart Foundation, National Institute for Health - National Heart Lung and Blood Institute (NIH-NHLBI), Alnylam Pharmaceuticals, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, Roche. Personal consultancy fees from: Alnylam Pharmaceuticals, AnaCardio, AstraZeneca, Bayer, Cardurion, Cytokinetics, Novartis, River BioMedics, Biohaven Pharmaceuticals, Chugai Pharmaceuticals, Protherics Medicine Developments Ltd., DalCor Pharmaceuticals. Personal lecture fees: Alkem Metabolics, Astra Zeneca, Canadian Medical and Surgical Knowledge, Centrix Healthcare, Emcure Pharmaceuticals, Eris Lifesciences, Hikma Pharmaceuticals, Imagica Health, Intas Pharmaceuticals, J.B. Chemicals & Pharmaceuticals, Lupin Pharmaceuticals, Medscape/Heart.Org., ProAdWise Communications, Radcliffe Cardiology, Sun Pharmaceuticals, Translational Medicine Academy, Regeneron, MCI India, Hilton Pharmaceuticals, IMEDIC Pharmaceuticals Micro Labs Ltd., At the Limits Ltd., ARMGO Pharmaceuticals. Data Safety Monitoring Boards: WCG Clinical Services. He is a director of Global Clinical Trial Partners Ltd (which provides clinical trial services such as endpoint committees and educational programmes).

**Dr. Rizkala** is an employee of Novartis.

**Correspondence:** British Heart Foundation Cardiovascular Research Centre,
University of Glasgow, 126 University Place,
Glasgow, G12 8TA, United Kingdom.
Tel: +441413303479 Fax: +441413306955
Email:john.mcmurray@glasgow.ac.uk
# ABSTRACT

**Objectives:** To investigate the EQ-5D-3L Level Sum Score (LSS) in patients with heart failure (HF) and reduced (HFrEF) and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and the effect of sacubitril/valsartan on this score using patient-level data from the PARADIGM-HF and PARAGON-HF trials.

**Methods:** The LSS was calculated by summating the 3 levels (1-3) for each of the 5 domains (minimum sum score=5; maximum sum score=15). Patient characteristics and outcomes were compared across LSS tertiles (T1-T3) at baseline. Cox models were used to evaluate the primary endpoint (first HF hospitalization or cardiovascular death) according to tertiles of LSS. Changes in LSS severity at 8 months were analysed using ordinal logistic regression models to estimate the effect of sacubitril/valsartan versus enalapril or valsartan.

**Results:** Of 13,195 patients, 12,974 had a baseline LSS. Compared to lower LSS, patients with higher (worse) scores were older, more often women and White, and had more comorbidities and more severe HF. At 8 months, patients assigned to sacubitril/valsartan experienced more improvement and less worsening of LSS versus the comparator: OR:1.16 (95%CI: 1.08-1.24). Sacubitril/valsartan also reduced the risk of the primary outcome across LSS tertiles: T1: HR: 0.87 (95%CI: 0.75-1.00); T2: 0.80 (95%CI: 0.71-0.90); T3: 0.87 (95%CI: 0.77-0.97); P<0.05. Higher LSS was independently associated with a greater risk of the primary endpoint, and the achieved LSS at 8 months may be more strongly associated with subsequent outcomes.

**Conclusions:** Sacubitril/valsartan significantly reduced the risk of HF events and improved health status across the LSS spectrum in HFrEF and HFmrEF/HFpEF.
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2 **Clinical Trial Registration** https://www.clinicaltrials.gov. Unique identifiers: NCT01920711

3 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

4 **Keywords:** Quality of life; EQ-5D-3L; sacubitril/valsartan; heart failure; symptoms

5

6

INTRODUCTION

7 Heart failure (HF) is a progressive condition associated with significant morbidity, mortality, and
8 poor health-related quality-of-life (HRQL).¹ While clinical outcomes such as hospitalization and
9 mortality remain key endpoints in HF trials, HRQL is increasingly recognized as an important
10 measure of therapeutic efficacy.²⁻⁴ The EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire
11 is a standardized, validated, and widely used instrument for assessing generic HRQL across
12 various conditions, although there are few data in HF.¹,⁵⁻⁸ In practice, EQ-5D is valued for its
13 brevity and utility indexing (for cost-effectiveness).⁹⁻¹¹ The Level Sum Score (EQ-5D-3L-LSS),
14 derived from the EQ-5D-3L, provides a composite measure of health status by summing patient
15 responses on three severity levels (1="no problem", 2="some problem", 3="extreme problem")
16 across five dimensions: mobility, self-care, usual activities, pain/discomfort, and
17 anxiety/depression.¹²

18 Studies have demonstrated that higher EQ-5D scores (worse HRQL) are associated with a greater
19 risk of adverse clinical outcomes in patients with HF, irrespective of LVEF.13-17 However, there are
20 few data on the effects of therapeutic interventions for HF on EQ-5D. Early evidence from the
21 CARE-HF trial demonstrated that cardiac resynchronization therapy (CRT) significantly improved
22 quality of life, including EQ-5D scores, and that these benefits were sustained over long-term
1 follow-up.<sup>18,19</sup> Similarly, in the HF-ACTION trial, aerobic exercise training led to a modest

2 improvement in EQ-5D visual analogue scale (VAS) score compared with usual care at 3 months.<sup>20</sup>

3 More recently, in the DAPA-HF and DELIVER trials, dapagliflozin improved EQ-5D scores and

4 multiple HRQL dimensions, including mobility, self-care, usual activities, and possibly

5 anxiety/depression.<sup>16,17</sup> The EQ-5D was also employed in two trials using sacubitril/valsartan, an

6 angiotensin receptor-neprilysin inhibitor (ARNI), to evaluate patient-reported health status. The

7 first, the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact

8 on Global Mortality and Morbidity in Heart Failure), demonstrated superiority over an

9 angiotensin-converting enzyme inhibitor in patients with HF and reduced LVEF (HFrEF).<sup>21</sup> In

10 patients with HF and mildly reduced or preserved LVEF (HFmrEF/HFpEF), the PARAGON-HF

11 trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved

12 Ejection Fraction) showed that sacubitril/valsartan led to a non-significant reduction in the

13 composite endpoint of total HF hospitalizations and cardiovascular mortality when compared with

14 an angiotensin II receptor blocker (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01;

15 P=0.06).<sup>22,23</sup>

16 In the present study, we examined the effects of sacubitril/valsartan on EQ-5D-3L-LSS and its

17 dimensions over time in patients with HFrEF and HFmrEF/HFpEF, using data from PARADIGM-

18 HF and PARAGON-HF trials. We also evaluated the relationship between baseline EQ-5D-3L

19 scores and patient characteristics.

20
# METHODS

1

## 2 Trials and patients

In this *post-hoc* analysis, we conducted a pooled analysis of patient-level data from PARADIGM-HF (NCT01035255) and PARAGON-HF (NCT01920711). The study designs, baseline characteristics, and primary outcomes of these trials have been published.²¹,²² In brief, both PARADIGM-HF and PARAGON-HF were multinational, multicenter, phase 3, randomized, double-blind clinical trials that assessed the efficacy and safety of sacubitril/valsartan compared to a renin-angiotensin system (RAS) comparator (enalapril or valsartan, respectively) in patients with HF and LVEF≤40% (HFrEF, PARADIGM-HF) or LVEF≥45% (HFmrEF/HFpEF, PARAGON-HF). In PARADIGM-HF, sacubitril/valsartan was compared to enalapril, a well-established and effective therapy for HFrEF, whereas in PARAGON-HF, it was compared to valsartan, which is not an established treatment for HFpEF and whose efficacy in HFmrEF remains uncertain. The key inclusion and exclusion criteria are summarized in the **Supplementary Material**, and a complete list of inclusion and exclusion criteria is available in the primary results publications.²¹,²² All patients provided written informed consent, and both study protocols were approved by Ethics Committees at each participating site.

