CME Evidence-Based Practice Answering clinical questions▲ with the best sources VOLUME 8 NUMBER 1 JANUARY 2005 WHAT’S INSIDE TRANSFORMING PRACTICE HELP DESK 3 3 What factors predict a successful smoking cessation attempt? ■ ■ 4 ■ Vitamin D prevents falls in the elderly Is antiviral therapy for acute, localized herpes zoster safe and effective? Daily vitamin D supplementation can be added to the list of strategies to prevent falls in the elderly DAVID WHITE, MD, Columbia, MO What preoperative evaluation is indicated for a patient with left bundle-branch block? Summary of evidence ■ 5 What is the best treatment for obsessive-compulsive disorder? ■ ■ 6 What is best treatment for chronic prostatitis in a middle-aged man? ■ 7 ■ ■ What are the effects of fish oil in patients with type 2 diabetes? A meta-analysis with results pooled from 5 trials of vitamin D supplementation showed a 22% reduction in the rate of “at least one fall.” The benefit was seen within 8 to 12 weeks—significantly sooner than would be expected if fracture rate reduction was simply due to increased bone mineral density. One fall was prevented for every 15 patients treated with vitamin D. Multiple interventions have been shown to be effective for the prevention of falls in the elderly.1 These include: Balance and gait training Muscle-strengthening exercises Gradual discontinuation of psychotropic drugs Targeted interventions based on multifactorial risk assessment ■ ■ EVIDENCE IN PERSPECTIVE 9 ■ ■ Effects of Helicobacter pylori eradication in chronic users of nonsteroidal anti-inflammatory drugs DRUG PROFILE 11 Spironolactone for congestive heart failure and other conditions EDITORS RAMINDER KUMAR, MD University of Chicago DAVID WHITE, MD Columbia, MO A recent meta-analysis2 has shown that an additional intervention—daily vitamin D supplementation—is also effective for reducing the number of falls by 20%. Only 15 patients (mean age 70 years) would need to be treated with vitamin D to prevent one fall. Falls are common among the elderly. Approximately one-third of persons older than 65 fall each year.3 One in 10 of these falls results in serious injury (fracture, subdural hematoma, other head injury, etc).4 The risk of falling increases with the number of a patient's risk factors, ranging from 8% for elderly persons with no risk factors, to 78% for those with 4 or more risk factors (TABLE). continued TRANSFORMING PRACTICE CONTINUED TABLE Risk factors for falls in the elderly5 ■ ■ ■ ■ ■ ■ Muscle weakness History of falls Gait deficit Balance deficit Use of assist device Visual deficit ■ ■ ■ ■ ■ Arthritis Impaired activities of daily living Depression Cognitive impairment Age > 80 years Risk factors are listed in decreasing strength of association. Vitamin D supplementation: a new tactic for fall prevention New evidence suggests another intervention— vitamin D supplementation—may also prevent falls in elderly persons. Previously demonstrated to have a protective effect against nonvertebral fractures,7,8 this benefit was seen within 8 to 12 weeks— significantly sooner than would be expected if fracture rate reduction was simply due to increased bone mineral density. Known interventions for fall prevention Clearly, reducing risk of falling is an important objective for persons older than 65. A summary of interventions shown to be effective for fall prevention, based on a systematic review last updated July 2003,6 follows. MULTIFACTORIAL HEALTH/ENVIRONMENTAL RISK FACTOR SCREENING, WITH TARGETED INTERVENTIONS BASED ON INDIVIDUAL RISK PROFILES Multifactorial targeted screening and intervention strategies were found to reduce falls in unselected populations by 27% (4 trials, 1,651 participants, pooled relative risk [RR]=0.73; 95% confidence interval [CI], 0.63–0.85). In targeted populations at increased risk of falling due to previous falls or known risk factors, the reduction in falls was 14% (5 trials, 1,176 participants, pooled RR=0.86; 95% CI, 0.76–0.98). MUSCLE STRENGTHENING, GAIT AND BALANCE TRAINING Individually prescribed home programs by trained health professionals were found to reduce falls by 20% (3 trials, 566 participants, pooled RR=0.80; 95% CI, 0.66–0.98). GRADUAL WITHDRAWAL OF PSYCHOTROPIC MEDICATION Reduction or elimination of psychotropicmedication reduced falls by up to two-thirds (1 trial, 93 participants, relative hazard=0.34; 95% CI, 0.16–0.74). TAI CHI BALANCE TRAINING IN UNTARGETED POPULATIONS Tai Chi methods taught by nonprofessionals to persons 70 years of age and older recruited from community sites, and not targeted due to any risk factors, reduced falls by about 50% (1 trial, 200 participants, risk ratio=0.51; 95% CI, 0.36–0.73). META-ANALYSIS Because of the strong association between falls and fractures, trials have examined whether vitamin D supplementation exerts part of its protective effect through the prevention of accidental falls. As these trials had shown mixed results, a meta-analysis of randomized controlled trials (RCTs) was published in April 2004.2 To be eligible for inclusion in the meta-analysis, studies had to be double-blind RCTs that examined the effectiveness of any type of vitamin D for fall prevention. The primary outcome of interest was the rate of low-trauma falls in community-dwelling or institutionalized individuals aged 60 or older. Studies that focused on patients with unstable health states, alcoholism, or patients recently discharged from a hospital were excluded. Five RCTs were identified that met inclusion/exclusion criteria, for a total of 1,237 individuals (mean age, 70). Duration of vitamin D therapy ranged from 2 months to 3 years. Although all 5 trials individually demonstrated some reduction in falls for patients taking vitamin D, in 4 of these 5 trials the effect did not achieve statistical significance. When the results of the 5 studies were pooled, a 22% reduction in the rate of “at least one fall” was reported (corrected pooled odds ratio [OR]=0.78; 95% CI, 0.64–0.92). The absolute risk of falling was reduced by 7% in these patients (30% in vitamin D group vs 37% in control group), so that one fall was prevented