Download April 2004 - Family Physicians Inquiries Network

CME
Evidence-Based Practice
Answering clinical questions▲
with the best sources
VOLUME 7
NUMBER 4
APRIL 2004
WHAT’S INSIDE
TRANSFORMING PRACTICE
HELP DESK
3
3 What is the best treatment
for corneal abrasion?
Atherosclerosis as a chronic
inflammatory disease:
A new conceptual approach
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What are the signs and symptoms
of mesenteric artery occlusion
and how do you test for it?
5 Is guaifenesin safe during pregnancy?
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In patients with depression, is treatment
with antidepressants more effective than
counseling or a combination of the 2?
6 How does skin adhesive compare
with suturing for superficial lacerations?
For those at intermediate risk of cardiovascular disease,
measuring levels of high-sensitivity C-reactive protein
may help direct evaluation and therapy
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What is the best treatment and monitoring
approach for venous thromboembolism
during pregnancy?
7 Does decreasing fat intake reduce
the likelihood of breast cancer in women
with significant family history?
Summary of evidence
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DRUG PROFILE
9
Memantine first drug approved by FDA
for moderate-to-severe Alzheimer’s
EVIDENCE IN PERSPECTIVE
How should we treat ulcers
of aphthous stomatitis?
11
In a meta-analysis, men whose C-reactive protein (CRP) values were in
the highest third had an odds ratio of 2.13 for development of cardiovascular disease (CVD) compared with that of men in the lowest third.
CRP level is a stronger predictor of cardiovascular events than lowdensity lipoprotein cholesterol level in otherwise healthy women.
Of known inflammatory markers, high-sensitivity CRP (hs-CRP) has
the analyte and assay characteristics most conducive to use in practice.
Just as the discovery of Helicobacter pylori as the prime causative agent in
duodenal ulcer disease brought about a change in our way of thinking, a
transformation is occurring with regard to our knowledge about coronary
artery disease and atherosclerosis. Accumulating evidence demonstrates
an association between various serum markers of inflammation and the
development of myocardial ischemia and infarction. Chronic inflammation may play a key role in the cause, and therefore potentially the
diagnosis and treatment, of atherosclerosis.
C-reactive protein a key marker
EDITORS
BERNARD EWIGMAN, MD, MSPH
University of Chicago
DAVID WHITE, MD
Columbia, MO
A study published in 1994 showed that hospitalized patients with unstable
angina who had normal creatine kinase and cardiac troponin T levels, but
elevations of CRP, had, on average, 4.8 subsequent ischemic episodes in the
continued
TRANSFORMING PRACTICE
CONTINUED
hospital, compared with 1.8 such episodes in patients
with nonelevated CRP levels.1 Since the publication of
these findings, a large body of evidence has demonstrated that CRP is a powerful prospective independent risk factor for CVD.
In a meta-analysis of nested, case-control, population-based prospective studies published in 2000,
men whose CRP values were in the highest third had
an odds ratio of 2.13 for development of CVD, compared with those in the lowest third.2 This outcome
was calculated after controlling for other known risk
factors of CVD (smoking; increased body mass index;
increased levels of blood pressure, total cholesterol,
high-density lipoprotein cholesterol, and triglycerides).
A study published in 2002 found that CRP
level is a stronger predictor of cardiovascular events
than the low-density lipoprotein cholesterol level
in otherwise healthy women followed for a mean of
8 years.3 Furthermore, the inclusion of CRP levels
added prognostic information to that conveyed by
the Framingham risk score.3
Other markers for risk of CVD
Other biochemical markers for inflammation are
associated with increased risk of CVD.
Elevated fibrinogen levels: One early study of
healthy men and women followed in the Framingham cohort demonstrated an association between
elevated fibrinogen levels and risk for CVD.4 This
increase in risk was significant even after controlling for other CVD risk factors.
