Download file (Class Review: Loop Diuretics)

Nick Wytiaz
University of Pittsburgh
Allegheny General Hospital
March 11, 2012
[email protected]
THERAPEUTIC CLASS REVIEW: LOOP DIURETICS IN HEART FAILURE
I.
Overview
Loop diuretics are used in the management of edema associated with congestive heart failure (CHF),
cirrhosis, and renal disease, including the nephrotic syndrome. Four loop diuretics are currently available in
the US: bumetanide, ethacrynic acid, furosemide, and torsemide.
Multiple clinical trials have demonstrated the ability of loop diuretics to increase urinary sodium excretion
while attenuating the physical symptoms associated with volume overload in patients with CHF1. Given their
clinical effects, loop diuretics are recommended as first-line therapy for “patients admitted to the hospital
with HF and evidence of significant fluid overload”1.
II.
Pharmacology / Pharmacokinetics
All loop diuretics work by inhibiting the Na-K-Cl transporter at the luminal surface in the ascending limb of
the Loop of Henle, resulting in decreased reabsorption of Na, Cl, and water.2. In addition, furosemide is
thought to also exert its action by interfering with the Na-K pump and anion exchange while ethacrynic acid
may also work via an additional mechanism unique of the other three1.
Table 1. Pharmacokinetic Properties of Loop Diuretics3
Property
Furosemide
Bumetanide
Bioavailability (%)
10-100 (avg 50)
80-100
Affected by food
Yes
Yes
Metabolism
50% renal
50% hepatic
Half-Life (h)
1.5-2
1
- renal dysfunction
2.8
1.6
- hepatic dysfunction
2.5
2.3
- heart failure
2.7
1.3
Onset (min)
- PO
30-60
30-60
- IV
5
2-3
Elimination
88% renal
81% renal
12% hepatic
2% hepatic
Torsemide
80-100
No
80% hepatic
3-4
4-5
8
6
Ethacrynic Acid
~100
No
hepatic
1
unavailable
unavailable
unavailable
30-60
unavailable
24% renal
30-60
5
67% renal
33% hepatic
While all loop diuretics are similar in time of onset, peak effect, and duration of action, differences exist in
metabolism, half-life, elimination, bioavailability, and the effect of food on absorption1. Bioavailability is least
predictable with furosemide, while half-life is longest with torsemide. Differences in metabolism and
excretion may also provide advantages of one agent over another in certain disease states (i.e. torsemide in
hepatic impairment and HF). Based solely on pharmacokinetic properties, furosemide seems to be inferior to
the other three agents. However, the clinical significance of these differences must be defined.
III.
Safety / Adverse Effects
Loop diuretic therapies are most often associated with electrolyte imbalances, the most common of which are
hypokalemia, hypomagnesaemia, hyponatremia and hypochloremia. The risk of electrolyte imbalances is
similar between the four agents, each of which carries a FDA Black Box Warning for the danger. Differences,
however, are seen in other adverse effects. Ototoxicity is most common in ethacrynic acid and, as a result,
greatly limits its routine use3. Furosemide is also associated with ototoxicity, though to a lesser degree than
ethacrynic acid. Long-term torsemide treatment of cirrhosis with ascites has been associated with the onset
of encephalopathy.
IV.
Efficacy / Comparative Effectiveness
Multiple studies have sought to assess the efficacy of furosemide vs. torsemide in the treatment of patients
with heart failure. Summaries of the trials are as follows:
1. Murray et al4. assessed the impact of furosemide and torsemide on hospital readmissions secondary to HF
exacerbations over a 12-month period. Overall demographics were similar between the groups, the only
difference being an increase in previous hospital admissions for HF in the torsemide group vs. the furosemide
group (25% vs 11%; p = 0.01). The study demonstrated that patients in the torsemide group were
significantly less likely to be readmitted for HF and for all CV causes. The torsemide group also experienced
fewer inpatient days and had less fatigue. The authors largely attributed the benefit to the more reliable
absorption of torsemide, compared with furosemide. Limitations of the study include open-label design, small
sample size, and a localized population. A majority of the patients were female and African American, which
may not be consistent with the overall population for HF.
