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 al4 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]=1.31, 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=1.39; P=.042), and pump failure death (HR=1.51; 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.
TABLE
Clinical effects of diuretics in congestive heart failure
| OUTCOME | TRIAL DESCRIPTION | N | RESULTS (REPORTED AS OR) | 95% CI | P VALUE | NNT |
|---|---|---|---|---|---|---|
| Death | 3 placebo-controlled | 221 | 0.25 | 0.07–0.84 | .03 | 12.5 |
| Admissions | 4 placebo-controlled | 448 | 0.31 | 0.15–0.62 | .001 | 8.5 |
| 4 active-controlled | 150 | 0.34 | 0.10–1.21 | .10 | 12.8 | |
| Exercise capacity | 6 active-controlled | 174 | 0.37 | 0.10–0.64 | .007 | * |
| *Unable to calculate NNT due to lack of uniform reporting of exercise times. | ||||||
| OR, odds ratio; CI, confidence interval; NNT, number needed to treat. | ||||||
| Source: Faris et al, Int J Cardiol 2002.4 | ||||||