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Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124) [Display omitted] [ABSTRACT FROM AUTHOR]

The SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) and SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trials demonstrated that sotagliflozin, an SGLT1 and SGLT2 inhibitor, improves outcomes in individuals with type 2 diabetes who have heart failure (HF) or kidney disease. We assessed the efficacy of sotagliflozin on HF clinical outcomes in individuals with differing baseline glycosylated hemoglobin (HbA1c) levels. We included all adults from SCORED and SOLOIST-WHF. The primary outcome was a composite of cardiovascular death, hospitalizations for HF, and urgent visits for HF. The efficacy of sotagliflozin compared with placebo was evaluated by baseline HbA1c using competing-risk marginal proportional hazards models. We identified 11,744 adults. Individuals with HbA1c ≤7.5% experienced the primary outcome at a lower rate in the sotagliflozin group (11.2 per 100 person-years) than the placebo group (15.5 per 100 person-years) (HR: 0.73; 95% CI: 0.57-0.93). Similarly, individuals with HbA1c of 7.6% to 9.0% experienced the primary outcome at a lower rate in the sotagliflozin group (7.3 per 100 person-years) than the placebo group (9.4 per 100 person-years) (HR: 0.77; 95% CI: 0.63-0.96). These findings were also consistent among individuals with HbA1c >9.0%, with a primary outcome rate in the sotagliflozin group (7.8 per 100 person-years) that was lower than the placebo group (11.6 per 100 person-years) (HR: 0.65; 95% CI: 0.50-0.84). The efficacy of sotagliflozin was consistent by baseline HbA1c level (P for interaction = 0.58). In individuals with type 2 diabetes and either HF or kidney disease, sotagliflozin reduced HF outcomes irrespective of baseline HbA1c. [Display omitted] [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time. In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation. Associations between a deterioration of eGFR to <25 mL/min/1.73 m2, efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to <25 mL/min/1.73 m2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P < 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to <25 mL/min/1.73 m2 (P interaction = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to <25 mL/min/1.73 m2; however, rates remained similar between treatment groups including among those who remained on study drug. Patients with deterioration of eGFR to <25 mL/min/1.73 m2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124 ; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213) [Display omitted] [ABSTRACT FROM AUTHOR]

Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region. The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates. [Display omitted] [ABSTRACT FROM AUTHOR]

Patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) experience a high burden of symptoms, physical limitations, and poor quality of life; improving health status is a key goal of management. In a prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, we examine effects of dapagliflozin on health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ). The DELIVER trial randomized patients with symptomatic HFmrEF/HFpEF to dapagliflozin 10 mg or placebo. KCCQ was evaluated at randomization, 1, 4, and 8 months; KCCQ Total Symptom Score (TSS) was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles; Cox models examined effects of dapagliflozin on clinical outcomes. We evaluated the effects of dapagliflozin on KCCQ-TSS, Physical Limitations (PLS), Clinical Summary (CSS), and Overall Summary (OSS) domains. Responder analyses compared proportions of dapagliflozin vs placebo-treated patients with clinically meaningful changes in KCCQ. A total of 5,795 patients had baseline KCCQ (median KCCQ-TSS 72.9). The effects of dapagliflozin on reducing cardiovascular death/worsening HF appeared more pronounced in patients with greater baseline symptom burden (lowest-to-highest KCCQ-TSS tertile: HR: 0.70 [95% CI: 0.58-0.84]; 0.81 [95% CI: 0.65-1.01]; 1.07 [95% CI: 0.83-1.37]; P interaction = 0.026). Dapagliflozin improved KCCQ-TSS, -PLS, -CSS, and -OSS at 8 months (2.4, 1.9, 2.3, and 2.1 points higher vs placebo; P < 0.001 for all). Dapagliflozin-treated patients experienced improvements in KCCQ-TSS regardless of EF (P interaction = 0.85). Fewer dapagliflozin-treated patients had deterioration, and more had improvements in all KCCQ domains at 8 months. The clinical benefits of dapagliflozin in HFmrEF/HFpEF appear especially pronounced in those with greater baseline symptom impairment. Dapagliflozin improved all KCCQ domains and the proportion of patients experiencing clinically meaningful changes in health status. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213) [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Recent guidelines support consideration of sodium-glucose cotransporter-2 inhibitors in the long-term management of heart failure (HF) with mildly reduced or preserved ejection fraction. Patients and clinicians may be interested in the expected lifetime benefits of sodium-glucose cotransporter-2 inhibitors in this population.Objectives: This study aimed to estimate event-free survival gains from long-term use of dapagliflozin in patients with HF with mildly reduced or preserved ejection fraction overall and in clinically relevant subgroups.Methods: In this prespecified analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we applied validated nonparametric age-based methods to extrapolate potential gains in survival free from the primary endpoint (cardiovascular death or worsening HF event) from long-term use of dapagliflozin. Eligible participants had symptomatic HF, left ventricular ejection fraction >40%, elevated natriuretic peptide levels, and structural heart disease. For every year between the ages of 55 and 85 years, we estimated event-free survival using age at randomization rather than time from randomization as the time horizon. Residual lifespan free from a primary endpoint was estimated based on area under the survival curve in each arm.Results: Among 6,263 participants, mean survival free from the primary endpoint for a 65-year-old participant was 12.1 years (95% CI: 11.0-13.2 years) with dapagliflozin and 9.7 years (95% CI: 8.8-10.7 years) with placebo, representing a 2.3-year (95% CI: 0.9-3.8 years) event-free survival gain (P = 0.002). Treatment gains in survival free from the primary endpoint ranged from 2.0 years (95% CI: -0.6 to 4.6 years) in a 55-year-old to 1.2 years (95% CI: -0.1 to 2.4 years) in a 75-year-old patient. Mean event-free survival was greater with dapagliflozin than with placebo across all 14 subgroups.Conclusions: Treatment with dapagliflozin is projected to extend event-free survival by up to 2.0 to 2.5 years among middle-aged and older individuals with HF with mildly reduced or preserved ejection fraction. (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]; NCT03619213). [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes compared with sinus rhythm, and may modify the effects of therapy.Objectives: This study examined the effects of dapagliflozin according to the presence or not of AF in the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial.Methods: A total of 6,263 patients with HF with New York Heart Association functional class II-IV, left ventricular ejection fraction >40%, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomized to dapagliflozin or placebo. Clinical outcomes and the effect of dapagliflozin, according to AF status, were examined. The primary outcome was a composite of cardiovascular death or worsening HF.Results: Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% had paroxysmal AF, and 38.7% had persistent/permanent AF. The risk of the primary endpoint was higher in patients with AF, especially paroxysmal AF, driven by a higher rate of HF hospitalization: no AF, HF hospitalization rate per 100 person-years (4.5 [95% CI: 4.0-5.1]), paroxysmal AF (7.5 [95% CI: 6.4-8.7]), and persistent/permanent AF (6.4 [95% CI: 5.7-7.1]) (P < 0.001). The benefit of dapagliflozin on the primary outcome was consistent across AF types: no AF, HR: 0.89 (95% CI: 0.74-1.08); paroxysmal AF, HR: 0.75 (95% CI: 0.58-0.97); persistent/permanent AF, HR: 0.79 (95% CI: 0.66-0.95) (Pinteraction = 0.49). Consistent effects were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the KCCQ-TSS.Conclusions: In DELIVER, the beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, irrespective of type of AF at baseline. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. [DELIVER]; NCT03619213). [ABSTRACT FROM AUTHOR]

Background: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death.Objectives: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization.Methods: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death.Results: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients.Conclusions: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213). [ABSTRACT FROM AUTHOR]

Background: The use of guideline-directed medical therapy (GDMT) is underprescribed in patients with heart failure with reduced ejection fraction (HFrEF).Objectives: This study sought to examine whether targeted and tailored electronic health record (EHR) alerts recommending GDMT in eligible patients with HFrEF improves GDMT use.Methods: PROMPT-HF (PRagmatic trial Of Messaging to Providers about Treatment of Heart Failure) was a pragmatic, EHR-based, cluster-randomized comparative effectiveness trial. A total of 100 providers caring for patients with HFrEF were randomized to either an alert or usual care. The alert notified providers of individualized GDMT recommendations along with patient characteristics. The primary outcome was an increase in the number of GDMT classes prescribed at 30 days postrandomization. Providers were surveyed on knowledge of guidelines and user experience.Results: The study enrolled 1,310 ambulatory patients with HFrEF from April to October 2021. Median age was 72 years; 31% were female; 18% were Black; and median left ventricular ejection fraction was 32%. At baseline, 84% of participants were receiving β-blockers, 71% received a renin-angiotensin-aldosterone system inhibitor, 29% received a mineralocorticoid receptor antagonist, and 11% received a sodium-glucose cotransporter-2 inhibitor. The primary outcome occurred in 176 of 685 (26%) participants in the alert arm vs 117 of 625 (19%) in the usual care arm, thus increasing GDMT class prescription by >40% after alert exposure (adjusted relative risk: 1.41; 95% CI: 1.03-1.93; P = 0.03). The number of patients needed to alert to result in an increase in addition of GDMT classes was 14. A total of 79% of alerted providers agreed that the alert was effective at enabling improved prescription of medical therapy for HF.Conclusions: A real-time, targeted, and tailored EHR-based alerting system for outpatients with HFrEF led to significantly higher rates of GDMT at 30 days when compared with usual care. This low-cost intervention can be rapidly integrated into clinical care and accelerate adoption of high-value therapies in heart failure. (PRagmatic trial Of Messaging to Providers about Treatment of Heart Failure [PROMPT-HF; NCT04514458]). [ABSTRACT FROM AUTHOR]

