Publications by authors named "Brian L Claggett"

85 Publications

Treatment Effects of Sacubitril/Valsartan Compared With Valsartan by Ejection Fraction in Patients With Recent Hospitalization.

J Card Fail 2021 Jun 13. Epub 2021 Jun 13.

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.cardfail.2021.05.020DOI Listing
June 2021

Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial.

Eur J Heart Fail 2021 Jun 7. Epub 2021 Jun 7.

Division of Cardiology, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Sacubitril/valsartan improves morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Whether initiation of sacubitril/valsartan limits the use and dosing of other elements of guideline-directed medical therapy for HFrEF is unknown. We examined the effects of sacubitril/valsartan, compared with enalapril, on β-blocker and mineralocorticoid receptor antagonist (MRA) use and dosing in a large randomized clinical trial.

Methods And Results: Patients with full data on medication use were included. We examined β-blocker and MRA use in patients randomized to sacubitril/valsartan vs. enalapril through 12-month follow-up. New initiations and discontinuations of β-blocker and MRA were compared between treatment groups. Overall, 8398 (99.9%) had full medication and dose data at baseline. Baseline use of β-blocker and MRA at any dose was 87% and 56%, respectively. Mean doses of β-blocker and MRA were similar between treatment groups at baseline and at 6-month and 12-month follow-up. New initiations through 12-month follow-up were infrequent and similar in the sacubitril/valsartan and enalapril groups for β-blockers [37 (9.0%) vs. 42 (10.2%), P = 0.56] and MRA [127 (7.6%) vs. 143 (9.2%), P = 0.10]. Among patients on MRA therapy at baseline, there were fewer MRA discontinuations in patients on sacubitril/valsartan as compared with enalapril at 12 months [125 (6.2%) vs. 187 (9.0%), P = 0.001]. Discontinuations of β-blockers were not significantly different between groups in follow-up (2.2% vs. 2.6%, P = 0.26).

Conclusions: Initiation of sacubitril/valsartan, even when titrated to target dose, did not appear to lead to greater discontinuation or dose down-titration of other key guideline-directed medical therapies, and was associated with fewer discontinuations of MRA. Use of sacubitril/valsartan (when compared with enalapril) may promote sustained MRA use in follow-up.
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http://dx.doi.org/10.1002/ejhf.2259DOI Listing
June 2021

Development and external validation of prognostic models to predict sudden and pump-failure death in patients with HFrEF from PARADIGM-HF and ATMOSPHERE.

Clin Res Cardiol 2021 Aug 8;110(8):1334-1349. Epub 2021 Jun 8.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.

Background: Sudden death (SD) and pump failure death (PFD) are the two leading causes of death in patients with heart failure and reduced ejection fraction (HFrEF).

Objective: Identifying patients at higher risk for mode-specific death would allow better targeting of individual patients for relevant device and other therapies.

Methods: We developed models in 7156 patients with HFrEF from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, using Fine-Gray regressions counting other deaths as competing risks. The derived models were externally validated in the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) trial.

Results: NYHA class and NT-proBNP were independent predictors for both modes of death. The SD model additionally included male sex, Asian or Black race, prior CABG or PCI, cancer history, MI history, treatment with LCZ696 vs. enalapril, QRS duration and ECG left ventricular hypertrophy. While LVEF, ischemic etiology, systolic blood pressure, HF duration, ECG bundle branch block, and serum albumin, chloride and creatinine were included in the PFD model. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.67 and 0.78 after correction for optimism, respectively. The observed and predicted incidences were similar in each quartile of risk scores at 3 years in each model. The performance of both models remained robust in ATMOSPHERE.

Conclusion: We developed and validated models which separately predict SD and PFD in patients with HFrEF. These models may help clinicians and patients consider therapies targeted at these modes of death.