for every 15 patients treated with vitamin D (95% CI, 8–53). To test the effect size when studies meeting less stringent inclusion criteria were included (lack of “fall” definition, patients with unstable health status, recent hospital discharge), a sensitivity analysis was performed. The addition of 5 such RCTs (8,764 continued on page 8 2 Evidence-Based Practice Help Desk CONCISE ANSWERS TO PHYSICIANS’ CLINICAL QUESTIONS What factors predict a successful smoking cessation attempt? Use of sustained-release bupropion, higher dosages of bupropion, male sex, longest previous abstinent period of less than 24 hours or longer than 4 weeks, and fewer cigarettes per day smoked each independently predict success at the end of a 7-week course of therapy. Patients who abstain from smoking on their quit date are dramatically more likely to remain abstinent at 6 months than patients who do not. A secondary analysis of a randomized controlled trial (RCT) designed to determine optimal bupropion dosage for patients who want to quit smoking1 was performed to determine which, if any, factors predicted success with smoking cessation.2 A total of 615 motivated healthy adult men and women who smoked at least 15 cigarettes per day were randomly assigned to placebo or bupropion sustained-release treatment, 100, 150, or 300 mg/d, for 7 weeks (total duration of study was 52 weeks: 7 weeks of treatment and 45 weeks of follow-up). At the end of 7 weeks of treatment, the rates of smoking cessation, as confirmed by carbon monoxide measurements, were 19% in the placebo group, 29% in the 100-mg group, 39% in the 150-mg group, and 44% in the 300-mg group (P<.001). When bupropion dosage was controlled for, multiple logistic regression analysis showed that male sex (P=.014), longest previous abstinent period of either less than 24 hours or longer than 4 weeks (P=.002), and lower number of cigarettes smoked per day (P<.001) at the time of entry into the study each independently predicted successful quitting. Another interesting study demonstrated that abstinence from smoking on the quit date predicted success.3 Data from 2 randomized nicotine replacement (patch) trials were divided into a derivation sample (159 patients) and a validation sample (48 patients) to determine which factors best predicted success at 6 months. Patients had to be smoking more than 1 pack per day and be motivated to quit. Abstinence was determined by patient self-report, and confirmed by exhaled carbon dioxide concentration (<8 ppm). Abstinence rate at 6 months was 24% in the derivation sample and 25% in the validation sample. For patients who smoked on their quit day, 3 of 96 (3.1%) in the derivation set and 0 of 13 (0.0%) in the validation set were abstinent at 6 months, compared with 16 of 63 (25.4%) and 12 of 32 (37.5%), respectively, among patients who abstained on the quit day. Using a logistic regression analysis on the derivation set of patients, the researchers found that quit date abstinence strongly predicted successful abstinence at 6 months (odds ratio 10.6; 95% confidence interval [CI], 2.9–38.7). This finding was confirmed in the validation set. The authors concluded that smoking on the quit date may be an indication to either postpone the cessation attempt, or to adjust the therapy. Knowledge of the factors that predict who is more or less likely to succeed when they try to quit smoking may help clinicians individualize adjunctive measures, particularly for individuals at highest risk to fail. Supplementary medical therapy (nicotine patch or bupropion), addition of or increased frequency of counseling, and increased frequency of contact and support for patients who are more likely to fail are reasonable interventions. Further research may help to determine which of these or other measures are most effective in helping such patients. [SOR: A, based on multiple RCTs] 1. Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997; 337:1195–1202. 2. Dale LC, Glover ED, Sachs DP, et al. Bupropion for smoking cessation: predictors of successful outcome. Chest 2001; 119:1357–1364. 3. Westman EC, Behm FM, Simel DL, Rose JE. Smoking behavior on the first day of a quit attempt predicts long-term abstinence. Arch Intern Med 1997; 157:335–340. Is antiviral therapy for acute, localized herpes zoster safe and effective? Antiviral agents reduce the duration of pain from herpes zoster and hasten clearing of lesions for immunocompetent individuals with localized herpes zoster. Antiviral therapy early in the course of the rash does not reduce the rate of postherpetic neuralgia but does reduce the duration of pain due to postherpetic neuralgia. Evidence-Based Practice 3 Help Desk 500-mg famciclovir group and 2.3 (95% CI, 1.5–3.3) for the 750-mg famciclovir group. Postherpetic neuralgia developed in 186 (44%) of patients. The incidence of this complication did not differ between treatment groups. Duration of pain associated with postherpetic neuralgia was reduced by a factor of 1.7 (P=.02) for the 500-mg famciclovir group and 1.9 (P=.005) for the 750-mg famciclovir group. The median times to resolution of postherpetic neuralgia were 63 days for the 500mg famciclovir group, 61 days for the 750-mg famciclovir group, and 119 days for the placebo group. Famciclovir was well tolerated, with a safety profile similar to that of placebo. Antiviral therapy can be expected to modestly hasten the resolution of lesions, reduce the duration of pain significantly, and decrease the duration of viral shedding in immunocompetent adult patients with herpes zoster. Treatment should begin within 72 hours of the onset of lesions. These drugs all appear to be safe. The TABLE provides reasonable regimens.4 Valacyclovir reduced length of pain and prevented postherpetic neuralgia better than acyclovir in a head-to-head comparison and is less expensive than either famciclovir or acyclovir. Valacyclovir is a good first-choice treatment of acute herpes zoster. [SOR: A, based on multiple RCTs] TABLE Regimens to treat localized herpes zoster.4 Drug Dose Frequency Price Valacyclovir (Valtrex) 1 g PO 3 times a day for 7 days $118.69 