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## 18 European Quality of Life Questionnaire-5 dimensions-3 levels: EuroQoL (EQ-5D-3L)

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# 1 Clinical outcomes

2 The primary endpoint in PARADIGM-HF was the composite of CV death or first HF hospitalization, and in PARAGON-HF a composite of total (first and recurrent) HF hospitalizations and CV death causes.²¹,²² In the present analyses, we examined both outcomes as well as the time to first HF hospitalization, and death (due to CV, non-CV, and all causes).

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# 7 Statistical Analysis

8 Baseline characteristics were summarized using medians with interquartile ranges (Q1-Q3) for continuous variable, and frequencies with percentages for categorical variables according to the EQ-5D-3L-LSS tertiles (T1-T3). Group comparisons were conducted with the Jonckheere-Terpstra test for continuous variables and the Cochran-Armitage test for a binary variable to assess trends across different EQ-5D-3L-LSS groups.

13 The cumulative incidence of time-to-first-event outcome according to each LSS tertile and severity levels of individual dimensions was estimated using the Kaplan-Meier method. The association between EQ-5D-3L-LSS and each outcome was evaluated using Cox proportional hazards regression models with patients in EQ-5D-3L-LSS T1 (i.e. LSS=5) as the reference group, stratified according to geographic region and study. Negative binomial regression analysis, adjusted for geographic region and trial with an offset for follow-up time, was performed to compare the composite of total (first and repeat) HF hospitalizations and CV death, across EQ-5D categories. The above analyses also adjusted for: age, sex, heart rate, systolic blood pressure (SBP), body mass index (BMI), New York Heart Association (NYHA) functional class, LVEF, estimated glomerular filtration rate (eGFR), N-terminal pro B-type natriuretic peptide (NT-proBNP), log-transformed), atrial fibrillation, history of myocardial infarction (MI), diabetes, and stroke.
24 The effect of sacubitril/valsartan compared to a RAS inhibitor was calculated as a rate ratio (RR)
1 and 95% confidence interval (95%CI) derived from negative binomial regression models for total
2 (first and recurrent) events or as a hazard ratio (HR) and 95%CI from Cox proportional hazards
3 models for time-to-first events.

4 To examine the longitudinal changes in EQ-5D dimensions, individual patient trajectories were
5 visualized using Sankey diagrams, which captured shifts in severity categories from baseline to
6 the 8-month follow-up assessment.

7 The treatment effects of sacubitril/valsartan on EQ-5D dimension scores were assessed at baseline
8 and 8 months follow-up, with no imputation for missing data. Changes in EQ-5D severity
9 categories at 8 months were classified as 'improved', 'no change', or 'worsened'. An ordinal logistic
10 regression model was used to evaluate the effect of sacubitril/valsartan on changes in EQ-5D
11 dimension scores with results reported as overall odds ratios (ORs) representing the likelihood of
12 experiencing improvement versus deterioration in EQ-5D dimension scores. The same statistical
13 approach was applied to analyze EQ-5D-3L-LSS categories. A subgroup analysis was performed
14 to assess the effect of sacubitril/valsartan on EQ-5D-3L-LSS by sex (men and women) given the
15 previously observed effect modification by sex in the PARAGON-HF trial.²²

16 All statistical analyses were conducted using Stata/SE version 18.0 (Stata Corp, College Station,
17 TX). A two-tailed p-value <0.05 was considered statistically significant for all tests.

## RESULTS

20 Of the 13,195 patients randomized in PARADIGM-HF and PARAGON-HF, 12,974 completed the
21 EQ-5D-3L questionnaire at baseline, and 11,915 (90.3%) at the 8-month follow-up visit
22 (Supplementary Table 1). The distribution of responses across the five EQ-5D-3L dimensions for
1 the entire cohort is detailed in **Supplementary Table 1** and **Supplementary Figure 1**, while the
2 distributions for each trial are shown in **Supplementary Table 2** (PARADIGM-HF) and 3
4 (PARAGON-HF), respectively. The categorization of patients based on individual EQ-5D-3L-LSS
5 scores is illustrated in **Supplementary Figure 2**, while stratifications by tertiles are presented in
6 **Supplementary Table 1** (overall cohort), **Table 1** (HFrEF), **Table 2** (HFmrEF/HFpEF), and the
7 **Graphical abstract**, with additional breakdowns by HF phenotype in **Supplementary Tables**
8 2&3.

8

9

Patient characteristics according to EQ-5D-3L-LSS

10 Baseline characteristics according to EQ-5D-3L-LSS are summarized in **Table 1** (HFrEF), **Table 2** (HFmrEF/HFpEF), and **Supplementary Tables 4-5** (overall cohort). Same results for EQ-5D
11
12 VAS are reported in **Supplementary Table 6**.

13

Demographic and clinical characteristics

14 Compared to patients in the best LSS tertile (lowest scores, best HRQL), those in worse LSS
15 tertiles (higher scores, worse HRQL) were generally older, and more frequently female and White.
16
17 They also had a higher heart rate and SBP, and higher proportions of obesity and other
18 comorbidities including atrial fibrillation, coronary artery disease, stroke, diabetes, lung disease,
anaemia, and chronic kidney disease (CKD).

19

Heart failure characteristics and treatments

20 Compared to patients with worse EQ-5D-3L-LSS, patients in better LSS tertiles were more likely
to have longer duration HF, higher LVEF, and more severe HF, as indicated by worse NYHA
21
22 functional class and lower Kansas City Cardiomyopathy Questionnaire (KCCQ) and EQ-VAS
23 scores. They also had lower eGFR. Interestingly, NT-proBNP levels did not differ meaningfully
across tertiles of baseline EQ-5D-3L-LSS, with no significant trend observed (P for trend = 0.45).

2

3

EQ-5D-3L individual dimension scores

The distribution of EQ-5D-3L responses across individual dimensions is shown in **Supplementary**

**Tables 1-3 and Supplementary Figure 1.** The proportion of patients reporting no/some/extreme

problems was 52.9/46.9/0.2% for mobility ("walking about"), 83.7/15.8/0.6% for self-care

("washing or dressing myself); 57.3/40.3/2.5% for usual activities ("work, study, housework,

family or leisure activities"), 52.9/44.3/2.8% for pain/discomfort, and 67.6/30.5/1.9% for

anxiety/depression (Supplementary Figure 1). Compared with patients with HFrEF, those with

HFmrEF/HFpEF reported more problems in the mobility and pain/discomfort dimensions.

Specifically, 53.6% of patients with HFmrEF/HFpEF reported some problems with mobility

compared with 43.1% in HFrEF, and 48.4% of patients with HFmrEF/HFpEF reported some

problems with pain/discomfort versus 41.9% in HFrEF. A greater proportion of patients with

HFmrEF/HFpEF also reported extreme problems with pain/discomfort (4.4% vs 1.9%). In contrast,

the proportions reporting issues in self-care, usual activities, and anxiety/depression were generally

similar between the two groups (Supplementary Table 7).

The baseline characteristics according to responses to each EQ-5D-3L dimension are presented in

**Supplementary Tables 8-12.** Compared to patients who reported no issues in any dimension (T1,

LSS=5), those experiencing greater impairment were generally older, more frequently female, and

exhibited a higher prevalence of comorbidities, along with characteristics suggesting more severe

HF.

