Cochrane for Clinicians
Putting Evidence into Practice
Diuretics for Treatment of Patients with Heart Failure?
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Clinical Scenario
A 60-year-old woman with known heart failure presents with worsening dyspnea and increased lower-extremity edema.
Clinical Question
Should diuretics be used for treatment of patients with heart failure?
Evidence-Based Answer
Compared with other active medications, diuretics can improve exercise capacity in patients with heart failure by about 30 percent. Withdrawal of diuretic therapy from patients with heart failure may increase the risk of hospital readmission or death. About eight deaths are prevented for every 100 patients treated.1
Cochrane Abstract
Background. Chronic heart failure is a major cause of morbidity and mortality worldwide. Diuretics are regarded as the first-line treatment for patients with congestive heart failure because they provide symptomatic relief. The effects of diuretics on disease progression and survival remain unclear.
Objectives. To assess the harms and benefits of diuretics for chronic heart failure.
Search Strategy. The authors1 searched the Cochrane Central Register of Controlled Trials (Issue 2, 2004), MEDLINE 1966-2004, EMBASE 1980-2004, and HERDIN database. They hand searched pertinent journals and inspected reference lists of papers. They also contacted manufacturers and researchers in the field.
Selection Criteria. Only double-blind, randomized controlled trials of diuretic therapy comparing one diuretic with placebo or one diuretic with another active agent (e.g., angiotensin-converting enzyme [ACE] inhibitors, digoxin) in patients with chronic heart failure were eligible for inclusion.
Data Collection and Analysis. Two reviewers independently abstracted the data and assessed the eligibility and methodologic quality of each trial. Extracted data were entered into the Review Manager version 4.2 computer software and analyzed by determining the odds ratio (for dichotomous data) and difference in means (for continuous data) of the treated group compared with control groups. The likelihood of heterogeneity of the study population was assessed by the chi-square test. If there was no evidence of statistical heterogeneity, and pooling of results was clinically appropriate, a combined estimate was obtained using the fixed-effects model.
Primary Results. The authors included 14 trials (525 participants); seven were placebo controlled, and seven compared diuretics against other agents such as ACE inhibitors or digoxin. The authors analyzed the data for mortality and for worsening heart failure. Mortality data were available in three of the placebo-controlled trials (202 participants). Mortality rates were lower among participants treated with diuretics than among those receiving placebo (odds ratio [OR] for death = 0.24; 95% confidence interval [CI], 0.07 to 0.83; P = .02). Admission for worsening heart failure was reduced in those taking diuretics in two trials (169 participants; OR = 0.07; 95% CI, 0.01 to 0.52; P = .01). In four trials comparing diuretics with active control (91 participants), diuretics improved exercise capacity in participants with chronic heart failure (weighted mean difference = 0.72; 95% CI, 0.40 to 1.04; P < .0001).
Reviewers' Conclusions. The available data from several small trials show that in patients with chronic heart failure, conventional diuretics appear to reduce the risk of death and worsening heart failure compared with placebo. Compared with active control, diuretics appear to improve exercise capacity.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
Practice Pointers
Heart failure affects more than 5 million persons in the United States,2 and loop diuretics have been a standard component of treatment for heart failure since they were introduced in the 1960s. In recent years, there has been growing evidence for the use of other medications in the management of heart failure, including angiotensin-converting enzyme (ACE) inhibitors,3 beta blockers,4 aldosterone antagonists,5 and angiotensin-receptor blockers (ARBs),6 as well as further investigation of the use of digitalis.7 With these advances, the specific benefits of diuretics and their place in the management of heart failure has become less clear.
