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

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 At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days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 When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6–22.1] versus 14.1 [95% CI, 10.1–18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20–2.54), P =0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76–1.66]); time period-by-treatment interaction, P =0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo ( P 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.

The Impact of the Withdrawal of SGLT2 Inhibitors on Clinical Outcomes in Patients with Heart Failure

“…In the additional trial after the end of the EMPEROR-Reduced and the EMPEROR-Preserved trials, patients withdrawn from treatment with empagliflozin showed an increased risk of HF events and worsening health status compared with patients withdrawn from the placebo [ 6 ]. Although the results of this trial indicate that the cessation of SGLT2i treatment may have deleterious consequences, some patients are unable to continue SGLT2i due to adverse events or chronic disease [ 16 ].…”

“…Furthermore, a recent RCT demonstrated that the risk of cardiovascular death or hospitalization for HF increased in patients withdrawn from empagliflozin [ 6 ]. This finding suggested a chronic effect of SGLT2i in patients with HF even after years of treatment, which dissipated after withdrawal of the drug.…”

Using combinational diuretics across the spectrum of renal function

“…Sodium–glucose cotransporter 2 inhibitors (SGLT2‐I) should be used across the entire spectrum of left ventricular ejection fraction as a disease‐modifying drug, rather independent of congestion status. Importantly, continuation of SGLT2‐I should be emphasized as even short‐term withdrawal is associated with a worse outcome as evidenced by a recent analysis of the EMPEROR trials 13 . Loop diuretics remain the cornerstone for alleviating volume overload.…”

“…Importantly, continuation of SGLT2-I should be emphasized as even short-term withdrawal is associated with a worse outcome as evidenced by a recent analysis of the EMPEROR trials. 13 Loop diuretics remain the cornerstone for alleviating volume overload. True loop diuretic resistance is perhaps less frequent than historically thought.…”