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1

Effect of sacubitril/valsartan on EQ-5D-3L individual dimension scores

2

Changes in EQ-5D-3L dimension scores from baseline to 8 months are shown in **Figures 1-2**

3

(pain/discomfort, and anxiety/depression) and **Supplementary Figures 3-5** (mobility, self-care,

4

usual activities). Treatment with sacubitril/valsartan was associated with a reduced likelihood of

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deterioration in all dimensions by 8 months: mobility: 11.8% vs. 13.0%, self-care: 8.1% vs. 9.0%,

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usual activities: 14.0% vs. 15.8%, pain/discomfort:15.1% vs. 17.1%, and anxiety/depression: 13.4%

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vs. 14.9% (**Supplementary Figure 6, Figure 3**). Patients treated with sacubitril/valsartan

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demonstrated a greater improvement in mobility scores compared to placebo (12.2% vs. 11.3%).

9

Individuals randomized to sacubitril/valsartan were more likely to experience improvement rather
than deterioration across multiple EQ-5D dimensions, including mobility (OR 1.13, 95%CI 1.04-

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1.23; p=0.005), self-care (1.12, 1.01-1.25; p=0.037), usual activities (1.14, 1.05-1.24; p=0.001) at

11

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the 8-month follow-up (**Supplementary Figure 6, Figure 3**).

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At 8 months, sacubitril/valsartan was also associated with greater overall improvement and less
worsening in EQ-5D-3L-LSS compared to the active comparator: OR:1.16 (95%CI: 1.08-1.24)

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(Supplementary Figure 7). Findings were consistent in individual trials (Graphical abstract).

16

Similar findings were also observed irrespective of sex (Supplementary Figure 8).

17

The effect of sacubitril/valsartan on EQ-5D VAS is presented in **Supplementary Table 13**.

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19

Association between EQ-5D-3L-LSS and clinical outcomes

20

The association between EQ-5D-3L-LSS and clinical outcomes is presented in **Supplementary**

21

**Tables 14-16** (overall cohort, HFrEF, and HFmrEF/HFpEF), **Figures 4-5** (composite of

22

cardiovascular death or first heart failure hospitalization, and all-cause death), **Supplementary**
Figures 9-10 (first heart failure hospitalization, and cardiovascular death), and Graphical abstract. Patients with higher EQ-5D-3L-LSS (i.e. worse HRQL) had a significantly higher risk of all outcomes evaluated. Compared with patients in the best LSS tertile (T1, LSS=5), those in T2 (LSS 6-7) had a 21% higher risk of first HF hospitalization or CV death (HR=1.21; 95%CI: 1.10-1.33), while those in T3 (LSS 8-15) had a 50% higher risk (HR=1.50; 95%CI: 1.37-1.65), with corresponding rates (95% confidence interval) per 100 person-years for this composite outcome for T1, T2, and T3 of 8.6 (8.0-9.3), 10.0 (9.4-10.6), 12.2 (11.6-12.9), respectively.

Although adjustments for prognostic factors, including NT-proBNP, attenuated the hazard ratios, higher EQ-5D-3L-LSS (i.e. worse HRQL) remained significantly associated with worse outcomes after adjustment (Supplementary Tables 14-16). The association between EQ-5D VAS and the outcomes showed similar results (Supplementary Table 17, Figures 4-5, and Supplementary Figures 9-10). The relationship between EQ-5D-3L-LSS at 8 months and subsequent clinical outcomes is presented in Supplementary Table 18.

Associations between individual EQ-5D-3L dimension scores and outcomes revealed a pattern similar to that seen for the overall EQ-5D-3L-LSS (Figures 4-5, and Supplementary Figures 9-10: (A) mobility, (B) self-care, (C) usual activities, (D) pain/discomfort, and (E) anxiety/depression.

Sacubitril/valsartan, compared with a RAS comparator, reduced the risk of the primary outcome across LSS tertiles: T1: HR=0.87 (95%CI: 0.75-1.00); T2: 0.80 (95%CI: 0.71-0.90); T3: 0.87 (95%CI: 0.77-0.97); $P_{interaction}=0.59$ (Supplementary Tables 19: overall cohort, Tables 3-4: HFrEF and HFmrEF/HFpEF). Similar findings were also observed for HF hospitalization, CV death, all-cause death, and total HF hospitalizations and CV death.
DISCUSSION

In this pooled analysis of PARADIGM-HF and PARAGON-HF, we found higher EQ-5D-3L-LSS (i.e. worse HRQL) was associated with a greater risk of HF-related hospitalizations and mortality.

Importantly, treatment with sacubitril/valsartan improved patient-reported functioning (reflected by the mobility, self-care, and usual activities dimensions of EQ-5D) in patients with HFrEF and HFmrEF/HFpEF. To our knowledge, this study represents the first large-scale investigation evaluating the impact of sacubitril/valsartan on both the overall EQ-5D-3L-LSS and EQ-5D-3L dimension-specific scores in patients with HFrEF and HFmrEF/HFpEF. These findings highlight the potential clinical utility of EQ-5D as a tool for assessing HRQL in HF and evaluating the effectiveness of HF treatments.

The relationship between EQ-5D-3L-LSS and clinical outcomes aligns with prior studies demonstrating a correlation between EQ-5D scores and disease-specific HRQL measures, including the Minnesota Living with Heart Failure Questionnaire (MLHFQ), KCCQ, and NYHA functional class.<sup>19,24-28</sup> Patients with worse baseline EQ-5D-3L-LSS had a significantly greater risk of adverse HF outcomes, even after adjusting for established prognostic markers such as NT-proBNP levels. A similar pattern was also observed across individual domain scores and the VAS.

This reinforces the potential usefulness of incorporating HRQL assessments into routine clinical practice, as they provide valuable prognostic information beyond traditional biomarkers and clinical variables.<sup>20</sup> Furthermore, EQ-5D provides a broader, generic assessment of patient well-being and enables cross-disease evaluations as it is not a HF-specific tool.<sup>1,29</sup>

Contrary to expectation, NT-proBNP levels were similar across tertiles of baseline EQ-5D-3L-LSS in HFmrEF/HFpEF. This suggests that the EQ-5D may capture aspects of health status, including physical functioning, symptoms (pain/discomfort), and mental well-being, that are not fully
reflected by traditional biomarkers such as natriuretic peptides. This further reinforces the potential value of integrating patient-reported outcomes into clinical assessment, particularly in patients with HFmrEF/HFpEF. On the other hand, as expected, we did observe a significant trend in NT-proBNP levels across EQ-5D categories in DAPA-HF and DELIVER trials. The discrepancies between those findings and ours may be explained by differences in trial design: (i) the presence of a run-in period in PARADIGM-HF and PARAGON-HF; (ii) the timing of NT-proBNP measurement at screening rather than at randomization; and (iii) the use of an active comparator rather than placebo. Additionally, differences in the EQ-5D instrument versions used (EQ-5D-3L vs EQ-5D-5L) may also have contributed to the observed variation.