Amyloid A, white blood cells, albumin: In the
meta-analysis cited above,2 the adjusted odds ratio for
the development of CVD was 1.65 in men with elevated serum amyloid A protein compared with men
who had nonelevated levels; 1.12 in men with an elevated white blood cell count; and 0.67 in men with
serum albumin levels in the upper third of patients
(low albumin level confers greater risk for CVD).
Homocysteine: Elevated serum homocysteine levels
have also been associated with increased risk of
CVD. A meta-analysis of 20 prospective studies
showed that elevated homocysteine levels were
associated with an increased risk of ischemic heart
disease, deep vein thrombosis with or without
pulmonary embolus, and stroke.5 Again, these associations were statistically significant even after
controlling for other known CVD risk factors.
2 Evidence-Based Practice
Recommendations in progress
The American Heart Association and the Centers
for Disease Control and Prevention released a report
last year entitled “Markers of inflammation and
cardiovascular disease.”6 For the practicing physician, the most salient take-home point is that the
benefits of using serum markers of inflammation
such as hs-CRP have not yet been established.
Nonetheless, the report provides a useful summary of the evidence for inflammation as a key pathogenic mechanism in atherosclerosis, characteristics desirable
in a CVD risk predictor, laboratory tests to assess inflammation, and evidence for association of inflammatory
markers with CVD: clinical and epidemiological studies
(including primary and secondary prevention), recommendations for use of inflammatory markers in clinical and public health practice, and recommendations
for research. We summarize the key conclusions here.
Using C-reactive protein
Because the strongest independent association was
found with hs-CRP, the panel limited its recommendations primarily to this test.6 Cutoff points for
hs-CRP levels were used to designate risk status:
<1 mg/L indicates low risk
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continued on page 8
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 web-based 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.
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.
Evidence in Perspective: The editors select topics covered in the highest
quality evidence-based sources (eg, Cochrane, Clinical Evidence) and provide a clinical perspective and guidance for applying the evidence specifically in primary care practice.
Help Desk
CONCISE ANSWERS TO PHYSICIANS’ CLINICAL QUESTIONS
What is the best treatment
for corneal abrasion?
For patients with corneal abrasions, patching the eye
is not helpful and may, in fact, be harmful (leading
to increased discomfort or loss of binocular vision).
Cycloplegic (cyclopentolate 1% or homatropine 2%)
drops can be used for pain relief. A beneficial effect
of topical antibiotics has not been demonstrated in
randomized controlled trials (RCTs).
A common medical myth is that corneal abrasions
should be patched for up to 24 hours after the time of
injury in all cases. The rationale is that blinking
increases discomfort and slows healing of the corneal
epithelium. The authors of a systematic review of this
question evaluated the validity of this practice.1
A total of 7 RCTs were found that compared
patching with no patching for patients older than 6
years; the outcomes of interest were pain and rates
of healing. For 5 of these trials, the data could be
combined. The results showed that healing rates
were not significantly different between patched
and unpatched patients. Pain outcomes were not
combined, but in 4 of the trials no difference in
pain was found between the 2 groups, and in 2
studies patients who did not receive a patch reported
significantly less pain.
At least 2 subsequent RCTs have supported
these conclusions. In one, 163 patients presenting to
the emergency room with corneal abrasions were
randomized to receive either patching with topical
antibiotic ointment or antibiotic ointment alone.2 At
24 and 48 hours, healing rates were similar between
the 2 groups (58% vs 65% and 83% vs 86% for
patched vs unpatched patients, respectively).
Additionally, the initial discomfort was relieved in
66% vs 60% at 24 hours and in 75% vs 81% of
patients at 48 hours.
In a second small trial, the same question was
addressed with pediatric patients.3 Thirty-seven
patients aged 3 to 17 presenting to the emergency
room with corneal abrasions were assigned to
receive patch or no patch, with both groups receiving topical antibiotics. All patients were seen again
between 20 and 24 hours after the injury. No differ-
ences were noted between the 2 groups with regard
to rates of healing or pain. Whether this study was of
sufficient size to detect small differences in healing
rates or pain between the 2 groups was unclear.
