Diuretics are one of the most widely used drugs in the management of patients with heart failure, irrespective of its etiology or its severity. Their advent marked a milestone in the therapy of heart failure, amongst which drugs acting on the Loop of Henle have achieved the pre-eminent role. The first generation of these compounds, the archetype of which is frusemide, is relatively short-acting and is associated with significant kaliuresis. It also exhibits high intra-patient and inter-patient variability in bioavailability. Recently, a long-acting loop diuretic, torsemide has been introduced. This newsletter reviews how the introduction of torsemide has revolutionized the therapy of heart failure.

The bioavailability, pharmacokinetics and pharmacodynamics of torsemide and frusemide were determined in a randomized crossover clinical trial in 16 patients with compensated heart failure (2). Unlike frusemide which showed a delayed Tmax, the rapidity of onset of effect was not affected (Table). Bioavailability of torsemide was also greater and less variable than that of frusemide. This high bioavailability also ensures that the change from intravenous therapy to oral therapy becomes easier as both the doses are equivalent. Torsemide also has a longer duration of action as compared to frusemide because of its longer half-life.

References
1. Clin Pharmacokinet 1998; 34: 1-24
2. Clin Pharmacol Ther 1995; 57: 601-609

Single 20 mg intravenous doses of torsemide or frusemide administered to 21 patients with severe acute congestive heart failure resulted in comparable reductions in left ventricular preload as measured by pulmonary capillary wedge pressure and pulmonary arterial pressure (1). However, reduction in right atrial pressure (implying a greater reduction in preload) was greater with torsemide.

Reference: Drugs1991: 41(1): 81-103

111 patients were statistically evaluated. 54 patients started with 5 mg torsemide, 35 of them continued on this dose till the end of the study (group 1.1). In the remaining 19 patients, the dose was increased to 10 mg torsemide (group 1.2). 57 patients started with 10 mg and 42 continued on it till the end of the study (group 2.1); in 15 patients the dose was increased to 20 mg (group 2.2). Within the 4 groups, body weight decreased significantly. There was no significant difference in body weight either before or after treatment between the groups that received either 5 or 10 mg torsemide during the whole study. 28 patients had residual edema at the beginning of the study. In only 5 of them was this found at the end of the study, 23 became free of edema. The 83 patients without edema remained free of edema throughout the trial.

Hence, patients who were stabilized on frusemide 40 mg/day maintained disease control when switched to 5 to 20 mg/day doses of torsemide. It can also be said from this study that the status of compensation obtained with a maintenance therapy of 40 mg frusemide once daily could be maintained in all 83 patients without edema and even ameliorated in 23 out of 28 patients with residual edema with torsemide doses of 5 to 20 mg once daily.

In another study (2), the efficacy of torsemide 20 mg daily was compared with torsemide 10 mg and frusemide 40 mg daily for 6 weeks in 69 patients with chronic heart failure pretreated for 14 days with frusemide 40 mg daily. While torsemide 10 mg and frusemide 40 mg daily were equally effective in decreasing body weight, pulmonary congestion and cardiac enlargement, torsemide 20 mg was much more effective, decreasing bodyweight by a mean of 2.7 kg and increasing the proportion of patients free from edema from 9% to 83% at 6 weeks. It would appear from this study that torsemide represents a potential alternative to frusemide in patients with chronic congestive heart failure for whom diuretic therapy is indicated.

References
1. Arzneim Forschung 1988; 38: 184-187
2. Drugs 1991; 41: 81-103

Traditionally, diuretics were thought to only have a symptomatic effect in CHF patients by inducing diuresis. However, the Randomised Aldactone Evaluation Study (RALES) clearly showed that spironolactone, a diuretic with aldosterone-receptor antagonist activity, significantly reduced the incidence of mortality in CHF patients. Aldosterone activity has been shown to promote myocardial fibrosis, potassium and magnesium depletion, sympathetic activation, parasympathetic inhibition and baroreceptor dysfunction. It is possible that the anti-aldosterone effect of spironolactone may account for the reduction in mortality rate in CHF patients.