The prevalence of problems (“some” or “extreme”) across individual EQ-5D dimensions was: mobility 47%, self-care 16%, usual activities 43%, pain/discomfort 47%, and anxiety/depression 32%. In DAPA-HF and DELIVER trials, higher proportions of participants reported problems in all EQ-5D dimensions (63%, 33%, 60%, 55%, and 43% in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, respectively).¹⁷ This may reflect the use of the EQ-5D-5L in DAPA-HF/DELIVER, rather than the EQ-5D-3L in PARADIGM-HF/PARAGON-HF. The EQ-5D-5L was introduced later to enhance measurement precision and reduce ceiling and floor effects observed with the EQ-5D-3L, and our findings support the view that the EQ-5D-5L may have greater sensitivity.³⁰ Moreover, participants in the DAPA-HF trial exhibited poorer baseline health status, as indicated by lower KCCQ scores and less favorable prognostic profiles. While overall EQ-5D-3L-LSS scores were broadly similar between patients with HFrEF and HFmrEF/HFpEF, domain-specific differences were observed. Notably, patients with HFmrEF/HFpEF more frequently reported impairments in mobility and experienced greater levels of pain or discomfort than those with HFrEF. These findings align with the demographic and
1 clinical profile of patients with HFpEF, who are often older, more likely to be women, and have a
2 higher burden of comorbidities such as obesity, arthritis, or musculoskeletal disorders that may
3 impact physical function and pain perception. These observations highlight the importance of
4 considering domain-specific health status in addition to summary scores, particularly when
5 evaluating patients with different HF phenotypes.

6 Consistent with other studies, we found high proportions of patients experiencing pain/discomfort
7 and anxiety/depression, domains that differ from disease-specific instruments and which are often
8 underrecognized in HF. Few studies have investigated pain in outpatients with HF. Pain may stem
9 from comorbid conditions rather than HF *per se*.¹⁷ Interestingly, pain/discomfort was the only
10 dimension that did not improve with sacubitril/valsartan or dapagliflozin, suggesting that HF
11 therapies may not directly address this domain.¹⁷ Patients reporting greater pain were also more
12 likely to have multiple comorbid conditions, a trend consistent with these individuals exhibiting
13 worse scores across other EQ-5D-3L dimensions. Moreover, more severe pain was associated with
14 more advanced heart failure, as reflected by higher NYHA functional class. Unfortunately, none
15 of the trials included captured specific concomitant conditions that may contribute directly to
16 chronic pain, such as osteoarthritis, spinal disorders, connective tissue diseases, or chronic
17 inflammatory conditions. The pain-related burden in HF patients warrants further exploration.
18 Beyond the influence of comorbidities, some evidence suggests that HF itself may exacerbate pain
19 perception through central sensitization due to heightened nociceptive signalling and increased
20 pain sensitivity, potentially amplifying discomfort from underlying diseases.³¹ This
21 neurobiological dysregulation may also explain why some HF patients report debilitating pain,
22 even in the absence of significant musculoskeletal abnormalities. On the other hand, self-reported
23 pain may reflect broader emotional distress or negative affect, rather than specific physical
1 pathology, and responses can be shaped by general pessimism and unhappiness rather than careful
2 symptom appraisal.

3 Additionally (and perhaps related), psychological distress is another underappreciated component
4 of HRQL impairment in HF. In the Swedish Heart Failure Registry, 40% of patients with HFrEF
5 and 44% of those with HFpEF reported experiencing some degree of anxiety or depression, as also
6 assessed by EQ-5D-3L.32 In the current study, it was 32% and 33% in HFrEF and HFmrEF/HFpEF,
7 respectively. This difference may reflect the selected nature of patients enrolled in trials or might
8 be attributed to more comprehensive clinical management and closer patient follow-up in our trial
9 populations, underscoring the potential impact of structured care on mental health outcomes in HF
10 patients.

11 Sacubitril/valsartan improved EQ-5D-3L-LSS over 8 months, with patients receiving this
12 treatment experiencing greater improvement (21.3% versus 19.9%) and less worsening (19.0%
13 versus 21.7%) compared to a RAS blocker. This effect was consistent irrespective of HF phenotype
14 or sex. Treatment benefit was also observed on mobility, self-care, and usual activities domains,
15 suggesting that sacubitril/valsartan contributes to functional improvements in daily living. These
16 findings also align with improvements in the disease-specific KCCQ with sacubitril/valsartan. 33,34
17 Our study extends these observations to the generic EQ-5D-3L, reinforcing its applicability across
18 diverse HF populations. In addition to the present results with sacubitril/valsartan, other trials
19 assessing HRQL in HF, such as DAPA-HF and DELIVER, have also shown a beneficial effect of
20 dapagliflozin in improving EQ-5D-LSS, VAS, and utility index score.16,17

21 Detailed analysis of individual EQ-5D-3L dimensions provides insights into which aspects of
22 patient well-being are most impacted by HF and which are most responsive to treatment.
23 Compared with the comparator, sacubitril/valsartan significantly improved functional domains
1 (mobility, self-care, and usual activities), which are essential for independent living and overall
2 well-being. This is consistent with previous findings from PARADIGM-HF, where
3 sacubitril/valsartan enhanced KCCQ physical and social limitation scores.³³,³⁵ Similarly, in the
4 CARE-HF study, cardiac resynchronization therapy (CRT) was associated with a significant
5 improvement in disease-specific quality of life (Minnesota Living with Heart Failure) at 18 months,
6 with a mean between-group difference of 10.7 points (95% CI: 7.6–13.8), primarily driven by
7 enhanced physical functioning.¹⁸ Although the change in anxiety/depression was directionally
8 similar it was of borderline statistical significance. This domain did demonstrate a significant
9 improvement in a patient-level meta-analysis of DAPA-HF and DELIVER and the discrepancy
10 between these analyses may again reflect the use of the EQ-5D-3L versus EQ-5D-5L.¹⁷
11 By contrast, pain/discomfort showed only a small and non-significant change with HF therapy,
12 consistent with the analyses of DAPA-HF/DELIVER.

## Limitations

14 This study has similar limitations to other analyses of the EQ-5D-LSS.¹⁷ Although there are always
15 questions about response bias and potential differences between responders and non-responders,
16 the response rate to the questionnaire was high (98.3% at baseline and 90.3% at 8 months). This
17 study focused on sacubitril/valsartan, so findings may not apply to other HF therapies, and
18 confounding from comorbidities could have influenced the results.

19

## Conclusions

21 Both the overall EQ-5D-3L-LSS and its individual dimension scores were correlated with clinical
22 characteristics and outcomes. Treatment with sacubitril/valsartan led to reductions in HF-related
1 events across the tertiles of baseline EQ-5D-3L-LSS in patients with both HFrEF and

2 HFmrEF/HFpEF. Additionally, improvements were observed across multiple EQ-5D dimensions,

3 particularly in mobility, self-care, and usual activities, and overall HRQL in patients receiving

4 sacubitril/valsartan.