Objectives: We sought to evaluate whether pre-procedural glucose levels are associated with contrast-induced acute kidney injury (CI-AKI) after coronary angiography. Background: Although diabetes is a known risk factor for CI-AKI in patients undergoing coronary angiography, whether elevated pre-procedural glucose levels (regardless of pre-existing diabetes) are associated with higher risk for CI-AKI is unknown. Methods: We evaluated 6,358 patients with acute myocardial infarctions undergoing coronary angiography. Patients were stratified into 5 pre-procedural glucose groups: <110 mg/dl, 110 to <140 mg/dl, 140 to <170 mg/dl, 170 to <200 mg/dl, and ≥200 mg/dl. Logistic regression models were used to evaluate the relationship between glucose levels and risk for CI-AKI, first in the entire cohort and then in patients with and without established diabetes. The primary outcome was CI-AKI (≥0.3 mg/dl absolute or ≥50% relative serum creatinine increase during 48 h after the procedure). Results: The relationship between pre-procedural glucose and CI-AKI varied markedly in patients with and without diabetes. There was a strong association between glucose and CI-AKI risk in patients without diabetes (CI-AKI rates across the 5 glucose groups from lowest to highest: 8.2%, 9.9%, 12.4%, 14.9%, and 24.3%; p < 0.001), but not in patients with diabetes (20.9%, 16.1%, 16.3%, 14.8%, and 19.2%, respectively; p = 0.24; p for glucose × diabetes interaction <0.001). After adjusting for confounders (including baseline glomerular filtration rate), the relationship between higher glucose and greater CI-AKI risk persisted in patients without diabetes (odds ratios [95% confidence intervals] for glucose groups of 110 to <140 mg/dl, 140 to <170, mg/dl 170 to <200 mg/dl, and ≥200 mg/dl: 1.31 [1.00 to 1.71], 1.51 [1.11 to 2.10], 1.58 [1.03 to 2.43], and 2.14 [1.46 to 3.14] vs. glucose <110 mg/dl, respectively), but this relationship was not seen in patients with established diabetes. Conclusions: Elevated pre-procedural glucose is associated with greater risk for CI-AKI in patients without known diabetes who undergo coronary angiography in the setting of acute myocardial infarction. Measures used to prevent CI-AKI should be considered in these patients. [Copyright &y& Elsevier]

Patients with diabetes, in particular patients with type 2 diabetes, are at a 2- to 4-fold higher risk of cardiovascular mortality compared with their nondiabetic peers. Patients with diabetes are also more likely to have silent ischemia and less likely to survive a myocardial infarction than nondiabetic patients. Recent studies with electron beam computed tomography (EBCT) have shown that subclinical atherosclerosis is common in patients with diabetes, and studies with myocardial perfusion scintigraphy (with single-photon emission computed tomography) or stress echocardiography have demonstrated that between 25% and 50% of asymptomatic diabetic patients have ischemia during exercise or pharmacological stress and that a substantial proportion of these patients go on to develop major cardiovascular events within several years. Clearly, asymptomatic diabetic patients include a subset of individuals at high risk of cardiovascular disease who would benefit from improved risk stratification beyond that possible with risk factor scoring systems alone. Single-photon emission computed tomography, stress echocardiography, and possibly EBCT or multi-slice computed tomography, are emerging as valuable diagnostic tools for identifying asymptomatic diabetic patients who might require early and aggressive intervention to manage their cardiovascular risk. [Copyright &y& Elsevier]