2. Cosin et al5. conducted a study assessing mortality in 1377 patients with NYHA Class II–III HF from 231
centers in Spain who were receiving torsemide 10mg, furosemide 40mg. or other diuretics at the
recommended daily dosages for 12 months. Existing concomitant HF medications were continued and
documented during the study. Baseline characteristics did not differ significantly except that patients in the
furosemide and/or other diuretic group were more likely to be on other concurrent diuretic therapy (7.4% vs
0.9% in the torsemide group). The study showed that patients in the torsemide group had a significantly
lower overall and cardiac mortality rate. The proportion of patients showing a functional improvement in
NYHA class was also significantly greater in the torsemide group. Both groups showed a significant decrease
in potassium levels when compared with baseline. However, only 3% of torsemide patients vs. 30% of
furosemide/other diuretics patients required potassium supplementation, indicating that torsemide may
produce a lower incidence of hypokalemia. The authors concluded that torsemide may offer improvements in
mortality, morbidity, and functional improvement over furosemide/other diuretics. Limitations include the
inclusion of the “other diuretics” group in the furosemide data and open-label / cohort study design.
3. Muller et al6. conducted a study randomizing 237 hospitalized patients with NYHA Class II–IV HF to receive
either torsemide or furosemide, dosed at the discretion of the prescribing physician. Patients were followed
for 9 months. Five major HF symptoms (dyspnea, pulmonary rales, edema, nocturia, orthopnea) were rated
for severity. Prescribing physicians also rated the overall efficacy and tolerability as zero (bad) to 3 (very
good). Quality of life (QoL) was assessed monthly by phone calls using a simple questionnaire. Baseline
characteristics did not differ significantly, except that more patients in the furosemide group had renal
insufficiency (defined by SCr > 1.35 mg/dL). Results showed that only torsemide resulted in a statistically
significant overall improvement in NYHA functional class. No significant difference was seen between the two
groups in mean severity scores of HF symptoms or in the overall efficacy of therapy, as rated by treating
physicians. No significant differences were noted in rate of hospitalization or mortality. Neither treatment
had statistically relevant changes in potassium, magnesium, or urea. The authors concluded that torsemide
exhibits greater efficacy in reducing functional and social limitations associated with diuretic therapy when
compared with furosemide in patients with NYHA Classes II–IV HF. Additionally, torsemide appeared to
improve QoL more than furosemide. Limitations included open-label, subjective scales to determine QoL,
small sample size, and short duration.
4. Ramsay et al7. conducted a trial comparing a furosemide/ amiloride combination with a
bumetanide/potassium combination in 40 patients receiving outpatient treatment of HF. Study outcomes
included blood pressure, heart rate, body weight, dyspnea at rest and on exertion, orthopnea, edema,
patients’ and investigators’ global impression of the patients’ condition, and patients’ overall satisfaction with
treatment. Results showed that the bumetanide group showed a statistically significant improvement in
dyspnea at rest and on exertion compared with baseline. Improvements were also seen in the global
assessments of both groups. However, the bumetanide group did show a paradoxical increase in body weight.
The authors concluded that both combinations are effective treatments, but that patients taking the
furosemide combination were more satisfied with their medication. Limitations included small sample size,
comparison of a combination of diuretics (rather that a direct comparison of bumetanide and furosemide),
lack of similarity between groups at baseline, and subjective measures of efficacy.
Though limitations exist in each study, the findings suggest that torsemide may provide additional benefits
over furosemide in patients being treated for HF. However, not enough direct, comparative data is available
to assess the efficacy of furosemide vs. bumetanide or bumetanide vs. the other 3 loop diuretics.
V.
Cost-Effectiveness
Two studies were conducted comparing the cost-effectiveness of furosemide and torsemide.
