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Randomized Controlled Trial
. 2023 Sep 26;148(13):1011-1022.
doi: 10.1161/CIRCULATIONAHA.123.065748. Epub 2023 Aug 24.

Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure

Milton Packer  1   2 , Javed Butler  3   4 , Cordula Zeller  5 , Stuart J Pocock  6 , Martina Brueckmann  7   8 , João Pedro Ferreira  9   10 , Gerasimos Filippatos  11 , Muhammad Shariq Usman  12 , Faiez Zannad  10 , Stefan D Anker  13
Affiliations
Randomized Controlled Trial

Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure

Milton Packer et al. Circulation. .

Abstract

Background: It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy.

Methods: In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment.

Results: From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (P<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients.

Conclusions: These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifiers: NCT03057977 and NCT03057951.

Keywords: empagliflozin; heart failure; sodium-glucose transporter 2 inhibitors; substance withdrawal syndrome.

PubMed Disclaimer

Conflict of interest statement

Disclosures Dr Butler reports consulting fees from Abbott Fund, American Regent, Amgen, Applied Therapeutics, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiac Dimensions, Cardior, CVRx, Inc, Cytokinetics, Edwards Lifesciences, Element Sciences, Eli Lilly & Company, Impulse Dynamics, Imbria, Inventiva, Innolife, Janssen Global, Lexicon Pharmaceuticals, Liva Nova USA, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Novo Nordisk, Pharmacosmos, Roche Diagnostics, Occlutech, Relypsa, SQ Innovation, Sequana, Stelthpeptide, Vifor Pharma. Dr Zannad reports consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Cellprothera, Merck, Novartis, Novo Nordisk, Owkin, Pfizer, Servier Affaires Medicale, Vifor Fresenius. Dr Ferreira reports consulting fees from Boehringer Ingelheim. Dr Packer reports consulting fees from 89bio, Abbvie, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Medtronic, Moderna, Novartis, Reata, Relypsa, Salamandra. Dr Anker reports consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Brahms GmbH, Cardiac Dimensions, Cardior, Cordio, CVRx, Inc., Edwards Lifesciences, GlaxoSmithKline, Impulse Dynamics (USA) Inc., Novartis, Pfizer, Servier, V-Wave, Vectorious, Vifor International. Dr Pocock reports consulting fees from Boehringer Ingelheim. Drs Brueckmann and Zeller are employees of Boehringer Ingelheim. Dr Usman reports no conflicts.

Figures

Figure 1.
Figure 1.
CONSORT diagram. Source and disposition of randomized patients included in current analysis. Boldface number refers to total number of patients. The 3981 patients who completed the last-value-on-treatment and withdrawal period were also assessed (with respect to clinical, physiological, and laboratory variables) at baseline, 4 weeks after randomization, and 12 weeks after randomization. These data are shown in Figure 2B, Figure 3, and Table 3. SGLT2 indicates sodium-glucose cotransporter 2.
Figure 2.
Figure 2.
Effect of empagliflozin on clinical efficacy measures during initiation of double-blind therapy and after planned withdrawal of double-blind treatment. A, The incidence of cardiovascular death or hospitalization for heart failure from 90 days before the start of the closeout period to the end of the double-blind treatment period and during the ≈30-day withdrawal period. Shown in black are the between-group differences, expressed as hazard ratio (HR) and 95% CIs. Within-group differences for the 2 treatment periods are shown in red for the placebo group and blue for the empagliflozin group. Time-to-event plots for these data are shown in Figure S1. B, Values for KCCQ-CSS (±SE) at baseline, 12 weeks after randomization, the last value on double-blind treatment and at the end of the 30-day withdrawal period in the same cohort of 3928 patients who provided KCCQ-CSS data at the end of the planned withdrawal period. P values show the between-group difference between empagliflozin versus placebo (1) during initiation of treatment (“on-treatment effect,” assessed as between-group difference in the changes from baseline at 12 weeks of randomized treatment) and (2) at the end of the trial (“off-treatment effect,” assessed as between-group difference at the end of the withdrawal period compared with last value on double-blind treatment), on the basis of mixed model for repeated measures analyses. KCCQ-CSS indicates Kansas City Cardiomyopathy Questionnaire Clinical Summary Score.
Figure 3.
Figure 3.
Effect of empagliflozin on physiological and laboratory assessments during initiation of double-blind therapy and after planned withdrawal of double-blind treatment. Values at baseline (BL), 4 and 12 weeks after randomization, the last value on double-blind treatment (LVOT), and at the end of the 30-day withdrawal period (W) in the cohort of 3981 patients who provided data during the withdrawal period. Shown are adjusted mean changes from baseline±SE for all variables except for NT-proBNP, for which adjusted geometric mean ratio (95% CI) is displayed. P values on the left side of each graft represent the significance of between-group changes at 4 weeks from baseline, and P values on the right side of each graft represent the significance of between-group changes at the end of withdrawal compared with LVOT, on the basis of mixed model for repeated measures analyses. For NT-proBNP the analyses were performed on log-transformed values. The precise number of patients with available data for each physiological and laboratory assessment varied slightly but, in general, was ≈1850 to 2000 for each visit in each treatment group. BP indicates blood pressure; eGFR, estimated glomerular filtration rate; and NT-proBNP, N-terminal prohormone B-type natriuretic peptide.
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References

    1. Vaduganathan M, Claggett BL, Inciardi RM, Fonarow GC, McMurray JJV, Solomon SD. Estimating the benefits of combination medical therapy in heart failure with mildly reduced and preserved ejection fraction. Circulation. 2022;145:1741–1743. doi: 10.1161/CIRCULATIONAHA.121.058929 - PubMed
    1. Vaduganathan M, Docherty KF, Claggett BL, Jhund PS, de Boer RA, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, et al. . SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400:757–767. doi: 10.1016/S0140-6736(22)01429-5 - PubMed
    1. Packer M, Medina N, Yushak M. Role of the renin-angiotensin system in the development of hemodynamic and clinical tolerance to long-term prazosin therapy in patients with severe chronic heart failure. J Am Coll Cardiol. 1986;7:671–680. doi: 10.1016/s0735-1097(86)80479-x - PubMed
    1. Colucci WS, Alexander RW, Williams GH, Rude RE, Holman BL, Konstam MA, Wynne J, Mudge GH, Jr, Braunwald E. Decreased lymphocyte beta-adrenergic-receptor density in patients with heart failure and tolerance to the beta-adrenergic agonist pirbuterol. N Engl J Med. 1981;305:185–190. doi: 10.1056/NEJM198107233050402 - PubMed
    1. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med. 1987;317:799–804. doi: 10.1056/NEJM198709243171304 - PubMed

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