Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial

Key Points

Question  Is the effect of dapagliflozin in patients with heart failure and reduced ejection fraction consistent in men and women?

Findings  In this prespecified subgroup analysis of a randomized clinical trial that included 4744 patients, dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score, clinical summary score, and overall summary score and decreased the proportion with a deterioration, irrespective of sex.

Meaning  Dapagliflozin reduced the risk of worsening heart failure and death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction.

Importance  Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.

Objective  To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).

Design, Setting, and Participants  Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.

Interventions  Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy.

Main Outcomes and Measures  The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.

Results  A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of ≥5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of ≥5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.

Conclusions and Relevance  Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.

Trial Registration  ClinicalTrials.gov Identifier: NCT03036124

Women with heart failure (HF) are generally older, have a greater symptom burden, lower quality of life, and more comorbidity, yet have better survival and lower rates of hospitalization for HF than men with this condition.^1-8 Women may also respond differently to certain HF treatments than men, including cardiac resynchronization therapy, digoxin, sacubitril/valsartan, and intravenous ferric carboxymaltose.^9-15 Similarly, it has been suggested that the reduction in death in the large cardiovascular outcome trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors may be less in women than in men with type 2 diabetes.^16,17 Within the past 2 years, SGLT2 inhibitors have also been shown to be a valuable treatment for HF with reduced ejection fraction (HFrEF),^18,19 and it is clearly important to examine the effects of this therapy in women as well as men with HFrEF. In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF), dapagliflozin added to conventional guideline-recommended therapies reduced the risk of worsening HF events, cardiovascular death, and all-cause mortality and improved symptoms, physical function, and health-related quality of life in 4744 patients with HFrEF with and without type 2 diabetes.¹⁸ In this prespecified subgroup analysis of DAPA-HF, we examined the efficacy and safety of dapagliflozin compared with placebo in men and women.

The DAPA-HF trial was a randomized, double-blind, placebo-controlled trial in patients with HFrEF, evaluating the efficacy and safety of dapagliflozin, 10 mg, once daily compared with matching placebo, in addition to standard care. The design, baseline characteristics, and primary results of the trial are published.^18,20,21 The formal trial protocols and statistical analysis plan can be found in Supplement 1 and Supplement 2, respectively. The ethics committee of each of the 410 participating institutions in 20 countries approved the protocol, and all patients gave written informed consent.

Men and women 18 years or older with a diagnosis of HF for at least 2 months were eligible if they were in New York Heart Association functional class II through IV, had a left ventricular ejection fraction of 40% or less, were optimally treated with pharmacologic and device therapy for HF, and had an N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration of at least 600 pg/mL (≥400 pg/mL if hospitalized for HF within the previous 12 months and ≥900 pg/mL if atrial fibrillation/flutter irrespective of history of HF hospitalization) (to convert to nanograms per liter, multiply by 1). Key exclusion criteria included symptoms of hypotension or systolic blood pressure less than 95 mm Hg, estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m² or rapidly declining kidney function, and type 1 diabetes. A complete list of exclusion criteria is provided in the design article.²⁰ After randomization, follow-up visits were scheduled at 14 and 60 days and then at 120, 240, and 360 days and every 4 months thereafter.

The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent visit for worsening HF and administration of intravenous treatment for HF) or cardiovascular death, whichever occurred first. The secondary outcomes in the trial were the occurrence of HF hospitalization or cardiovascular death (we also examined the components of this composite); total HF hospitalizations (first and repeat) or cardiovascular death; change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) (we also examined the KCCQ overall summary score [KCCQ-OSS] and clinical summary score [KCCQ-CSS]); a composite worsening kidney function end point and all-cause death. Because of the small number of kidney events overall, this end point was not examined in this subgroup analysis. Prespecified exploratory end points included an expanded composite outcome (primary end point plus episodes of outpatient worsening)²² and change from baseline in eGFR, systolic blood pressure, body weight, and hematocrit.