Famciclovir (Famvir) 500 mg PO 3 times a day for 7 days $154.91 Acyclovir (Zovirax) 800 mg PO 5 times a day for 7 to 10 days $184.82, generic $42.56 In a meta-analysis of randomized placebocontrolled trials of acyclovir for the treatment of herpes zoster, 4 trials that included 691 patients were identified.1 When several important clinical outcomes were analyzed using Cox regression models, acyclovir caused a 2-fold reduction in pain duration. This beneficial effect was most prominent among patients older than 50. An RCT comparing the efficacy of acyclovir to that of valacyclovir found that valacyclovir was associated with earlier pain relief.2 A total of 1,141 immunocompetent adults at least 50 years of age with zoster were randomized to receive one of 3 treatment regimens. Group 1 received acyclovir 800 mg 5 times daily for 7 days; group 2 received valacyclovir 1g 3 times daily for 7 days; and group 3 received valacyclovir 1 g daily for 14 days. Patients were followed for 6 months. Median pain duration was 51 days for the acyclovir group, compared with 38 days (P=.001) and 44 days (P=.03) for the 7- and 14-day valacyclovir groups, respectively. Patients receiving valacyclovir were less likely to have postherpetic neuralgia at 6 months than those receiving acyclovir (19.3% vs 25.7%; number needed to treat [NNT]=16). Adverse events were similar in all groups. In an RCT comparing famciclovir with placebo,3 famciclovir accelerated lesion healing, reduced the duration of viral shedding, and resulted in faster resolution (although not the incidence) of postherpetic. A total of 419 adult patients with zoster were randomly assigned to receive 500 or 750 mg famciclovir or placebo 3 times daily for 7 days. Patients taking famciclovir had complete crusting of lesions about 1.5 times faster than patients receiving placebo (P=.02). Duration of viral shedding was also reduced by a factor of 2.0 (95% CI, 1.4–3.0) for the 4 Evidence-Based Practice 1. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis 1996; 22:341–347. 2. Beutner KR, Friedman DJ, Forszpaniak C, Andersen PL, Wood MJ. Valacyclovir compared with acyclovir for improved therapy for herpes zoster in immunocompetent adults. Antimicrob Agents Chemother 1995; 39:1546–1553. 3. Tyring S, Barbarash RA, Nahlik JE, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med 1995; 123:89–96. 4. Drugs for non-HIV viral infections. The Medical Letter 2002 Feb 4; 44(1123):9–16. What preoperative evaluation is indicated for a patient with left bundle-branch block? Patients with left bundle-branch block who have impaired functional capacity, who are to undergo a noncardiovascular procedure that is considered to be high surgical risk, should undergo preoperative noninvasive testing. Such testing could include a stress electrocardiogram or echocardiogram. Help Desk In an evidence-based guideline from the American College of Cardiology/American Heart Association Task Force updated in 2002,1 recommendations about appropriate preoperative evaluation of patients were based on predictors of perioperative cardiovascular risk and functional capacity of the patient. Left ventricular hypertrophy, left bundle-branch block, and nonspecific ST-T abnormalities are classified as “minor perioperative cardiovascular risk factors.” Functional capacity is determined according to metabolic equivalent (MET) scores. Persons with clinically important perioperative cardiac and long-term risk generally have MET scores of less than 4. Examples of activities such patients would be unable to perform would include light housework (washing dishes, dusting), walking up a flight of stairs, or walking on level ground at 4 miles per hour. For patients with minor perioperative risk factors (such as left bundle-branch block) who are not functionally impaired, the guideline recommends no specific further preoperative cardiovascular evaluation. The American College of Cardiology/American Heart Association Task Force suggested, however, that such patients may be candidates for postoperative risk assessment for educational purposes. If the patient with left bundle-branch block or other electrocardiographic abnormalities noted above has significant functional impairment (MET score <4), the Task Force recommended that noninvasive testing such as stress electrocardiogram or echocardiogram be performed preoperatively to further clarify risk status. If the outcome of such testing reveals the patient to be of low cardiovascular risk, no further preoperative testing is needed. If a high-risk cardiovascular condition is found, further testing such as coronary angiography should be performed, with subsequent management/ assessment based on the results. The complete guideline, which includes specific classifications of perioperative cardiovascular risk factors, examples of MET scores for various activity levels, a graphical algorithm demonstrating the stepwise evaluation of patients, and recommendations based on these parameters can be viewed at http://www.acc.org/clinical/guidelines/perio/ exec_summ/pdf/periop_execsumm.pdf. [SOR: C, based on consensus guideline] 1. ACC/AHA guideline update on perioperative cardiovascular evaluation for noncardiac surgery—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 2002; 105:1257–1267. What is the best treatment for obsessive-compulsive disorder? A combination of serotonin reuptake inhibitors (SRIs) and cognitive behavioral therapy (CBT) may be the most effective treatment for obsessivecompulsive disorder (OCD). Both SRIs and CBT have been to be effective when used alone and appear to be equivalent in effectiveness for short-term treatment. No significant differences were noted in the effectiveness among SRIs (selective or nonselective). SRIs have been shown to be superior to tricyclic antidepressants and monoamine oxidase inhibitors for patients with OCD. CBT has the advantage of teaching patients new skills and avoiding drug side effects. Systematic reviews of controlled trials have demonstrated effectiveness for multiple SRIs (selective and nonselective).1,2 Citalopram, clomipramine, fluoxetine, fluvoxamine, and