In an open-label randomized trial, Murray et al (1) tested the hypothesis that torsemide, a predictably absorbed diuretic, would have more favorable clinical outcomes than those treated with frusemide. The study was conducted in 234 patients with chronic heart failure. 113 patients received torsemide (20-80 mg) and 121 patients received frusemide (80-160 mg) for 1 year.

Compared with frusemide-treated patients, torsemide-treated patients were less likely to need readmission for heart failure or for all cardiovascular causes (Figure). Patients treated with torsemide had significantly fewer hospital days for heart failure (106 vs. 296 days). This study showed that patients with chronic heart failure who are treated with torsemide have improved clinical outcomes when compared with patients treated with frusemide.

These initial reports were further confirmed in a more recent large post-marketing surveillance study, which evaluated clinical symptoms and hospital admissions in 1750 chronic heart failure patients (2). The trial compared the 6-month period prior to starting torsemide with the 6-month period after initiation of torsemide. All patients received therapy with ACE inhibitors, and those given prior diuretic treatment (47%) were switched to torsemide. In the entire group of 1740 patients, there was a significant decrease in hospitalization rate after the initiation of torsemide, and this was noted in patients with or without prior diuretic treatment. In patients pre-treated with frusemide, 78 (18.7%) were hospitalized while receiving frusemide in the 6 months prior to the study, but only 9 (2.2%) were hospitalized in the 6 months after torsemide treatment was initiated.

Another large post-marketing surveillance study evaluated clinical symptoms in 1740 CHF people, comparing the 6-month period prior to starting torsemide with the 6-month period after initiation of torsemide (2). All patients received therapy with ACE inhibitors, and those given prior diuretic treatment (47%) were switched to torsemide. At the end of the study period nearly all patients had experienced improvement in clinical symptoms, and NYHA class improved in 75% of patients. Among patients who were pretreated with frusemide (n=418), 71% showed improvement in NYHA class 6 months after switching to torsemide.

In a retrospective study of 400 patients with congestive heart failure, greater proportion of torsemide recipients showed improvement in NYHA class as compared to frusemide recipients (38% vs. 24%) (2).

Several studies (1) have demonstrated that torsemide reduces the risk of hypokalemia in patients of CHF as compared to those treated with frusemide. Hypokalemia remains the main drawback among the existing loop diuretics as it can predispose a patient to severe electrolyte disturbances and fatal arrhythmias.

In the TORIC study (2), abnormal potassium levels (<3.5 mEq/l or >5 mEq/l) were reported in a significantly lower proportion of torsemide patients (12.9%) than patients receiving frusemide/other diuretics (17.9%). Throughout treatment, the mean serum potassium levels were higher in the torsemide group than in the frusemide group (Figure). Only 3% of patients treated with torsemide received potassium supplements vs. 30% of patients treated with frusemide/other diuretics. These results clearly suggest that torsemide is associated with a lower incidence of hypokalemia.

The antialdosterone effect of torsemide may be responsible for the lesser risk of hypokalemia observed with torsemide.

References
1. Pharmacotherapy 1995; 14: 514-521
2. Eur J Heart Fail 2002; 4: 507-513

CHF is a large burden on healthcare resources. Drug acquisition costs represent a relatively small proportion of the total costs of the disease. By far, the largest components of costs of treatment of CHF are associated with hospital admissions and long-term institutional nursing care. Reducing hospitalization rates and functional impairment due to CHF symptoms should be the means to obtaining cost saving in CHF treatment.

Diuretics are commonly used to treat volume overload in the management of CHF and it is estimated that 70% of patients with CHF are prescribed diuretics. Yet, despite this, one retrospective study of CHF hospital admissions found that 57% admissions were due to sodium retention leading to volume overload. Judicious use of diuretics can relieve sodium retention leading to pulmonary congestion and peripheral edema, and thus potentially keep patients out of the hospital.

There is sufficient data on cost effectiveness of torsemide in the management of CHF. Most studies suggest that torsemide reduces hospital admission costs due to CHF compared to frusemide. The primary factor that reduces cost with torsemide is reduced hospital admissions and readmissions. Thus, even if the drug acquisition cost of torsemide is slightly higher than frusemide, torsemide is more cost-effective due to decreased incidence of hospitalisations and lesser hospital days.

Reference
Pharmacoeconomics 2001; 19: 679-703