Loop Diuretic Dose Intensification versus Adjuvant Thiazide for Diuretic Resistance in Acute Heart Failure: Mechanistic Randomized Controlled Trial.

Abstract

Adjuvant thiazide improved diuretic response more than loop dose increase in patients with acute heart failure and diuretic resistance. The underlying diuretic resistance mechanism did not identify preferential response to either diuretic escalation strategy. The optimal therapy for loop diuretic resistance may differ if caused by resistance at the site of action in the loop of Henle (diuretic resistance at the loop of Henle [DR-Loop]) versus compensatory distal reabsorption (diuretic resistance due to distal sodium reabsorption [DR-Distal]). This study primarily aimed to compare diuretic strategies and explore whether targeting the underlying diuretic resistance mechanism could optimize diuretic response. Patients hospitalized with heart failure and diuretic resistance (6-hour cumulative natriuresis <100 mmol after intravenous [IV] loop diuretic) were randomized 1:1 to (<i>1</i>) 2.5× IV loop dose intensification or (<i>2</i>) IV chlorothiazide addition to the same loop diuretic. The primary trial outcome was the increase in 6-hour natriuresis between strategies. Exploratory analyses of diuretic resistance mechanism were performed. Diuretic resistance mechanisms were categorized using the fractional excretion of lithium (FE_Li), a metric evaluating sodium exit from the loop of Henle. DR-Loop was defined as a loop diuretic–induced increase in FE_Li below the median and DR-Distal as an increase in FE_Li above the median at the screening visit. Patients (mean age 68±12 years, 40% women) were randomized to loop dose intensification (<i>n</i>=51) or adjuvant thiazide (<i>n</i>=52). The primary outcome of increase in 6-hour natriuresis improved significantly with both strategies. However, chlorothiazide addition produced a significantly larger improvement in 6-hour natriuresis (107 mmol increase [95% confidence interval (CI), 81 to 132]) compared with loop augmentation (49 mmol increase [95% CI, 31 to 66]; treatment effect 58 mmol [95% CI, 27 to 89]; <i>P</i> < 0.001). Paradoxically, loop intensification augmented natriuresis less in patients with DR-Loop compared with DR-Distal (27±39 versus 75±77 mmol, respectively, <i>P</i> = 0.004), and adjuvant thiazide did not increase natriuresis more in patients with DR-Distal versus DR-Loop (92±71 versus 105±86 mmol, respectively, <i>P</i> = 0.54). Strategies of loop dose intensification and adjuvant thiazide both improved diuretic response, with a significantly larger augmentation of natriuresis with adjuvant thiazide. The underlying diuretic resistance mechanism did not identify a preferential response to either therapy. ClinicalTrials.gov, Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure NCT02546583.