5

6 Acknowledgements

7 None

8

9 Data availability

10 The data underlying this article will be shared on reasonable request to the corresponding author.

11

12 References

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1
2

<table><caption>Table 1: Baseline characteristics according to baseline EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire Level Sum Score (LSS) category divided by tertile in HFrEF.</caption><thead><tr><th></th><th>Tertile 1: 5</th><th>Tertile 2: 6-7</th><th>Tertile 3: 8-15</th><th>P-Value for trend</th></tr></thead><tbody><tr><td>N, (%)</td><td>2582 (31.2)</td><td>2944 (35.6)</td><td>2745 (33.2)</td><td></td></tr><tr><td>Age, yr</td><td>63 (56-71)</td><td>64 (57-73)</td><td>65 (58-73)</td><td>&lt;0.001</td></tr><tr><td><strong>Women</strong></td><td><strong>387 (15.0)</strong></td><td><strong>587 (19.9)</strong></td><td><strong>817 (29.8)</strong></td><td><strong>&lt;0.001</strong></td></tr><tr><td>Race</td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>White</td><td>1506 (58.3)</td><td>1882 (63.9)</td><td>2098 (76.4)</td><td></td></tr><tr><td>Black</td><td>141 (5.5)</td><td>168 (5.7)</td><td>117 (4.3)</td><td></td></tr><tr><td>Asian</td><td>617 (23.9)</td><td>535 (18.2)</td><td>295 (10.7)</td><td></td></tr><tr><td>Others</td><td>318 (12.3)</td><td>359 (12.2)</td><td>235 (8.6)</td><td></td></tr><tr><td>SBP, mmHg</td><td>120 (110-130)</td><td>120 (110-130)</td><td>121 (110-131)</td><td>&lt;0.001</td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>27.0 (24.2-30.4)</td><td>27.2 (24.4-30.8)</td><td>28.4 (25.0-32.5)</td><td>&lt;0.001</td></tr><tr><td>Atrial fibrillation (history)</td><td>825 (32.0)</td><td>1028 (34.9)</td><td>1214 (44.2)</td><td>&lt;0.001</td></tr><tr><td>MI</td><td>1014 (39.3)</td><td>1257 (42.7)</td><td>1307 (47.6)</td><td>&lt;0.001</td></tr><tr><td>Stroke</td><td>159 (6.2)</td><td>244 (8.3)</td><td>309 (11.3)</td><td>&lt;0.001</td></tr><tr><td>Diabetes mellitus</td><td>807 (31.3)</td><td>1011 (34.3)</td><td>1037 (37.8)</td><td>&lt;0.001</td></tr><tr><td>Time since HF diagnosis</td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>&le;1yr</td><td>889 (34.4)</td><td>902 (30.6)</td><td>677 (24.7)</td><td></td></tr><tr><td>&gt;1-5yrs</td><td>971 (37.6)</td><td>1095 (37.2)</td><td>1125 (41.0)</td><td></td></tr><tr><td>&gt;5yrs</td><td>722 (28.0)</td><td>947 (32.2)</td><td>943 (34.4)</td><td></td></tr><tr><td>Previous hospitalization for HF</td><td>1558 (60.3)</td><td>1842 (62.6)</td><td>1796 (65.4)</td><td>&lt;0.001</td></tr><tr><td><strong>NYHA III/IV</strong></td><td><strong>280 (10.8)</strong></td><td><strong>607 (20.7)</strong></td><td><strong>1159 (42.3)</strong></td><td><strong>&lt;0.001</strong></td></tr><tr><td><strong>KCCQ clinical summary score</strong></td><td><strong>94 (85-98)</strong></td><td><strong>82 (72-91)</strong></td><td><strong>60 (47-73)</strong></td><td><strong>&lt;0.001</strong></td></tr><tr><td>NT-proBNP, pg/ml</td><td>1473 (862-2876)</td><td>1602 (879-3301)</td><td>1760 (931-3572)</td><td>&lt;0.001</td></tr><tr><td>Atrial fibrillation/ flutter§§</td><td>1810 (1113-3101)</td><td>2067 (1174-3908)</td><td>2088 (1209-4215)</td><td>0.002</td></tr><tr><td>No atrial fibrillation/ flutter§§</td><td>1388 (806-2816)</td><td>1478 (828-3043)</td><td>1577 (826-3160)</td><td>0.004</td></tr><tr><td>LVEF, %</td><td>30 (25-34)</td><td>30 (25-34)</td><td>31 (26-35)</td><td>&lt;0.001</td></tr><tr><td>Creatinine, &micro;mol/L</td><td>95 (81-112)</td><td>97 (82-116)</td><td>94 (80-113)</td><td>0.44</td></tr><tr><td>eGFR, mL/min/1.73m<sup>2</sup></td><td>68 (56-81)</td><td>65 (53-79)</td><td>65 (52-78)</td><td>&lt;0.001</td></tr><tr><td>Diuretics</td><td>1974 (76.5)</td><td>2361 (80.2)</td><td>2297 (83.7)</td><td>&lt;0.001</td></tr><tr><td>Beta-blocker</td><td>2416 (93.6)</td><td>2742 (93.1)</td><td>2542 (92.6)</td><td>0.16</td></tr><tr><td>MRA</td><td>1423 (55.1)</td><td>1601 (54.4)</td><td>1580 (57.6)</td><td>0.07</td></tr><tr><td>Pacemaker</td><td>292 (11.3)</td><td>406 (13.8)</td><td>372 (13.6)</td><td>0.02</td></tr><tr><td>ICD#</td><td>377 (14.6)</td><td>474 (16.1)</td><td>374 (13.6)</td><td>0.30</td></tr></tbody></table>

3 Data are presented as median (25%-75% quartile) for continuous measures, and n (%) for categorical measures.

4 # Including CRT-D.
1 §§ Based on electrocardiogram.

2 BMI, body mass index; CRT-D, cardiac resynchronization therapy with defibrillator; eGFR, estimated glomerular filtration rate; HF, heart failure; HFrEF,

3 heart failure with reduced ejection fraction; ICD, implantable cardioverter defibrillator; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left

4 ventricular ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro B-type natriuretic peptide;