paroxetine were all found to be superior to placebo in these reviews, using the outcome of improvement on a well-validated 40-point symptom scale (Yale-Brown Obsessive Compulsive Scale). These same reviews found no differences of efficacy between different SRIs in head-to-head comparisons. The first review1 found that SRIs were more effective than tricyclic antidepressants (eg, desipramine, imipramine, and nortriptyline) as well as monoamine oxidase inhibitors (eg, clorgyline, phenelzine). Absolute benefit increases for the SRIs in this review ranged from 21.6% (NNT=5) to 61.3% (NNT=2). A subsequent RCT3 of 54 patients randomly assigned patients with OCD to receive fluoxetine, phenelzine, or placebo. Using the symptom scale noted above, patients receiving fluoxetine showed significantly more improvement than patients receiving either phenelzine or placebo after 10 weeks (P<.05). Evidence, which was reviewed in the December 2004 issue of Evidence-Based Practice, suggests that CBT is also effective for patients with OCD. In a study of 47 patients with OCD randomly assigned to receive either a 12-week course of CBT or no therapy, 69.6% of participants Evidence-Based Practice 5 Help Desk receiving CBT had a reduction of the Yale-Brown score of more than 35%, compared with only 4.2% of patients receiving no therapy (P<.001).4 Thus the number of patients needed to be treated for one additional patient to show substantial improvement was 2. A recently published randomized trial has now demonstrated similar beneficial effects of CBT in the pediatric population with OCD.5 A total of 112 children aged 7 to 17 with newly diagnosed OCD were randomly assigned to receive CBT alone, sertraline alone, a combination of both therapies, or pill placebo for 12 weeks. All 3 treatments were superior to placebo, and the combination of CBT and sertraline was more effective than either one alone. Remission (defined as Yale-Brown score <10) occurred in 3.6% with placebo, 21.4% with sertraline alone, 39.3% with CBT alone, and 53.6% with CBT plus sertraline. The difference in response rates between the CBT-alone and the sertraline-alone groups was not statistically significant. [SOR: A, based on systematic reviews] 1. Piccinelli M, Pini S, Bellantuono C, Wilkinson G. Efficacy of drug treatment in obsessive-compulsive disorder. A meta-analytic review. Br J Psychiatry 1995; 166:424–443. 2. Ackerman DL, Greenland S. Multivariate meta-analysis of controlled drug studies for obsessive-compulsive disorder. J Clin Psychopharmacol 2002; 22:309–317. 3. Jenike MA, Baer L, Minichiello WE, Rauch SL, Buttolph ML. Placebocontrolled trial of fluoxetine and phenelzine for obsessive-compulsive disorder. Am J Psychiatry 1997; 154:1261–1264. 4. Volpato Cordioli A, Heldt E, Braga Bochi D, et al. Cognitive-behavioral group therapy in obsessive-compulsive disorder: a randomized clinical trial. Psychother Psychosom 2003; 72:211–216. 5. Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA 2004; 292:1969–1976. What is best treatment for chronic prostatitis in a middle-aged man? Antibiotics or alpha-adrenergic blockers are often used for the treatment of chronic prostatitis. However, a systematic review1 most recently updated in 1999 concluded that “The routine use of antibiotics and alpha-blockers for chronic abacterial prostatitis is not supported by the existing evidence.” This conclusion was based on small, methodologically weak studies. According to the Clinical Evidence review2 updated in October 2003, the addition of alpha-adrenergic agents to antimicrobials is “likely to be beneficial” based on the 6 Evidence-Based Practice results of one small randomized trial,3 and the use of antibiotics alone is of “unknown” effectiveness, due to the lack of any identified placebo-controlled trials. A randomized placebo-controlled trial published in October 2004 evaluated the use of ciprofloxacin, tamsulosin, or a combination of the 2 for treating patients with chronic prostatitis.4 A total of 196 men with chronic prostatitis referred to urologists were randomly assigned to receive ciprofloxacin 500 mg twice daily, tamsulosin 0.4 mg once daily, both medications, or placebo for 6 weeks. Patients had to have symptoms of pain or discomfort in the pelvic region for 3 of the 6 preceding months. Additionally, eligible patients had to have at least “moderate” symptoms of chronic prostatitis based on a score of at least 15 points using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). This index comprises a series of 9 questions concerning the domains of pain, voiding, and quality of life; scores range from 0 to 43 (43 points=maximum symptoms for all 9 questions). Of the 196 patients, the mean time since originally being diagnosed with chronic prostatitis was 6.2 years, and the mean NIH-CPSI score at the time of randomization was 24.7 ± 5.9 points. The primary outcome of interest was change in NIH-CPSI scores from baseline. The mean reduction in symptom scores was 3.4 with placebo, 4.1 with dual therapy, 4.4 with tamsulosin, and 6.2 with ciprofloxacin. No statistically significant differences were noted within any of the groups, despite the study being adequately powered (80%, P<.05) to detect differences of at least 4 points. Similarly, no significant differences were found between treatment regimens. Thus evidence shows that the most commonly used treatments for chronic prostatitis lack efficacy. A therapeutic trial of either antibiotics or alphaadrenergic blockers may be warranted for individual patients who may experience a positive response not typical of the groups of men in these studies. Further research may help to identify subsets of patients whose prostatitis may be more likely to respond to these types of interventions, or to new interventions. One authoritative source recommends a trial of Sitz baths or nonsteroidal antiinflammatory agents for treatment of chronic prostatitis associated with pelvic pain.5 [SOR; A, based on a systematic review] Help Desk 1. McNaughton Collins M, Mac Donald R, Wilt T. Interventions for chronic abacterial prostatitis (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd. 2. Jang T, Stern J, Schaeffer A. Chronic prostatitis. Clin Evid 2004; 12:1251–1259. Last search October 2003. 