Thus, when tested, the “conventional”
approach to this common disorder—patching
corneal abrasions for 24 hours—fails to demonstrate
benefit in clinical trials. Furthermore, the risks of
patching (possible delayed healing, monocular vision
with attendant risk of injury, etc) should lead evidence-based practitioners to abandon this practice.
(Strength of recommendation [SOR]: A, based on
consistent findings in high-quality RCTs)
1.
Flynn CA, D’Amico F, Smith G. Should we patch corneal abrasions? A
meta-analysis. J Fam Pract 1998; 47:264–270.
2.
Le Sage N, Verreault R, Rochette L. Efficacy of eye patching for
traumatic corneal abrasions: a controlled clinical trial. Ann Emerg Med
2001; 38:129–134.
3.
Michael JG, Hug D, Dowd MD. Management of corneal abrasion in
children: a randomized clinical trial. Ann Emerg Med 2002; 40:67–72.
What are the signs and symptoms of mesenteric
artery occlusion and how do you test for it?
Acute mesenteric arterial occlusion is a medical
emergency and accounts for 1 of every 1000 hospital
admissions. Patients often present with nonspecific
signs and symptoms. The classic description of
“pain out of proportion to the physical findings” is
often used, but specific clinical findings for this disorder are lacking.
The typical patient is older than 50 years, and
early on may present with nausea, vomiting, or a
change in bowel habits. Peritoneal signs of an acute
abdominal process are often lacking. Patients often
have a history of cardiac or peripheral vascular disease. Patients who present in a more advanced stage
of mesenteric arterial occlusion have diffuse peritoneal signs, shock, and severe metabolic derangements. Such patients, who usually go to surgery,
have mortality rates of 70% to 90% when the diagnosis is not made preoperatively.1
Because a review of the literature revealed
numerous patients, many of whom were younger
than 50, who had acute mesenteric arterial occlusion
without the above risk factors, the American
Evidence-Based Practice
3
Help Desk
Computed tomography: as with
plain
abdominal x-rays, abnorDescription of FDA categories for drug use during pregnancy
malities are too nonspecific and
develop too late in the course of
Category
Description
the disease to be useful in estabA
Controlled studies show no risk. Adequate, well-controlled studies in preglishing the diagnosis.
nant women have failed to demonstrate a risk to the fetus in any trimester
The panel described selective
of pregnancy.
mesenteric artery angiography as
B
No evidence of risk in humans. Adequate, well-controlled studies in pregnant
the gold standard in the diagnosis
women have not shown increased risk of fetal abnormalities despite adverse
of acute mesenteric ischemia.2
findings in animals, or, in the absence of adequate human studies, animal
Although
the
sensitivity
studies show no fetal risk. The chance of fetal harm is remote, but remains
a possibility.
(74%–100%) and specificity
(100%) of this test are sufficient to
C
Risk cannot be ruled out. Adequate, well-controlled human studies are
justify reliance on its result, dislacking, and animal studies have shown a risk to the fetus or are lacking as
well. There is a chance of fetal harm if the drug is administered during
agreement exists regarding its use.
pregnancy; but the potential benefits may outweigh the potential risks.
This controversy is because
potential risks of the intervention
D
Positive evidence of risk. Studies in humans, or investigational or postmarketing data, have demonstrated fetal risk. Nevertheless, potential benefits
in low-risk patients with nonspefrom the use of the drug may outweigh the potential risk. For example, the
cific clinical findings may offset
drug may be acceptable if needed in a life-threatening situation or serious
its value. Furthermore, use of
disease for which safer drugs cannot be used or are ineffective.
selective
mesenteric
artery
X
Contraindicated in pregnancy. Studies in animals or humans, or investigaangiography in critically ill
tional or postmarketing reports, have demonstrated positive evidence of
patients—those most likely to
fetal abnormalities or risks which clearly outweighs any possible benefit to
the patient.
undergo laparotomy anyway—
may simply delay a potentially
Adapted from FDA use-in-pregnancy ratings.
