Trial Design and Oversight

The executive committee designed and oversaw the conduct and analysis of the trial in collaboration with the sponsor, AstraZeneca.12,13 The trial was conducted and reported in accordance with the protocol and the statistical analysis plan, both of which are available with the full text of this article at NEJM.org. The trial was approved by the ethics committee at each center. The safety of patients in the trial was overseen by an independent data and safety monitoring committee. The analyses conducted by the sponsor were replicated by an independent academic group at the University of Glasgow. The first draft of the manuscript was prepared by the first author, who had unrestricted access to the data, and was reviewed and edited by all the authors. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Patients

Eligibility requirements included an age of at least 18 years, an ejection fraction of 40% or less, and New York Heart Association (NYHA) class II, III, or IV symptoms. Patients were required to have a plasma level of N-terminal pro–B-type natriuretic peptide (NT-proBNP) of at least 600 pg per milliliter (or ≥400 pg per milliliter if they had been hospitalized for heart failure within the previous 12 months). Patients with atrial fibrillation or atrial flutter on baseline electrocardiography were required to have an NT-proBNP level of at least 900 pg per milliliter, regardless of their history of hospitalization for heart failure.

Patients were required to receive standard heart-failure device therapy (an implantable cardioverter–defibrillator, cardiac resynchronization therapy, or both) and standard drug therapy, including an angiotensin-converting–enzyme inhibitor, an angiotensin-receptor blocker, or sacubitril–valsartan plus a beta-blocker, unless such use was contraindicated or resulted in unacceptable side effects. In addition, the use of a mineralocorticoid receptor antagonist was encouraged. Drug doses were individually tailored, in accordance with guideline recommendations. Patients with type 2 diabetes continued to take their glucose-lowering therapies, but doses could be adjusted as required. Specifically, the dose of insulin and sulfonylurea could be reduced to minimize the risk of hypoglycemia (e.g., in patients with a glycated hemoglobin level of <7%).

Exclusion criteria included recent treatment with or unacceptable side effects associated with an SGLT2 inhibitor, type 1 diabetes mellitus, symptoms of hypotension or a systolic blood pressure of less than 95 mm Hg, and an estimated glomerular filtration rate (eGFR) below 30 ml per minute per 1.73 m2 of body-surface area (or rapidly declining renal function).

Trial Procedures

All the patients provided written informed consent and entered a 14-day screening period, during which the trial inclusion and exclusion criteria were checked and baseline information gathered. After this screening, patients were randomly assigned to receive either dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in accordance with the sequestered, fixed-randomization schedule, with the use of balanced blocks to ensure an approximate 1:1 ratio of the two regimens. Investigators used an interactive voice- or Web-response system to determine treatment assignment. Randomization was stratified on the basis of a diagnosis of type 2 diabetes (i.e., an established diagnosis or a glycated hemoglobin level of ≥6.5% [≥48 mmol per mole]) confirmed at screening.

Patients were evaluated at 14 days and 60 days after randomization, with a focus on assessment of heart failure and volume status, adverse events, and an evaluation of renal function and potassium levels. Additional trial visits were scheduled at 4 months and at 4-month intervals thereafter (Fig. S1 in the Supplementary Appendix, available at NEJM.org). The full schedule of assessments is provided in the trial protocol. Dapagliflozin or placebo was to be discontinued if pregnancy or diabetic ketoacidosis occurred. Dose reduction (to 5 mg daily of dapagliflozin or placebo) or temporary discontinuation was permitted in case of an acute, unexpected decline in the eGFR, volume depletion, or hypotension (or to avoid these conditions), with a subsequent increase in dose or restarting of treatment, if possible.

Outcomes

The primary outcome was a composite of worsening heart failure or death from cardiovascular causes. An episode of worsening heart failure was either an unplanned hospitalization or an urgent visit resulting in intravenous therapy for heart failure.

A key secondary outcome was a composite of hospitalization for heart failure or cardiovascular death. The additional secondary outcomes were the total number of hospitalizations for heart failure (including repeat admissions) and cardiovascular deaths; the change from baseline to 8 months in the total symptom score on the Kansas City Cardiomyopathy Questionnaire, which is scored on a scale from 0 to 100, with a higher score indicating fewer symptoms and a change of 5 or more points considered to be clinically meaningful14; a composite of worsening renal function, which was defined as a sustained decline in the eGFR of 50% or greater, end-stage renal disease (defined as a sustained [≥28 days] eGFR of <15 ml per minute per 1.73 m2, sustained dialysis, or renal transplantation), or renal death; and death from any cause.12 All outcomes were adjudicated by the members of a clinical-events committee, who were unaware of trial-group assignments, according to prespecified criteria (with definitions listed in the Supplementary Appendix).15

The prespecified safety analyses included serious adverse events, adverse events associated with the discontinuation of a trial treatment, adverse events of interest (i.e., volume depletion, renal events, major hypoglycemic events, bone fractures, diabetic ketoacidosis, and amputations), a diagnosis of Fournier’s gangrene, and laboratory findings of note. Data on other adverse events were not routinely collected in view of the extensive previous collection of safety data regarding dapagliflozin.3

Statistical Analysis

We calculated that 844 primary outcome events would provide the trial with a power of 90% to detect a hazard ratio of 0.80 for the comparison between dapagliflozin and placebo, using a two-sided alpha level of 0.05. With an expected annual event incidence of 11% in the placebo group, we estimated that the enrollment of approximately 4500 patients would provide the required number of primary events, based on an anticipated recruitment period of 18 months and an average follow-up period of approximately 24 months. We used a closed testing procedure, with prespecified hierarchical testing of the primary and secondary outcomes. The type I error was controlled at a two-sided alpha level of 0.0499 for multiple comparisons across primary and secondary outcomes, with one interim efficacy analysis taken into account.

We included data from all the patients who had undergone randomization in the analyses of the primary and secondary outcomes, according to the intention-to-treat principle. Baseline characteristics were summarized as means and standard deviations, medians and interquartile ranges, or percentages. We used a mixed model for repeated measurement to analyze longitudinal measures (e.g., glycated hemoglobin level and body weight) and estimated the least-squares mean differences between treatment groups, together with 95% confidence intervals. Time-to-event data were evaluated with the use of Kaplan–Meier estimates and Cox proportional-hazards models, stratified according to diabetes status, with a history of hospitalization for heart failure and treatment-group assignment as fixed-effect factors; for the renal outcome, the baseline eGFR was included instead of a history of hospitalization for heart failure. We used the Cox models to calculate hazard ratios, 95% confidence intervals, and two-sided P values and used a semiparametric proportional-rates model to calculate total (including recurrent) events.16

We analyzed the total symptom score on the Kansas City Cardiomyopathy Questionnaire as a composite, rank-based outcome, incorporating patient vital status at 8 months along with a change in score from baseline to 8 months in surviving patients, using the rank analysis of covariance method, with a corresponding win ratio used to estimate the magnitude of treatment effect.17 We assessed the consistency of the treatment effect among 14 prespecified subgroups. The safety analyses were performed in patients who had undergone randomization and received at least one dose of dapagliflozin or placebo. We used Fisher’s exact test to compare the incidence of adverse events. All the analyses were performed with the use of Stata software, version 15 (StataCorp) and R, version 3.5.1 (R Foundation for Statistical Computing).