Furosemide

* Evidence-Based Answer

No large-scale randomized, placebo-controlled trials evaluate furosemide's effect on mortality and long-term morbidity in diastolic or systolic dysfunction. In short-term studies, furosemide reduces edema, reduces hospitalizations, and improves exercise capacity in the setting of systolic dysfunction (strength of recommendation [SOR]: B, based upon low-quality randomized controlled trials). Furosemide and other diuretics reduce symptomatic volume overload in diastolic and systolic dysfunction (SOR: C, based on expert opinion).

There is potential morbidity with the use of high-dose loop diuretics (volume contraction, electrolyte disturbances, and neuroendocrine activation). (1-3) Use of high-dose loop diuretics for systolic dysfunction is associated with increased mortality, sudden death, and pump failure death (SOR: B, based on retrospective analyses of large-scale randomized controlled trials). However, diuretic resistance or disease severity may explain these latter findings.

* Evidence Summary

Faris et al (4) conducted a meta-analysis of randomized controlled trials that used diuretics (pertanide, furosemide, furosemide-hydrochlorothiazide) in congestive heart failure (TABLE). (4) Of the 18 trials, 8 were placebo-controlled and 10 used active controls (diuretics vs angiotensin-converting enzyme [ACE] inhibitors, digoxin, or ibopamine, a dopamine agonist). Three placebo-controlled trials (N=221) showed an absolute risk reduction in death of 8% in diuretic-treated patients (number needed to treat [NNT]=12.5). Four placebo-controlled trials (N=448) showed a significantly lower rate of admissions for worsening failure among diuretic-treated patients (NNT=8.5), and 4 of the active-controlled trials (N=150) showed a nonsignificant trend toward decreased admissions. Six active-controlled studies (N=174) showed significantly increased exercise capacity for patients on diuretics. One of these latter trials also assessed quality of life, edema, and New York Heart Association (NYHA) class, and demonstrated no change in these outcomes in the treatment and placebo groups. (5)

The studies used in this meta-analysis had numerous shortcomings: the individual trials had small numbers of patients (N=14-139), short follow-up periods (typically 4-8 weeks), and inadequate statistical power to clearly demonstrate morbidity/mortality reductions. There was significant heterogeneity between studies. Crossover studies were included, some studies did not clearly report masking and assessment of outcome measures, and assessment of study validity was not clear. Studies employed a variety of diuretic types and doses, used different controls, and did not clarify, whether patients' congestive heart failure was caused primarily by diastolic or systolic dysfunction.

It is worth noting that diuretic use also carries some risk. One large retrospective study evaluated 6796 patients using potassium-sparing diuretics vs non-potassium-sparing diuretics in the Studies of Left Ventricular Dysfunction (SOLVD) trial. (6) Rates of hospitalization or death from worsening congestive heart failure were significantly higher in the non-potassium-sparing diuretic population than in the nondiuretic population (relative risk [RR]=l.31, 95% confidence interval [CI], 1.09-1.57; number needed to harm=5.78). This increased risk was not found for patients taking potassium-sparing diuretics (RR=0.99; 95% CI, 0.76-1.30).

Another retrospective study of SOLVD patients found a significant and independent association with increased risk of arrhythmic death among patients taking non-potassium-sparing diuretics (RR=1.33; 95% CI, 1.05-1.69). (7)

A retrospective study of 1153 patients with NYHA Class III to IV heart failure, who were enrolled in the Prospective Randomized Amlodipine Survival Evaluation (PRAISE), found high diuretic doses to be independently associated with mortality (adjusted hazard ratio [HR]=1.37; P=.004), sudden death (HR=l.39; P=.042), and pump failure death (HR=I.51; P=.034). (8)

The authors caution that there is no proof of causation between furosemide and death; diuretic resistance may explain the poor outcomes, or the use of loop diuretics at high doses may be proxy of more severe illness, and thus poorer outcome.

* Recommendations from Others

The American College of Cardiology recommends using diuretics in the setting of left ventricular systolic dysfunction and fluid retention (level of evidence [LOE]: A), and recommends using diuretics in diastolic dysfunction to control pulmonary congestion and peripheral edema (LOE: C). (9)

The European Society of Cardiology notes that no randomized controlled trials have assessed survival effects of diuretics in congestive heart failure, but recommends using diuretics for symptomatic treatment of volume overload (LOE: A). This society also cites evidence that diuretic use improves exercise tolerance (LOE: B). They recommend that diuretics be used always in addition to an ACE inhibitor, that loop diuretics be used if symptoms are more than mild and if glomerular filtration rate (GFR) <30 cc/min, and that thiazide diuretics can be used with loop diuretics for synergistic effects in severe congestive heart failure. (10)

REFERENCES

(1.) Reyes AJ. Diuretics in the treatment of patients who present congestive heart failure and hypertension. J Hum Hypertens 2002; 16 Suppl 1:S104-S113.

(2.) van Kraaij D J, Jansen RW, Gribnau FW, Hoefnagels WH. Diuretic therapy in elderly heart failure patients with and without left ventricular systolic dysfunction. Drugs Aging 2000; 16:289-300.

(3.) Kramer BK, Schweda F, Riegger GAJ. Diuretic treatment and diuretic resistance in heart failure. Am J Med 1999; 106:90-96.

(4.) Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A. Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials. Int J Cardiol 2002; 82:149-158.

(5.) Parker JO. The effects of oral ibopamine in patients with mild heart failure--a double blind placebo controlled comparison to furosemide. The Ibopamine Study Group. Int J Cardiol 1993; 40: 221-227.

(6.) Domanski M, Norman J, Pitt B, et al. Diuretic use, progressive heart failure, and death in patients in the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coil Cardiol 2003; 42:705-708.

(7.) Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999; 100:1311-1315.

(8.) Neuberg GW, Miller AB, O'Connor CM, et al. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J 2002; 144:31-38.

(9.) Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001. American College of Cardiology. Last updated March 12, 2002. Available at: www.acc.org/clinical/guidelines/failure/hf_index.htm. Accessed on March 4, 2005.

(10.) Remme WJ, Swedberg K; Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22:1527-1560.

* Clinical Commentary

Helpful in the acute setting, diuretics shouldn't be used alone chronically

Furosemide and the other loop diuretics are very satisfying to use clinically. The patient in heart failure arrives at the hospital dypsneic, cyanotic, and terrified. After a single large dose of medication, the patient diureses and begins to feel good again quite quickly.

The practitioner, however, needs to be wary of the resulting impression that diuretics are "good" for heart failure. ACE inhibitors, beta blockers, and (in severe cases) spironolactone are "good" for heart failure because they prolong lives. One must not allow diuretic therapy--started for acute decompensation--to prevent use of more important long-term medications by causing dehydration, hypotension, or electrolyte disturbances.

Jon Neher, MD, Valley Medical Center, Renton, Wash

Amrit Singh, MD, Jean Blackwell, MLS, University of North Carolina, Chapel Hill

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