3. Barbalias GA, Nikiforidis G, Liatsikos EN. Alpha-blockers for the treatment of chronic prostatitis in combination with antibiotics. J Urol 1998; 159:883–887. 4. Alexander RB, Propert KJ, Schaeffer AJ, et al. Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial. Ann Intern Med 2004; 141:581–589. 5. Meyrier A, Fekete T. Chronic prostatitis/chronic pelvic pain syndrome. Available at: UpToDate: http://www.utdol.com/application/topic.asp? file=genr_med/32607&type=A&selectedTitle=2~5. What are the effects of fish oil in patients with type 2 diabetes? Fish oil has been shown to lower triglycerides and raise low-density lipoprotein (LDL) cholesterol levels in patients with type 2 diabetes mellitus. The effect of this dietary supplement on patientimportant outcomes (morbidity, glycemic control, mortality) is unknown. In a systematic review last updated in May 2001,1 18 trials including 823 participants were identified. In these randomized, placebocontrolled studies fish oil supplementation was the only intervention for patients with type 2 diabetes. Reported outcomes included triglyceride levels, high-density lipoprotein (HDL) and LDL cholesterol levels, hemoglobin A1c (HbA1c) levels, and fasting blood sugar. Outcomes of mortality or vascular events were not reported. The range of fish oil doses was from 3 to 18 g/d, and the mean length of follow-up was 12 weeks. The pooled data showed a modest reduction in triglycerides (–49.6 mg/dL; 95% CI –62.9 to –35.4 mg/dL) in patients using fish oil compared with placebo. Although this change was statistically significant, clinically it was of trivial importance. LDL cholesterol level increased in patients using fish oil supplement by 8.1 mg/dL (95% CI, 0.77–15.9 mg/dL), again a statistically significant difference although not a clinically important increase. No effect was found on fasting glucose, HbA1c levels, or HDL cholesterol levels. The triglyceride lowering effect and the elevation in LDL cholesterol were most marked in trials that recruited participants with hypertriglyceridemia and who used higher doses of fish oil. No adverse effects were noted. Thus fish oil supplementation has no clinically important effect on glycemic control or LDL or HDL cholesterol levels. Whether fish oil supplementation has an effect on vascular events or mortality in patients with type 2 diabetes mellitus remains unknown. Given the lack of biochemical effect, a beneficial effect on these clinical outcomes seems unlikely. [SOR: A, based on a systematic EBP review] David White, MD Columbia, MO 1. Farmer A, Montori V, Dinneen S, Clar C. Fish oil in people with type 2 diabetes mellitus (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd. CME CREDIT This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Michigan State University, College of Human Medicine. Michigan State University, College of Human Medicine, is accredited by the ACCME to provide continuing medical education for physicians. Michigan State University, College of Human Medicine, designates this educational activity for a maximum of 3 hours in category 1 credit toward AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he or she actually spent in the educational activity. It is estimated that this educational activity will require 3 hours to complete. The learning objectives of the Evidence-Based Practice newsletter are to become knowledgeable about evidence-based solutions to commonly encountered clinical problems, to understand how ground-breaking research is changing the practice of family medicine, and to become conversant with balanced appraisals of drugs that are currently being marketed to physicians and/or consumers. The editors of this educational material may review studies that discuss commercial products or devices as well as the unapproved/investigative use of commercial products/devices. The editors of this educational material report that they do not have significant relationships that create, or may be perceived as creating, a conflict relating to this educational material. Statements and opinions expressed in abstracts and communications herein are those of the author(s) and not necessarily those of the Publisher nor the endorsing organization of this newsletter. Neither the Publisher nor the organization endorsing this newsletter guarantees, warrants, or endorses any methods, product, instructions, procedures, techniques, or ideas mentioned in the newsletter. The Publisher, Editors, and the organization endorsing this newsletter disclaim any liability, loss or risk, personal or otherwise, which may arise, directly or indirectly, from any use or operation of any methods, products, instructions, procedures, techniques, or ideas contained in the material herein. Evidence-Based Practice (ISSN 1095-4120) is published monthly by the Family Physicians Inquiries Network, Inc, 409 W. Vandiver Drive, Bldg 4, Suite 202, Columbia, MO 65202. Telephone: 573-256-2066, Fax: 573-2562078. E-mail: [email protected]. Subscription rates for 2005: U.S. Individual $149 (includes FPIN database access), U.S. Institutions $159 (newsletter only), $399 (newsletter with FPIN database access), International Individual $179 (includes FPIN database access), International Institutions $209 (newsletter only), $459 (newsletter with FPIN database access). Back issues: U.S. $17; International $19. Third Class postage paid at Columbia, MO 65202. The GST number for Canadian subscribers is 124002536. Postmaster: Send address changes to FPIN, Inc, 409 W. Vandiver Drive, Bldg 4, Suite 202, Columbia, MO 65202; Attn: Tonya Wolff. Copyright © 2005 by Family Physicians Inquiries Network, Inc. Evidence-Based Practice 7 TRANSFORMING PRACTICE CONTINUED FROM PAGE 2 total patients) diminished the effect size to a 13% reduction in falls. This finding does not appear to be due to chance (corrected OR=0.87; 95% CI, 0.80–0.96). No discernible relation between effect size and sex or length of treatment was detected in subgroup analyses. The data were insufficient to