1. Stroupe et al8. conducted a prospective, randomized, open-label trial to assess the healthcare expenditures
of 193 patients with HF receiving either furosemide or torsemide. Patients admitted for HF while receiving
furosemide were subsequently randomized to receive torsemide or furosemide, with dosing left at the
discretion of the attending physician. Inpatient, outpatient (including ED and pharmacy costs), and total costs
were calculated for each patient for all healthcare encounters during the 1-year period. Inpatient costs were
also calculated from all cardiovascular causes. No significant difference was observed between the torsemide
and furosemide groups for outpatient costs. A difference, however, was seen in inpatient costs, which were
significantly lower in the torsemide group for all causes (p = 0.023), all cardiovascular causes (p < 0.001), and
HF (p < 0.001). The mean total direct healthcare costs associated with HF among torsemide patients were
lower than for furosemide patients, but the difference was not statistically significant.
It is important to note that, at the time of the study, torsemide was only available as a branded product. Thus,
it can be assumed that the cost savings would be even more pronounced today now that torsemide is
available generically (Table 2). Limitations include open-label design, a largely female and African American
patient population.
2. Noe et al9. conducted a 6-month study comparing torsemide and furosemide for clinical, QoL, and
pharmacoeconomic outcomes in 240 patients with NYHA Classes II–III HF. Results showed clinical outcomes,
changes in NYHA functional class, all-cause mortality, CV mortality, and adverse events to be similar between
the two groups. As for the economic outcomes, cost associated with acquisition of the therapies was
significantly higher in the torsemide group. However, no significant differences were seen in costs related to
total HF/CV medications, HF-related physician visits, and CV-related hospitalizations. The authors concluded
that neither torsemide nor furosemide provided a significant cost advantage over the other.
Given the results of these two studies, their limitations, and the lack of additional pharmacoeconomic data, a
clear cost benefit cannot be established for one loop diuretic over another. Aside from pharmacoeconomic
studies, drug acquisition costs show little difference between the three generically available agents. Only
ethacrynic acid (Edecrin) is not available generically and, thus, has a much higher acquisition cost (Table 2).
VI.
Summary
Table 2. Summary Comparison of Loop Diuretics3
Medication
Indications
Initial Dose
Bumetanide
Edema from
PO: 0.5-2mg x1,
(Bumex)
HF, liver, or
redoes in 4-5h PRN
kidney disease Schedule BID – TID
PO: 0.5, 1, 2 mg
Max: 10mg/day
tabs
IV: 0.5-1mg
IM/IV:
Max: 10mg/day
0.25mg/mL
Ethacrynic acid - Edema from
PO: 50mg QD or
(Edecrin)
HF, liver, or
0.5-1 mg/kg/day
kidney disease Max: 200mg BID
PO: 25mg
- Short-term
IV: 50mg or 0.5
IV
management
mg/kg/dose x1
of ascites
Max: 100mg/dose
Furosemide
- Edema from
PO: Edema
Cost (AWP)
Generic:
1mg tab: $0.45
1mg/4mL inj:
$1.75
Comments
- 1mg = 40mg furosemide
- Little comparative data with
other agents
Brand:
25mg tab: $3.78
50mg inj:
$731.23
- Consider in pts unresponsive to
other diuretics given unique MOA
- More ototoxicity than other loops
- Only loop without a sulfa group in
chemical makeup. May be useful
for pts with sulfa allergies or
allergic reaction to other loop or
thiazide diuretics.