Trial Registration Number: PARADIGM-HF: ClinicalTrials.gov NCT01035255, ATMOSPHERE: ClinicalTrials.gov NCT00853658.
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http://dx.doi.org/10.1007/s00392-021-01888-xDOI Listing
August 2021

Accuracy of ICD-10 Diagnostic Codes to Identify COVID-19 Among Hospitalized Patients.

J Gen Intern Med 2021 Jun 7. Epub 2021 Jun 7.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Heart & Vascular Center and Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.

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http://dx.doi.org/10.1007/s11606-021-06936-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183587PMC
June 2021

Recommendations for Statistical Reporting in Cardiovascular Medicine: A Special Report From the American Heart Association.

Circulation 2021 Jul 25;144(4):e70-e91. Epub 2021 May 25.

Department of Cardiovascular Diseases Medicine, Mayo Clinic College of Medicine, Rochester, MN (V.L.R.).

Statistical analyses are a crucial component of the biomedical research process and are necessary to draw inferences from biomedical research data. The application of sound statistical methodology is a prerequisite for publication in the American Heart Association (AHA) journal portfolio. The objective of this document is to summarize key aspects of statistical reporting that might be most relevant to the authors, reviewers, and readership of AHA journals. The AHA Scientific Publication Committee convened a task force to inventory existing statistical standards for publication in biomedical journals and to identify approaches suitable for the AHA journal portfolio. The experts on the task force were selected by the AHA Scientific Publication Committee, who identified 12 key topics that serve as the section headers for this document. For each topic, the members of the writing group identified relevant references and evaluated them as a resource to make the standards summarized herein. Each section was independently reviewed by an expert reviewer who was not part of the task force. Expert reviewers were also permitted to comment on other sections if they chose. Differences of opinion were adjudicated by consensus. The standards presented in this report are intended to serve as a guide for high-quality reporting of statistical analyses methods and results.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055393DOI Listing
July 2021

Effect of Ejection Fraction on Clinical Outcomes in Patients Treated With Omecamtiv Mecarbil in GALACTIC-HF.

J Am Coll Cardiol 2021 Jul 17;78(2):97-108. Epub 2021 May 17.

Cytokinetics, Inc., South San Francisco, California, USA.

Background: In GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) (n = 8,256), the cardiac myosin activator, omecamtiv mecarbil, significantly reduced the primary composite endpoint (PCE) of time-to-first heart failure event or cardiovascular death in patients with heart failure and reduced ejection fraction (EF) (≤35%).

Objectives: The purpose of this study was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil.

Methods: Outcomes in patients treated with omecamtiv mecarbil were compared with placebo according to EF.

Results: The risk of the PCE in the placebo group was nearly 1.8-fold greater in the lowest EF (≤22%) compared with the highest EF (≥33%) quartile. Amongst the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the PCE (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased, with a 17% relative risk reduction for the PCE in patients with baseline EF ≤22% (n = 2,246; hazard ratio: 0.83; 95% confidence interval: 0.73 to 0.95) compared with patients with EF ≥33% (n = 1,750; hazard ratio: 0.99; 95% confidence interval: 0.84 to 1.16; interaction as EF by quartiles, p = 0.013). The absolute reduction in the PCE increased with decreasing EF (EF ≤22%; absolute risk reduction, 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared with no reduction in the highest EF quartile.

Conclusions: In heart failure patients with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug's mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).
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http://dx.doi.org/10.1016/j.jacc.2021.04.065DOI Listing
July 2021

Prognostic Value of Natriuretic Peptides and Cardiac Troponins in COVID-19.

Circulation 2021 07 17;144(2):177-179. Epub 2021 May 17.

Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (J.W.C., B.L.C., K.S.J., M.V., A.S.B., S.D.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270227PMC
July 2021

Effects of Sacubitril/Valsartan on Serum Lipids in Heart Failure with Preserved Ejection Fraction.

J Am Heart Assoc 2021 May 16:e022069. Epub 2021 May 16.

