Diuretics and Heart Failure

Congestive heart failure (CHF) is one of the most common chronic conditions in the United States, affecting an estimated 5.7 million people[1] and is the leading diagnosis for hospitalized patients. The most frequent presenting symptom for patients with CHF is dyspnea, which is often attributed to pulmonary edema and occurs in 93% of patients.[2] The second most frequent symptom is peripheral edema, occurring in 70%.[2] Naturally, one of the mainstays of therapy has been to target hypervolemia through the use of diuretics.

The therapeutic effects of diuretics have been known for centuries, and they were perhaps the first treatment available for CHF. As early as the 1600s, mercurial-based diuretics were used for the treatment of edema, termed dropsy. The 20th century saw the advent of carbonic anhydrase inhibitors, followed by thiazide diuretics, and finally loop diuretics. Currently, diuretics remain some of the most commonly prescribed drugs in the United States. Diuretics have proven to be an integral component to the treatment of acute and chronic heart failure, and their use has been extensively studied. Their efficacy in improving symptoms such as dyspnea and edema is clear; however, little data support a mortality benefit or an alteration in disease progression.

For many years, diuretics have been the cornerstone for treatment of both acute and chronic heart failure. Guidelines for the use of diuretics in both the inpatient and outpatient setting are largely based on expert opinion. Diuretics clearly improve hemodynamics and symptoms, although many studies have not been able to demonstrate a mortality benefit. In part, their effectiveness may be limited by adverse effects including electrolyte imbalances and neurohormonal activation. As new treatments for heart failure emerge, future research must address how diuretics fits into the armamentarium.

Pharmacology

Knowledge of the pharmacology of diuretics is essential in understanding their function in the management of heart failure. The current available loop diuretics are furosemide, torsemide, bumetanide, and ethacrynic acid. They inhibit the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle. By effectively inhibiting sodium reabsorption, they also reduce water reabsorption. The loop diuretics bind to the luminal surface of the transporter; thus, they must be secreted into the tubular lumen. As the glomerular filtration rate is reduced, luminal secretion is decreased, and less drug reaches the active site.[3]

Oral absorption of furosemide widely varies. Bumetanide and torsemide have greater bioavailability and more predictable pharmacokinetics. All of the loop diuretics except ethacrynic acid contain a sulfonamide group. Individuals who are allergic to sulfonamide antibiotics may be allergic to sulfonamide diuretics, although recent research suggests that the cross-reactivity is low.[4] Ethacrynic acid is rarely used other than in individuals with sulfa allergies.

Thiazide diuretics are most commonly used to treat hypertension, although they can be adjuncts in the management of heart failure. They inhibit the Na-Cl symporter in the distal convoluted tubule, leading to decreased sodium and water reabsorption. Spironolactone inhibits the aldosterone receptor in the cortical collecting duct, also limiting sodium and water reabsorption. Its diuretic effect is relatively weak, and its onset of action is slow.

Mechanism of action

The pulmonary and peripheral edema seen in CHF are the result of multiple physiologic disturbances. Decreased cardiac output leads to relative renal hypoperfusion that stimulates neurohormonal activation of the renin-angiotensin-aldosterone axis. Sodium and free water retention occur, resulting in an increase in both volume and pressure in capacitance vessels. Hydrostatic pressure elevation leads to fluid extravasation into peripheral tissues as well as the lungs.

The Frank-Starling law describes the mechanism whereby a normal heart under a physiologic range of filling pressures increases stroke volume proportionally with an increase in preload. In contrast, in acute decompensated heart failure, a myopathic heart subjected to very elevated filling pressures is not able to effectively increase stroke volume. Acute elevation of left ventricular preload (end-diastolic pressure) directly leads to elevated left atrial pressures and pulmonary edema. Diuretics reduce intravascular volume, leading to a decrease in central venous pressure, right and left heart filling pressures, and pulmonary vascular pressures. Venous capacitance increases, and intrapulmonary fluid returns to the circulation. The left ventricular volume is smaller, and cardiac output typically increases. In the setting of mitral regurgitation, the reduced left ventricular volume improves mitral leaflet coaptation and decreases the regurgitant volume.

Complication prevention

Diuretic resistance explains why some patients require high doses of diuretics or have a decreased response to diuretics over time. Several mechanisms contribute to diuretic resistance. The “braking phenomenon” refers to a short-term resistance following a bolus dose and may be related to neurohormonal activation that acts to preserve intravascular volume.[3] A longer term resistance may be due to compensatory hypertrophy of the distal convoluted tubule, which avidly reabsorbs sodium and counteracts the natriuretic effects of loop diuretics. Additionally, as the GFR decreases, a higher dose of diuretic is necessary to achieve therapeutic effect. Finally, GI absorption and subsequent bioavailability of oral diuretics may be impaired in heart failure due to bowel wall edema.

The efficacy of diuretics in improving symptoms of heart failure such as dyspnea and edema has long been documented. However, numerous studies examining the effects of diuretics on clinical outcomes in heart failure patients have generally been disappointing. Several studies have uncovered a correlation of diuretic dose with renal dysfunction, sudden death, hospital length of stay, and overall mortality.[5, 6, 7] However, diuretic dose itself is a marker of heart failure and renal failure severity and may not contribute directly to poor outcomes.

Diuretic use in the heart failure patient does carry certain risks. Various electrolyte abnormalities can occur. Inhibition of the Na-K-2Cl channel leads to increased sodium delivery to the distal tubule and cortical collecting duct. Via the ENaC channel (Na-K antiporter), distal sodium is reabsorbed at the expense of potassium loss, resulting in hypokalemia. Hypomagnesemia can occur as well, potentiating the hypokalemia. This imbalance may contribute to arrhythmias.

Chloride losses can lead to a hypochloremic metabolic alkalosis. Significant alkalosis can decrease respiratory drive in a patient with respiratory failure. Hyponatremia can also occur with diuretics, more commonly with thiazide than loop diuretics, and especially if large amounts of free water are ingested. Although hyponatremia itself is rarely symptomatic, its occurrence is a marker of poor prognosis.

Diuretic use can lead to worsening renal function. Whether higher diuretic doses directly lead to the development of renal failure (cardio-renal syndrome) or are simply a marker for patients at risk is debatable. Newer data suggest that renal failure is more closely associated with elevation of central venous pressure than relative intravascular volume depletion from high dose diuretics.[8]

Because diuretics acutely decrease left ventricular preload, they can lead to a reflex neurohormonal stimulation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone axis.[9] Numerous studies have determined that activation of these pathways contributes to the pathophysiology of heart failure, thus potentially undermining the benefits of diuretic use. This mechanism may also explain why various studies have failed to show a mortality benefit from diuretics use. Concurrent treatment with neurohormonal blockade (ie, vasodilators, beta blockers, renin-angiotensin-aldosterone system antagonists) may improve outcomes, although this has not been systematically studied.

A study sought to determine the use of intravenous fluids in the early care of patients with acute decompensated heart failure (HF) who are treated with loop diuretics. The study found that among 131,430 hospitalizations for HF, 13,806 (11%) were in patients treated with intravenous fluids during the first 2 days. The study concluded that many patients who are hospitalized with HF and receive diuretics also receive intravenous fluids during their early inpatient care, and the proportion varies among hospitals. Such practice is associated with worse outcomes and warrants further investigation.[10, 11]

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%