Guidelines released by the American Heart Association (AHA) and the American College of Cardiology (ACC) in 2005 proposed a staging system to describe the progression of heart failure as a chronic disease and made new recommendations for its medical management using a stage-based assessment of disease severity in individual patients (Table 1).2 For patients at high risk of developing heart failure (stage A), the guidelines recommend controlling risk factors and using ACE inhibitors or ARBs in patients with vascular disease; for patients who have cardiac structural abnormalities but have never developed clinical heart failure (stage B), the guidelines recommend beta blockers and ACE inhibitors or ARBs, as well as close monitoring for the development of clinical heart failure. Diuretics are recommended for the control of fluid retention in patients with clinical heart failure or a history of heart failure symptoms (stage C), as well as for patients with refractory end-stage heart failure (stage D) who need close attention to fluid balance and control of fluid retention.2
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table 1 ACC/AHA Heart Failure Staging System |
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Stage |
Description |
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A |
Patients at high risk of developing heart failure |
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B |
Patients with cardiac structural abnormalities or remodeling (e.g., left ventricular dysfunction from a prior infarction) who have not developed heart failure symptoms |
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C |
Patients with cardiac structural abnormalities or remodeling and current or prior symptoms of heart failure |
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D |
Patients with refractory end-stage heart failure |
| ACC = American College of Cardiology; AHA = American Heart Association. Information from reference 2. |
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The studies retrieved by this Cochrane review1 mainly were small, older trials, and most used loop diuretics such as furosemide (Lasix). The applicability of their findings to current heart failure management is limited by several factors. First, some of the diuretic studies excluded patients with reduced ejection fractions, whereas current evidence-based recommendations for heart failure management are based on studies of ACE inhibitors, ARBs, and beta blockers in patients with documented systolic dysfunction. One of the diuretic withdrawal trials also excluded patients with a "positive cardiac history" because diuretics were "judged to be mandatory" in these patients. Thus, these studies failed to truly evaluate the necessity of diuretics in patients with more severe clinical heart failure. Second, all the studies were completed before beta blockers became a standard part of recommended heart failure therapy; and third, the three studies that reported mortality all had relatively short follow-up (four, 12, and 52 weeks) and so could not provide data on long-term benefits of diuretic therapy for mortality in heart failure.
Nevertheless, the review does shed some light on the role of diuretics in the long-term management of heart failure. Three studies showed a reduction in mortality among patients taking diuretics, but most deaths occurred in two trials that studied withdrawal of diuretics from clinically stable patients. Two trials of diuretic withdrawal found lower hospital readmission rates among patients who continued to take diuretics. There also was evidence in active-control and crossover studies that diuretics helped improve exercise capacity. Although the evidence to support the use of diuretics in heart failure management is limited in scope and quality, it is unlikely that there will be any future high-quality, placebo-controlled trials to shed further light on this issue.
Based on the available evidence, it appears safe to conclude that diuretics can improve exercise tolerance for patients with heart failure, and that patients with heart failure who are taking diuretics may be at increased risk of hospital readmission or death if the diuretics are withdrawn. Diuretics should be used for relief of heart failure symptoms, with appropriate use of ACE inhibitors and beta blockers, as well as aldosterone antagonists and digoxin, in line with the AHA/ACC recommendations for treatment of patients with stages C and D heart failure.2
REFERENCES
1. Faris R, Flather MD, Purcell H, Poole-Wilson PA, Coats AJ. Diuretics for heart failure. Cochrane Database Syst Rev 2006;(1):CD003838.
2. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 guideline update for the diagnosis 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. Circulation 2005;112:e154-235.
3. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000;355:1575-81.
4. Lee S, Spencer A. Beta-blockers to reduce mortality in patients with systolic dysfunction: a meta-analysis. J Fam Pract 2001;50:499-504.
5. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.
6. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction [Published correction appears in Ann Intern Med 2005;142:391]. Ann Intern Med 2004;141:693-704.
7. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2004;(2):CD002901.
The Author
William E. Cayley, Jr., M.D., M.Div., is assistant professor at the University of Wisconsin Eau Claire Family Medicine Residency Program, Eau Claire, and practices at the Sacred Heart and Luther hospitals in Eau Claire.