Division of Cardiology Department of Medicine Brigham and Women's Hospital Boston MA.

Background Dyslipidemia is common in heart failure with preserved ejection fraction (HFpEF). Sacubitril/valsartan improves insulin sensitivity and augments natriuretic peptide (NP) signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4,744 participants from PARAGON-HF with available screening lipids. During follow-up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16-week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate (cGMP)/creatinine [a biomarker of NP activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides -5.0% (-6.6%, -3.5%), increased high-density lipoprotein cholesterol (HDL-c) +2.6% (+1.7%, +3.4%), and increased low-density lipoprotein cholesterol (LDL-c) +1.7% (+0.4%, +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (p-interaction<0.001), and at 16-weeks by -13.0% (-18.1%, -7.6%), or -29.9 (-44.3, -15.5) mg/dL, in this group. Adjusting for the change in urinary cGMP/creatinine significantly attenuated treatment effects on triglycerides and HDL-c, but not LDL-c, while adjusting for other biomarkers did not significantly alter the treatment effects. Conclusions Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was substantially stronger in those with elevated baseline triglycerides. Modest increases in HDL-c and LDL-c cholesterol were also observed with therapy. The underlying mechanism(s) of changes in HDL-c and triglycerides are related to sacubitril/valsartan's effects on NP activity.
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http://dx.doi.org/10.1161/JAHA.121.022069DOI Listing
May 2021

Specific Electrocardiograph Intervals Predict Hospitalization with Atrial Fibrillation in Those with Chronic Kidney Disease.

Am J Nephrol 2021 5;52(5):412-419. Epub 2021 May 5.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

Introduction: Atrial fibrillation (AF) is common in patients with chronic kidney disease (CKD) and is associated with higher rates of hospitalization compared to those without AF. Whether routine electrocardiographic parameters are predictive of future hospitalizations with AF is not clear.

Methods: The present study is an analysis of a prospective cohort of 2,759 patients without baseline AF from the Chronic Renal Insufficiency Cohort, a large prospective multicenter study of patients with nondialysis-dependent CKD. Unadjusted and adjusted Cox regression models were fit to examine the association of baseline categories of QTc, QRS, and PR intervals with time to first hospitalization with AF. Restricted cubic splines were used to display nonlinear associ-ations.

Results: The mean age of subjects at baseline was 58 ± 11 years, 55% were male, and 44% were Black. The mean follow-up was 6.6 years during which 224 participants experienced a hospitalization with AF. The association of baseline QTc interval with risk of AF hospitalization was nonlinear, such that the lowest and highest quartiles of QTc (<407 and >431 ms, respectively) had higher adjusted risk of AF hospitalization, compared with the second quartile (407-416 ms) (aHR Q1:Q2 1.58, 95% CI 1.03-2.41; p = 0.03; aHR Q4:Q2 1.84, 95% CI 1.22-2.78; p < 0.01). Longer QRS was associated with a higher risk of hospitalization with AF among the subgroup of patients with a history of heart failure (HF). PR interval was not associated with AF hospitalization.

Discussion/conclusion: The association of QTc with risk for hospitalization with AF among patients with CKD is nonlinear, while the association of longer QRS with AF hospitalization is restricted to patients with baseline HF. Electrocardiography may represent a simple and widely accessible method for risk stratification of future AF in patients with CKD.
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http://dx.doi.org/10.1159/000515670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263478PMC
May 2021

NT-proBNP versus routine clinical risk factors as a predictor of cardiovascular events or death in people with dysglycemia - A brief report from the ORIGIN trial.

J Diabetes Complications 2021 Jul 16;35(7):107928. Epub 2021 Apr 16.

The Population Health Research Institute and the Department of Medicine, McMaster University and Hamilton Health Sciences, Hamilton, Canada.

