The Myth of Metolazone-Does Dose Timing with Loop Diuretics Matter?

Background There is a lack of evidence to support dosing of metolazone for sequential nephron blockade. The ideal frequency of metolazone administration as well as whether administration 30 to 60 minutes prior to the loop diuretic is warranted is unknown. This study assessed the frequency and timing of dosing of metolazone for differences in effectiveness and safety in combination with loop diuretic therapy in patients with acute decompensated heart failure (ADHF). Methods This was a single center, retrospective cohort study including adult subjects admitted for ADHF who were thiazide diuretic naive and received intravenous loop diuretic monotherapy prior to metolazone administration. Subgroup analyses were conducted based on timing of administration of metolazone 1) less than 30 minutes, 2) 30-60 minutes, and 3) greater than 60 minutes prior to the next loop diuretic dose as well as the frequency of metolazone dosing (intermittent, daily, or twice daily). The primary endpoint was net change in weight with net urine output as a secondary endpoint. Safety endpoints included an increase in serum creatinine (SCr) by >0.5 mg/dL from baseline, hypokalemia, hypomagnesemia, hyponatremia, and change in systolic blood pressure. Results We studied 174 patients with a median age of 69 years, median ejection fraction 40%, and median baseline SCr of 1.65 mg/dL. There was no difference in net change in weight, hypokalemia, hypomagnesemia, or change in systolic blood pressure among dosing strategies. The median net urine output in patients dosed intermittently, daily, or twice daily was -3845 mL, -5339 mL, and -6218 mL, respectively (p=0.05). Among patients receiving metolazone less than 30 minutes, 30-60 minutes, and over 60 minutes prior to the loop diuretic, an increase in SCr from baseline occurred in 36.7%, 17.1%, and 16.5%, respectively (p=0.045), and hyponatremia occurred in 40%, 48.6%, and 22%, respectively (p=0.006). An increase in SCr from baseline occurred in 29.9%, 11.4%, and 16.7% of patients receiving intermittent, daily, or twice daily dosing, respectively (p=0.015). Conclusions No dosing strategy of metolazone appeared to be more effective, although concurrent administration with loop diuretics was associated with more worsening renal function and hyponatremia. These results suggest that administering metolazone at least 60 minutes prior to loop diuretics may be safer and still efficacious. Larger prospective studies are needed to confirm these results.