Prespecified safety analyses included serious adverse events, adverse events leading to discontinuation of trial treatment, and adverse events of interest, including volume depletion, kidney adverse events, bone fracture, amputation, major hypoglycemia, diabetic ketoacidosis, and Fournier gangrene. In this analysis, we also assessed specific causes of discontinuation of trial treatment. Safety analyses were performed in patients who had undergone randomization and received at least 1 dose of either dapagliflozin or placebo (8 randomized patients were excluded from the safety analysis).

Baseline characteristics were summarized as frequencies with percentages, means with standard deviation (SD), or medians with interquartile ranges. Differences in baseline characteristics were tested using the χ² test for categorical variables and the Wilcoxon test and 2-sample t test for nonnormal and normally distributed continuous variables, respectively.

Time-to-event data for the primary outcome and secondary clinical outcomes according to sex, regardless of treatment allocation, were evaluated using the Kaplan-Meier estimator and Cox proportional-hazards models, stratified according to diabetes status, with a history of HF hospitalization and treatment-group assignment as fixed-effect factors to calculate hazard ratios (HRs), 95% CIs, and 2-sided P values. The models for all-cause death did not include adjustment for a history of HF hospitalization. In addition, adjusted HRs from models including age, heart rate, systolic blood pressure, body mass index, HF etiology, left ventricular ejection fraction, NYHA functional class, NT-proBNP, atrial fibrillation, and estimated glomerular filtration rate were reported.

To compare the effects of dapagliflozin vs placebo on the primary outcome and secondary clinical outcomes in men and women, respectively, time-to-event data were evaluated with the Kaplan-Meier estimator and Cox proportional-hazards models, stratified according to diabetes status, with a history of HF hospitalization and treatment-group assignment as fixed-effect factors. The models for all-cause death were not adjusted for a history of HF hospitalization. Total, including, recurrent, events were evaluated with semiparametric proportional-rates models.²³ The difference between treatment groups in the change in KCCQ scores from baseline to 8 months in surviving patients according to sex was analyzed using 2-sample t test. Responder analyses examining proportions of patients with a deterioration (decrease in KCCQ-TSS/OSS/CSS of ≥5 points) and clinically important improvement (increase in KCCQ-TSS/OSS/CSS of ≥5 points) in symptoms, physical function, and health-related quality of life at 8 months according to sex were conducted with the treatment effect expressed as an odds ratio (OR), and missing KCCQ values were accounted for with multiple imputation using methods previously described.²⁴

Longitudinal measures, including eGFR, systolic blood pressure body weight, and hematocrit, were analyzed using a mixed-effect model for repeated measurements (adjusted for baseline values, visit, randomized treatment, and interaction of treatment and visit with a random intercept and slope per patient). The least squares mean differences between treatment groups were estimated with 95% CIs and plotted for each group. The efficacy of dapagliflozin according to sex in patients with and without diabetes separately was also examined; Cox proportional-hazards models for the time-to-event analyses were not stratified according to diabetes status.

All analyses were conducted using Stata, version 16.1 (StataCorp) and SAS, version 9.4 (SAS Institute). A P value of .05 was considered statistically significant.

A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%) (Figure 1). Baseline characteristics according to sex are presented in Table 1. Compared with men, women were older, more often Black (and less often Asian), less likely to have atrial fibrillation (AF; both as a history and on electrocardiogram [ECG]), chronic obstructive pulmonary disease, and anemia, and had a lower eGFR. However, women had a higher systolic blood pressure, heart rate, and baseline NT-proBNP in those without AF on their ECG. Women were also less likely to have an ischemic etiology and prior myocardial infarction. Women had a higher ejection fraction but worse NYHA functional class and lower KCCQ scores (ie, more symptoms, worse physical function, and worse health-related quality of life) than men. With respect to background HF therapy, women were more often treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and less frequently treated with sacubitril/valsartan. Women were less likely than men to have received a defibrillating device (an implantable cardioverter-defibrillator or cardiac resynchronization therapy with a defibrillator).

