Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF

Abstract

Background: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo.

Methods: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms.

Results: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization.

Conclusions: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Keywords: diuretics; heart failure; sodium-glucose transporter 2 inhibitors.

Conflict of interest statement

Dr Anand reports receiving fees for serving as US national leader of a trial from AstraZeneca; fees for serving on a steering committee from ARCA Biopharma, Amgen, LivaNova, and Novartis; fees for serving on an end-point committee from Boehringer Ingelheim; fees for serving as chair of a data and safety monitoring board from Boston Scientific; and advisory board fees from Zensun. Dr Bělohlávek reports receiving advisory board fees from Novartis and Pfizer and lecture fees from Getginge. Drs Bengtsson, Greasley, Lindholm, and Sjöstrand report being employed by AstraZeneca. Dr de Boer has received grant support (paid to University Medical Center Groningen [UMCG]), consulting fees, and lecture fees from AstraZeneca, grant support (paid to UMCG) from Bristol-Myers Squibb, grant support (paid to UMCG) and consulting fees from Abbott, grant support (paid to UMCG) and lecture fees from Roche, and consulting fees from MandalMed and is a minority shareholder in scPharmaceuticals. Dr Böhm reports receiving lecture fees from Amgen, Bayer, Servier, Medtronic, Boehringer Ingelheim, Vifor Pharma, and Bristol-Myers Squibb; grant support and lecture fees from AstraZeneca; and grant support from Deutsche Forschungsgemeinschaft. Dr Boulton has received personal fees from AstraZeneca. Dr DeMets has received consulting fees from Frontier Science, Actelion, Bristol-Myers Squibb, Medtronic, Boston Scientific, GlaxoSmithKline, and Merck and has received consulting fees from and is owner of DL DeMets Consulting. Dr. Docherty has received grant support from Novartis. Dr Howlett reports receiving grant support, consulting fees, and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Servier; consulting fees and lecture fees from Novo Nordisk; consulting fees from Janssen; and grant support, consulting fees, lecture fees, and provision of drugs from Pfizer. Dr Inzucchi reports receiving advisory fees from AstraZeneca and Zafgen; lecture fees, consulting fees, fees for serving as a clinical trial publications committee member, reimbursement for medical writing, and travel support from Boehringer Ingelheim; fees for serving on a steering committee and travel support from Sanofi-Lexicon; lecture fees, consulting fees, and travel support from Merck; and advisory fees and travel support from vTv Therapeutics and Abbott-Alere. Dr Katova reports receiving fees for serving as national coordinator of a trial from Novartis and AstraZeneca. Dr. Køber has received lecture fees from Novartis and Bristol-Myers Squibb. Dr Kosiborod has received grant support, honoraria, and research support from AstraZeneca; grant support and honoraria from Boehringer Ingelheim; and honoraria from Sanofi, Amgen, Novo Nordisk, Merck (Diabetes), Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia Therapeutics, Novartis, Applied Therapeutics, Amarin, and Eli Lilly. Dr Langkilde reports being employed by and holding shares in AstraZeneca. Dr. Ljungman reports receiving lecture fees and advisory board fees from AstraZeneca, lecture fees from Novartis, and advisory board fees from Pfizer. Dr Martinez has received personal fees from AstraZeneca as honoraria. Dr O’Meara has received fees for serving on a clinical trial (paid to her institution), consulting fees, and lecture fees from AstraZeneca, Bayer, Amgen, and Novartis; consulting fees from Merck; fees for serving on a clinical trial (paid to her institution) from American Regent; and consulting fees and lecture fees from Pfizer and Boehringer Ingelheim. Dr Sabatine reports receiving grant support (paid to Brigham and Women’s Hospital) and consulting fees from Amgen, AstraZeneca, Intarcia Therapeutics, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; receiving consulting fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix, Esperion, IFM Therapeutics, and Ionis Pharmaceuticals; receiving grant support (paid to Brigham and Woman’s Hospital) from Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda Pharmaceutical; and serving as a member of the TIMI (Thrombolysis in Myocardial Infarction) Study Group, which receives grant support (paid to Brigham and Women’s Hospital) from Abbott, Aralez Pharmaceuticals, Roche, and Zora Biosciences. Dr Solomon reports receiving grant support and consulting fees (all fees listed paid to Brigham and Women’s Hospital) from Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics; grant support from Bellerophon Therapeutics, Celladon, Ionis Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos Therapeutics; consulting fees from Akros Pharma, Corvia Medical, Ironwood Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac Dimensions, Tenaya Therapeutics, and Daiichi Sankyo; and fees for serving on a data and safety monitoring board from Janssen. Dr Tereshchenko reports receiving lecture fees from Servier, Pfizer, Novartis, and Boehringer Ingelheim; Dr Verma reports receiving grant support, lecture fees, and advisory board fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, and Merck; lecture fees from Sun Pharmaceutical Industries and EOCI Pharmacomm; grant support and advisory board fees from Amgen; and lecture fees and advisory board fees from Sanofi and Eli Lilly. Dr. Jhund reports receiving consulting fees, advisory board fees, and lecture fees from Novartis; advisory board fees from Cytokinetics; and grant support from Boehringer Ingelheim. Dr. McMurray reports receiving fees (all fees listed paid to Glasgow University) for serving on a steering committee from Bayer; fees for serving on a steering committee, fees for serving on an end-point committee, and travel support from Cardiorentis; fees for serving on a steering committee and travel support from Amgen and Oxford University–Bayer; fees for serving as principal investigator of a trial and travel support from Theracos; fees for serving on a steering committee and travel support from AbbVie; fees for serving on a steering committee from DalCor Pharmaceuticals; fees for serving on a data and safety monitoring committee from Pfizer and Merck; fees for serving on an executive committee, fees for serving as co–principal investigator of a trial, fees for serving on a steering committee, fees for serving on an executive committee, travel support, and advisory board fees from Novartis; fees for serving as co–principal investigator for a trial, fees for serving on a steering committee, and travel support from GlaxoSmithKline; fees for serving on a steering committee from Bristol-Myers Squibb; and fees for serving on a steering committee, fees for serving on an end-point adjudication committee, and travel support from Vifor Pharma–Fresenius. The other authors report no conflicts.

Figures

Figure 1.

Change in loop diuretic dose over time in all patients.

Figure 2.

Forest plot of efficacy outcomes according to diuretic therapy at baseline.

Figure 3.

Changes in laboratory and clinical measures according to diuretic therapy at baseline.