Diuretics and Heart Failure Technique

Diuretics are a mainstay of the outpatient management of heart failure. Most patients with advanced heart failure require diuretics daily in order to maintain fluid balance. Sodium restriction, typically less than 2 g daily, is essential. Each clinical visit should include weight measurement and targeted questioning regarding diuretic effectiveness. Electrolytes and renal function need to be frequently monitored during diuretic titration and at least every 6 months in patients on stable long-term diuretics.

One of the most common outpatient regimens is once daily furosemide. However, given its serum half-life of only 1.5 hours, the kidney is not exposed to diuretics for an extended period of time and is still avidly retaining sodium and free water. More frequent dosing intervals of furosemide should thus be considered. Patients who become less responsive to a specific diuretic may benefit from switching to another agent in the same class. An increase in effective dose may indicate diuretic resistance. Additionally, failure to restrict dietary sodium intake and usage of nonsteroidal anti-inflammatory drugs (NSAIDs) must also be considered.

Patients with high medical literacy can be instructed to weigh themselves at home daily and titrate their own diuretic doses. If they record weight gain of 2-3 lbs over a 24-hour period, they can take an extra dose of diuretic and call their physician. Such an approach helps detect hypervolemia before symptoms develop and may prevent full exacerbations.

A cohort study that included 2,761 patients hospitalized for acute heart failure who were divided in early and delayed “door-to-diuretic times” (≤60 min and >60 min) reported that the early or delayed timing of diuretics initiation was not associated with clinical outcomes. ^[12]

In the inpatient treatment of acute decompensated heart failure, an intravenous (IV) dose of a loop diuretic is typically given. IV dosing has more rapid onset of action and predictable pharmacokinetics than oral dosing. Limited data are available to direct the use of diuretics, and most recommendations are based on consensus opinions. ^[13] When choosing the dosing regimen, consider both the dose and frequency. A threshold effect is common. For example, if a 40 mg furosemide bolus fails to result in significant diuresis, continuing to use the 40 mg dose every 6 hours is unlikely to be effective. Many would recommend doubling the dose to 80 mg, assuring its efficacy, and then choosing a dosing interval.

The serum half-life of the drug must be considered when selecting the dosing interval. For example, the serum half-life of IV furosemide is 1.5 hours; therefore, by 6 hours (4 half-lives), the effects of furosemide would be expected to be minimal. Renal failure frequently accompanies heart failure exacerbations. The selected dose needs to be progressively higher as the GFR decreases. Diuretic dose has proven to be a reliable indicator of heart failure severity. ^[14]

Relatively few trials have explored differences in efficacy among the loop diuretics in treating heart failure. Among open-label studies comparing torsemide to furosemide, one demonstrated decreased mortality, one showed decreased heart failure hospitalizations, and two found improvement in New York Heart Association functional class. ^{[15, 16, 17]} One small open-label study comparing bumetanide to furosemide revealed no significant difference in signs or symptoms of heart failure. ^[18]

The multicenter DOSE study explored the effects of high dose versus low dose diuretic use in acute decompensated heart failure. High-dose furosemide led to greater diuresis and improvement in overall symptoms compared to a low-dose regimen. Renal dysfunction was more common in the high-dose group, although at 60 days follow-up, creatinine levels were similar in both groups. ^[19]

Continuous diuretic infusion is an alternative to bolus injection. Continuous infusion prevents the rapid fluctuations in intravascular volume status and concomitant sympathetic activation that commonly occurs after a bolus dose. Continuous infusion also ensures that the nephrons are continuously exposed to a therapeutic dose of diuretic. Furthermore, continuous infusion may lead to an overall lower diuretic dose, limiting toxicity such as ototoxicity. The DOSE study was the most comprehensive trial to investigate the effects of continuous versus bolus diuretic dosing regimens in acute decompensated heart failure. ^[19] No difference in the primary end-point of patient symptoms or change in serum creatinine concentration was seen. However, the total dose of diuretics was lower in the continuous infusion arm.