Women had a lower risk of worsening HF or cardiovascular death (adjusted HR, 0.72; 95% CI, 0.61-0.85) and the expanded composite outcome (primary end point plus episodes of outpatient worsening) (adjusted HR, 0.80; 95% CI, 0.69-0.92) compared with men. Risks of the composite of HF hospitalization or cardiovascular death, HF hospitalization and cardiovascular death individually, and all-cause death are also shown in eTable 1 in Supplement 3. Women had a lower risk of these outcomes compared with men, even after adjustment for other prognostic variables, including LVEF and NT-proBNP.

Dapagliflozin reduced the risk of worsening HF or cardiovascular death to the same extent in men (HR, 0.73; 95% CI, 0.63-0.85) and women (HR, 0.79; 95% CI, 0.59-1.06), with no interaction between sex and effect of treatment (P for interaction = .67) (Figure 2 and Table 2).

Hazard ratios, rate ratios (RRs), and ORs for the effect of dapagliflozin compared with placebo on the secondary clinical end points are displayed in Table 2 and eFigure 1A-H in Supplement 3. The effect of dapagliflozin was consistent in men and women for all secondary end points: HF hospitalization or cardiovascular death (men: HR, 0.73; 95% CI, 0.63-0.85; women: HR, 0.80; 95% CI, 0.59-1.08; P for interaction = .64), HF hospitalization (men: HR, 0.69; 95% CI, 0.57-0.84; women: HR, 0.73; 95% CI, 0.51-1.06; P for interaction = .83), cardiovascular death (men: HR, 0.84; 95% CI, 0.69-1.02; women: HR, 0.76; 95% CI, 0.49-1.16; P for interaction = .68), the expanded composite outcome (men: HR, 0.70 95% CI, 0.62-0.80; women: HR, 0.83; 95% CI, 0.65-1.07; P for interaction = .25), recurrent HF hospitalization or cardiovascular death (men: RR, 0.77; 95% CI, 0.65-0.91; women: RR, 0.69; 95% CI, 0.49-0.96; P for interaction = .54), and all-cause death (men: HR, 0.82; 95% CI, 0.69-0.98; women: HR, 0.85; 95% CI, 0.58-1.24; P for interaction = .84).

In women, the mean increase in KCCQ-TSS from baseline to 8 months was 6.0 and 6.1 in the placebo and dapagliflozin groups, respectively, whereas in men, the mean increase in KCCQ-TSS was 2.5 and 6.1 in the placebo and dapagliflozin groups, respectively (P for interaction  = .046). However, the mean increases in KCCQ-CSS (men, 2.3 and 5.3 with placebo and dapagliflozin, respectively; women, 5.1 and 6.1 with placebo and dapagliflozin, respectively) and KCCQ-OSS (men, 3.3 and 5.9 with placebo and dapagliflozin, respectively; women, 5.8 and 7.0 with placebo and dapagliflozin, respectively) from baseline to 8 months were greater with dapagliflozin, with consistent effects in women and men (P for interaction = .22 and .34, respectively). The proportion of patients with an improvement of KCCQ-TSS of at least 5 points was greater with dapagliflozin, compared with placebo, with consistent effects in men (OR, 1.18; 95% CI, 1.11-1.27) and women (OR, 1.06; 95% CI, 0.92-1.22) (P for interaction = .14). Conversely, the proportion of patients with a decrease in KCCQ-TSS of at least 5 points was smaller in those treated with dapagliflozin compared with placebo in men (OR, 0.81; 95% CI, 0.75-0.88) and women (OR, 0.92; 95% CI, 0.79-1.06) (P for interaction = .15). The effects of dapagliflozin on the proportion of patients with an improvement and deterioration in KCCQ-CSS and KCCQ-OSS, respectively, were similar (Table 2).