5 NYHA, New York Heart Association; SBP, systolic blood pressure; yr, year.

6

<table><caption>Table 2: Baseline characteristics according to baseline EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire Level Sum Score (LSS) category divided by tertile in HFmrEF/HFpEF.</caption><thead><tr><th></th><th>Tertile 1: 5</th><th>Tertile 2: 6-7</th><th>Tertile 3: 8-15</th><th>P-Value for trend</th></tr></thead><tbody><tr><td>N, (%)</td><td>1091 (23.2)</td><td>1796 (38.2)</td><td>1816 (38.6)</td><td></td></tr><tr><td>Age, yr</td><td>72 (66-78)</td><td>74 (67-79)</td><td>74 (68-79)</td><td>&lt;0.001</td></tr><tr><td><strong>Women</strong></td><td><strong>423 (38.8)</strong></td><td><strong>891 (49.6)</strong></td><td><strong>1110 (61.1)</strong></td><td><strong>&lt;0.001</strong></td></tr><tr><td>Race</td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>White</td><td>776 (71.1)</td><td>1477 (82.2)</td><td>1573 (86.6)</td><td></td></tr><tr><td>Black</td><td>23 (2.1)</td><td>37 (2.1)</td><td>42 (2.3)</td><td></td></tr><tr><td>Asian</td><td>239 (21.9)</td><td>207 (11.5)</td><td>150 (8.3)</td><td></td></tr><tr><td>Others</td><td>53 (4.9)</td><td>75 (4.2)</td><td>51 (2.8)</td><td></td></tr><tr><td>SBP, mmHg</td><td>130 (120-140)</td><td>130 (120-140)</td><td>130 (120-140)</td><td>0.40</td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>28.6 (25.4-32.0)</td><td>29.8 (26.5-33.4)</td><td>30.9 (27.3-35.1)</td><td>&lt;0.001</td></tr><tr><td>Atrial fibrillation (history)</td><td>581 (53.3)</td><td>942 (52.5)</td><td>992 (54.6)</td><td>0.39</td></tr><tr><td>MI</td><td>226 (20.7)</td><td>422 (23.5)</td><td>409 (22.5)</td><td>0.36</td></tr><tr><td>Stroke</td><td>90 (8.3)</td><td>170 (9.5)</td><td>241 (13.3)</td><td>&lt;0.001</td></tr><tr><td>Diabetes mellitus</td><td>413 (37.9)</td><td>759 (42.3)</td><td>838 (46.1)</td><td>&lt;0.001</td></tr><tr><td>Time since HF diagnosis</td><td></td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>&le;1yr</td><td>508 (46.6)</td><td>728 (40.6)</td><td>693 (38.3)</td><td></td></tr><tr><td>&gt;1-5yrs</td><td>347 (31.9)</td><td>636 (35.5)</td><td>663 (36.7)</td><td></td></tr><tr><td>&gt;5yrs</td><td>234 (21.5)</td><td>430 (24.0)</td><td>453 (25.0)</td><td></td></tr><tr><td>Previous hospitalization for HF</td><td>503 (46.1)</td><td>854 (47.6)</td><td>884 (48.7)</td><td>0.18</td></tr><tr><td><strong>NYHA III/IV</strong></td><td><strong>92 (8.4)</strong></td><td><strong>297 (16.5)</strong></td><td><strong>550 (30.3)</strong></td><td><strong>&lt;0.001</strong></td></tr><tr><td><strong>KCCQ clinical summary score</strong></td><td><strong>91 (81-96)</strong></td><td><strong>78 (67-88)</strong></td><td><strong>60 (47-72)</strong></td><td><strong>&lt;0.001</strong></td></tr><tr><td>NT-proBNP, pg/ml</td><td>891 (468-1542)</td><td>939 (466-1657)</td><td>878 (464-1612)</td><td>0.73</td></tr><tr><td>Atrial fibrillation/ flutter§§</td><td>1539 (1162-2246)</td><td>1559 (1175-2291)</td><td>1672 (1166-2325)</td><td>0.26</td></tr><tr><td>No atrial fibrillation/ flutter§§</td><td>603 (377-992)</td><td>603 (387-1136)</td><td>596 (375-1025)</td><td>0.69</td></tr><tr><td>LVEF, %</td><td>56 (50-62)</td><td>57 (50-62)</td><td>57 (51-63)</td><td>0.006</td></tr><tr><td>Creatinine, &micro;mol/L</td><td>94 (78-112)</td><td>93 (77-112)</td><td>91 (76-111)</td><td>0.037</td></tr><tr><td>eGFR, mL/min/1.73m<sup>2</sup></td><td>62 (50-77)</td><td>61 (49-74)</td><td>59 (47-73)</td><td>&lt;0.001</td></tr><tr><td>Diuretics</td><td>1031 (94.5)</td><td>1707 (95.0)</td><td>1759 (96.9)</td><td>0.001</td></tr></tbody></table>
<table><tr><td>Beta-blocker</td><td>864 (79.2)</td><td>1443 (80.3)</td><td>1443 (79.5)</td><td>0.97</td></tr><tr><td>MRA</td><td>309 (28.3)</td><td>439 (24.4)</td><td>473 (26.0)</td><td>0.30</td></tr><tr><td>Pacemaker</td><td>79 (7.2)</td><td>168 (9.4)</td><td>203 (11.2)</td><td>&lt;0.001</td></tr><tr><td>ICD#</td><td>4 (0.4)</td><td>8 (0.4)</td><td>6 (0.3)</td><td>0.81</td></tr></table>

Data are presented as median (25%-75% quartile) for continuous measures, and n (%) for categorical measures.

# Including CRT-D.

§§ Based on electrocardiogram.

BMI, body mass index; CRT-D, cardiac resynchronization therapy with defibrillator; eGFR, estimated glomerular filtration rate; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; ICD, implantable cardioverter defibrillator; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; yr, year.

<table><caption>Table 3: Effect of randomized treatment on outcomes according to baseline EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire Level Sum Score (LSS) category divided by tertile in HFrEF</caption><thead><tr><th rowspan="2"></th><th colspan="2">Tertile 1: 5</th><th colspan="2">Tertile 2: 6-7</th><th colspan="2">Tertile 3: 8-15</th><th rowspan="2">Interaction P-Value</th></tr><tr><th>Sacubitril/ Valsartan</th><th>Active RAS comparator<sup>d</sup></th><th>Sacubitril/ Valsartan</th><th>Active RAS comparator<sup>d</sup></th><th>Sacubitril/ Valsartan</th><th>Active RAS comparator<sup>d</sup></th></tr></thead><tbody><tr><td>N</td><td>1289</td><td>1293</td><td>1487</td><td>1457</td><td>1350</td><td>1395</td><td></td></tr><tr><td><strong>CV death or HF hospitalization</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>245 (19.0)</td><td>290 (22.4)</td><td>292 (19.6)</td><td>392 (26.9)</td><td>363 (26.9)</td><td>416 (29.8)</td><td></td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>8.9 (7.8-10.1)</td><td>10.7 (9.6-12)</td><td>9.3 (8.3-10.4)</td><td>13.3 (12-14.7)</td><td>13.4 (12.1-14.9)</td><td>13.9 (12.1-14.9)</td><td></td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>0.83 (0.70-0.98)</td><td></td><td>0.70 (0.60-0.81)</td><td></td><td>0.88 (0.76-1.01)</td><td></td><td>0.10</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>0.81 (0.68-0.96)</td><td></td><td>0.72 (0.62-0.84)</td><td></td><td>0.90 (0.78-1.04)</td><td></td><td>0.10</td></tr><tr><td><strong>First HF hospitalization</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>136 (10.6)</td><td>167 (12.9)</td><td>186 (12.5)</td><td>243 (16.7)</td><td>209 (15.5)</td><td>235 (16.9)</td><td></td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>4.9 (4.2-5.8)</td><td>6.2 (5.3-7.2)</td><td>5.9 (5.1-6.8)</td><td>8.2 (7.3-9.3)</td><td>7.7 (6.8-8.9)</td><td>8.7 (7.6-9.9)</td><td></td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>0.80 (0.63-1.00)</td><td></td><td>0.71 (0.59-0.86)</td><td></td><td>0.90 (0.74-1.08)</td><td></td><td>0.27</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>0.76 (0.61-0.96)</td><td></td><td>0.74 (0.61-0.89)</td><td></td><td>0.92 (0.76-1.11)</td><td></td><td>0.22</td></tr><tr><td><strong>CV death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>147 (11.4)</td><td>184 (14.2)</td><td>166 (11.2)</td><td>231 (15.9)</td><td>236 (17.5)</td><td>268 (19.2)</td><td></td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>5.1 (4.3-6.0)</td><td>6.4 (5.5-7.3)</td><td>5.0 (4.3-5.8)</td><td>7.2 (6.3-8.2)</td><td>8.1 (7.1-9.2)</td><td>9.0 (8.0-10.1)</td><td></td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>0.80 (0.64-0.99)</td><td></td><td>0.69 (0.57-0.84)</td><td></td><td>0.89 (0.75-1.07)</td><td></td><td>0.16</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>0.80 (0.64-0.99)</td><td></td><td>0.72 (0.59-0.89)</td><td></td><td>0.92 (0.77-1.09)</td><td></td><td>0.17</td></tr><tr><td><strong>Non-CV death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>
<table><tbody><tr><td>N (%)</td><td>31 (2.4)</td><td>24 (1.9)</td><td>48 (3.2)</td><td>45 (3.1)</td><td>38 (2.8)</td><td>40 (2.9)</td><td></td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>1.1 (0.8-1.5)</td><td>0.8 (0.6-1.2)</td><td>1.4 (1.1-1.9)</td><td>1.4 (1-1.9)</td><td>1.3 (0.9-1.8)</td><td>1.3 (1.0-1.8)</td><td></td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>1.28 (0.75-2.17)</td><td></td><td>1.02 (0.68-1.53)</td><td></td><td>0.97 (0.62-1.52)</td><td></td><td>0.71</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>1.21 (0.71-2.08)</td><td></td><td>1.05 (0.70-1.58)</td><td></td><td>0.92 (0.58-1.44)</td><td></td><td>0.78</td></tr><tr><td><strong>All-cause death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>190 (14.7)</td><td>218 (16.9)</td><td>221 (14.9)</td><td>287 (19.7)</td><td>288 (21.3)</td><td>320 (22.9)</td><td></td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>6.6 (5.7-7.6)</td><td>7.5 (6.6-8.6)</td><td>6.6 (5.8-7.5)</td><td>8.9 (8-10)</td><td>9.8 (8.8-11)</td><td>10.7 (9.6-12.0)</td><td></td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>0.87 (0.72-1.06)</td><td></td><td>0.74 (0.62-0.88)</td><td></td><td>0.92 (0.78-1.70)</td><td></td><td>0.20</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>0.87 (0.71-1.05)</td><td></td><td>0.77 (0.65-0.92)</td><td></td><td>0.93 (0.79-1.90)</td><td></td><td>0.26</td></tr><tr><td><strong>Total HF hospitalizations and CV death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N</td><td>349</td><td>444</td><td>478</td><td>642</td><td>565</td><td>657</td><td></td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>12.0 (10.4-14.0)</td><td>15.3 (13.4-17.5)</td><td>14.3 (12.4-16.4)</td><td>20.0 (17.8-22.5)</td><td>19.3 (17.0-21.9)</td><td>22.0 (19.7-24.6)</td><td></td></tr><tr><td>Unadjusted RR (95%CI)<sup>c</sup></td><td>0.76 (0.60-0.95)</td><td></td><td>0.64 (0.52-0.79)</td><td></td><td>0.88 (0.72-1.06)</td><td></td><td>0.11</td></tr><tr><td>Adjusted RR (95%CI)<sup>b</sup></td><td>0.72 (0.58-0.90)</td><td></td><td>0.63 (0.52-0.77)</td><td></td><td>0.83 (0.70-1.00)</td><td></td><td>0.16</td></tr></tbody></table>

