Combination of loop diuretics with thiazide-type diuretics in heart failure

J Am Coll Cardiol. 2010 Nov 2;56(19):1527-34. doi: 10.1016/j.jacc.2010.06.034.


Volume overload is an important clinical target in heart failure management, typically addressed using loop diuretics. An important and challenging subset of heart failure patients exhibit fluid overload despite significant doses of loop diuretics. One approach to overcome loop diuretic resistance is the addition of a thiazide-type diuretic to produce diuretic synergy via "sequential nephron blockade," first described more than 40 years ago. Although potentially able to induce diuresis in patients otherwise resistant to high doses of loop diuretics, this strategy has not been subjected to large-scale clinical trials to establish safety and clinical efficacy. We summarize the existing literature evaluating the combination of loop and thiazide diuretics in patients with heart failure in order to describe the possible benefits and hazards associated with this therapy. Combination diuretic therapy using any of several thiazide-type diuretics can more than double daily urine sodium excretion to induce weight loss and edema resolution, at the risk of inducing severe hypokalemia in addition to hyponatremia, hypotension, and worsening renal function. We provide considerations about prudent use of this therapy and review potential misconceptions about this long-used diuretic approach. Finally, we seek to highlight the need for pragmatic clinical trials for this commonly used therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Diuretics / administration & dosage*
  • Drug Resistance / drug effects
  • Drug Resistance / physiology
  • Drug Therapy, Combination
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Humans
  • Kidney / drug effects
  • Kidney / physiology
  • Randomized Controlled Trials as Topic / trends
  • Sodium Chloride Symporter Inhibitors / administration & dosage*
  • Sodium Potassium Chloride Symporter Inhibitors / administration & dosage*


  • Diuretics
  • Sodium Chloride Symporter Inhibitors
  • Sodium Potassium Chloride Symporter Inhibitors