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Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure
Study Questions:
What is the effectiveness of combination diuretic regimens to overcome loop diuretic resistance (DR) in acute heart failure (AHF)?
Methods:
The 3T trial investigators conducted 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. All patients received concomitant high-dose IV furosemide infusions. The primary outcome was 48-hour weight loss. The author(s) utilized student’s t-test for the primary outcome and continuous data with parametric distributions and the Kruskal-Wallis test for outcomes that were continuous data with nonparametric distributions.
Results:
The cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 hours during high-dose loop diuretics (IV furosemide 612 ± 439 mg/day). All three 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, -2.9 to 0.6]; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg), (0.5 kg [95% confidence interval, -1.5 to 2.4]; p = 0.456) resulted in more weight loss at 48 hours. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ between metolazone (7.78 [IQR, 6.59-10.10] L) and chlorothiazide (8.77 [IQR, 7.37-10.86] L; p = 0.245) or tolvaptan (9.70 [IQR, 6.36-13.81] L; p = 0.160). Serum sodium decreased less with tolvaptan than metolazone (+4 ± 5 vs. -1 ± 3 mEq/L; p = 0.001), but 48-hour spot urine sodium was lower with tolvaptan (58 ± 25 mmol/L) than metolazone (104 ± 16 mmol/L; p = 0.002) and chlorothiazide (117 ± 14 mmol/L; p < 0.001).
Conclusions:
The authors concluded that in this moderate-sized diuretic resistance trial, weight loss was excellent with addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics without a detectable between-group difference.
Perspective:
This single-center trial compared three combination diuretic strategies to overcome diuretic resistance and reports that, combined with high-dose IV furosemide, neither chlorothiazide nor tolvaptan was better than metolazone by metrics of weight loss or urine output. Furthermore, each strategy restored diuretic efficacy and facilitated decongestion. Additional studies are needed to assess the significance of urine sodium output with combination diuretic therapies to ascertain if the same poor prognostic relationship exists as with loop diuretic monotherapy or if restoration of diuretic response is of cardinal importance.
Keywords: Chlorothiazide, Diuretics, Furosemide, Heart Failure, Metolazone, Sodium, Sodium Potassium Chloride Symporter Inhibitors, Weight Loss
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