John McMurray

BackgroundThere is a paucity of data on the clinical characteristics, management, and outcomes of women compared with men with heart failure in low-income and middle-income countries compared with high-income countries. We examined sex differences in risk factors, clinical characteristics, and treatments, and prospectively assessed the risk of heart failure hospitalisation and mortality in patients with heart failure in 40 high-income, middle-income, and low-income countries.MethodsParticipants aged 18 years or older with heart failure were enrolled from Dec 20, 2016, to Sept 9, 2020 in the prospective Global Congestive Heart Failure (G-CHF) study from 257 centres in 40 high-income, middle-income, and low-income countries. Participants were followed up until May 25, 2023. We recorded the demographic characteristics, medical history, and treatments of participants. We prospectively recorded data on …

Aims Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early discharge, preventing hospitalizations, and in palliative care. A high-concentration, pH-neutral furosemide formulation has been developed for SC administration via a small patch infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of a new SC furosemide formulation with conventional IV furosemide and describe the first use of a bespoke mini-pump to administer this formulation. Methods and results A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over 5 h) was investigated. The first study was a PK/PD study of SC furosemide compared with 80 mg IV furosemide administered …

Aim To investigate the effects of Cimlanod, a nitroxyl donor with vasodilator properties, on water and salt excretion after an administration of an intravenos bolus of furosemide. Methods and results In this randomized, double‐blind, mechanistic, crossover trial, 21 patients with left ventricular ejection fraction <45%, increased plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and receiving loop diuretics were given, on separate study days, either an 8 h intravenous (IV) infusion of cimlanod (12 μg/kg/min) or placebo. Furosemide was given as a 40 mg IV bolus four hours after the start of infusion. The primary endpoint was urine volume in the 4 h after the bolus of furosemide during infusion of cimlanod compared with placebo. Median NT‐proBNP at baseline was 1487 (interquartile range: 847–2665) ng/L. Infusion of cimlanod increased cardiac output and reduced blood pressure …

Aim Blood urea nitrogen (BUN) to creatinine ratio is associated with worse outcomes in acute heart failure (HF) but little is known about its importance in chronic HF. Methods and results We combined individual patient data from clinical trials (HF with reduced ejection fraction [HFrEF]: PARADIGM‐HF, ATMOSPHERE and DAPA‐HF, and HF with preserved ejection fraction [HFpEF]: PARAGON‐HF and I‐PRESERVE). The primary outcome examined was a composite time to first HF hospitalization or cardiovascular death; its components and all‐cause death were also examined. Each HF phenotype was categorized according to median BUN/creatinine ratio, generating four groups that is, HFpEF ≤ and >median BUN/creatinine ratio and HFrEF ≤ and >median BUN/creatinine ratio. The association between BUN/creatinine ratio and outcomes was evaluated using the Kaplan–Meier estimator and Cox proportional …

Background A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level. Methods Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes. Results Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211–0.310), and 1 499 (34.8%) in severely …

Aims Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated. Methods and results In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at …

Background Black people have a higher incidence and prevalence of heart failure (HF) than White people, and once HF has developed, they may have worse outcomes. There is also evidence that the response to several pharmacologic therapies may differ between Black and White patients. Objectives The authors sought to examine the outcomes and response to treatment with dapagliflozin according to Black or White race in a pooled analysis of 2 trials comparing dapagliflozin to placebo in patients with heart failure with reduced ejection fraction (DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]) and heart failure with mildly reduced ejection fraction/heart failure with preserved ejection fraction (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]). Methods Because most self-identified Black patients were enrolled in …

BackgroundWhether frailty influences the initiation of two cardioprotective diabetes drug therapies (ie, SGLT2 inhibitors and GLP-1 receptor agonists) in people with type 2 diabetes and cardiovascular disease is unknown. We aimed to assess rates of initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to frailty in people with type 2 diabetes and cardiovascular disease.MethodsFor this cross-sectional, nationwide study, all people with type 2 diabetes and cardiovascular disease in Denmark between Jan 1, 2015, and Dec 31, 2021, from six Danish health-data registers were identified. People younger than 40 years, with end-stage renal disease, with registered contraindications to SGLT2 inhibitors or GLP-1 receptor agonists, or with previous use of either drug therapy were excluded. The Hospital Frailty Risk Score was used to categorise people as either non-frail, moderately frail, or severely frail …