determine which dose or formulation of vitamin D was superior (if any), or whether supplementation with calcium played any role. Three of the 5 RCTs used cholecalciferol (vitamin D3), which is metabolized to 1,25-dihydroxycholecalciferol, the biologically active form of vitamin D and the agent that was used in the other 2 trials as the intervention. Two trials used 800 IU cholecalciferol daily and the third used 400 IU daily. When all 3 of these trials were analyzed together, the corrected OR for falling was 0.83 (95% CI, 0.65–1.06) But when the 2 studies using the higher dose (800 IU daily) of cholecalciferol were analyzed separately, the effect size was larger (corrected OR=0.65; 95% CI, 0.40–1.00) and not likely due to chance. For the 2 studies that utilized vitamin D, significant benefit was noted (corrected OR=0.71; 95% CI, 0.55–0.92). MECHANISM OF ACTION The proposed mechanism for this protective effect of vitamin D on fall prevention involves the biologically active form of vitamin D, 1,25-hydroxyvitamin D, which binds to a highly specific nuclear receptor in muscle tissue. This binding may explain the fact that elderly women who are given 1[alpha]hydroxyvitamin D have been shown to have an increase in the number and size of type II muscle fibers within 3 months of starting treatment.9 Supporting this proposed mechanism are studies that show that elderly patients who take vitamin D plus calcium are found to have improved body sway and increased musculoskeletal function compared with elderly patients receiving calcium alone.10,11 Evidence-based guideline for risk assessment and interventions Falls in the elderly are common, often resulting in significant morbidity and expense. An evidencebased guideline that can help direct physicians toward appropriate risk assessment and interventions demonstrated to significantly reduce the risk 8 Evidence-Based Practice of falls is available.6 Developed by the American Geriatrics Society, the British Geriatric Society, and the American Academy of Orthopaedic Surgeons Panel on Falls Prevention, the AGS/BGS/AAOS Guideline for the Prevention of Falls in Older Persons provides a useful algorithm for managing patients at risk for falling. This clinical practice guideline can be viewed and downloaded at http://www.americangeriatrics.org/products/ positionpapers/. Conclusion The results of the meta-analysis2 provide support for a new intervention. Although further research that may clarify the optimal dosage and form of vitamin D will be helpful, it is reasonable at this time to consider adding vitamin D 800 IU daily to the interventions clinicians suggest to their patients at risk for falls. The current recommended daily dose for vitamin D in the EBP elderly is 600 IU daily. REFERENCES 1. Tinetti ME. Clinical practice. Preventing falls in elderly persons. N Engl J Med 2003; 348:42–49. 2. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004; 291:1999–2006. 3. Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med 1988; 319:1701–1707. 4. Tinetti ME, Doucette J, Claus E, Marottoli R. Risk factors for serious injury during falls by older persons in the community. J Am Geriatr Soc 1995; 43:1214–1221. 5. Guideline for the prevention of falls in older persons. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention. J Am Geriatr Soc 2001; 49:664–672. 6. Gillespie LD, Gillespie WJ, Robertson MC, Lamb SE, Cumming RG, Rowe BH. Interventions for preventing falls in elderly people (Cochrane Review). In: The Cochrane Library, Issue 4, 2004 (last updated July 2003). Chichester, UK: John Wiley & Sons, Ltd. 7. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997; 337:670–676. 8. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med 1992; 327:1637–1642. 9. Sorensen OH, Lund B, Saltin B, et al. Myopathy in bone loss of ageing: improvement by treatment with 1 alpha-hydroxycholecalciferol and calcium. Clin Sci (Lond) 1979; 56:157–161. 10. Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women [published corrections appear in J Bone Miner Res 2001;16:1735 and J Bone Miner Res 2001; 16:1935]. J Bone Miner Res 2000; 15:1113–1118. 11. Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 2003; 18:343–351. EVIDENCE IN PERSPECTIVE Primary care guidance on reports from other sources Effects of Helicobacter pylori eradication in chronic users of nonsteroidal anti-inflammatory drugs H pylori eradication should be used in conjunction with maintenance antisecretory therapy for chronic NSAID users in whom PUD develops RAMINDER KUMAR, MD, Clinical Associate Professor, Department of Family Medicine, University of Chicago Helicobacter pylori eradication is not effective for most patients who use nonsteroidal antiinflammatory drugs (NSAIDs) chronically (regular NSAID or aspirin use >30 days). This is true regardless of current or past history of dyspepsia or peptic ulcer disease (PUD), whether complicated by bleeding or not. The only exception is chronic NSAID users in whom PUD develops while taking those drugs. Although H pylori eradication does not affect healing rates, maintenance antisecretory therapy after H pylori eradication is highly beneficial in preventing rebleeding from PUD or gastric outlet obstruction if continued low-dose aspirin or NSAID therapy is necessary. Therefore, H pylori eradication should be used in conjunction with maintenance antisecretory therapy in chronic NSAID users in whom PUD develops. REPORTED IN CLINICAL EVIDENCE Unknown effectiveness: H pylori eradication for healing NSAID-related PUD; H pylori eradication for prevention of NSAID-related peptic ulcers in people with previous ulcers or dyspepsia Although Clinical Evidence reports unknown effectiveness in NSAID users we find that distinguishing between chronic and new NSAID users is important. As we noted in last month's issue of EBP, H pylori eradication is definitely beneficial for new NSAID users. We conclude in our review of the evidence that H pylori eradication is not beneficial for chronic NSAID users with the exception noted above: maintenance antisecretory therapy following H pylori eradication in patients who develop PUD while taking