What are the causes and management strategies for diuretic resistance in heart failure (HF)?

From the Guidelines

Diuretic resistance in heart failure should be managed by escalating the dose of loop diuretics, such as furosemide, up to 600 mg daily, or switching to other loop diuretics like torsemide, and considering combination therapy with thiazide diuretics like metolazone, as recommended by the 2022 AHA/ACC/HFSA guideline 1. To address diuretic resistance, several strategies can be employed, including:

• Escalating the dose of the current loop diuretic, with furosemide doses up to 600 mg daily, as outlined in the guideline 1
• Switching to other loop diuretics like torsemide, which has increased oral bioavailability compared to furosemide 1
• Considering combination therapy with thiazide diuretics like metolazone, which can create sequential nephron blockade and enhance diuresis 1
• Addressing underlying causes of resistance, such as optimizing heart failure therapy, correcting hyponatremia, restricting sodium intake, and ensuring adequate blood pressure to maintain renal perfusion The choice of diuretic and dosing strategy should be individualized based on patient factors, such as renal function and sodium intake, as well as the specific characteristics of the diuretic, including its duration of action and potential for adverse effects, as outlined in the guideline 1. Key considerations in managing diuretic resistance include:
• Monitoring urine output and weight to assess response to diuretic therapy
• Adjusting diuretic doses and combinations based on patient response and tolerance
• Addressing potential causes of diuretic resistance, such as NSAID use or significant impairment of renal function or perfusion, as noted in the guideline 1

From the FDA Drug Label

1. 1 Treatment of Edema Edema associated with heart failure The recommended initial dose is 10 mg or 20 mg oral torsemide tablets once daily. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained.

• Diuretic Resistance in Heart Failure: The drug label does not directly address the concept of "diuretic resistance" in heart failure. However, it provides guidance on titrating the dose of torsemide if the diuretic response is inadequate.
• Management Approach: If a patient with heart failure does not respond adequately to the initial dose of torsemide, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained, without exceeding the maximum studied dose of 200 mg. 2

From the Research

Definition and Prevalence of Diuretic Resistance

• Diuretic resistance (DR) is a significant challenge in the treatment of heart failure, with a prevalence estimated to be around 25-30% of patients with heart failure 3.
• The development of diuretic resistance remains a significant challenge in the treatment of heart failure, with certain characteristics such as low systolic blood pressures, renal impairment, and atherosclerotic disease helping to predict its development 3.

Pathophysiology of Diuretic Resistance

• The underlying pathophysiology of diuretic resistance is likely multifactorial, with pharmacokinetic alterations, hormonal dysregulation, and the cardiorenal syndrome having significant roles 3.
• Decreases in renal perfusion and alterations in sodium handling that occur in an attempt to maintain circulatory homeostasis also contribute to diuretic resistance in patients with advanced heart failure 4.
• Erratic oral absorption in congested states and postdiuretic sodium retention are also thought to contribute to diuretic resistance 4.

Management of Diuretic Resistance

• The therapeutic approach to diuretic resistance typically involves increases in the diuretic dose and/or frequency, sequential nephron blockade, and mechanical fluid movement removal with ultrafiltration or peritoneal dialysis 3.
• Combination diuretic therapy may be useful to overcome increased sodium retention, and dopamine may improve renal perfusion 4.
• Intravenous diuretic administration, increasing diuretic doses, or changing diuretic agents can potentially overcome pharmacokinetic obstacles which contribute to drug resistance 4.
• Loop diuretics, such as furosemide and torasemide, are commonly used in the treatment of heart failure, with torasemide having different pharmacokinetic properties and additional effects compared to furosemide 5.

Predictors of Diuretic Resistance

• Certain characteristics, including low systolic blood pressures, renal impairment, and atherosclerotic disease, help predict the development of diuretic resistance 3.
• The analysis of data from selected papers demonstrated that diuretic resistance is common in hospitalized patients with advanced CHF and frequently associated with renal failure, which is secondary to CHF 6.
• Diuretic resistance appears to be common in patients with advanced CHF and it is mostly due to decreased cardiac output, low blood pressure, decreased glomerular filtration rate, decreased filtration of sodium, and increased tubular reabsorption of sodium 6.