Available at: www.perinatology.com/exposures/Drugs/FDACategories.htm.
life-saving intervention. Hence,
the timing and appropriateness of
this test should be determined
Gastroenterological Association developed a diagwith input from surgical and radiologist consultanostic guideline. The recommendation is that all
tion whenever possible.
patients who present with abdominal pain out of
This guideline, however, was based on limited
proportion to physical findings should have the
evidence. Most of the studies were case series, and
diagnosis of acute mesenteric ischemia considered
typically retrospective. Thus a “standardized
and pursued.2
approach” to the patient with suspected acute
mesenteric ischemia remains controversial. What
The same guideline indicated that no serum
we do know is that when suspected, the diagnosis
markers are sensitive or specific enough, particushould be aggressively pursued, up to and includlarly at the early stages of acute mesenteric
ing exploratory laparotomy. Because early surgical
ischemia, to reliably confirm or exclude the diagintervention results in a substantial reduction in
nosis. Other noninvasive tests were considered.
mortality for these patients, once considered, the
The conclusions of the panel regarding the utility
diagnosis should be assumed to be “present until
of these tests are as follows 2:
proven otherwise.” (SOR: C, based on a guideline
Plain x-ray films of the abdomen: abnormal
findings are late, nonspecific, and associated with
from a consensus of experts)
a high mortality rate for patients with acute
1. MacDonald PH, Beck IT. Ischemic disease of the intestine. In: Thomson
mesenteric ischemia (78% compared with 29%
ABR, Shaffer EA, eds. First Principles of Gastroenterology. 3rd ed.
Edmonton, Alberta: Astra; 2000:269. Available at: www.gastroremortality for patients with normal plain films)
source.com/GITextbook/en/Default.htm. Accessed March 16, 2004.
Duplex sonography: has inadequate sensitivity
2. American Gastroenterological Association Medical Position Statement:
guidelines on intestinal ischemia. Gastroenterology 2000; 118:951–953.
to be useful clinically
TABLE 1
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4 Evidence-Based Practice
Help Desk
Is guaifenesin safe during pregnancy?
TABLE 2
The FDA classifies guaifenesin as a category “C”
drug. This assessment means that risk cannot be
ruled out with regard to its use during pregnancy.
The FDA uses a categorization scheme to
describe the relative safety of drugs during pregnancy.
See TABLE 1 for a summary.1
In the case of guaifenesin, therefore, caution
should be used in recommending its use, particularly during the first trimester. TABLE 2 presents FDA
categories for common over-the-counter medications
used for minor coughs and colds.2 A complete review
of the subject of the use of over-the-counter medications in pregnancy has been published recently.2
1.
FDA use-in-pregnancy ratings. Available at: www.perinatology.com/exposures/Drugs/FDACategories.htm. Accessed March 16, 2004.
2.
Black RA, Hill DA. Over-the-counter medications in pregnancy. Am Fam
Physician 2003; 67:2517–2524. Available at: http://www.aafp.org/
afp/20030615/2517.html. Accessed March 16, 2004.
FDA use-in-pregnancy categorization for
commonly used over-the-counter drugs to
treat symptoms of upper respiratory infection
FDA category
Chlorpheniramine
B
Pseudoephedrine hydrochloride
B
Diphenhydramine
B
Clemastine fumarate
B
Guaifenesin
C
Dextromethorphan hydrobromide
C
Adapted from Black RA, Hill DA. Over-the-counter medications in
pregnancy. Am Fam Physician 2003; 67:2517–2524.
Available at: www.aafp.org/afp/20030615/2517.html.
In patients with depression, is treatment
with antidepressants more effective
than counseling or a combination of the 2?
Evidence suggests that the combination of either cognitive therapy or psychological counseling in addition
to the use of antidepressants is superior to psychotherapy alone for patients with severe depression.