- BID dosing preferred for most
*No generic
available
Generic:
(Lasix)
PO: 20, 40, 80
mg tabs; 10
mg/mL susp
IM/IV
Torsemide
(Demadex)
PO: 5, 10, 20,
100mg tabs
IV
HF, liver, or
kidney disease
- Mild-mod
HTN alone or
in combo
- Edema from
HF, liver, or
kidney disease
- Mild-mod
HTN alone or
in combo
20-80mg x1
Schedule QD-BID
Max:600mg/day
40mg tab: $0.16
40mg/4mL:
$1.38
due to shorter duration
Generic:
10mg tab: $0.70
20mg/2mL vial:
$8.76
- 20mg = 40mg furosemide
Better absorbed than furosemide
- May have benefit in HF
HTN
20-40mg BID
IV/IM: 20-40mg x1
Schedule QD-BID
Max: 100mg/day
PO/IV:
HF or Renal Disease
10-20mg QD
Max: 200mg/dose
Cirrhosis
5-10mg QD initially
Max=40mg/dose
HTN
5mg QD initially
Max: 10mg/day
While the most commonly used loop diuretic for the treatment of HF is furosemide, other agents may provide
a benefit in certain individuals. ACC/AHA Guidelines mention that some patients might respond more
favorably to torsemide because of the drug’s superior absorption and prolonged duration of action. 2
Studies have found that torsemide decreases left-ventricular remodeling, improves outcomes, and decreases
mortality compared with furosemide in patients with HF. 3 Additionally, both torsemide and bumetanide have
better oral bioavailability and also appear to be less affected by food when compared with furosemide. The
superior bioavailability is thought to be the primary reason torsemide showed decreased rates of
hospitalization in the treatment of HF when compared with furosemide.
As for bumetanide, the lack of studies and data make it difficult to draw conclusions and recommendations
for using bumetanide over furosemide and/or torsemide. In reviewing safety, all loop diuretics seem to have
comparable risks of electrolyte imbalances. However, ethacrynic acid is associated with and increased risk of
ototoxicity. In comparing costs, ethacrynic acid, which is only available as a branded product, has by far the
highest acquisition cost. Based on pharmacoeconomic studies, torsemide may provide a potential cost savings
when compared to furosemide.
Based on pharmacokinetic characteristics, safety and efficacy data, and cost comparison, torsemide may
provide a benefit over furosemide for patients with edema associated with HF. However, this review is
limited to the use of loop diuretics in heart failure, so conclusions should not be extrapolated to other
indications such as hypertension or edema from liver or kidney disease.
References:
1. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM,
Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW. 2009 focused update incorporated into the
ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the
American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J
Am Coll Cardiol. 2009;53:e1–90.
2. Min B, White CM. A review of critical differences among loop, thiazide, and thiazide-like diurectics. Hosp
Pharm. 2009;44(2):129-149.
2. PL Detail-Document. Comparison of Commonly Used Diuretics. Pharmacist’s Letter/Prescriber’s Letter.
February 2012.
3. Wargo KA, Banta WM. A comprehensive review of the loop diuretics: should furosemide be first line? Ann
Pharmacother. 2009;43:1836-47.
4. Murray MD, Deer MM, Ferguson JA, et al. Open-label randomized trial of torsemide compared with
furosemide therapy for patients with heart failure. Am J Med. 2001;111:513-20.
5. Cosin J, Diez J, on behalf of the TORIC investigators. Torsemide in chronic heart failure: results of the TORIC
study. Eur J Heart Fail. 2002;4:507-13.
6. Müller K, Gamba G, Jaquet F, et al. Torsemide vs furosemide in primary care patients with chronic heart
failure NYHA II to IV—efficacy and quality of life. Eur J Heart Fail. 2003;5:793-801.
7. Ramsay F, Crawford RJ, Allman S, et al. An open comparative study of two diuretic combinations,
frusemide/amiloride (`Frumil') and bumetanide/potassium chloride (`Burinex'K), in the treatment of
congestive cardiac failure in hospital out-patients. Curr Med Res Opin. 1988;10:682-9.
8. Stroupe KT, Forthofer MM, Brater DC, Murray MD. Healthcare costs of patients with heart failure treated
with torsemide or furosemide. Pharmacoeconomics. 2000;17:429-40.
9. Noe LL, Vreeland MG, Pezzella SM, et al. A pharmacoeconomic assessment of torsemide and furosemide in
the treatment of patients with congestive heart failure. Clin Ther. 1999;21:854-66.