NSAIDs. H pylori eradication in chronic NSAID users Four randomized controlled trials addressing the issue were found. These included different groups of patients and different outcomes (TABLE). Remarkably, all 4 studies showed no benefit of H pylori eradication in patients who were on chronic NSAID therapy, whether or not they had current or past PUD (complicated or uncomplicated) or dyspepsia. H pylori eradication did not lead to higher healing rates for current PUD, lower rates of dyspepsia, or prevention of new ulcers.1–4 H pylori eradication when compared with maintenance omeprazole therapy did not decrease rebleeding rates in patients with bleeding PUD who continued to take NSAIDs other than aspirin.3 For patients in whom upper gastrointestinal bleeding developed while taking low-dose aspirin, H pylori eradication led to similar rebleeding rates as maintenance omeprazole therapy when aspirin was resumed at 80 mg/day.3 However, maintenance therapy with lansoprazole after H pylori eradication in patients with aspirin-related complicated PUD (bleeding or gastric outlet obstruction [GOO]) led to substantially decreased recurrence rates of complications (bleeding, GOO, perforation) (1.6%) when compared with placebo (14.8%; adjusted hazard ratio=9.6; 95% confidence interval [CI], 1.2–76.1; P=.008).5 Maintenance lansoprazole therapy after H pylori eradication in patients with nonaspirin NSAID-related PUD led to fewer recurrences of symptomatic and complicated ulcers (4.5%; 95% CI, 0–23) as compared with no maintenance treatment (42.9%; 95% CI, 22–66; EBP P=.0025).6 Evidence-Based Practice 9 EVIDENCE IN PERSPECTIVE CONTINUED TABLE Helicobacter pylori eradication in patients on chronic NSAID therapy Study Number of patients Types of patients included HPE Rx Control Rx Endpoint Precentage of patients meeting endpoint with HPE Rx (95% CI) Precentage of patients meeting endpoints with control Rx (95% CI) P Hawkey CJ et al1 285 Current or prior PUD/ dyspepsia or both HPE + OM 20 mg QD x 4 wks + NSAIDs* (n=142) OM 20 mg x 4 wks* (n=143) Dyspepsia free at 6 months 56% (47%–65%) 53% (44%–62%) .80 Chan FK et al2 195 Bleeding PUD HPE + OM 20 mg QD x 8 wks (n=93) OM 20 mg x 8 wks* (n=102) PUD healing at 8 wks 83% 86% .50 Chan FK et al3 250 Bleeding from HPE x 1 wk PUD or and no erosions maintenance from low-dose Rx + aspirin aspirin treated 80 mg QD until healed (n=125) OM x 6 months Recurrent GI + aspirin in bleeding at 80 mg QD 6 months (n=125) 1.9% (-0.7% to 4.5%) 0.9% (-0.8% to 2.6%) ARR= 1% (95% CI, (-1.9% to 3.9%) 150 Bleeding from PUD or erosions on nonaspirin NSAIDs treated until healed HPE x 1 wk and no maintenance Rx + NSAID (n=75) OM x 6 months Recurrent GI + NSAID bleeding at (n=75) 6 months 18.8% (9.5%– 28.1%) 4.4% (-0.5% to 9.3%) P=.005 ARR=14.4% (95% CI, 4.4%– 24.4%) 140 No current or prior PUD or erosive esophagitis HPE x 2 wks (n=70) 7.1% (2%–16%) 8.6% (3%–18%) 1.00 Lai KC et al4 Placebo x 2 wks (n=70) Endoscopic ulcers at 12 wks * Patients with unhealed ulcers at 4 weeks received OM for 4 more weeks. ARR, absolute risk reduction; CI, confidence interval; GI, gastrointestinal; HPE, Helicobacter pylori eradication; NSAID, nonsteroidal anti-inflammatory drug; OM, omeprazole; PUD, peptic ulcer disease; QD, every day; Rx, therapy. REFERENCES 1. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomized controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study. Helicobacter Eradication for Lesion Prevention [published correction appears in Lancet 1998; 352:1634]. Lancet 1998; 352:1016–1021. 2. Chan FK, Sung JJ, Suen R, et al. Does eradication of Helicobacter pylori impair healing of nonsteroidal anti-inflammatory drug associated bleeding peptic ulcers? A prospective randomized study. Aliment Pharmacol Ther 1998; 12:1201–1205. STATEMENT OF PURPOSE Evidence-Based Practice (EBP) addresses the most important patient care questions asked by practicing family physicians, using the best sources of evidence in a brief, clinically useful format. NEWSLETTER TOPICS Transforming Practice: Research evidence on diagnostic testing or treatment periodically accumulates to a “tipping point” that warrants a change in practice. Each month the editors select one topic for which a substantial change in clinical practice seems justified. Help Desk: Practicing family physicians submit questions about specific patient problems to the Family Practice Inquiries Network (FPIN; www.fpin.org). Practicing physicians within the FPIN organization then single out the questions of greatest interest through a webbased voting system. The EBP editors search the highest quality sources for best evidence (Cochrane, Clinical Evidence, US Preventive Services Task Force, AHRQ Evidence Based Guidelines). If definitive answers are not available from these sources, the editors turn to high-quality, well-referenced sources (UpToDate, DynaMed, National Guideline Clearinghouse, University Pathologists Consortium Medical Databases). Other resources are used at the editors’ discretion. 3. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med 2001; 344:967–973. 4. Lai KC, Lau CS, Ip WY, et al. Effect of treatment of Helicobacter pylori on the prevention of gastroduodenal ulcers in patients receiving long-term NSAIDs: a double-blind, placebo controlled trial. Aliment Pharmacol Ther 2003; 17:799–805. 5. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002; 346:2033–2038. Drug Profile: Pharmaceutical information is promoted directly to consumers as well as physicians, and is readily available on the Internet and in other mass media. In each issue of EBP, the editors objectively review the advantages and disadvantages of a featured medication based on scientific evidence. 6. Lai KC, Lam SK, Chu KM, et al. Lansoprazole reduces ulcer relapse after eradication of Helicobacter pylori in nonsteroidal anti-inflammatory drug users—a randomized trial. Aliment Pharmacol Ther 2003; 18:829–836. Evidence in Perspective: The editors select topics covered in the highest quality evidencebased sources (eg, Cochrane, Clinical Evidence) and provide a clinical perspective and guidance for applying the evidence specifically in primary care practice. 