Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction

Abstract

Importance: Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies.

Objective: To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization.

Design, setting, and participants: This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment.

Exposures: None.

Main outcomes and measures: Composite of cardiovascular death or worsening HF.

Results: A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94]; P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjusted P = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, -1.9% to 6.1%), 4.1% (95% CI, -3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend).

Conclusions and relevance: In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin.

Trial registration: ClinicalTrials.gov Identifier NCT03036124.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Berg is supported by Harvard Catalyst KL2/Catalyst Medical Research Investigator Training (National Center for Advancing Translational Sciences grant UL 1TR002541) and has received research grant support to his institution from AstraZeneca outside the submitted work. Dr Jhund reports his employer (University of Glasgow) has been paid by AstraZeneca for his involvement in the DAPA-HF trial and the DELIVER trial, as well as fees for AstraZeneca speaker and advisory board work, during the conduct of the study; Dr Jhund has received consulting, advisory board, and speaker’s fees from Novartis, advisory board fees from Cytokinetics, and grants and personal fees for advisory board participation from Boehringer Ingelheim outside the submitted work. Dr Docherty reports his employer (University of Glasgow) is paid by AstraZeneca for his involvement in the DAPA-HF trial, and he has received personal fees from AstraZeneca during the conduct of the study and grants from Novartis and personal fees from Eli Lilly outside the submitted work. Ms Murphy reports being a member of the TIMI Study Group, which has received research grant support through Brigham and Womenʼs Hospital from Abbott, Amgen, Anthos Therapeutics, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Regeneron Pharmaceuticals Inc, Roche, Siemens Healthcare Diagnostics Inc, Takeda, The Medicines Company, and Zora Biosciences. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving grants and personal fees from AstraZeneca during the conduct of the study and grants from Amarin, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, HLS Therapeutics, Janssen, Pfizer, and PhaseBio and personal fees from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly, EOCI Pharmacomm, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group outside the submitted work. Dr Inzucchi reports personal fees and nonfinancial support from AstraZeneca as a consultant during the conduct of the study and personal fees and nonfinancial support from Boehringer Ingelheim (including being a publications committee member for a clinical trial and receiving fees for lectures, consulting, travel, and medical writer costs as an in-kind value), Sanofi/Lexicon (as a committee member for a clinical trial), Merck (for consulting and lectures), Zafgen, VTV Therapeutics (for consulting), Esperion (for consulting), Abbott/Alere (for consulting), and Novo Nordisk (for travel and as a steering committee member for a clinical trial) outside the submitted work. Dr Køber reports being an executive committee member for the DAPA-HF study (payment from which will be administered by Rigshospitalet University Hospital) from AstraZeneca and receiving personal speaker’s honorarium fees from AstraZeneca during the conduct of the study and personal fees from Novo, Novartis, and Bristol Myers Squibb as a speaker outside the submitted work. Dr Kosiborod reports personal fees from AstraZeneca during the conduct of the study; grants, personal fees, and other support from AstraZeneca; grants and personal fees from Boehringer Ingelheim; and personal fees for consulting from Sanofi, Amgen, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck (Diabetes), Janssen, Bayer, Glytec, Novartis, Applied Therapeutics, Amarin, Eli Lilly, and Vifor Pharma outside the submitted work. Dr Langkilde is an employee and shareholder of AstraZeneca during the conduct of the study and outside the submitted work. Dr Martinez reports personal fees from AstraZeneca during the conduct of the study. Dr Bengtsson is an employee of AstraZeneca. Dr Ponikowski reports personal fees from and participation in clinical trials with AstraZeneca and Boehringer Ingelheim during the conduct of this study; personal fees from Amgen, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, Cibiem, Impulse Dynamics, Renal Guard Solutions, Sanofi, Bristol Myers Squibb, Respicardia, and Radcliffe Group; personal fees from Pfizer, Servier, Respicardia, and Berlin-Chemie; participation in clinical trials with Amgen and Novartis; being a co–principal investigator of the RESHAPE-HF trial with Abbott Vascular; and grants and personal fees from and participation in clinical trials with Vifor Pharma outside the submitted work. Dr Sjöstrand is an employee and shareholder of AstraZeneca. Dr Solomon reports grants from AstraZeneca to his institution during the conduct of the study and grants to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos and personal fees from Abbott, Actelion, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Ironwood, Lilly, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Sanofi Pasteur, Tenaya, Dinaqor, Tremeau, CellProThera, Moderna, and American Regent for consulting outside the submitted work. Dr McMurray is an employee of the University of Glasgow, which has been remunerated by AstraZeneca (who market dapagliflozin) for his work on the DAPA-HF, DELIVER, and DETERMINE trials (trials using dapagliflozin) and related meetings and activities, with travel costs paid; Cardiorentis for his time as a steering committee member for the ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and related meetings and activities, with travel costs paid; Amgen for his participation in GALACTIC-HF trial and related meetings, with travel costs paid; Bayer for his time as a steering committee member for the FINEARTS-HF trial; Oxford University/Bayer for his time as a steering committee member for the ACE trial and related meetings, with travel costs paid; Theracos for his time as a principal investigator for the BEST trial and related meetings, with travel costs paid; GlaxoSmithKline as a co–principal investigator and steering committee member, respectively, for the Harmony-Outcomes trial and the ASCEND-D and ASCEND-ND trials, as well as related meetings, with travel costs paid; Vifor-Fresenius and Kidney Research UK via Kings College Hospital for his time as a steering committee member for the PIVOTAL trial, on an end point adjudication committee for this trial, and in related meetings, with travel costs paid by Kings College Hospital; DalCor for DalCor Pharmaceuticals for his time as steering committee member for the Dal-GenE trial, with travel costs paid; Pfizer; Merck for work on a data safety monitoring committee for the MK-3102 program and the VICTORIA trial; Bristol Myers Squibb for his time as a steering committee member for the STAND-UP clinical trial; Alnylam for his time on an advisory board committee for the ALN-AGT trial and related meetings; AbbVie for his time as a steering committee member for the SONAR trial and related meetings, with travel costs paid; Cyclerion for consulting; Cardurion for his participation in a company advisory board; Novartis for his time on a company advisory board and as an executive committee member and co–principal investigator of the ATMOSPHERE study, co–principal investigator of the PARADIGM-HF trial, and an executive and steering committee member for PARACHUTE-HF, PARADISE-MI, and PERSPECTIVE trials and related meetings and presentations, with travel costs paid; and Servier, for his time on a steering committee member for the GALACTIC-HF trial. Dr McMurray also reports personal lecture fees from Abbott, Hickma, Sun Pharmaceuticals, and Servier outside the submitted work. Dr Sabatine reported an institutional research grant from AstraZeneca to the TIMI Study Group during the conduct of the study and institutional research grants from Amgen, Anthos Therapeutics, Bayer, Daiichi Sankyo, Eisai, Intarcia, GlaxoSmithKline, Janssen Research and Development, the Medicines Company, MedImmune, Merck, Novartis, Pfizer Quark Pharmaceuticals, Poxel, and Takeda to the TIMI Study Group outside the submitted work; personal fees for consulting for Althera, Amgen Consulting, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, CVS Caremark, DalCor, Dr Reddy's Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Ionis, Janssen Research and Development, the Medicines Company, MedImmune, Merck, and Novartis. Dr Sabatine is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche, and Zora Biosciences. No other disclosures were reported.

