Dapagliflozin vs. Metolazone in Heart Failure Resistant to Loop Diuretics - DAPA-RESIST

Sep 01, 2023
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Dharam J. Kumbhani, MD, SM, FACC
Trial Sponsor:
National Health Service Greater Glasgow & Clyde and The University of Glasgow; AstraZeneca.
Date Published:
08/12/2023
Original Posted Date:
09/01/2023
References

Contribution To Literature:

The DAPA-RESIST trial showed that in patients with acute decompensated heart failure complicated by diuretic resistance, dapagliflozin was not more effective than metolazone in improving congestion, as measured by net weight loss.

Description:

The goal of the trial was to compare the additional decongestive effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin versus metolazone in acute decompensated heart failure (ADHF) requiring intravenous (IV) loop diuretics complicated by diuretic resistance.

Study Design

  • Randomized
  • Multicenter
  • Open-label
  • Active comparator

Patients with ADHF regardless of left ventricular ejection fraction (LVEF) with diuretic resistance were randomized to receive dapagliflozin 10 mg daily (n = 30) or metolazone 5 or 10 mg daily (n = 31) for up to 3 consecutive days. IV loop diuretic and metolazone doses were left to provider discretion and could be adjusted during the study period. Either treatment could be stopped, continued, or changed for the other after 72 hours.

  • Total number of enrollees: 61
  • Duration of follow-up: 90 days
  • Median patient age: 79 years
  • Percentage female: 54%

Inclusion criteria:

  • Age ≥18 years
  • Hospitalized for ADHF requiring IV loop diuretic
  • Diuretic resistance, defined as <1 kg decrease or <1 L net negative fluid balance over 24 hours despite ≥160 mg IV furosemide or equivalent
  • Persistent congestion, defined as peripheral edema, ascites, elevated jugular venous pressure, or pulmonary congestion on imaging
  • B-type natriuretic peptide (BNP) ≥100 pg/mL or N-terminal proBNP (NT-proBNP) ≥400 pg/mL
  • Expected hospital length of stay (LOS) >3 days

Exclusion criteria:

  • Type 1 diabetes mellitus
  • Estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2
  • Use of an SGLT2 inhibitor or thiazide diuretic <48 hours before randomization

Other salient features/characteristics:

  • Median time from admission to randomization: 6 days
  • Percentage LVEF ≤40%: 44%
  • Median eGFR: 41 mL/min/1.73 m2
  • Mean total daily IV furosemide dose at randomization: 244 mg
  • Crossover from metolazone to dapagliflozin and vice versa after 72 hours: 10% vs. 7%, respectively

Principal Findings:

The primary outcome, mean change in weight at 96 hours, for dapagliflozin vs. placebo, was: -3.0 vs. -3.6 kg, p = 0.11.

Secondary outcomes for dapagliflozin vs. placebo at 96 hours:

  • Mean cumulative furosemide dose after randomization: 977 vs. 704 mg
  • Loop diuretic efficiency, defined as weight loss per 40 mg furosemide equivalent: 0.15 vs. 0.25 kg/40 mg furosemide, p = 0.10
  • Median change in ADVOR congestion score: -2.2 vs. -2.6, p = 0.60

Safety outcomes for dapagliflozin vs. placebo at 96 hours:

  • Increase in serum creatinine >0.3 mg/dL: 47% vs. 50%, p = 1.00
  • Serum potassium ≤3.5 mmol/L: 50% vs. 63%, p = 0.44
  • Symptomatic hypotension: 0% vs. 13%, p = 0.11
  • Diabetic ketoacidosis: 0% vs. 0%
  • Median hospital LOS: 20 vs. 19 days, p = 0.41

All-cause mortality at 90 days was: 17% vs. 23%, p = 0.589. 

Interpretation:

The DAPA-RESIST trial demonstrates no improvement in decongestion with dapagliflozin compared with metolazone in diuretic-resistant patients admitted with ADHF. Diuretic resistance is a challenging scenario in HF management and commonly accompanies the cardiorenal syndrome, as reflected by the trial population’s median eGFR. Although this trial was not designed to test for noninferiority, decongestion measured by both the primary and secondary outcomes was similar between both treatment arms. Moreover, despite the dapagliflozin arm requiring greater cumulative loop diuretic dosing, there were numerically fewer episodes of hypokalemia and symptomatic hypotension with no difference in hospital LOS.

SGLT2 inhibitors are also now indicated in the chronic outpatient management of both HFrEF and HFpEF. The recent DICTATE-AHF trial demonstrated a trend toward improved diuretic efficiency in ADHF with dapagliflozin compared with placebo without a signal toward increased adverse events. Taken together, these data may suggest a role for the early initiation of SGLT2 inhibitors during IV diuresis and even in patients with diuretic resistance. Future investigation may be warranted to directly compare the efficacy and safety profiles of diuretic augmentation strategies, including SGLT2 inhibitors and acetazolamide.

References:

Yeoh SE, Osmanska J, Petrie MC, et al. Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics. Eur Heart J 2023;44:2966-77.

Editorial Comment: Martens P, Testani J, Damman K. Prevention and treatment of diuretic resistance in acute heart failure: when to use which combination of diuretics? Eur Heart J 2023;44:2978-81.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Acute Heart Failure, Ascites, Diuretics, Edema, Furosemide, Glomerular Filtration Rate, Heart Failure, Length of Stay, Metolazone, Natriuretic Peptide, Brain, Secondary Prevention, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume, Ventricular Function, Left, Weight Loss


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