1 a. Baseline model stratified by study and study-specific geographic region.

2 b. Further adjusted for age, sex, heart rate, SBP, BMI, NYHA functional class III/IV, LVEF, eGFR, NT-proBNP (log-transformed), atrial fibrillation, ischemic etiology, myocardial infarction, and stroke.

3 c. Adjusted for geographic region and study

4 d. Enalapril or Valsartan

5 BMI, body mass index; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; hosp. hospitalization; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure.

6

<table><caption>Table 4: Effect of randomized treatment on outcomes according to baseline EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire Level Sum Score (LSS) category divided by tertile in HFmrEF/HFpEF</caption><thead><tr><th rowspan="2"></th><th colspan="2">Tertile 1: 5</th><th colspan="2">Tertile 2: 6-7</th><th colspan="2">Tertile 3: 8-15</th><th rowspan="2">Interaction P-Value</th></tr><tr><th>Sacubitril/ Valsartan</th><th>Active RAS comparator<sup>d</sup></th><th>Sacubitril/ Valsartan</th><th>Active RAS comparator<sup>d</sup></th><th>Sacubitril/ Valsartan</th><th>Active RAS comparator<sup>d</sup></th></tr></thead><tbody><tr><td>N</td><td>549</td><td>542</td><td>880</td><td>916</td><td>930</td><td>886</td><td></td></tr><tr><td><strong>CV death or HF hospitalization</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>95 (17.3)</td><td>95 (17.5)</td><td>202 (23.0)</td><td>203 (22.2)</td><td>217 (23.3)</td><td>240 (27.1)</td><td></td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>6.4 (5.2-7.8)</td><td>6.5 (5.4-8.0)</td><td>8.5 (7.4-9.8)</td><td>8.3 (7.3-9.6)</td><td>9.0 (7.9-10.3)</td><td>10.6 (9.3-12.0)</td><td></td></tr></tbody></table>
<table><tbody><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>0.98 (0.74-1.30)</td><td>1.00 (0.82-1.22)</td><td>0.85 (0.70-1.02)</td><td>0.41</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>1.00 (0.75-1.34)</td><td>0.95 (0.78-1.16)</td><td>0.84 (0.70-1.01)</td><td>0.50</td></tr><tr><td><strong>First HF hospitalization</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>76 (13.8)</td><td>79 (14.6)</td><td>162 (18.4)</td><td>149 (16.3)</td><td>157 (16.9)</td><td>187 (21.1)</td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>5.1 (4.1-6.4)</td><td>5.4 (4.4-6.8)</td><td>6.8 (5.9-8)</td><td>6.1 (5.2-7.2)</td><td>6.5 (5.6-7.6)</td><td>8.2 (7.1-9.5)</td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>0.95 (0.69-1.30)</td><td></td><td>1.09 (0.87-1.36)</td><td></td><td>0.78 (0.63-0.97)</td><td>0.10</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>0.97 (0.70-1.33)</td><td></td><td>1.05 (0.83-1.31)</td><td></td><td>0.79 (0.64-0.98)</td><td>0.18</td></tr><tr><td><strong>CV death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>32 (5.8)</td><td>25 (4.6)</td><td>74 (8.4)</td><td>94 (9.9)</td><td>95 (10.2)</td><td>93 (10.5)</td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>2.0 (1.4-2.8)</td><td>1.6 (1.1-2.4)</td><td>2.8 (2.3-3.6)</td><td>3.4 (2.8-4.2)</td><td>3.6 (3-4.4)</td><td>3.6 (3.0-4.5)</td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>1.20 (0.71-2.03)</td><td></td><td>0.82 (0.60-1.11)</td><td></td><td>1.01 (0.76-1.34)</td><td>0.36</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>1.25 (0.73-2.13)</td><td></td><td>0.76 (0.55-1.03)</td><td></td><td>0.99 (0.74-1.32)</td><td>0.18</td></tr><tr><td><strong>Non-CV death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>23 (4.2)</td><td>31 (5.7)</td><td>24 (2.7)</td><td>30 (3.3)</td><td>53 (5.7)</td><td>54 (6.1)</td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>1.4 (1.0-2.2)</td><td>2.0 (1.4-2.8)</td><td>0.9 (0.6-1.4)</td><td>1.1 (0.8-1.6)</td><td>2.0 (1.5-2.6)</td><td>2.1 (1.6-2.8)</td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>0.73 (0.42-1.25)</td><td></td><td>0.81 (0.41-1.39)</td><td></td><td>0.96 (0.66-1.40)</td><td>0.70</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>0.67 (0.38-1.17)</td><td></td><td>0.75 (0.44-1.29)</td><td></td><td>0.93 (0.63-1.37)</td><td>0.71</td></tr><tr><td><strong>All-cause death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N (%)</td><td>61 (11.1)</td><td>58 (10.7)</td><td>112 (12.7)</td><td>131 (14.3)</td><td>165 (17.7)</td><td>152 (17.2)</td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>3.8 (3.0-4.9)</td><td>3.7 (2.9-4.8)</td><td>4.3 (3.6-5.2)</td><td>5.0 (4.2-5.9)</td><td>6.3 (5.4-7.3)</td><td>5.9 (5.1-7.0)</td></tr><tr><td>Unadjusted HR (95%CI)<sup>a</sup></td><td>1.01 (0.70-1.44)</td><td></td><td>0.86 (0.67-1.11)</td><td></td><td>1.07 (0.86-1.33)</td><td>0.46</td></tr><tr><td>Adjusted HR (95%CI)<sup>b</sup></td><td>0.99 (0.69-1.44)</td><td></td><td>0.82 (0.63-1.06)</td><td></td><td>1.06 (0.84-1.32)</td><td>0.35</td></tr><tr><td><strong>Total HF hospitalizations and CV death</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>N</td><td>170</td><td>158</td><td>342</td><td>367</td><td>363</td><td>446</td></tr><tr><td>Rate per 100 patient-years (95%CI)</td><td>10.7 (8.3-13.6)</td><td>10.1 (7.9-12.9)</td><td>13.2 (11.1-15.6)</td><td>13.9 (11.7-16.5)</td><td>13.8 (11.9-16.0)</td><td>17.4 (14.8-20.5)</td></tr><tr><td>Unadjusted RR (95%CI)<sup>c</sup></td><td>1.10 (0.76-1.57)</td><td></td><td>0.84 (0.65-1.09)</td><td></td><td>0.82 (0.65-1.05)</td><td>0.40</td></tr><tr><td>Adjusted RR (95%CI)<sup>b</sup></td><td>1.19 (0.84-1.68)</td><td></td><td>0.88 (0.69-1.12)</td><td></td><td>0.81 (0.64-1.03)</td><td>0.21</td></tr></tbody></table>