Changes in eGFR, systolic blood pressure, weight, and hematocrit, adjusting for baseline value, are shown in eFigure 2 in Supplement 3. There was an initial decrease in eGFR with dapagliflozin in both groups (placebo-corrected change in women at 4 months, −2.84 mL/min/1.73 m²; 95% CI, −4.09 to −1.60; men, −1.96 mL/min/1.73 m²; 95% CI, −2.61 to −1.31), although the between-treatment difference had attenuated by 8 months, with no interaction between sex and the effect of dapagliflozin (eFigure 2A in Supplement 3).

Systolic blood pressure declined in both patient groups (placebo-corrected decrease at 4 months, −1.69 mm Hg; 95% CI, −3.37 to −0.02 in women vs −1.88 mm Hg; 95% CI, −2.80 to −0.96 in men), with no interaction between sex and the effect of dapagliflozin (eFigure 2B in Supplement 3). Similarly, body weight declined with dapagliflozin in both men and women (placebo-corrected decrease at 4 months, −0.49 kg; 95% CI, −0.82 to –0.17 in women vs −0.80 kg; 95% CI, −1.00 to −0.60 in men), with no interaction between sex and the effect of dapagliflozin (eFigure 2C in Supplement 3).

Hematocrit increased with dapagliflozin in both men and women, with plateau reached after approximately 4 months (placebo-corrected increase, 2.13%; 95% CI, 1.74-2.53 in women vs 2.63%; 95% CI, 2.41-2.86 in men), with no interaction between sex and the effect of dapagliflozin (eFigure 2D in Supplement 3).

Data on the effects of dapagliflozin compared with placebo in men and women according to diabetes status are shown in eTable 2 in Supplement 3, respectively. In line with the main findings, dapagliflozin, compared with placebo, reduced the risk of worsening HF, cardiovascular death, and all-cause death, irrespective of sex, in both patients with and without diabetes.

The occurrence of the prespecified adverse events according to treatment assignment in men and women is shown in Table 3. In general, the proportions of patients who discontinued trial treatment or experienced adverse events according to treatment groups were similar in men and women, although women were more likely than men to discontinue study drug for any reason.

In this prespecified subgroup analysis of DAPA-HF, dapagliflozin added to conventional guideline-recommended therapies reduced the risk of worsening HF events, cardiovascular death, and all-cause death to a similar extent in both men and women. In addition, dapagliflozin increased the proportion of patients with a clinically important improvement in KCCQ-TSS and decreased the proportion with a deterioration in KCCQ-TSS in both men and women.

The proportion of women enrolled in DAPA-HF was similar to that in other HFrEF trials.^2,3,19,25-27 This prespecified subgroup analysis demonstrated substantial differences in the clinical profile between men and women, most of which confirmed known sex differences from contemporary HFrEF trials.^2,3,19,25,26 In DAPA-HF, women were older than men, were less likely to have an ischemic etiology (and prior myocardial infarction), had a slightly higher ejection fraction, and had greater physician-assessed functional limitation (higher NYHA functional class) and patient-reported symptoms, function, and quality of life (lower KCCQ-scores). Women also had worse kidney function and had a lower prevalence of AF than men, but the prevalence of diabetes and hypertension was similar in the 2 sexes. There has also been concern that women with HFrEF are less well treated than men. Reassuringly, and in line with other HFrEF trials,^1-3 we did not find any evidence of significant underuse of HF medications in women. Thus, a similar proportion of men and women received ACE inhibitors/ARBs/sacubitril/valsartan, β-blockers, and mineralocorticoid receptor antagonists, and a higher proportion of women were treated with at least 50% of a guideline-recommended target dose. However, women were less likely than men to have a defibrillating device implanted. Although there was a higher proportion of men with a lower LVEF in DAPA-HF, data from HFrEF trials suggest that sex differences in HF etiology, NYHA functional class, ejection fraction, rhythm, and QRS duration may not fully account for the disparity in implantable cardioverter-defibrillator use.¹ This apparent underuse of defibrillating devices in women with HFrEF warrants further study.

