Evidence-Based Practice CME ▲

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