Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors and Angiotensin Receptor–Neprilysin Inhibitors for Heart Failure in Black Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Black patients have a disproportionately high incidence of heart failure (HF).1 Black patients present at an earlier age with HF and have worse outcomes compared to non-black patients.1 Despite this, they are often underrepresented in clinical trials.2 Targeted trials in this high-risk population such as the African American Heart Failure (A-HeFT) trial have been infrequent.3 The disparate effects of established classes of HF therapeutics including beta-blockers, renin–angiotensin–aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs) according to race have been previously described.4, 5 The efficacy of newer medical therapies in black patients with HF remains an important and unanswered question. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in HF irrespective of ejection fraction (EF) to compare outcomes in black versus non-black patients with a specific focus on angiotensin receptor–neprilysin inhibitors (ARNIs) and sodium–glucose cotransporter 2 (SGLT2) inhibitors. The protocol for this systematic review and meta-analysis was pre-registered with PROSPERO (CRD42022332988). We searched MEDLINE, Embase, and Cochrane CENTRAL databases from inception to December 2022 using a librarian-reviewed search strategy to identify relevant citations. We included any trial assessing the effects of either an SGLT2 inhibitor or ARNI compared with placebo/standard of care, which (i) was conducted in patients with HF irrespective of EF and (ii) published race-stratified data. Pairs of reviewers independently screened studies and in duplicate for eligibility. Our primary outcome of interest was the composite of HF hospitalization and cardiovascular death. In DAPA-HF, DELIVER and SOLOIST-WHF, urgent visits for HF were also included in the primary outcome and SOLIST-WHF reported total events as opposed to time to first event.6-8 Secondary outcomes included cardiovascular death, all-cause mortality and total HF hospitalizations. Analyses were performed using RevMan 5.4. We present Mantel–Haenzel point estimates of odds ratios (OR) with 95% confidence intervals (CI) generated using the random effects model. We used the generic inverse variance and DerSimonian and Laird random effects method to pool hazard ratios (HR).9 We assessed for interaction between subgroups using a test for heterogeneity as described by Borenstein and Higgins.10 We assessed risk of bias using the Cochrane Collaboration tool. We screened 933 citations in total for eligibility, of which eight RCTs were included.6-8, 11-21 Five trials published a dedicated sub-analysis in black patients.14-17, 19 We judged all RCTs included in this analysis to be at a low risk of bias in all domains. Of the 36 054 patients in the eight included trials, 1796 (5.0%) were reported to be black. Black patients were well-represented (35.9%) in the PIONEER-HF trial, which was the only trial conducted in the setting of acute decompensated HF and which was a biomarker-endpoint trial not powered for clinical outcomes.12, 16 We report study characteristics including detailed demographic information in online supplementary Table S1. In each of the five trials which reported race-stratified demographics, black patients were significantly younger, more likely to be female and less likely to have atrial fibrillation. Black patients in the placebo/standard of care arms of five trials had a significantly higher rate of HF hospitalization/cardiovascular death compared with non-black/white patients (25.4% vs. 19.5%; OR 1.55, 95% CI 1.27, 1.89); this was consistent in both trials of HF with reduced EF (HFrEF) (OR 1.64, 95% CI 1.23, 2.19) and HF with mildly reduced (HFmrEF)/preserved EF (HFpEF) patients (OR 1.37, 95% CI 0.98, 1.92, p-interaction = 0.43). There were insufficient data available to pool secondary outcomes. In a pooled analysis of five trials in HF irrespective of EF (Figure 1A), SGLT2 inhibitors reduced the composite of cardiovascular death/HF hospitalization to a similar degree in black (HR 0.71, 95% CI 0.52, 0.99) and white patients (HR 0.79, 95% CI 0.73, 0.86, p-interaction = 0.54). Stratifying by EF, in two trials of SGLT2 inhibitors in patients with HFrEF a greater reduction in the composite of cardiovascular death/HF hospitalization was observed in black patients (HR 0.53, 95% CI 0.37, 0.76) compared with white patients (HR 0.83, 95% CI 0.74, 0.93; p-interaction = 0.02). In two trials of SGLT2 inhibitors in with HFmrEF/HFpEF, a similar reduction in the composite of cardiovascular death/HF hospitalization was observed in black patients (HR 0.86, 95% CI 0.57, 1.30) compared to white patients (HR 0.80, 95% CI 0.72, 0.88; p-interaction = 0.71). For the outcome of cardiovascular death (Figure S1), effect estimates in black patients (HR 0.74, 95% CI 0.49, 1.12) were not significantly different from those in white patients (HR 0.91, 95% CI 0.79, 1.06, p-interaction = 0.35) in four trials of HF patients, irrespective of EF – a finding which was similarly observed in a sub-group of two trials conducted in HFrEF. Data were unavailable for other secondary outcomes. In two trials of an ARNI conducted in patients with HFrEF, the reduction in the composite of cardiovascular death/HF hospitalization (Figure 1B) was similar in both black patients (HR 0.67, 95% CI 0.40, 1.11) and non-black/white patients (HR 0.80, 95% CI 0.72, 0.89; p-interaction = 0.49). Reported rate ratios for the primary outcome from one trial of an ARNI in HFpEF were 0.69 (95% CI 0.24, 1.99) in black patients compared with 0.83 (95% CI 0.71, 0.97; p-interaction not provided) in white patients. Data were unavailable for secondary outcomes. There are three key conclusions from this work. First, these data add to the growing body of evidence that black patients with HF have worse outcomes compared with non-black patients.1, 22 Second, our results demonstrate that ARNIs and SGLT2 inhibitors appear to be just as efficacious in black patients with HF compared with non-black patients with a suggestion of potentially greater benefit of SGLT2 inhibitors in black patients with HFrEF. Limitations which must be considered when interpreting these results include the small number of black patients enrolled in these trials and the possibility of confounding. Prior analyses have suggested that some HF therapies such as spironolactone may be less effective in black patients.4, 22 Finally, our results highlight the need to increase representation of black patients in HF trials. There is a crucial need for focused research into medical therapy for this high-risk and historically understudied population. This should be a key priority for future clinical investigations. Conflict of interest: C.D.M. reports advisory board honoraria/consulting fees from Amgen, AstraZeneca, BioAge, Boehringer Ingelheim and PhaseBio and DSMB stipends from Beth Israel Deaconess Medical Center, Cerus and Takeda; he is supported by a Merit Award from the University of Toronto Department of Anesthesiology and Pain Medicine. J.B. reports consulting relationships with Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana Medical, and Vifor Pharma. T.M.Y. reports consulting relationships with Abbott, Medtronic, BlueRock Therapeutics, Aziyo Biologics, and Novo Nordisk. D.L.B. discloses the following relationships - Advisory Board: AngioWave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: AngioWave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. S.V. holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management Inc, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group. He is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. All other authors have nothing to disclose. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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