Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial

Abstract

Objectives: This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR).

Background: Combination diuretic regimens to overcome loop DR are commonly used but with limited evidence.

Methods: This study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss.

Results: The cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: -2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: -1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. -1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001).

Conclusions: In this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253).

Keywords: acute heart failure; diuretic resistance; diuretics; heart failure; thiazide; tolvaptan.

Figure 1:. Patient flow diagram

While the primary analysis was performed on an intention-to-treat basis, a supplemental per protocol analysis was performed only in patients receiving all study diuretic doses. AHF= acute heart failure; LHC = left heart catheterization; MD = treating physician”

Figure 2A:. Laboratory value trends

Trend of serum sodium (mEq/L) - (Metolazone = blue circles; Chlorothiazide = red squares; Tolvaptan = green triangles). 2B: Trend of serum chloride (mEq/L). 2C: Trend of serum potassium (mEq/L). 2D: Trend of eGFR

Central Illustration.. 48-hour diuretic efficacy

Part A: 48-hour cumulative weight loss – Mean ± SD Weight loss over 48 hours. Part B: 48-hour cumulative urine output – Median (IQR) urine output over 48 hours