In line with previous findings, women had lower rates of HF hospitalization, cardiovascular death, and all-cause death than men, even after adjustment for NT-proBNP and other prognostic variables.^1,4,5,7,8 The lower rate of HF hospitalization, despite a lower competing risk of death, is particularly notable. The explanation for the better outcomes in women is uncertain, though it is possible that sex-specific differences in cardiac remodeling may partially account for this difference.^1,28,29

Women may respond differently to certain HF treatments than men owing to sex-related differences in pharmacokinetics (drug absorption, distribution, metabolism, and excretion) and pharmacodynamics.^30-34 In the Digitalis Investigators Group trial (DIG), higher concentrations of digoxin (>1.2 ng/mL) were associated with a greater risk of death in women, compared with men.^13,14 Other studies have demonstrated that women achieve greater reductions in the risk of all-cause death, cardiovascular death, death or HF hospitalization, and ventricular arrhythmias or sudden cardiac death with cardiac resynchronization therapy compared with men.^10-12 In 2020, in the Randomized, Double-blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Subjects Admitted for Acute Heart Failure trial (AFFIRM-AHF),⁹ treatment with intravenous ferric carboxymaltose reduced the risk of the primary composite outcome of total HF hospitalizations and CV mortality in men but not in women hospitalized for acute heart failure with concomitant iron deficiency and a left ventricular ejection fraction of less than 50%.⁹ In light of these differences, it is important to establish the efficacy and safety of new HF treatments in both men and women. Moreover, there has been some uncertainty about the effect of SGLT2 inhibitors according to sex; specifically, the reduction in cardiovascular death and death from any cause with SGLT2 inhibitors in cardiovascular outcome trials appears to be less in women with diabetes than in men.^16,17 In this prespecified subgroup analysis of DAPA-HF, dapagliflozin reduced the risk of the primary outcome of a worsening HF event or cardiovascular death to a similar extent in men and women. In addition, the benefit of dapagliflozin on other clinical end points, including HF hospitalization (both first and recurrent), cardiovascular death, and all-cause death, was consistent, irrespective of sex. These data are reassuring and clearly underline the substantial and clinically important benefits of dapagliflozin, irrespective of sex, in an optimally treated cohort of patients with HFrEF.

Apart from their action in the kidney proximal tubule, the potential additional actions of SGLT2 inhibitors remain speculative and include improvement in myocardial metabolism, reduction of cardiac fibrosis, improvements in endothelial function, cardiac sodium-hydrogen exchange inhibition, and alterations in adipokines, cytokine production, and epicardial adipose tissue mass, among others.^35-42 However, several clinical trials have shown that SGLT2 inhibition reduces left ventricular filling pressure and has favorable effects on left ventricular remodeling, including reductions in left ventricular diastolic and systolic volumes.^43-46

The effects of dapagliflozin on eGFR, body weight, systolic blood pressure, and hematocrit were directionally similar in women and men. In this respect, it is worth noting that women had worse kidney function than men at baseline, which should have resulted in less glucosuria and diuresis than in men, yet women had similar clinical benefits. Also, the modest effect of dapagliflozin on systolic blood pressure in both men and women with HFrEF is reassuring given the concerns of low blood pressure as a potential barrier to intensify guideline-directed medical therapy and achieve target doses.