In patients with diabetes and cardiovascular or renal comorbidities, circulating levels of the N-terminal fragment of prohormone B-type natriuretic peptide (NT-proBNP) have similar discriminatory ability as multivariate models for prediction of cardiovascular events or death. We validated this finding in patients with dysglycemia not selected for co-existing cardiorenal diseases.
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http://dx.doi.org/10.1016/j.jdiacomp.2021.107928DOI Listing
July 2021

Global Differences in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

Circ Heart Fail 2021 Apr 19;14(4):e007901. Epub 2021 Apr 19.

National Heart Centre Singapore (J.T., C.S.P.L.).

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial.

Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region.

Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction >0.05).

Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007901DOI Listing
April 2021

Worsening Heart Failure Episodes Outside a Hospital Setting in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial.

JACC Heart Fail 2021 May 7;9(5):374-382. Epub 2021 Apr 7.

Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objectives: This study sought to evaluate the frequency and prognostic implications of urgent heart failure (HF) visits in a large global clinical trial of HF with preserved ejection fraction (HFpEF).

Background: Episodes of worsening HF managed without hospitalization are common and prognostically important in HF with reduced ejection fraction (EF). The significance of these ambulatory worsening HF events in HFpEF is uncertain.

Methods: PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) randomly assigned 4,796 patients with HFpEF (≥45%) to treatment with sacubitril/valsartan vs. valsartan with a primary composite endpoint of total HF hospitalizations and cardiovascular death. Urgent ambulatory HF visits requiring intravenous diuretic treatment were prospectively collected and adjudicated by a blinded committee. We examined the effect of study treatment on a prespecified expanded composite of cardiovascular death and worsening HF events (including HF hospitalizations and urgent HF visits) and the effect of each type of HF event on subsequent mortality.

Results: Of 884 first worsening HF events, 66 (7.5%) were urgent HF visits. Patients whose first episode of worsening HF event was an urgent visit had similar age, comorbidities, baseline N-terminal prohormone of B-type natriuretic peptide, and Meta-Analysis Global Group in Chronic Heart Failure risk scores to those in whom the first HF event was a hospitalization (all comparisons p > 0.05). Regardless of the treatment setting, patients with a first episode of worsening HF had higher rates of subsequent death (19.2 per 100 patient-years; 95% confidence interval [CI]: 16.9 to 21.8 for HF hospitalization and 10.1 per 100 patients-years; 95% CI: 5.4 to 18.7 for urgent HF visit) compared with those who did not experience worsening HF (death rate 4.0 per 100 patient-years; 95% CI: 3.6 to 4.4). Including total urgent HF visits in the composite study endpoint added 95 total events and would have shortened the trial duration needed for event accrual. The addition of urgent HF visits in a prespecified composite endpoint reinforced the treatment efficacy of sacubitril/valsartan compared with valsartan (rate ratio 0.86; 95% CI: 0.75 to 0.99; p = 0.040).

Conclusions: Like HF hospitalizations, worsening HF events treated in the ambulatory setting are prognostically important in HFpEF. Inclusion of these events in the composite primary endpoint underscores the benefit of sacubitril/valsartan compared with valsartan in PARAGON-HF. (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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http://dx.doi.org/10.1016/j.jchf.2021.01.014DOI Listing
May 2021

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

Circ Heart Fail 2021 03 12;14(3):e008052. Epub 2021 Mar 12.

Division of Cardiovascular, Brigham and Women's Hospital, Boston, MA (L.E.R., B.L.C., M.A.P., A.S.D., S.D.S.).

Background: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction.

Methods: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality.

Results: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], <0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], <0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction <0.05 for both outcomes).

Conclusions: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.008052DOI Listing
March 2021

Hemodynamic Effects of Sacubitril-Valsartan Versus Enalapril in Patients With Heart Failure in the EVALUATE-HF Study: Effect Modification by Left Ventricular Ejection Fraction and Sex.

Circ Heart Fail 2021 03 5;14(3):e007891. Epub 2021 Mar 5.

Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (S.D.S., A.M.S., B.L.C., A.S.D.).

Background: Treatment with sacubitril-valsartan reduces mortality and heart failure (HF) events in HF with reduced ejection fraction and may reduce HF hospitalization in women with HF with preserved ejection fraction.

Methods: EVALUATE-HF randomized 464 participants (109 women) with HF with reduced ejection fraction to sacubitril-valsartan or enalapril for 12 weeks. Documented left ventricular ejection fraction (LVEF) ≤0.40 within the prior 12 months was required, although core laboratory LVEF>0.40 was permitted. Assessments of aortic stiffness (pulse pressure and characteristic impedance, Z) were performed at baseline and at trough and 4 hours postdose at weeks 4 and 12.

Results: In models of change from baseline adjusted for baseline value, treatment with sacubitril-valsartan produced greater overall reductions in mean arterial pressure (treatment group difference, -3.0±0.8 mm Hg, <0.001) and pulse pressure (-3.0±0.8 mm Hg, <0.001). Postdose reductions in Z were greater in the sacubitril-valsartan group (-16±6 dyne×second/cm, =0.012). Post hoc analyses found evidence of effect modification by LVEF (interaction =0.036). With LVEF<0.40, postdose reductions in Z were greater in the sacubitril-valsartan group (trough, -3±8 dyne×second/cm versus post-dose, -17±8 dyne×second/cm; interaction =0.024) with no sex difference (treatment×sex interaction, =0.3). With LVEF≥0.40, treatment with sacubitril-valsartan was associated with greater overall reductions in Z in women (women, -80±21 dyne×second/cm versus men, -20±13 dyne×second/cm; interaction =0.019).

Conclusions: In prespecified analyses that include pre- and postdose assessments at 4 and 12 weeks, treatment with sacubitril-valsartan was associated with greater postdose reductions in aortic Z. In a post hoc analysis, sacubitril-valsartan was associated with sustained reductions in Z in women with LVEF≥0.40. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02874794.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007891DOI Listing
March 2021

Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial.

Eur J Heart Fail 2021 05 8;23(5):776-784. Epub 2021 Mar 8.

British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan.

Methods And Results: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up.

Conclusions: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.
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http://dx.doi.org/10.1002/ejhf.2134DOI Listing
May 2021

Dynamic changes in cardiovascular and systemic parameters prior to sudden cardiac death in heart failure with reduced ejection fraction: a PARADIGM-HF analysis.

Eur J Heart Fail 2021 Feb 9. Epub 2021 Feb 9.

Division of Cardiovascular, Brigham and Women's Hospital, Boston, MA, USA.

Aims: Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment.

Methods And Results: We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (P  < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05).

Conclusions: Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.
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http://dx.doi.org/10.1002/ejhf.2120DOI Listing
February 2021

Impact of diabetes on serum biomarkers in heart failure with preserved ejection fraction: insights from the TOPCAT trial.

ESC Heart Fail 2021 04 12;8(2):1130-1138. Epub 2021 Jan 12.

Division of Cardiology, Montreal Heart Institute and Université de Montréal, 5000 rue Bélanger, Montreal, QC, H1T 1C8, Canada.

Aims: Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non-diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non-DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature.

Methods And Results: Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high-sensitivity C-reactive protein, pro-collagen type III amino-terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP-1), and galectin-3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high-sensitivity troponin T (hs-TnT), a marker of myocyte death, in DM patients. Elevated pro-collagen type III amino-terminal peptide and galectin-3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs-TnT and for TIMP-1, with greater biomarker reductions among those with diabetes treated with spironolactone.

Conclusions: The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti-fibrotic fashion in patients with diabetes, reflected by changes in hs-TnT and TIMP-1 levels over time.
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http://dx.doi.org/10.1002/ehf2.13153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006665PMC
April 2021

Clinical Outcomes in Patients With Heart Failure Hospitalized With COVID-19.