In patients who have limited response either to higher bolus dosing or continuous infusion of loop diuretics, a thiazide diuretic can be added to achieve what has been termed sequential nephron blockade. Common agents include chlorothiazide, hydrochlorothiazide, and the thiazide-like diuretic metolazone. Adjunctive use of thiazides can overcome the resistance to loop diuretics associated with reactive hypertrophy of the distal convoluted tubule (DCT) of the nephron. By blocking the Na-Cl channel in the DCT, they hinder the avid sodium reabsorption that limits loop diuretic efficacy. Numerous studies have demonstrated augmented diuresis with a combined loop/thiazide diuretic regimen. ^[20] Across studies, the efficacy appears similar regardless of the specific thiazide or loop diuretics used.

Many physicians dose metolazone 30 minutes prior to dosing the loop diuretic to ensure the distal Na-Cl channel is already blocked when the increased sodium reaches the DCT. However, no evidence suggests that timing of metolazone dose has any effect. Moreover, particularly in edematous patients the absorption of metolazone varies and can take several hours to reach peak concentration. ^[21] For patients who have a significantly reduced GFR or diuretic resistance, sequential nephron blockade can be extended to include the proximal convoluted tubule, with acetazolamide, and the cortical collecting duct, with spironolactone. No clinical study demonstrated whether such a regimen improves diuresis, symptoms, or clinical outcomes.

Combining loop and thiazide diuretics does carry certain risks that are necessary to consider. The markedly increased sodium delivery to the cortical collecting duct leads to a significant potassium wasting. Frequently monitor potassium, often twice daily, and aggressively replete. Excessive urine chloride loss can lead to hypochloremic metabolic alkalosis. Additionally, the rapid decrease in intravascular volume can precipitate hypotension. Increases in serum creatinine frequently occur secondary to prerenal physiology. Temporary discontinuation of both the loop and thiazide diuretics may be necessary in the setting of massive diuresis or potassium loss.

Determining the appropriate end-point for diuresis can be challenging. Clinical symptoms, (dyspnea, edema), exam (jugular venous pulse, edema, crackles), and laboratory values should be used to guide therapy. Often physicians will stop active diuresis once the BUN levels begin to rise. The patient’s weight should be measured at this point and be documented as the patients euvolemic (or “dry”) weight. Prior to discharge, the diuretics should be converted from an intravenous to an oral regimen. Because oral efficacy can be hard to predict, monitor the patients in the hospital for a day on the oral regimen to determine the dose efficacy.

The aldosterone antagonists spironolactone and eplerenone have been shown to be effective therapies for chronic heart failure, based on the RALES and EPHESUS studies. ^{[22, 23]} Although these agents are technically diuretics, at the low doses studied, the primary effect of these drugs lies in their inhibition of aldosterone rather than diuretic action. They may be beneficial in counteracting the hypokalemia from loop diuretics. They may also enhance diuresis in the resistant patient, but there is no outcomes data to support the use of higher dose of aldosterone antagonist diuretics in heart failure.

Vasopressin antagonists

The vasopressin antagonist tolvaptan has been studied in patients with heart failure. By inhibiting the vasopressin receptor in the distal nephron, it leads to an aquaresis. The medication is particularly appealing because it both causes volume loss and combats the hyponatremia which is common in heart failure and a poor prognostic indicator. The EVEREST trial explored the effects of short term use of tolvaptan versus placebo in addition to standard therapy (including diuretics) in acute heart failure. ^[24] Serum sodium level increased with tolvaptan use. Patients treated with tolvaptan also had more rapid improvement in symptoms, although no significant difference was noted by day 7 or discharge. The appropriate use of tolvaptan among the currently available treatments for acute heart failure remains to be determined.

Ultrafiltration

Because diuretic use in advanced heart failure can be particularly challenging, ultrafiltration (UF) has been studied as an alternative means for reducing intravascular volume and managing pulmonary congestion. The UNLOAD study was a randomized controlled trial of UF versus intravenous diuretics in patients with acute decompensated heart failure. ^[25] At 48 hours, greater weight loss was noted with UF, although dyspnea scores were similar. Additionally, no significant difference was noted in the percentage of patients who developed a rise in creatinine. Ninety-day hospital readmission was lower in patients who had received UF. Further studies need to address the optimum UF regimen, as well as safety and efficacy, before UF can be recommended routinely in the management of heart failure.

The following are contraindications to UF ^[26] :

• Evidence of hemodynamic instability
• Acute coronary syndromes, including myocardial infarction and unstable angina
• Serum creatinine level of >3.0 mg/dL
• Hematocrit of >45%