Address correspondence to William E. Cayley, Jr., M.D., M.Div., Augusta Family Medicine Clinic, Eau Claire Family Medicine Residency, University of Wisconsin, Dept. of Family Medicine, 617 West Clairemont, Eau Claire, WI 54701 (e-mail: bcayley@yahoo.com). Reprints are not available from the author.
Cochrane Briefs
Clinical Question
Are laxatives effective for the treatment of symptomatic hemorrhoids in adults?
Evidence-Based Answer
Fiber has a consistent beneficial effect in the treatment of symptomatic hemorrhoids for up to three months' follow-up as measured by overall symptoms and bleeding.
Practice Pointers
Hemorrhoid treatment options include medical management, rubber-band ligation, sclerotherapy, coagulation, and surgical hemorrhoidectomy depending on the type of hemorrhoid and the frequency and severity of symptoms. The goal of first-line medical management is to minimize constipation and associated straining. Clinical practice guidelines recommend the use of fiber despite inconclusive evidence about its effectiveness in improving symptoms.
Alonso-Coello and colleagues reviewed the literature and identified seven randomized controlled trials comparing the effectiveness of fiber versus placebo in adults 23 to 71 years of age with symptomatic hemorrhoids. The trials studied several types of fiber including ispaghula husk, Plantago ovata or psyllium, sterculia, and unprocessed bran for a treatment duration of one to 18 months. Study size ranged between 28 and 92 participants with a mean of 50. Six of the seven trials assessed the degree of improvement of individual symptoms (e.g., bleeding, pain, itching, prolapse) or overall symptoms measured at six weeks' and three months' follow-up. One study examined rubber-band ligation plus fiber versus rubber-band ligation alone for third-degree hemorrhoids (defined as hemorrhoids that prolapse with straining but are reducible) and measured recurrence rate and the need for repeat procedures at 18 months.
The results of five studies reporting overall symptoms were pooled and showed a 53 percent reduction in the risk of persistent symptoms or lack of improvement. Of those taking fiber, 16 to 40 percent did not improve compared with 23 to 61 percent of those taking placebo. The four studies that reported bleeding as an individual outcome found a trend or a significant difference in favor of the fiber group. Pooled analysis of the two studies evaluating pain or discomfort showed a nonsignificant trend in favor of fiber. Likewise, the pooled analysis of three studies showed a nonsignificant difference between fiber and placebo for persistent prolapse. The two studies that evaluated itching did not find a significant difference between the groups. The one study examining rubber-band ligation plus fiber versus rubber-band ligation alone reported that the number of long-term recurrences was fewer overall in the group that received fiber (15 versus 45 percent, respectively) at 18 months' follow-up.
The most common side effects with fiber were gastrointestinal symptoms, typically starting at the study onset, and these generally were not severe enough for participants to discontinue fiber. The rate of side effects varied considerably among studies, with some studies reporting no side effects and others reporting up to a 50 percent incidence of gastrointestinal bloating.
The American Gastroenterological Association recommends adequate water and fiber intake as the mainstay of medical management and suggests that topical steroids and analgesics also may be useful in relieving hemorrhoidal symptoms.1
Source: Alonso-Coello P, et al. Laxatives for the treatment of hemorrhoids. Cochrane Database Syst Rev 2005;(4):CD004649.
REFERENCE
1. American Gastroenterological Association medical position statement: diagnosis and treatment of hemorrhoids. Gastroenterology 2004;126:1461-2.
Are Atypical Antipsychotics Safe in Patients with Alzheimer's Disease?
Clinical Question
Are atypical antipsychotic medications safe and effective for the treatment of behavioral and psychological disturbances in patients with Alzheimer's disease?