A key goal of HF management is to improve patients’ health status by reducing the symptom burden and improving physical function and quality of life. In this study, sex modified the effect of dapagliflozin on the mean change in KCCQ-TSS from baseline to 8 months, with a borderline P value for interaction. In men, dapagliflozin, compared with placebo, significantly increased the mean KSSQ-TSS at 8 months, whereas no increase was observed in women. Although the explanation for this is uncertain, it is likely to be a chance finding, especially given that the mean increase in KCCQ-CSS and KCCQ-OSS was greater with dapagliflozin, with consistent effects in women and men. Moreover, comparisons of differences in mean KCCQ-scores between groups do not adequately reflect clinically meaningful changes in individual patients because the effects are averaged in the entire subpopulations. From a clinical perspective, the proportions of individual patients who experience clinically important changes in symptoms, physical function, and health-related quality of life are more informative. Importantly, dapagliflozin increased the proportion of patients with a clinically significant improvement in symptoms, physical function, and health-related quality of life (increase in KCCQ-TSS, KCCQ-CSS, and KCCQ-OSS of ≥5 points) at 8 months and reduced the proportion with a clinically meaningful deterioration (decrease in KCCQ-TSS, KCCQ-CSS, and KCCQ-OSS of ≥5 points), irrespective of sex. Collectively, these data provide further support for dapagliflozin as a new treatment option for HFrEF.

Despite concerns that women experience more adverse drug reactions than men and are more likely to discontinue treatment,^33,47 data on safety and tolerability in DAPA-HF were reassuring. However, women overall were more likely to discontinue study treatment (including placebo) compared with men, although the proportion of women and men who discontinued treatment owing to adverse events was similar. In addition, study drug discontinuation and serious adverse events were not more frequently reported in the dapagliflozin group than in the placebo group in both men and women. Although SGLT2 inhibitors are associated with an increased risk of genitourinary infection, including genital mycotic infection, in patients with diabetes, and more so in women,^48-53 these data were not collected routinely in DAPA-HF. However, it is reassuring that the proportion of women and men who discontinued treatment owing to genital infection was low. Taken together, our data support that dapagliflozin is a safe and well-tolerated treatment in patients with HFrEF, irrespective of sex.

The findings of this study should be viewed in the context of potential limitations. Although sex was a predefined subgroup analysis, the assessment of the secondary and exploratory clinical outcomes by sex was done post hoc. The proportion of women in DAPA-HF was relatively low but similar to other global HFrEF trials. Thus, women continue to be underrepresented in HF trials, and greater efforts should be made to increase the proportion of women in HF (and other cardiovascular) trials.⁵⁴ The inclusion and exclusion criteria precluded the enrollment of hospitalized and other very high-risk patients. These limitations might affect the generalizability of our results.

In DAPA-HF, dapagliflozin, compared with placebo, reduced the risk of worsening HF events, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women. These findings provide further support for dapagliflozin as a new treatment option for patients with HFrEF.

Corresponding Author: John J. V. McMurray, MD, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Pl, Glasgow G12 8TA, Scotland (john.mcmurray@glasgow.ac.uk).

Accepted for Publication: January 29, 2020.

Published Online: March 31, 2021. doi:10.1001/jamacardio.2021.0379

Author Contributions: Drs McMurray and Jhund had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Butt, Diez, Langkilde, Sjostrand, Martinez, Ponikowski, Solomon, Jhund, McMurray, Køber.

Acquisition, analysis, or interpretation of data: Butt, Docherty, Petrie, Schou, Kosiborod, O'Meara, Katova, Ljungman, Ogunniyi, Langkilde, Sjostrand, Lindholm, Bengtsson, Ponikowski, Sabatine, Jhund, McMurray, Køber.

Drafting of the manuscript: Butt, Docherty, Schou, McMurray.

Critical revision of the manuscript for important intellectual content: Docherty, Petrie, Schou, Kosiborod, O'Meara, Katova, Ljungman, Diez, Ogunniyi, Langkilde, Sjostrand, Lindholm, Bengtsson, Martinez, Ponikowski, Sabatine, Solomon, Jhund, McMurray, Køber.

Statistical analysis: Butt, Docherty, Jhund, Køber.

Obtained funding: Katova, Langkilde.

Administrative, technical, or material support: Petrie, Kosiborod, Ljungman.

Supervision: Petrie, Langkilde, Sjostrand, Martinez, Ponikowski, Solomon, Jhund, McMurray, Køber.