In a nonsystematic review of the literature, 6
randomized controlled trials were found that compared the use of antidepressants plus psychotherapy
to the use of psychotherapy alone.1 A total of 595
patients aged 18 to 80 years were included. A positive outcome was defined as a Hamilton depression
score rating of less than 7 for 4 weeks, with a followup period of 16 weeks. Nonmedical interventions
included either interpersonal psychotherapy (12–16
weekly sessions focusing on improving interpersonal functions) or cognitive therapy (20 sessions over
12–16 weeks focusing on changing dysfunctional
beliefs and negative automatic thoughts). Only
patients with severe depression showed a more
favorable outcome at 16 weeks using the combination of antidepressants and psychotherapy (P=.001)
compared with psychotherapy alone. No significant
difference was noted in response rates of patients
with mild-to-moderate depression.
In a subsequent randomized controlled trial of
681 patients (mean age=43) with chronic mild-tomoderate depression, the use of cognitive behavioral
OTC drug
therapy alone was compared with the use of the antidepressant nefazodone and with the combination of
both interventions.2 As above, the Hamilton depression score rating system was used as the primary outcome measure, and all patients at baseline had a
score of 20 or higher (indicative of clinically significant depression). A satisfactory response was defined
as a reduction of the baseline score of 50% and a score
of 15 or less at 10 and 12 weeks of follow-up. Over the
course of the study 48% of patients using either psychotherapy or medical therapy alone had a satisfactory response, compared with 73% of patients receiving both therapies (P<.001). This difference in
response rates would indicate that for every 4 patients
treated with combination therapy, 1 will have significant relief from depression who would not have
responded to either single intervention alone (number needed to treat=4).
Thus, despite the limited evidence available,
some support can be found for the idea that the
combination of psychotherapy and antidepressants
is more effective than either intervention alone.
Further studies are needed to confirm these findings
and to help identify which patients are most likely
to benefit. (SOR: C, based on the use of nonpatient-oriented outcomes)
1.
Thase ME, Greenhouse JB, Frank E, et al. Treatment of major depression
with psychotherapy or psychotherapy-pharmacotherapy combinations.
Arch Gen Psychiatry 1997; 54:1009–1015.
Evidence-Based Practice
5
Help Desk
2.
Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone,
the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000;
342:1462–1470.
How does skin adhesive compare
with suturing for superficial lacerations?
Skin adhesives are equivalent to traditional wound
closure techniques with regard to cosmetic appearance of the wound at follow-up. When compared
with standard care, such adhesives offer the advantages of causing less pain and decreased procedure
time associated with the management of simple
traumatic lacerations.
In a systematic review of the literature,
researchers analyzed the results of 8 randomized
controlled trials that compared the outcomes for
patients receiving adhesive skin closure vs standard
skin closure and that compared the outcomes of different skin adhesives.1 The lacerations were all traumatic (nonsurgical) and were simple, in the sense
that they were linear low-tension wounds.
Outcomes of cosmetic appearance at follow-up and
pain were measured using standardized scales. The
researchers found that:
Skin adhesives were equivalent to standard care
with regard to cosmetic appearance at follow-up
This equivalence showed no variation between
children and adults
The use of skin adhesives was associated with
significantly less pain
The use of skin adhesives was associated with a
significantly reduced procedure time (mean procedure time 5.6 minutes shorter; 95% CI –8.2 to –3.1
compared with standard care)
Also, a small but statistically significant chance
of increased risk of wound dehiscence was associated
with the use of skin adhesives vs standard care. The
magnitude of this risk was such that for every 25
patients treated with skin adhesive, 1 additional case of
wound dehiscence would occur when compared with
standard management of simple traumatic lacerations.
A comparison of 2 different skin adhesives
(butyl cyanoacrylate [Histoacryl] vs octyl cyanoacrylate [Dermabond]) for the closure of pediatric
facial lacerations revealed they were equivalent with
regard to cosmesis, pain, time for procedure, and
complications. (SOR: A, based on a systematic
review with consistent findings)
1.
