AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain. METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs. CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.
Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23â¯338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23â¯338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435â¯851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957â¯505 years of life (95% CI, 534â¯475-1â¯380â¯535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.
AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.
OBJECTIVES: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes. METHODS: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method. RESULTS: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes. CONCLUSIONS: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial.
BACKGROUND: In PARAGLIDE-HF, among patients with ejection fraction (EF) >40%, stabilized after worsening heart failure (WHF), sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared to valsartan alone, despite more symptomatic hypotension (SH). Concern over SH may be limiting use of sacubitril/valsartan in appropriate patients. METHODS: We characterized patients by the occurrence of SH (investigator-reported) after randomization to either sacubitril/valsartan or valsartan. A key trial inclusion criterion was systolic blood pressure (SBP) ≥100 mmHg for the preceding 6 hours and no SH. We also compared outcomes based on baseline SBP stratified by the median blood pressure. The primary endpoint was time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: a) cardiovascular death, b) HF hospitalizations, c) urgent HF visits, and d) change in NT-proBNP. RESULTS: Among 466 randomized patients, 92 (19.7%) experienced SH (sacubitril/valsartan, N=56 [24.0%]; valsartan, N=36 [15.5%], p=0.020). The median time to the first SH event was similar between treatment arms (18 days vs. 15 days, respectively, p=0.42) as was the proportion of first SH events classified as "serious" by investigators. Patients who experienced SH with sacubitril/valsartan were more likely to be White (OR 1.87 [95%CI: 0.31, 11.15]), to have a lower baseline SBP (per 10mmHg increase OR 0.68 [95%CI: 0.55, 0.85]), or to have a left ventricular ejection fraction (LVEF) of >60% (OR 2.21 [95%CI: 1.05, 4.65]). Time-averaged change in NT-proBNP did not differ between patients with baseline SBP ≥128 mmHg vs. SBP<128mmHg (interaction p=0.43). The composite hierarchical outcome for sacubitril/valsartan in patients with baseline SBP≥128mmHg had a win ratio of 1.34 ([95%CI: 0.91, 1.99], p=0.096) vs SBP<128mmHg with a win ratio of 1.09 ([95%CI: 0.73, 1.66], p=0.62; interaction p value=0.42). CONCLUSION: Among patients with LVEF>40% stabilized after WHF, incident SH was more common with sacubitril/valsartan compared with valsartan. SH was associated with lower baseline SBP, White race, and higher LVEF. Treatment benefits with sacubitril/valsartan may be more pronounced in patients with higher baseline SBP and lower LVEF (≤ 60%). (Funded by Novartis Pharmaceutical Corporation; ClinicalTrials.gov number, NCT03988634.) ABBREVIATIONS: : HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT-proBNP, amino terminal-pro b-type natriuretic peptide; SBP, systolic blood pressure; WHF, worsening heart failure.
Introduction: Women experience excess cardiovascular risk compared to men in the setting of similar metabolic disease burden. This consistent finding could be related to sex differences in the vascular response to various forms of metabolic stress. In this study we examine the association of both systemic and organ-specific metabolic stress with vascular health in women and men. Methods: We conducted an observational study of 4,299 adult participants (52% women, aged 59±13 years) of the National Health and Nutrition Examination Survey (NHANES) 2017-2018 cohort and 110,225 adult outpatients (55% women, aged 64±16 years) of the Cedars-Sinai Medical Center (CSMC) 2019 cohort. We used natural splines to examine the association of systemic and organ-specific measures of metabolic stress including body mass index (BMI), hemoglobin A1c (HbA1c), hepatic FIB-4 score, and CKD-EPI estimated glomerular filtration rate (eGFR) on systolic blood pressure (SBP). Piecewise linear models were generated using normal value thresholds (BMI <25 kg/m 2 , HbA1c <5.7%, FIB-4 <1.3, and eGFR ≥90 ml/min), which approximated observed spline breakpoints. The primary outcome was increase in SBP (relative to a sex-specific physiologic baseline SBP) in association with increase in level of each metabolic measure. Results: Women compared to men demonstrated larger magnitudes and an earlier onset of increase in SBP per increment increase across all metabolic stress measures. The slope of SBP increase per increment of each metabolic measure was greater for women than men particularly for metabolic measures within the normal range, with slope differences of 1.71 mmHg per kg/m2 of BMI, 9.61 mmHg per %HbA1c, 6.45 mmHg per FIB-4 unit, and 0.37 mmHg per ml/min decrement of eGFR in the NHANES cohort (P difference <0.05 for all). Overall results were consistent in the CSMC cohort. Conclusions: Women exhibited greater vascular sensitivity in the setting of multiple types of metabolic stress, particularly in periods representing the transition from metabolic health to disease. These findings underscore the importance of involving early metabolic health interventions as part of efforts to mitigate vascular risks in both women and men.
