Diuretic Therapy for Heart Failure Patients

Felker GM, Ellison DH, Mullens W, Cox ZL, Testani JM.
Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol 2020;75:1178-1195.

The following are key points to remember from this state-of-the-art review on diuretic therapy for patients with heart failure (HF):

  1. Chronic kidney disease (CKD) is a strong predictor of adverse outcome in HF, and CKD impairs the “reserve” available for the kidneys to respond to the insult posed by congestion.
  2. In normal circumstances, renal blood flow (RBF) is around 20% of cardiac output and mainly determined by differences in renal arterial and venous pressure. In HF, both natriuresis and maximal free water excretion are decreased. RBF and glomerular filtration rate (GFR) are autoregulated by three major mechanisms: the myogenic response, the macula densa tubuloglomerular feedback, and renin secretion. All three of these processes serve to maintain the GFR constant, but at the expense of renin-angiotensin-aldosterone system activation. HF is also characterized by a low distal tubular flow secondary to increased fractional reabsorption in the proximal parts of the tubules and often concomitantly decreased GFR.
  3. Given the central role of volume expansion in the pathogenesis of congestive HF, diuretic agents, particularly loop diuretics, are among the cornerstones of treatments for HF. Effective diuretic action requires four discrete steps: 1) ingestion and gastrointestinal absorption (if given orally), 2) delivery to the kidney, 3) secretion into the tubule lumen; and 4) binding to the transport protein—each one of these steps is discussed in this review.
  4. Initial loop diuretic dosing in patients hospitalized with HF and congestion: For patients on long-term loop diuretic agents, 2.5 times their outpatient dose on a mg per mg basis, demonstrated safety and efficacy in the DOSE trial. For example, for patients taking 40 mg of oral furosemide twice daily as an outpatient, initial intravenous (IV) dosing would be 100 mg of furosemide IV twice daily. For patients not receiving long-term loop diuretic agents, 40-80 mg IV BID of furosemide or the equivalent is a reasonable, empiric, starting dose. Due to post-dosing Na+ retention, IV loop-diuretic agents should usually be given at least twice daily.
  5. Adjustment of diuretic dosing: Subsequent doses of loop diuretic agents should be guided by clinical response to initial doses. For a sufficient dose of loop diuretic agent, urine output should measurably increase within 2 hours. If there is not an adequate response to initial dose, there is no need to wait until the next scheduled dose to increase dosing. Because the dose-response curve to loop diuretic agents is logarithmic, substantial increases in dose (i.e., doubling) are usually required for improved diuretic response. Urine Na+ monitoring may also be an effective strategy to guide diuretic dosing, although not yet tested in large studies.
  6. Responding to increasing serum creatinine during diuretic therapy for congestion: Although clinical context is key, increases in serum creatinine (up to a 0.5 mg/dl increase) during diuretic treatment are common and do not always necessitate stopping or decreasing loop diuretic dosing, especially if congestion is persistent. Clinical trial data suggest that such changes are usually transient and associated with similar or even better long-term outcomes in the setting of effective decongestion.
  7. Diuretic resistance versus diuretic efficacy: A quantitative definition of diuretic resistance with utility in both clinical and research scenarios remains elusive. Qualitatively, diuretic resistance can be described as an inadequate rate/quantity of natriuresis despite an adequate diuretic regimen. A major problem in transitioning from a qualitative to a useful quantitative definition is that an adequate diuretic regimen is subjective and varies with the clinical context. Chronic diuretic treatment greatly increases the capacity of the distal nephron to reabsorb delivered sodium chloride (NaCl), leading to the secondary decline in natriuresis (the “braking phenomenon”). This process occurs in every patient given a diuretic agent, as net NaCl excretion returns to equal NaCl intake at steady state; when this occurs despite persistent congestion, these same mechanisms contribute to diuretic resistance.
  8. Dealing with diuretic resistance: Identification of the resistance mechanism(s) can facilitate individualized strategies to improve diuretic response. Combination nephron blockade by adding a thiazide-like diuretic agent (most often metolazone) to loop diuretic agents often results in robust diuresis, but there is substantial risk of electrolyte abnormalities with this approach. The dose of loop diuretic agent at which combination nephron blockade should be initiated is an area of uncertainty. Other combination strategies with loop diuretic agents are being or have been tried in patients refractory to standard approaches including acetazolamide (ongoing ADVOR trial), diuretic doses of mineralocorticoid receptor antagonists, e.g., >50 mg/d spironolactone (ATHENA-HF trial), low-dose dopamine in HF with reserved ejection fraction (ROSE-AHF trial), low-dose nesiritide, tolvaptan, and SGLT-2 inhibitors.
  9. Adjusting chronic loop diuretic dosing during optimization of guideline-directed medical therapy (GDMT): In general, the goal of long-term dosing is use of the lowest dose that permits effective maintenance of volume status. Optimization of GDMT may allow reduction in loop diuretic dosing, and dose reduction may be required to mitigate the risk of hypotension or volume depletion (i.e., after initiation of sacubitril-valsartan).
  10. Withdrawal of diuretics: Observational data suggest that HF patients who can be managed chronically without a loop diuretic agent generally have a good prognosis. One question that arises clinically, but for which there are very little data, is whether oral diuretic agents can be withdrawn in patients with HF who are clinically stable.


Kudos to the authors who succinctly discuss pathophysiology and practical facets of diuretic therapy for patients with HF—a MUST read for those managing HF patients.

Clinical Topics: Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure

Keywords: Acetazolamide, Aminobutyrates, Cardiac Output, Creatinine, Diuresis, Diuretics, Furosemide, Glomerular Filtration Rate, Heart Failure, Hypotension, Kidney Diseases, Pharmacology, Renal Circulation, Renal Insufficiency, Chronic, Renin-Angiotensin System, Sodium Chloride, Sodium Potassium Chloride Symporter Inhibitors, Spironolactone

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