Conflict of Interest Disclosures: Dr Docherty reported personal fees from AstraZeneca and the University of Glasgow during the conduct of the study and personal fees from Eli Lilly outside the submitted work. Dr Petrie reported grants from AstraZeneca during the conduct of the study; grants from Boehringer Ingelheim, Novo Nordisk, Novartis, and SQ Innovations and personal fees from Boehringer Ingelheim, Takeda, and Bayer outside the submitted work. Dr Schou reported lecture fees from other from Boehringer Ingelheim, AstraZeneca, and NOVP outside the submitted work. Dr Kosiborod reported grants from Astra Zeneca and Boehringer Ingelheim and personal fees from Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck (Diabetes), Novo Nordisk, Sanofi, and Vifor Pharma outside the submitted work. Dr Katova reported personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca and Novartis outside the submitted work. Dr Ljungman reported personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca, Novartis, and Pfizer outside the submitted work. Dr Ogunniyi reported grants from AstraZeneca during the conduct of the study and grants from AstraZeneca, Boehringer Ingelheim, and Zoll and personal fees from Alnylam, and Pfizer outside the submitted work. Drs Langkilde and Sjostrand reported being a full-time employee and shareholder of AstraZeneca during the conduct of the study. Dr Lindholm reported being an AstraZeneca employee. Dr Bengtsson reported being an AstraZeneca employee. Dr Martinez reported personal fees from AstraZeneca during the conduct of the study. Dr Ponikowski reported personal fees and other support from AstraZeneca during the conduct of the study; personal fees from Boehringer Ingelheim, Vifor Pharma, Amgen, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, Cibiem, Impulse Dynamics, Renal Guard Solutions, Radcliffe-Group, BMS, and Respicardia; and other support from AbbottVascular, Boehringer Ingelheim, Novartis, Amgen, Vifor, and Bayer outside the submitted work. Dr Sabatine reported grants from AstraZeneca Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital and personal fees from AstraZeneca during the conduct of the study; personal fees from Althera, Amgen, Antho, Bristol-Mysers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Dyrnamix, Esperion, IFM, Intarcia, Janssen Research and Development, Medicines Company, Medimmune, Merck, Novartis; grants from Amgen, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Regeneron, Roche, and Zora Biosciences. Dr Solomon reported grants from AstraZeneca Grants to institution during the conduct of the study; grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, National Health Institute/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos; and personal fees from Abbott, Actelion, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GSK, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Sanofi-Pasteur, Tenaya, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent outside the submitted work. Dr Jhund reported other support from AstraZeneca during the conduct of the study; other support from Novartis; and grants and personal fees from Boehringer-Ingelheim outside the submitted work. Dr McMurray reported other support from AstraZeneca; nonfinancial support from Cytokinetics, Bayer, Theracos, Oxford University, Dalcor, Merck, GlaxoSmithKline, Bristol Myers Squibb, Vifor-Fresenius, Kidney Research UK, Alnylam, Abbvie, Cyclerion, Cardurion; and personal fees from Amgen, Abbott, Hickma, Sun Pharmaceuticals, and Servier outside the submitted work. Dr Køber reported personal fees from AstraZeneca during the conduct of the study and from Novo, Boehringer and Novartis outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by AstraZeneca. Dr McMurray was supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217.

Role of the Funder/Sponsor: Representatives of AstraZeneca were involved with the executive committee in the design and conduct of the study. Site monitoring and data management were carried out by AstraZeneca. Data analysis was carried out at Glasgow University. Interpretation of the data and preparation of the manuscript was carried out by the executive committee, including representatives of AstraZeneca. Review and approval of the of the manuscript, as well as the decision to submit the manuscript for publication, was taken by all authors, including representatives of AstraZeneca. AstraZeneca had no veto of the right to publish or control over which journal to submit.

Data Sharing Statement: See Supplement 4.

Meeting Presentation: This manuscript was presented at the ESC Heart Failure Meeting; June 15, 2020.