JACC Heart Fail 2021 01;9(1):65-73

Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Objectives: The purpose of this study was to evaluate in-hospital outcomes among patients with a history of heart failure (HF) hospitalized with coronavirus disease-2019 (COVID-19).

Background: Cardiometabolic comorbidities are common in patients with severe COVID-19. Patients with HF may be particularly susceptible to COVID-19 complications.

Methods: The Premier Healthcare Database was used to identify patients with at least 1 HF hospitalization or 2 HF outpatient visits between January 1, 2019, and March 31, 2020, who were subsequently hospitalized between April and September 2020. Baseline characteristics, health care resource utilization, and mortality rates were compared between those hospitalized with COVID-19 and those hospitalized with other causes. Predictors of in-hospital mortality were identified in HF patients hospitalized with COVID-19 by using multivariate logistic regression.

Results: Among 1,212,153 patients with history of HF, 132,312 patients were hospitalized from April 1, 2020, to September 30, 2020. A total of 23,843 patients (18.0%) were hospitalized with acute HF, 8,383 patients (6.4%) were hospitalized with COVID-19, and 100,068 patients (75.6%) were hospitalized with alternative reasons. Hospitalization with COVID-19 was associated with greater odds of in-hospital mortality as compared with hospitalization with acute HF; 24.2% of patients hospitalized with COVID-19 died in-hospital compared to 2.6% of those hospitalized with acute HF. This association was strongest in April (adjusted odds ratio [OR]: 14.48; 95% confidence interval [CI]:12.25 to 17.12) than in subsequent months (adjusted OR: 10.11; 95% CI: 8.95 to 11.42; p <0.001). Among patients with HF hospitalized with COVID-19, male sex (adjusted OR: 1.26; 95% CI: 1.13 to 1.40) and morbid obesity (adjusted OR: 1.25; 95% CI: 1.07 to 1.46) were associated with greater odds of in-hospital mortality, along with age (adjusted OR: 1.35; 95% CI: 1.29 to 1.42 per 10 years) and admission earlier in the pandemic.

Conclusions: Patients with HF hospitalized with COVID-19 are at high risk for complications, with nearly 1 in 4 dying during hospitalization.
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http://dx.doi.org/10.1016/j.jchf.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833294PMC
January 2021

Improvement of Health Status Following Initiation of Sacubitril/Valsartan in Heart Failure and Reduced Ejection Fraction.

JACC Heart Fail 2021 01 11;9(1):42-51. Epub 2020 Nov 11.

Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA; Baim Institute for Clinical Research, Boston, Massachusetts, USA. Electronic address:

Background: Treatment of heart failure with reduced ejection fraction (EF) may improve patient-reported health outcomes.

Objectives: The purpose of this study was to determine timing and magnitude of change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores following initiation of sacubitril/valsartan and interaction with change in amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations.

Methods: From a single-arm, open-label study of patients initiated on sacubitril/valsartan, KCCQ-23 scores and NT-proBNP were obtained at baseline and follow-up through 12 months. Cross-sectional and longitudinal analyses evaluated magnitude and rate of change in KCCQ-23 scores and associations with NT-proBNP. Patient-level data from the randomized EVALUATE-HF study were used as historic controls.

Results: The analysis cohort (n = 678, age 64.7 years, 71.5% men, EF 28.9%) had a baseline KCCQ-23 overall score (OS) of 65.6. Following sacubitril/valsartan initiation, the majority (n = 412; 60.8%) of participants experienced a rise in KCCQ-23 OS ≥10 points; 26.0% increased by ≥20 points. Comparable improvement in KCCQ-23 scores was seen in various subgroups. Change in KCCQ-23 OS was inversely associated with change in circulating NT-proBNP concentrations. Among a control group of patients in EVALUATE-HF, linear rate of change in KCCQ-12 OS/14-day interval in the enalapril arm was 0.37 points (p = 0.06), whereas in the sacubitril/valsartan arm, scores increased at a rate of 1.19 points (p < 0.001), nearly identical to this dataset (1.08 points; p < 0.001).