10 Evidence-Based Practice DRUG PROFILE Objective reviews of drugs in family medicine Spironolactone for congestive heart failure and other conditions Spironolactone is effective for carefully selected patients with CHF, and also for treatment of hirsutism, ascites, and primary hyperaldosteronism RAMINDER KUMAR, MD, Clinical Associate Professor, Department of Family Medicine, University of Chicago Five years ago the RALES trial showed that spironolactone (Aldactone) improved outcomes significantly for patients with New York Heart Association (NYHA) class IV congestive heart failure (CHF). Severe hyperkalemia, a known adverse effect of spironolactone, was seen in only 2% of patients.1 However, a recent study from Ontario has shown that spironolactone prescription rates increased markedly after publication of RALES, as did rates of hospitalization and mortality from hyperkalemia, with no decrease in rates of readmission for CHF or all-cause mortality.2 This study showed that spironolactone must be used with great caution in patients with CHF. Here we review the role of spironolactone in CHF as well as its other uses. Spironolactone (Aldactone), a potassium-sparing diuretic, is an aldosterone antagonist. The drug also decreases the conversion of testosterone to its active metabolite, dihydrotestosterone (DHT), and blocks the DHT receptor. Congestive heart failure In a large, multicenter, randomized, double-blind controlled trial (RALES), 1,663 patients with severe CHF (NYHA class IV within 6 months before enrollment and NYHA class III or IV at time of enrollment) were randomized to receive spironolactone or placebo.1 The inclusion criteria were left ventricular ejection fraction less than 35% and treatment with angiotensin-converting enzyme inhibitors, loop diuretics, and, in most cases, digoxin. Patients were excluded if they had a serum creatinine concentration of more than 2.5 mg/dL, serum potassium concentration of more than 5.0 mEq/L, and several other factors. Spironolactone was initiated at 25 mg/day and increased to 50 mg/day for lack of effect or reduced to 25 mg every other day if hyperkalemia developed. Potassium levels were checked every 4 weeks for 12 weeks and then every 3 months for up to 1 year. The trial was stopped early after a mean follow-up of 24 months. Benefits of spironolactone included decreased all-cause mortality (relative risk [RR]=0.70; 95% confidence interval [CI], 0.60–0.82; P<.001); decreased hospitalization for worsening CHF (RR=0.65; 95% CI, 0.54–0.77, P<.001); and improvement in NYHA class (P<.001). The mortality was decreased from all cardiac causes (RR=0.69; 95% CI, 0.58–0.82; P<.001); progression of CHF (RR=0.64; 95% CI, 0.51–0.89; P<.001); and sudden death (RR=0.71, 95% CI, 0.54–0.95; P=.02). The side effects significantly higher than placebo were gynecomastia (9% vs 1%) or breast pain (10% vs 1%). Severe hyperkalemia was seen in only 2% of patients. Five years later, in a report based on computerized prescription records of the Ontario Drug Benefit Program in patients aged 66 years or older, researchers reported that after publication of the RALES study, spironolactone prescription rates increased markedly, as did rates of hospitalization and mortality from hyperkalemia, with no decrease in rates of readmission for CHF or allcause mortality.2 Significant differences were noted in the characteristics of these patients and patients enrolled in the RALES trail. Evidence-Based Practice 11 DRUG PROFILE CONTINUED Few patients in practice meet the inclusion criteria of the RALES study. In one report only 25% of hospitalized elderly patients (65 years or older) with CHF met the inclusion criteria of the RALES study.3 The importance of using spironolactone in carefully selected patients and anticipating and monitoring for hyperkalemia can not be overemphasized. Adverse effects Spironolactone can cause hyperkalemia, which can cause fatal arrhythmias. However, hyperkalemia due to spironolactone is rare in the absence of risk factors (volume depletion, severe CHF, hemolysis, rhabdomyolysis, frail elderly, adrenal insufficiency, urinary tract obstruction, numerous drugs) or renal dysfunction. Without changes in diet, new onset of other risk factors, or dose changes of diuretics or clinical condition, most electrolyte problems with diuretics occur in the first 2 weeks of therapy. Therefore monitoring for hyperkalemia is likely to be most beneficial during this time period.7 Spironolactone, because it blocks the DHT receptor, can cause gynecomastia or breast pain and impotence. The potential for these effects should be EBP discussed with patients before treatment. Other indications for spironolactone HIRSUTISM A recent Cochrane systematic review found spironolactone to be effective for treatment of hirsutism that is idiopathic or associated with the polycystic ovary syndrome. Hirsutism in these conditions is associated with increased testosterone levels.4 ASCITES IN PATIENTS WITH CIRRHOSIS Spironolactone has been found to be more effective than furosemide in patients with cirrhosis. However, the general recommendation is that patients should be treated with a combination of the 2 drugs to avert hyperkalemia.5 PRIMARY HYPERALDOSTERONISM Evidence-Based Practice Spironolactone is effective in the treatment of hyperaldosteronism due to idiopathic hyperaldosteronism and for patients with aldosterone-producing adenoma who are not surgical candidates.6 Family Physicians Inquiries Network, Inc. 409 West Vandiver Drive Building 4, Suite 202 Columbia, MO 65202 REFERENCES 1. N Engl J Med 1999; 341:709–717. 2. N Engl J Med 2004; 351:543–551. 3. Am Heart J 2003; 146:250–257. 4. Cochrane Database Syst Rev 2003; (4):CD000194. 5. N Engl J Med 1994; 330:337–342. 6. Endocrinology 2003; 144:2208–2213. 7. UpToDate Online [serial online] 12.3. Available at: http://patients.uptodate.com/topic.asp?file=fldlytes/31342 [full report requires subscription]. Accessed October 21, 2004. PRESORTED STANDARD U.S. POSTAGE PAID LINCOLN, NE PERMIT # 365
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