Serum chloride and the response to hydrochlorothiazide in patients with acute heart failure: a post-hoc analysis from the CLOROTIC trial.

Introduction and objectives: Hypochloremia is associated with worse prognosis and diuretic resistance in acute heart failure (AHF). This study investigated whether serum chloride is associated with the efficacy and safety of hydrochlorothiazide in patients with AHF.

Methods: This post-hoc analysis included all 230 patients from the CLOROTIC (Safety and efficacy of the combination of loop with thiazide-type diuretics in patients with decompensated heart failure) trial, randomized to oral hydrochlorothiazide or placebo in addition to intravenous furosemide. The impact of baseline serum chloride on the treatment effect of hydrochlorothiazide on the main trial endpoints was assessed.

Results: At baseline, hypochloremia (< 96 mmol/L) and hyperchloremia (> 106 mmol/L) were observed in 17% and 9% of patients, respectively. The effect of hydrochlorothiazide was more pronounced in patients with hypo- or normochloremia than in those with hyperchloremia for several efficacy endpoints (weight loss at 72 or 96hours, 24-hour diuresis, and diuresis per milligram of furosemide); only weight loss at 72hours showed a significant interaction (P = .02). However, when baseline chloride was modeled as a continuous variable, no significant interaction was observed with primary or secondary efficacy endpoints. Similarly, no significant interaction was found between serum chloride and the effect of hydrochlorothiazide on mortality or rehospitalization. Regarding safety endpoints, baseline hypochloremia was significantly associated with an increased risk of hypokalemia (potassium< 3.5 mmol/L) in patients allocated to hydrochlorothiazide (P = .029), with no significant interaction between hydrochlorothiazide and baseline chloride for the other safety outcomes.

Conclusions: In patients with AHF, the addition of hydrochlorothiazide to loop diuretics enhances decongestion regardless of the baseline serum chloride. (ClinicalTrials.gov: NCT01647932; EudraCT Number: 2013-001852-36).