Conclusions: Treatment of heart failure with reduced EF with sacubitril/valsartan is associated with rapid and significant improvement in KCCQ-23 scores which was significantly related to change in NT-proBNP. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).
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http://dx.doi.org/10.1016/j.jchf.2020.09.012DOI Listing
January 2021

Estimating the Lifetime Benefits of Treatments for Heart Failure.

JACC Heart Fail 2020 12 7;8(12):984-995. Epub 2020 Oct 7.

BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. Electronic address:

Objectives: This study compared ways of describing treatment effects. The objective was to better explain to clinicians and patients what they might expect from a given treatment, not only in terms of relative and absolute risk reduction, but also in projections of long-term survival.

Background: The restricted mean survival time (RMST) can be used to estimate of long-term survival, providing a complementary approach to more conventional metrics (e.g., absolute and relative risk), which may suggest greater benefits of therapy in high-risk patients compared with low-risk patients.

Methods: Relative and absolute risk, as well as the RMST, were calculated in heart failure with reduced ejection fraction (HFrEF) trials.

Results: As examples, in the RALES trial (more severe HFrEF), the treatment effect metrics for spironolactone versus placebo on heart failure hospitalization and/or cardiovascular death were a hazard ratio (HR) of 0.67 (95% confidence interval [CI]: 0.5 to 0.77), number needed to treat = 9 (7 to 14), and age extension of event-free survival +1.1 years (-0.1 to + 2.3 years). The corresponding metrics for EMPHASIS-HF (eplerenone vs. placebo in less severe HFrEF) were 0.64 (0.54 to 0.75), 14 (1 to 22), and +2.9 (1.2 to 4.5). In patients in PARADIGM-HF aged younger than 65 years, the metrics for sacubitril/valsartan versus enalapril were 0.77 (95% CI: 0.68 to 0.88), 23 (15 to 44), and +1.7 (0.6 to 2.8) years; for those aged 65 years or older, the metrics were 0.83 (95% CI: 0.73 to 0.94), 29 (17 to 83), and +0.9 (0.2 to 1.6) years, which provided evidence of a greater potential life extension in younger patients. Similar observations were found for lower risk patients.

Conclusions: RMST event-free (and overall) survival estimates provided a complementary means of evaluating the effect of therapy in relation to age and risk. They also provided a clinically useful metric that should be routinely reported and used to explain the potential long-term benefits of a given treatment, especially to younger and less symptomatic patients.
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http://dx.doi.org/10.1016/j.jchf.2020.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720789PMC
December 2020

NT-proBNP by Itself Predicts Death and Cardiovascular Events in High-Risk Patients With Type 2 Diabetes Mellitus.

J Am Heart Assoc 2020 10 23;9(19):e017462. Epub 2020 Sep 23.

Cardiovascular Division Brigham & Women's Hospital Harvard Medical School Boston MA.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) improves the discriminatory ability of risk-prediction models in type 2 diabetes mellitus (T2DM) but is not yet used in clinical practice. We assessed the discriminatory strength of NT-proBNP by itself for death and cardiovascular events in high-risk patients with T2DM. Methods and Results Cox proportional hazards were used to create a base model formed by 20 variables. The discriminatory ability of the base model was compared with that of NT-proBNP alone and with NT-proBNP added, using C-statistics. We studied 5509 patients (with complete data) of 8561 patients with T2DM and cardiovascular and/or chronic kidney disease who were enrolled in the ALTITUDE (Aliskiren in Type 2 Diabetes Using Cardiorenal Endpoints) trial. During a median 2.6-year follow-up period, 469 patients died and 768 had a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, stroke, or heart failure hospitalization). NT-proBNP alone was as discriminatory as the base model for predicting death (C-statistic, 0.745 versus 0.744, =0.95) and the cardiovascular composite outcome (C-statistic, 0.723 versus 0.731, =0.37). When NT-proBNP was added, it increased the predictive ability of the base model for death (C-statistic, 0.779 versus 0.744, <0.001) and for cardiovascular composite outcome (C-statistic, 0.763 versus 0.731, <0.001). Conclusions In high-risk patients with T2DM, NT-proBNP by itself demonstrated discriminatory ability similar to a multivariable model in predicting both death and cardiovascular events and should be considered for risk stratification. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00549757.
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http://dx.doi.org/10.1161/JAHA.120.017462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792415PMC
October 2020