1. a. Baseline model stratified by study and study-specific geographic region.

2. b. Further adjusted for age, sex, heart rate, SBP, BMI, NYHA functional class III/IV, LVEF, eGFR, NT-proBNP (log-transformed),

3. atrial fibrillation, ischemic etiology, myocardial infarction, and stroke.

4. c. Adjusted for geographic region and study
1 d. Enalapril or Valsartan

2 BMI, body mass index; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure; HFmrEF, heart failure

3 with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; hosp. hospitalization; HR, hazard ratio; LVEF, left ventricular

4 ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure.

5

6

7
Figure Legends

**Figure 1:** Distribution and changes in answers to the EuroQol 5-Dimension 3-Level (EQ-5D-3L) "pain/discomfort" question from baseline to 8 months follow-up. (A) Distribution and Sankey plot for the active comparator group; (B) Distribution and Sankey plot for the Sacubitril/Valsartan group. Only values ≥50 in the subgroups were shown in the Sankey plot. Bars represent the number of patients in each EQ-5D-5L category. Colors indicate the distribution of EQ-5D-3L scores at randomization and after 8 months of follow-up. Patients with missing EQ-5D-3L assessments are not displayed.

**Figure 2:** Distribution and changes in answers to the EuroQol 5-Dimension 3-Level (EQ-5D-3L) "anxiety/depression" question from baseline to 8 months follow-up. (A) Distribution and Sankey plot for the active comparator group; (B) Distribution and Sankey plot for the Sacubitril/Valsartan group. Only values ≥50 in the subgroups were shown in the Sankey plot. Bars represent the number of patients in each EQ-5D-3L category. Colors indicate the distribution of EQ-5D-3L scores at randomization and after 8 months of follow-up. Patients with missing EQ-5D-3L assessments are not displayed.

**Figure 3:** Effect of sacubitril/valsartan versus active comparator on EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire dimension over time (8 months). (A) HFrEF (B) HFmrEF/HFpEF.

**Figure 4:** Cumulative incidence of the composite outcome according to baseline EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire. (A) "Mobility" domain; (B) "self-care" domain; (C) "usual activities" domain; (D) "pain/discomfort" domain; (E) "anxiety/depression" domain; (F) Level Sum Score (LSS) category divided by tertile; (G) Visual Analog Scale (VAS) category divided by tertile. The patients reported "Some problem" and "Extreme problem" were combined into one group due to a small number in the worst category of "mobility" domain (n=27) and "self-care" domain (n=73).

CV, cardiovascular; HF, heart failure.

**Figure 5:** Cumulative incidence of all-cause death according to baseline EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire. (A) "Mobility" domain; (B) "self-care" domain; (C) "usual activities" domain; (D) "pain/discomfort" domain; (E) "anxiety/depression" domain; (F) Level Sum Score (LSS) category divided by tertile; (G) Visual Analog Scale (VAS) category divided by tertile. The patients reported "Some problem" and "Extreme problem" were combined into one group due to a small number in the worst category of "mobility" domain (n=27) and "self-care" domain (n=73).

**Graphical abstract** Sacubitril/valsartan and health status measured using the EuroQol 5-Dimension 3-Level (EQ-5D-3L) questionnaire Level Sum Score (LSS) in patients with HFrEF and HFpEF. All the EQ-5D dimensions and severity levels contribute equally when calculating the LSS (A). Irrespective of HF phenotype, sacubitril/valsartan compared to a RAS comparator (enalapril or valsartan) improved patient health status between baseline and 8 months as assessed with LSS (B-HFrEF and C- HFmrEF/HFpEF). Worse baseline EQ-5D-3L-LSS was associated
1 with a higher risk of subsequent clinical outcomes.

2 HF, heart failure; HFpEF, heart failure with preserved ejection fraction; OR, odds ratio; RAS,

3 renin-angiotensin system.

<figure><img src="image_2.png" /><figcaption>Figure 1
258x207 mm (x DPI)</figcaption></figure>

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A

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B

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>Figure 2
258x208 mm (x DPI)</figcaption></figure>

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A

OR of being in
a better category

1.13 (1.01-1.26)
p=0.026

1.15 (1.00-1.32)
p=0.043

1.14 (1.03-1.27)
p=0.011

1.09 (0.98-1.20)
p=0.10

1.12 (1.01-1.24)
p=0.036

<figure><img src="image_7.png" /></figure>

B

OR of being in
a better category

1.13 (0.98-1.30)
p=0.09

1.09 (0.92-1.30)
p=0.31

1.14 (1.00-1.30)
p=0.048

1.05 (0.92-1.19)
p=0.47

1.03 (0.90-1.18)
p=0.66

<figure><img src="image_8.png" /><figcaption>Figure 3
189x183 mm (x DPI)</figcaption></figure>

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<figure><img src="image_15.png" /><figcaption>Figure 4
194x289 mm (x DPI)</figcaption></figure>

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<figure><img src="image_16.png" /></figure>

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<figure><img src="image_22.png" /><figcaption>Figure 5
194x289 mm (x DPI)</figcaption></figure>

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<figure><img src="image_23.png" /></figure>

**Population:** Individual patient meta-analysis of PARADIGM-HF and PARAGON-HF trials.

**Groups:** Patients were categorized based on EQ-5D-3L LSS category by tertile:

a) 5 (n=3673), b) 6-7 (n=4740), c) 8-15 (n=4561).

A

EuroQol 5-Dimension Questionnaire: Level Sum Score (LSS)

The 5 dimensions

● Mobility ("walking around")

● Self-care ("washing or dressing self")

● Usual activities ("e.g., work, study, housework, family or leisure activities")

● Pain/discomfort ("pain or discomfort")

● Anxiety/depression ("anxious or depressed")

The 3 levels

● No problem (1)

● Some problem (2)

● Extreme problem (3)

Score

Level Sum Score

Minimum =5 [Best]
 score of 1 for each dimension)

Maximum =15 [Worst]
 score of 3 for each dimension)

B

HFrEF

<figure><img src="image_24.png" /></figure>

<figure><img src="image_25.png" /></figure>

C

HFmrEF/HFpEF

<figure><img src="image_26.png" /></figure>

<figure><img src="image_27.png" /></figure>

Graphical Abstract
124x180 mm (x DPI)

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