Farion K, Osmond MH, Hartling L, et al. Tissue adhesives for traumatic
lacerations in children and adults (Cochrane Review). In: The Cochrane
Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons.
What is the best treatment and monitoring
approach for venous thromboembolism
during pregnancy?
Pregnancy is thought to be a risk factor for the
development of deep venous thromboembolism
(DVT). A case-control study was performed that
looked for factors that might confer increased risk
for the development of DVT in otherwise healthy
individuals.1 Increased risk was defined as having
an odds ratio for the development of DVT of more
than 1.0 with P<.05. Pregnancy was one of the
identified “triggering” or transient conditions
found to carry an increased risk for developing
DVT. Others included violent effort, muscular
trauma, deterioration of general condition, immobilization, long-distance travel, and infectious disease. The management of DVT in pregnancy is
complicated because of the known teratogenicity of
warfarin (Coumadin). Therefore, heparin for the
duration of pregnancy is the recommended
approach.
In a review of the topic of using antithrombotic agents during pregnancy,2 the following recommendations were made:
Adjusted-dose low molecular-weight heparin
(LMWH) throughout pregnancy OR
Intravenous unfractionated heparin (UFH) in a
bolus followed by continuous infusion to maintain
the activated partial thromboplastin time in the
therapeutic range for at least 5 days, followed by
adjusted-dose subcutaneous UFH for the remainder of the pregnancy.
Discontinuation of heparin therapy 24 hours prior
to elective induction of labor.
Postpartum anticoagulation therapy should be
administered for at least 6 weeks.
LMWH dosage is determined by body weight,
according to the manufacturer's recommendations, and thus would need to be adjusted in most
cases as the pregnancy progresses. (SOR: C, expert
opinion)
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1.
Samama MM. An epidemiologic study of risk factors for deep vein
thrombosis in medical outpatients: the Sirius study. Arch Intern Med
2000; 160:3415–3420.
2.
Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001; 119:122S–131S.
continued
6 Evidence-Based Practice
Help Desk
Does decreasing fat intake reduce
the likelihood of breast cancer in women
with significant family history?
Because of limitations of available evidence, the
best answer to this question must be extrapolated
from studies that may bear indirectly on the subject. Based on such an extrapolation, reducing fat
intake is unlikely to lower the likelihood of breast
cancer in women with significant family histories.
The evidence is conflicting as to whether any
association exists between dietary fat intake and the
likelihood of breast cancer. One of the early studies
that described a possible relationship between fat
intake and breast cancer was a case-control study
that involved the prognosis of women with diagnosed breast cancer.1 Prospective cohort studies,
which are a stronger study-design type for examining risk factors for the development of disease, have
subsequently been conducted. A meta-analysis of 7
such studies, which included a total of 337,819
patients and 4980 cases of breast cancer, demonstrated no association and found no reduction in
risk, even among women whose energy intake from
fat was less than 20% of total energy intake.2 More
recently, in a report from the Nurses’ Health Study,
it was concluded that no relation exists between the
amount or type of fat consumed and the development of breast cancer.3 This study included 88,795
women followed for 14 years, of whom 2956 developed breast cancer.
When evidence is lacking that would help clinicians and their patients to make good decisions
regarding health care, the results of studies that may
have an indirect connection to the question at hand
may need to be extrapolated. The case of whether a
patient with a family history of breast cancer is likely, by dietary changes, to reduce her own risk of
breast cancer, should take into account individual
patient factors, as well as the evidence. Does the
patient want to do “whatever she can” to help
reduce her risk, even if no direct evidence supports
this dietary change? Are there other reasons for the
patient to consider a low-fat diet? The answers to
questions such as these may be just as important as
the “evidence” for helping clinicians and their
patients make healthcare decisions. (SOR: C, based
on extrapolation of findings from epidemiologic
EBP
studies only)
1.