Background Heart failure (HF) is associated with impaired physical function and poor quality of life and affects health status more profoundly than many other chronic diseases. Objectives The authors examined the effects of dapagliflozin on specific physical and social limitations as reported by patients in the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial. Methods The effect of dapagliflozin on the change from baseline to 8 months in each of the individual physical and social activity limitation questions answered by patients completing the Kansas City Cardiomyopathy Questionnaire (KCCQ), and overall scores, were examined with mixed-effects models and responder analyses. Results In total, 4,269 (90.0%) and 3,955 (83.4%) patients had complete data for both the physical and social activity limitation scores at baseline and 8 months, respectively. Compared with placebo …

Carbohydrate antigen 125 in HFrEF and the effect of dapagliflozin: findings from DAPA-HF - Enlighten Publications Skip to main content Accessibility information Site navigation Study Research About us Student life Alumni Support us Contact Site tools AZ Lists Subjects AZ Staff AZ Academic units AZ University of Glasgow logo Home Enlighten Publications Enlighten Publications About Latest Additions Search Browse Browse by Author Browse by Year Browse by Journal Browse by Research Funder Name Browse by Colleges/Schools Open Access ORCID My Publications Login Carbohydrate antigen 125 in HFrEF and the effect of dapagliflozin: findings from DAPA-HF Docherty, KF et al. (2023) Carbohydrate antigen 125 in HFrEF and the effect of dapagliflozin: findings from DAPA-HF. Journal of the American College of Cardiology, (Accepted for Publication) [img] Text 297832.pdf - Accepted Version Restricted to …

Aim Patients with heart failure (HF) often suffer from a range of comorbidities, which may affect their health status. The aim of this study was to assess the impact of different comorbidities on health status in patients with HF and reduced (HFrEF) and preserved ejection fraction (HFpEF). Methods and results Using individual patient data from HFrEF (ATMOSPHERE, PARADIGM‐HF, DAPA‐HF) and HFpEF (TOPCAT, PARAGON‐HF) trials, we examined the Kansas City Cardiomyopathy Questionnaire (KCCQ) domain scores and overall summary score (KCCQ‐OSS) across a range of cardiorespiratory (angina, atrial fibrillation [AF], stroke, chronic obstructive pulmonary disease [COPD]) and other comorbidities (obesity, diabetes, chronic kidney disease [CKD], anaemia). Of patients with HFrEF (n = 20 159), 36.2% had AF, 33.9% CKD, 33.9% diabetes, 31.4% obesity, 25.5% angina, 12.2% COPD, 8.4% stroke, and 4.4 …

Aim Chronic obstructive pulmonary disease (COPD) is common in heart failure with a mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and is associated with worse outcomes. In a pre‐specified analysis of DELIVER, we investigated the relationship between COPD status and outcomes, and the efficacy and safety of dapagliflozin, compared with placebo, according to COPD status. Methods and results Patients with severe pulmonary disease (including COPD) were excluded from the trial. The primary outcome was a composite of cardiovascular death or worsening heart failure. Of the 6261 patients with data on baseline COPD status, 694 (11.1%) had a known history of this condition. The risk of the primary endpoint was higher in patients with mild‐to‐moderate COPD compared with those without COPD (adjusted hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.08–1.51). The benefit of …

BackgroundMechanistically, sacubitril/valsartan may potentiate natriuretic responses early after initiation. Expert consensus documents suggest consideration of diuretic dose reduction on sacubitril/valsartan initiation. Yet, limited data exist on the effects of sacubitril/valsartan on the background of varying diuretic regimens or on diuretic requirements over time.ObjectivesTo assess 1) safety/efficacy of sacubitril/valsartan vs. valsartan according to baseline diuretic use and 2) the effects of sacubitril/valsartan vs. valsartan on post-baseline patterns of diuretic use.MethodsThis was a post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction). We evaluated the treatment effect of sacubitril/valsartan on the primary composite outcome (total HF hospitalizations and CV death) and total HF hospitalizations alone using semiparametric proportional …