Importance: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions. Objective: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics. Design, Setting, and Participants: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10â¯638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023. Exposures: Protein aptamers, measured at study V3 and V5. Main Outcomes and Measures: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty. Results: A total of 4877 protein aptamers were measured among 10â¯638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF. Conclusions and Relevance: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.
BACKGROUND: The extent to which infection versus vaccination has conferred similarly durable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity during the Omicron era remains unclear. METHODS: In a cohort of 4496 adults under continued serological surveillance throughout the first year of Omicron-predominant SARS-CoV-2 transmission, we examined incidence of new infection among individuals whose last known antigenic exposure was either recent (<90 days) or remote (≥90 days) infection or vaccination. RESULTS: We adjudicated 2053 new-onset infections occurring between 15 December 2021 through 22 December 2022. In multivariable-adjusted analyses, compared to individuals whose last known exposure was remote vaccination, those with recent vaccination (odds ratio [OR], 0.82 [95% confidence interval {CI}, .73-.93]; P = .002) or recent infection (OR, 0.14 [95% CI, .05-.45]; P = .001) had lower risk for new infection within the subsequent 90-day period. Given a significant age interaction (P = .004), we found that remote infection compared to remote vaccination was associated with significantly greater new infection risk in persons aged ≥60 years (OR, 1.88 [95% CI, 1.13-3.14]; P = .015) with no difference seen in those <60 years (1.03 [95% CI, .69-1.53]; P = .88). CONCLUSIONS: During the initial year of Omicron, prior infection and vaccination both offered protection against new infection. However, remote prior infection was less protective than remote vaccination for individuals aged ≥60 years. In older adults, immunity gained from vaccination appeared more durable than immunity gained from infection.
AIM: Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non-steroidal MRA finerenone. The FINEARTS-HF trial is designed to evaluate the long-term efficacy and safety of the selective non-steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. METHODS: FINEARTS-HF is a global, multicentre, event-driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II-IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml (or B-type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT-proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. CONCLUSIONS: The FINEARTS-HF trial will determine the efficacy and safety of the non-steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04435626 and EudraCT 2020-000306-29.
BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).
Cardiomyopathy, Hypertrophic , Exercise Test , Humans , Double-Blind Method , Male , Middle Aged , Female , Cardiomyopathy, Hypertrophic/drug therapy , Cardiomyopathy, Hypertrophic/physiopathology , Aged , Oxygen Consumption/drug effects , Ventricular Outflow Obstruction/drug therapy , Ventricular Outflow Obstruction/physiopathology , Ventricular Outflow Obstruction/etiology , Adult , Cardiac Myosins/antagonists & inhibitors , Exercise Tolerance/drug effects , Valsalva Maneuver , Benzylamines , Uracil/analogs & derivatives
BACKGROUND: Machine learning-based approaches that seek to accomplish individualized treatment effect prediction have gained traction; however, some salient challenges lack wider recognition. METHODS: We describe key methodologic considerations for individualized treatment effect prediction models using data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial for spironolactone in heart failure with preserved ejection fraction. The causal survival forest algorithm was used for model development. Calibration and discrimination were evaluated using a bootstrapping-based internal validation procedure. Observed benefits were described for predicted benefit quartiles and quartiles of a known effect modifier: ejection fraction. A negative control analysis with noncardiovascular death as the outcome was implemented to detect confounding. RESULTS: Among 3445 participants, 671 events occurred over a median of 3.3 years of follow-up. In internal validation, a higher average observed benefit was noted among patients in the highest quartile of predicted benefit. The median (interquartile range) of the observed restricted mean survival time difference at 3.3 years at the highest quartile of model-predicted benefit was 62 days (32 to 83) and was 47 days (26 to 67) at the lowest quartile of ejection fraction. Body-mass index had higher contribution to prediction of benefit relative to other included measures (33.7% vs. glomerular filtration rate [27.3%], ejection fraction [15.1%], and younger age [12.8%]) No benefit was observed for noncardiovascular death at higher model-predicted benefit quartiles, although benefit for noncardiovascular death was observed at lower quartiles. CONCLUSIONS: Carefully applied and validated predictive models hold promise in identifying heterogeneous treatment effects and are useful for hypothesis generation regarding the role of phenotypic characteristics in modifying the benefit of experimental interventions in clinical trials. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00094302.).