Serum uric acid, influence of sacubitril-valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF.

Eur J Heart Fail 2020 11 30;22(11):2093-2101. Epub 2020 Sep 30.

Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Aims: This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril-valsartan reduces SUA and use of SUA-related therapies.

Methods And Results: We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37-1.90]. The treatment effect of sacubitril-valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P-value for interaction = 0.14). Sacubitril-valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31-0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 mg/dL vs. -0.32 mg/dL) (P-value for interaction = 0.031). Sacubitril-valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (P < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity troponin T (P < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA.

Conclusions: Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril-valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.
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http://dx.doi.org/10.1002/ejhf.1984DOI Listing
November 2020

Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF.

J Am Coll Cardiol 2020 08;76(5):503-514

Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina; Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina. Electronic address:

Background: Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.

Objectives: This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).

Methods: N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.

Results: At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.

Conclusions: Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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http://dx.doi.org/10.1016/j.jacc.2020.05.072DOI Listing
August 2020

Pre-existing traits associated with Covid-19 illness severity.

PLoS One 2020 23;15(7):e0236240. Epub 2020 Jul 23.

Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.

Importance: Certain individuals, when infected by SARS-CoV-2, tend to develop the more severe forms of Covid-19 illness for reasons that remain unclear.

Objective: To determine the demographic and clinical characteristics associated with increased severity of Covid-19 infection.

Design: Retrospective observational study. We curated data from the electronic health record, and used multivariable logistic regression to examine the association of pre-existing traits with a Covid-19 illness severity defined by level of required care: need for hospital admission, need for intensive care, and need for intubation.

Setting: A large, multihospital healthcare system in Southern California.

Participants: All patients with confirmed Covid-19 infection (N = 442).

Results: Of all patients studied, 48% required hospitalization, 17% required intensive care, and 12% required intubation. In multivariable-adjusted analyses, patients requiring a higher levels of care were more likely to be older (OR 1.5 per 10 years, P<0.001), male (OR 2.0, P = 0.001), African American (OR 2.1, P = 0.011), obese (OR 2.0, P = 0.021), with diabetes mellitus (OR 1.8, P = 0.037), and with a higher comorbidity index (OR 1.8 per SD, P<0.001). Several clinical associations were more pronounced in younger compared to older patients (Pinteraction<0.05). Of all hospitalized patients, males required higher levels of care (OR 2.5, P = 0.003) irrespective of age, race, or morbidity profile.

Conclusions And Relevance: In our healthcare system, greater Covid-19 illness severity is seen in patients who are older, male, African American, obese, with diabetes, and with greater overall comorbidity burden. Certain comorbidities paradoxically augment risk to a greater extent in younger patients. In hospitalized patients, male sex is the main determinant of needing more intensive care. Further investigation is needed to understand the mechanisms underlying these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236240PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377468PMC
August 2020

Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan: The DAPA-HF Trial.

JACC Heart Fail 2020 10 8;8(10):811-818. Epub 2020 Jul 8.

BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland.

Objectives: This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in 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) trial.

Background: Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown.

Methods: DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group.

Results: A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan.

Conclusions: Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124).
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http://dx.doi.org/10.1016/j.jchf.2020.04.008DOI Listing
October 2020
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