Holm LE, Nordevang E, Hjalmar ML, Lidbrink E, Callmer E, Nilsson B.
Treatment failure and dietary habits in women with breast cancer. J Natl
Cancer Inst 1993; 85:32–36.
2.
Hunter DJ, Spiegelman D, Adami HO, et al. Cohort studies of fat intake
and the risk of breast cancer—a pooled analysis. N Engl J Med 1996;
334:356–361.
3.
Holmes MD, Hunter DJ, Colditz GA, et al. Association of dietary intake of
fat and fatty acids with risk of breast cancer. JAMA 1999; 281:914–920.
Correction
A publisher’s production error resulted in a misprinting of the
warfarin dosage table that appeared in the February 2004
issue. The corrected table appears below.
Useful algorithm for initiating oral anticoagulant therapy
Another interesting development is a new method of achieving
desired target INR values in patients being started on oral anticoagulant therapy.4 Patients with nonrheumatic atrial fibrillation
who were referred for oral anticoagulant therapy were prescribed 5 mg warfarin for 4 days. On day 5, INR determinations
were made, and subsequent dosing of warfarin was at the discretion of each patient’s physician. Once patients had achieved
a stable INR between 2.0 and 3.0, the resulting maintenance
dose was compared with each patient’s INR on day 5. The relation between the 2 (eventual weekly warfarin dose vs INR on day
5) revealed a hyperbolic relationship. From this information a
TABLE was developed, which accurately calculated the weekly
warfarin dose that would result in the desired INR based on the
INR achieved on day 5.
TA
BLE
TABLE
Weekly warfarin dosing for anticoagulation
based on INR on day 5
INR on
Day 5
Dosing
(mg / wk)
INR on
Day 5
Dosing
(mg / wk)
1.0
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
2.5
2.6
71
57
48
43
39
35
33
31
29
27
26
24
23
22
21
20
19
2.7
2.8
2.9
3.0
3.1
3.2
3.3
3.4
3.5
3.6
3.7
3.8
3.9
4.0
4.1
4.2
4.3
4.4
18
17
16.5
16
15
14
13.5
13
12
11.5
11
10.5
10
9
8.5
8
7.5
7
*According to this scheme a warfarin maintenance dose of 20 mg/wk is
predicted for a patient with an INR of 2.5 on day 5.
Evidence-Based Practice
7
TRANSFORMING PRACTICE
CONTINUED FROM PAGE 2
1–3 mg/L indicates average risk
>3 mg/L indicates high risk
Three classes of recommendations—IIa, IIb, and
III—were created according to the strength of
underlying clinical evidence.6
5. Serial testing of hs-CRP should not be used to
monitor effects of treatment. (SOR: C)
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Key questions moving forward
The role of testing for hs-CRP remains poorly defined.
Even in those situations for which testing may be useful, the benefits of such an approach are uncertain.
Despite a rapidly growing knowledge base in
support of atherosclerosis as a chronic inflammatory disease, and the identification of specific laboratory markers associated with an increased risk
for CVD, many questions must be answered
before the clinical implications of this knowledge
can be fully understood.
For example, will risk assessments that include
hs-CRP measurements identify patients who otherwise would have been missed?
Will risk assessments that include hs-CRP
measurements lead to better treatment outcomes?
Will screened populations fare better than
unscreened populations in morbidity and mortality? No studies have been conducted to answer
this question.
Would screening or testing for elevated hsCRP levels be more cost-effective in particular subsets of the population? To so identify patients at
increased risk of CVD without knowing whether
interventions would favorably modify their risk
could cause them undue stress and anxiety.
Although these questions and others remain
to be adequately answered, the evolving concept of
inflammation as a causative factor in atherosclerosis appears likely to have profound implications for
EBP
diagnosis, treatment, and prognosis.