Evidence-Based Answer
Although the atypical antipsychotic medications risperidone (Risperdal) and olanzapine (Zyprexa) are modestly efficacious in reducing aggression, routine use is not justified. Both drugs are associated with serious adverse cerebrovascular events and extrapyramidal symptoms. Use of atypical antipsychotics in dementia significantly increases mortality (odds ratio [OR] = 1.7).
Practice Pointers
More than 50 percent of persons with Alzheimer's disease experience behavioral and psychological disturbances, which often are the stimulus for placement in residential or nursing home care. Antipsychotic medications have been used widely to mitigate these symptoms in patients with Alzheimer's disease, despite their known adverse effects. Because much data remain unpublished by pharmaceutical companies, the risk of serious adverse events from the use of atypical antipsychotics is not widely recognized.
Ballard and Waite systematically reviewed the published and unpublished literature on atypical antipsychotics in patients with Alzheimer's disease and found 16 randomized, double-blind studies that evaluated these agents. They concluded that, compared with placebo, there was a significant improvement in aggression in patients treated with risperidone or olanzapine and an improvement in psychosis in patients treated with risperidone. However, risperidone was associated with a significantly higher incidence of serious adverse cerebrovascular events (OR = 3.64; 95% confidence interval [CI], 1.72 to 7.69) and extrapyramidal side effects (for 2 mg daily, OR = 3.39; 95% CI, 1.69 to 6.80). Other adverse effects included somnolence, upper respiratory tract infections, edema, urinary tract infections, and fever. There were insufficient data to examine the impact of these medications on cognitive function.
In April 2005, the U.S. Food and Drug Administration (FDA) completed a meta-analysis1 of clinical studies assessing the use of atypical antipsychotics for the treatment of behavioral disorders in older patients with dementia. The results demonstrated a high death rate in patients treated with atypical antipsychotics compared with those receiving placebo.1 The FDA subsequently requested that the manufacturers of these drugs add a boxed warning to their drug labeling describing this risk and noting that these drugs are not approved for this indication.1
In practice, limited use of atypical antipsychotics in patients with Alzheimer's disease may be considered when patients display a serious, life-threatening risk to themselves or others. Nonpharmacologic treatment options include educating caregivers about managing behavioral symptoms, using lighting to reduce nighttime confusion and restlessness, simplifying tasks, and adhering to predictable routines.2 Sensory enhancement, social contact, behavior therapy, and environmental interventions3 also may decrease the occurrence of agitated behaviors. A clinical guideline3 on the nonpharmacologic management of dementia from the University of Iowa Gerontological Nursing Interventions Research Center is available at http://www.guideline.gov.
The opinions and assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the U.S. Air Force or Department of Defense.
Source: Ballard C, et al. Atypical antipsychotics for aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev 2006;(1):CD003476.
REFERENCES
1. U.S. Food and Drug Administration. Public Health Advisory. Deaths with antipsychotics in elderly patients with behavioral disturbances. April 11, 2005. Accessed May 9, 2006, at: http://www.fda.gov/cder/drug/advisory/antipsychotics.htm.
2. California Workgroup on Guidelines for Alzheimer's Disease Management. Guidelines for Alzheimer's disease management. Los Angeles, Calif.: Alzheimer's Association of Los Angeles, Riverside and San Bernardino Counties, 2002. Accessed May 9, 2006, at: http://www.guideline.gov/summary/summary.aspx?ss=14&doc_id=3157&string=.
3. McGonigal-Kenney ML, Schutte DL. Non-pharmacologic management of agitated behaviors in persons with Alzheimer disease and other chronic dementing conditions. Iowa City, Iowa: University of Iowa Gerontological Nursing Interventions Research Center, Research Dissemination Core, 2004. Accessed May 9, 2006, at: http://www.guideline.gov/summary/summary.aspx?ss=14&doc_id=6221&string=.
The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.
This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab003838.html.
A collection of Cochrane for Clinicians published in AFP is available at http://www.aafp.org/afp/cochrane.
| Copyright © 2006 by the American
Academy of Family Physicians. |
