Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Nov 28;148(22):1735-1745.
doi: 10.1161/CIRCULATIONAHA.123.066506. Epub 2023 Aug 26.

Outpatient Worsening Among Patients With Mildly Reduced and Preserved Ejection Fraction Heart Failure in the DELIVER Trial

Safia Chatur #  1 , Muthiah Vaduganathan #  1 , Brian L Claggett  1 , Jonathan W Cunningham  1 , Kieran F Docherty  2 , Akshay S Desai  1 , Pardeep S Jhund  2 , Rudolf A de Boer  3 , Adrian F Hernandez  4 , Silvio E Inzucchi  5 , Mikhail N Kosiborod  6 , Carolyn S P Lam  7 , Felipe A Martinez  8 , Sanjiv J Shah  9 , Magnus Petersson  10 , Anna Maria Langkilde, John J V McMurray  2 , Scott D Solomon  1
Affiliations

Outpatient Worsening Among Patients With Mildly Reduced and Preserved Ejection Fraction Heart Failure in the DELIVER Trial

Safia Chatur et al. Circulation. .

Abstract

Background: Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing clinical decompensation are ultimately hospitalized. Outpatient intensification of diuretics is common in response to symptoms of worsening HF, yet its prognostic and clinical relevance, specifically for patients with HF with mildly reduced or preserved ejection fraction, is uncertain.

Methods: In this prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we assessed the association between various nonfatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. We further examined the treatment effect of dapagliflozin on an expanded composite end point of cardiovascular death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification.

Results: In DELIVER, 4532 (72%) patients experienced no worsening HF event, whereas 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had an HF hospitalization, and 271 (4%) died of cardiovascular causes as a first presentation. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10 [8-12] per 100 patient-years) than those without a worsening HF event (4 [3-4] per 100 patient-years) but similar to rates of subsequent death after an urgent HF visit (10 [6-18] per 100 patient-years). Patients with an HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35 [31-40] per 100 patient-years). The addition of outpatient diuretic intensification to the adjudicated DELIVER primary end point (cardiovascular death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1122 to 1731 (a 54% increase). Dapagliflozin reduced the need for outpatient diuretic intensification alone (hazard ratio, 0.72 [95% CI, 0.64-0.82]) and when analyzed as a part of an expanded composite end point of worsening HF or cardiovascular death (hazard ratio, 0.76 [95% CI, 0.69-0.84]).

Conclusions: In patients with HF with mildly reduced or preserved ejection fraction, worsening HF requiring oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

Keywords: disease progression; heart failure; heart failure, diastolic; heart failure, systolic; hospitalization; sodium-glucose transporter 2 inhibitor.

PubMed Disclaimer

Conflict of interest statement

Disclosures Dr Chatur is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. Dr Vaduganathan has received research grant support, has served on advisory boards, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr Cunningham has been a consultant for Roche Diagnostics, Occlutech, and KCK. Dr Docherty reports receiving grant support from Novartis and lecture fees from Eli Lilly. Dr Desai has received research grant support from AstraZeneca, Alnylam, and Novartis; and has received consulting fees and honoraria from Abbott, AstraZeneca, Alnylam, Boehringer-Ingelheim, Boston Scientific, Biofourmis, Corvidia, DalCor Pharma, Novartis, Relypsa, and Regeneron. Dr Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis, advisory board fees from Cytokinetics, and grant support from Boehringer Ingelheim. Dr de Boer’s institution, the University Medical Centre Groningen, has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). Dr Hernandez has received research grant support from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Suib, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Lam is supported by a clinician scientist award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics, has served as a consultant or was on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and WebMD Global LLC; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim/Lilly, Novo Nordisk, Merck, Pfizer and Bayer; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Martinez has received personal fees from AstraZeneca. Dr Shah has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Solomon has received either personal or institutional research support for DELIVER from AstraZeneca. Drs Petersson and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received grants from, and his employer was paid by, AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study. His employer was paid by Novartis, Amgen, Bristol-Myers Squibb, Bayer, Abb-vie, Dal-Cor, Kidney Research UK, and Cardurion, and he received grants from the British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI, and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health.

Figures

Figure 1.
Figure 1.
Manifestations of first worsening HF events. Breakdown of first worsening HF events by type (A) and pathways of worsening heart failure after oral diuretic intensification (B) and urgent HF visit (C). *A total of 28 patients experienced an urgent HF visit after oral diuretic intensification. CV indicates cardiovascular; and HF, heart failure.
Figure 2.
Figure 2.
Prognosis after first nonfatal worsening HF event. A, Death after first worsening HF events. Time scale for patients with first worsening HF events (red, green, and blue lines) is time after worsening HF event, and time scale for patients without worsening HF event (black dotted line) is time from randomization. B, Death after a varying degree of loop diuretic dose escalation (from baseline) expressed as furosemide equivalent dose (mg). HF indicates heart failure; IQR, interquartile range; py, patient-years; and WHF, worsening heart failure.
Figure 3.
Figure 3.
KCCQ-TSS health status trajectories before and after first outpatient or inpatient worsening HF event. HF indicates heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; and TSS, Total Symptoms Score.
Figure 4.
Figure 4.
Treatment effect on the DELIVER primary composite outcome of cardiovascular death or worsening HF (HF hospitalization or urgent HF visit) and the extended composite outcome including oral diuretic intensification. CV indicates cardiovascular; HF, heart failure; and HR, hazard ratio.
See this image and copyright information in PMC

Comment in

References

    1. Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, et al. ; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387:1089–1098. doi: 10.1056/NEJMoa2206286 - PubMed
    1. Solomon SD, Dobson J, Pocock S, Skali H, McMurray JJ, Granger CB, Yusuf S, Swedberg K, Young JB, Michelson EL, et al. ; Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Investigators. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116:1482–1487. doi: 10.1161/CIRCULATIONAHA.107.696906 - PubMed
    1. Greene SJ, Bauersachs J, Brugts JJ, Ezekowitz JA, Lam CSP, Lund LH, Ponikowski P, Voors AA, Zannad F, Zieroth S, et al. . Worsening heart failure: nomenclature, epidemiology, and future directions: JACC review topic of the week. J Am Coll Cardiol. 2023;81:413–424. doi: 10.1016/j.jacc.2022.11.023 - PubMed
    1. Madelaire C, Gustafsson F, Stevenson LW, Kristensen SL, Køber L, Andersen J, D’Souza M, Biering-Sørensen T, Andersson C, Torp-Pedersen C, et al. . One-year mortality after intensification of outpatient diuretic therapy. J Am Heart Assoc. 2020;9:e016010. doi: 10.1161/JAHA.119.016010 - PMC - PubMed
    1. Docherty KF, Jhund PS, Anand I, Bengtsson O, Böhm M, de Boer RA, DeMets DL, Desai AS, Drozdz J, Howlett J, et al. . Effect of dapagliflozin on outpatient worsening of patients with heart failure and reduced ejection fraction: a prespecified analysis of DAPA-HF. Circulation. 2020;142:1623–1632. doi: 10.1161/CIRCULATIONAHA.120.047480 - PMC - PubMed

Publication types

Associated data