Figures

Figure 1.. Hazard Ratios (HRs) by Day Postrandomization

A, Dapagliflozin vs placebo for the primary efficacy outcome; B, dapagliflozin vs placebo for the primary efficacy outcome in the first 100 days; C and D, the individual components of worsening heart failure (C) and cardiovascular death (D). The HRs and 95% CIs observed at the end of the trial for each outcome are provided as a point of reference. A reduction in the risk of the primary efficacy outcome of cardiovascular death or worsening heart failure event was statistically significant by 4 weeks after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94]; P = .03).

Figure 2.. Cumulative Incidence of Cardiovascular Death or Worsening Heart Failure Event at 2 Years by Timing of Most Recent Heart Failure Hospitalization Relative to Trial Enrollment

There was a stepwise gradient of risk for the primary efficacy outcome of cardiovascular death or worsening heart failure event according to timing of the most recent heart failure hospitalization. This risk gradient remained significant after adjusting for age, sex, race, left ventricular ejection fraction, baseline N-terminal pro-B-type natriuretic peptide concentration, and New York Heart Association class (compared with patients never hospitalized for HF, adjusted hazard ratios were 1.08 [95% CI, 0.90-1.29] and 1.30 [95% CI, 1.12-1.51] for those hospitalized >12 months ago and ≤12 months ago, respectively; P = .003).

Figure 3.. Treatment Effect of Dapagliflozin on the Primary Composite Outcome by Timing of Most Recent Heart Failure (HF) Hospitalization Relative to Trial Enrollment

Patients with a more recent hospitalization for HF experienced robust relative and absolute risk reductions in the primary efficacy outcome of cardiovascular death or worsening heart failure. ARR indicates absolute risk reduction; HR, hazard ratio.