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The term acute myocardial infarction (MI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI: ● Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference limit (URL) and with at least one of the following: y Symptoms of ischemia. y New or presumed new significant ST-segment–T wave (ST–T) changes or new left bundle branch block (LBBB). y Development of pathological Q waves in the ECG. y Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. y Identification of an intracoronary thrombus by angiography or autopsy. ● Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or before cardiac biomarker values would be increased. ● Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by elevation of cTn values (5 99th percentile URL) in patients with normal baseline values (99th percentile URL) or a rise of cTn values 20% if the baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia or (ii) new ischemic ECG changes or (iii) angiographic findings consistent with a procedural complication or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required. ● Stent thrombosis associated with MI when detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile URL. ● Coronary artery bypass grafting (CABG) related MI is arbitrarily defined by elevation of cardiac biomarker values (10 99th percentile URL) in patients with normal baseline cTn values (99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality. Criteria for prior myocardial infarction Any one of the following criteria meets the diagnosis for prior MI: ● Pathological Q waves with or without symptoms in the absence of non-ischemic causes. ● Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause. ● Pathological findings of a prior MI

Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45–0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76–1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66–1.17]) and those without HF (HR, 0.88 [95% CI, 0.74–1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43–0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62–0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34–0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89–1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40–0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86–1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

IMPORTANCE Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. OBJECTIVE To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. DESIGN, SETTING, AND PARTICIPANTS Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between

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