Background The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial assessed dapagliflozin versus placebo, in addition to standard therapy, in patients with chronic kidney disease (CKD) and albuminuria, and was terminated prematurely due to overwhelming efficacy. The study objective was to model the long-term clinical outcomes of DAPA-CKD beyond the trial follow-up. Methods A Markov model extrapolated event incidence per 1000 patients and CKD progression rates for patients receiving dapagliflozin or placebo over a 10-year time horizon. We derived treatment-specific CKD stage transition matrices using DAPA-CKD trial data. We extrapolated relevant efficacy endpoints using parametric survival equations for all-cause mortality and generalized estimating equations for recurrent events. Results When …

AimsWe conducted a meta-analysis of randomised controlled trials (RCTs) of implantable haemodynamic monitoring (IHM)-guided care.MethodsPubMed and Ovid MEDLINE were searched for RCTs of IHM in patients with heart failure (HF). Outcomes were examined in total (first and recurrent) event analyses.ResultsFive trials comparing IHM-guided care with standard care alone were identified and included 2710 patients across ejection fraction (EF) ranges. Data were available for 628 patients (23.2%) with heart failure with preserved ejection fraction (HFpEF) (EF ≥50%) and 2023 patients (74.6%) with heart failure with a reduced ejection fraction (HFrEF) (EF <50%). Chronicle, CardioMEMS and HeartPOD IHMs were used. In all patients, regardless of EF, IHM-guided care reduced total HF hospitalisations (HR 0.74, 95% CI 0.66 to 0.82) and total worsening HF events (HR 0.74, 95% CI 0.66 to 0.84). In patients …

Aim COVID‐19 may affect clinical risk in patients with heart failure. DELIVER began before and was conducted during the COVID‐19 pandemic. This study aimed to evaluate the association between COVID‐19 and clinical outcomes among DELIVER participants. Methods and results Participants with chronic heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) were randomized to dapagliflozin or placebo across 350 sites in 20 countries. COVID‐19 was investigator‐reported and the contribution of COVID‐19 to death was centrally adjudicated. We assessed (i) the incidence of COVID‐19, (ii) event rates before/during the pandemic, and (iii) risks of death after COVID‐19 diagnosis compared to risks of death in participants without COVID‐19. Further, we performed a sensitivity analysis assessing treatment effects of dapagliflozin vs. placebo censored at pandemic onset. Of 6263 …

ImportanceIn the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, dapagliflozin reduced the risk of time to first worsening heart failure (HF) event or cardiovascular death in patients with HF with mildly reduced or preserved ejection fraction (EF).ObjectiveTo evaluate the effect of dapagliflozin on total (ie, first and recurrent) HF events and cardiovascular death in this population.Design, Setting, and ParticipantsIn this prespecified analysis of the DELIVER trial, the proportional rates approach of Lin, Wei, Yang, and Ying (LWYY) and a joint frailty model were used to examine the effect of dapagliflozin on total HF events and cardiovascular death. Several subgroups were examined to test for heterogeneity in the effect of dapagliflozin, including left ventricular EF. Participants were enrolled from August 2018 to December 2020, and data were analyzed …

BACKGROUND Guideline‐recommended therapies that improve prognosis remain underused in clinical practice. Physical frailty may lead to underprescription of life‐saving therapy. We aimed to investigate the association between physical frailty and the use of evidence‐based pharmacological therapy for heart failure with reduced ejection fraction and the impact of this on prognosis. METHODS AND RESULTS The FLAGSHIP (Multicentre Prospective Cohort Study to Develop Frailty‐Based Prognostic Criteria for Heart Failure Patients) included patients hospitalized for acute heart failure, and data on physical frailty were collected prospectively. We analyzed 1041 patients with heart failure with reduced ejection fraction (aged 70 years; 73% male) and divided them by physical frailty categories using grip strength, walking speed, Self‐Efficacy for Walking–7 score, and Performance Measures for Activities of Daily …

Background 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. Objectives 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. Methods 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 …

BACKGROUND The rate of stroke in patients with heart failure (HF) and preserved ejection fraction but without atrial fibrillation (AF), is uncertain as is whether it is possible to reliably predict the risk of stroke in these patients. METHODS We validated a previously developed simple risk model for stroke among patients enrolled in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Systolic Function) and PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The risk model consisted of 3 variables: history of previous stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level. RESULTS Of the 8924 patients included in the pooled trial dataset, 5126 patients did not have AF at baseline. Among patients without AF, 190 (3.7%) experienced a stroke over a median follow …