Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions-Part II: Combination Therapy

Abstract

Purpose of review: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research.

Recent findings: We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

Keywords: Acetazolamide; Combination therapy; Decompensated HF; Digoxin; Diuretic treatment; Loop diuretic; Oral salt; Sodium-glucose co-transporter 2 inhibitors; Steroid; Thiazide; Tolvaptan.

Fig. 1

Mechanism of action of different diuretic agents. Abbreviations: CA, carbonic anhydrase; ACZ, acetazolamide; SGLT2I, sodium glucose co-transporter 2 inhibitor; THZ, thiazide; AVP, arginine vasopressin

Fig. 2

Conflicting and competing mechanisms of corticosteroid benefits and harm in patients with HF. ANP, atrial natriuretic peptide; NPR-A, natriuretic peptide receptor-A; AVP, arginine vasopressin; ACTH, adrenocorticotropic hormone

Fig. 3

Cumulative urine output in RCTs of combination diuretic therapy. Urine output was reported at 24 h in the CLOROTIC and SMAC-HF trials and was used to estimate urine output at 48 and 72 h; urine output was reported at 72 h in the DOSE and TACTICS trials and used to estimate urine output at 24 and 48 h. Urine output from the ADVOR, EMPA-RESPONSE-AHF, EMPAG-HF, OSPREY, and Liu et al. trials was estimated from the figures. Data collection on urine output stopped after 48 h in the ADVOR trial; 72 h urine output is estimated from values at 24 and 48 h. Abbreviations: plbo, placebo; HCTZ, hydrochlorothiazide; ACZ, acetazolamide; Empa, empagliflozin; NaCl, slow sodium; Tolv, tolvaptan; Pred, prednisolone; HSS, hypertonic saline solution