Heart Failure , Machine Learning , Mineralocorticoid Receptor Antagonists , Spironolactone , Humans , Heart Failure/drug therapy , Heart Failure/mortality , Heart Failure/physiopathology , Mineralocorticoid Receptor Antagonists/therapeutic use , Female , Male , Spironolactone/therapeutic use , Middle Aged , Aged , Stroke Volume/drug effects , Precision Medicine/methods , Treatment Outcome , Algorithms
AIMS: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. METHODS AND RESULTS: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. CONCLUSIONS: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.
Win statistics offer a new approach to the analysis of outcomes in clinical trials, allowing the combination of time-to-event and longitudinal measurements and taking into account the clinical importance of the components of composite outcomes, as well as their relative timing. We examined this approach in a post hoc analysis of two trials that compared dapagliflozin to placebo in patients with heart failure and reduced ejection fraction (DAPA-HF) and mildly reduced or preserved ejection fraction (DELIVER). The effect of dapagliflozin on a hierarchical composite kidney outcome was assessed, including the following: (1) all-cause mortality; (2) end-stage kidney disease; (3) a decline in estimated glomerular filtration rate (eGFR) of ≥57%; (4) a decline in eGFR of ≥50%; (5) a decline in eGFR of ≥40%; and (6) participant-level eGFR slope. For this outcome, the win ratio was 1.10 (95% confidence interval (CI) = 1.06-1.15) in the combined dataset, 1.08 (95% CI = 1.01-1.16) in the DAPA-HF trial and 1.12 (95% CI = 1.05-1.18) in the DELIVER trial; that is, dapagliflozin was superior to placebo in both trials. The benefits of treatment were consistent in participants with and without baseline kidney disease, and with and without type 2 diabetes. In heart failure trials, win statistics may provide the statistical power to evaluate the effect of treatments on kidney as well as cardiovascular outcomes.
Benzhydryl Compounds , Glomerular Filtration Rate , Glucosides , Heart Failure , Humans , Heart Failure/drug therapy , Heart Failure/physiopathology , Benzhydryl Compounds/therapeutic use , Glucosides/therapeutic use , Male , Female , Aged , Middle Aged , Stroke Volume , Treatment Outcome , Kidney/physiopathology , Kidney/drug effects , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Kidney Failure, Chronic/physiopathology , Kidney Failure, Chronic/drug therapy
AIM: High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza. METHODS: DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c. RESULTS: Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), pinteraction = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]. CONCLUSIONS: In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status.
Diabetes Mellitus , Influenza Vaccines , Influenza, Human , Pneumonia , Aged , Humans , Hospitalization , Influenza Vaccines/therapeutic use , Influenza, Human/epidemiology , Influenza, Human/prevention & control , Pneumonia/prevention & control , Pragmatic Clinical Trials as Topic
BACKGROUND: Patients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more "stable." OBJECTIVES: The authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a patient-level pooled analysis of 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). METHODS: A total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death. RESULTS: In total, 12.4% were hospitalized for HF within 3 months of randomization, 14.2% between 3 and 12 months, and 16.8% more than 1 year before randomization, whereas 56.5% had not been hospitalized. The risk of the primary endpoint was inversely associated with time from prior HF hospitalization, and patients with a recent HF hospitalization had the highest risk. Compared with placebo, dapagliflozin reduced the risk of the primary outcome across HF hospitalization category (0-3 months, HR: 0.66 [95% CI: 0.55-0.81]; 3-12 months, HR: 0.73 [95% CI: 0.59-0.90]; >1 year, HR: 0.91 [95% CI: 0.74-1.12]; and no prior hospitalization, HR: 0.83 [95% CI: 0.73-0.94]; Pinteraction = 0.09). The number of patients needed to treat with dapagliflozin to prevent 1 event over the median follow-up of 22 months was 13, 20, 23, and 28, respectively. The beneficial effect was consistent across the range of LVEF regardless of HF hospitalization category. CONCLUSIONS: The relative benefits of dapagliflozin were consistent across the range of LVEF regardless of the timing of the most recent HF hospitalization with a greater absolute benefit in patients with recent hospitalization.