CLASS IIA: CONFLICTING EVIDENCE/OPINION, WITH
WEIGHT IN FAVOR OF USEFULNESS/EFFICACY
1. The level of hs-CRP is an independent marker of
risk. For individuals judged to be at intermediate risk
by global risk assessment (10%–20% risk of congestive
heart failure within 10 years), measurement of hs-CRP
may help direct further evaluation and therapy in the
primary prevention of CVD. However, the benefits of
therapy based on this strategy are uncertain. (SOR: B)
2. When patients exhibit persistent, unexplained,
marked elevation of hs-CRP (>10 mg/L) after repeated
testing, evaluate for noncardiovascular causes. (SOR: B)
3. Of known inflammatory markers, hs-CRP has the
analyte and assay characteristics most conducive to
use in practice. (SOR: B)
4. Measure inflammatory markers twice (averaging
results), optimally 2 weeks apart, fasting or nonfasting, in metabolically stable patients. (SOR: B)
CLASS IIb: CONFLICTING EVIDENCE/OPINION, WITH
USEFULNESS/EFFICACY LESS WELL ESTABLISHED
1. The level of hs-CRP is an independent marker of
risk. Measurement of this value may be used at the
discretion of the physician as part of a global coronary
risk assessment in adults without known CVD. The
benefits of this strategy are uncertain. (SOR: C)
2. Measurement of hs-CRP levels may be useful in
motivating patients to improve lifestyle behaviors.
The benefits of this strategy are uncertain. (SOR: C)
REFERENCES
1.
Liuzzo G, Biasucci LM, Gallimore JR, et al. The prognostic value of Creactive protein and serum amyloid A protein in severe unstable angina.
N Engl J Med 1994; 331:417–424.
2.
Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ
2000; 321:199–204.
3.
Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive
protein and low-density lipoprotein. N Engl J Med 2002; 347:1557–1565.
4.
Kannel WB, Wolf PA, Castelli WP, D'Agostino RB. Fibrinogen and risk of cardiovascular disease. The Framingham Study. JAMA 1987; 258:1183–1186.
5.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease:
evidence on causality from a meta-analysis. BMJ 2002; 325:1202.
6.
Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation
and cardiovascular disease: application to clinical and public health
practice: a statement for healthcare professionals from the Centers for
Disease Control and Prevention and the American Heart Association.
Circulation 2003; 107:499–511.
CLASS III: PROCEDURE SHOULD NOT BE PERFORMED
1. Measuring hs-CRP levels to screen for cardiovascular risk should not be applied to the entire adult
population. (SOR: C)
2. Other inflammatory markers (cytokines, other acutephase reactants) should not be measured in addition
to hs-CRP to determine coronary risk. (SOR: C)
3. Application of secondary prevention measures should
not depend on hs-CRP determination. (SOR: A)
4. Application of management guidelines for acute
coronary syndromes should not depend on hs-CRP
levels. (SOR: A)
8 Evidence-Based Practice
DRUG PROFILE
Objective reviews of drugs in family medicine
Memantine first drug approved by FDA
for moderate-to-severe Alzheimer’s
Patients with moderate-to-severe Alzheimer’s disease who took memantine,
20 mg/d, for 28 weeks, exhibited improved cognition
Memantine hydrochloride (Namenda), a N-methylD-aspartate antagonist (NMDA), was recently
approved by the Food and Drug Administration
(FDA) as the first drug indicated for the treatment of
patients with moderate-to-severe Alzheimer’s disease.
Cholinesterase inhibitors have also been shown to
improve cognitive symptoms for patients with
mild-to-moderate Alzheimer’s only.
Cholinesterase inhibitors for milder disease
A substantial body of evidence has demonstrated that
the benefits of cholinesterase inhibitors, though modest, are significant in mild-to-moderate Alzheimer’s
disease. Two systematic reviews published in 2003
arrived at similar conclusions. One reviewed 29 randomized controlled trials (RCTs) that compared the
effectiveness of anticholinesterase inhibitors with
placebo. The outcome was a statistically significant
effect for anticholinesterase inhibitors, but questionable clinical significance.
Improvement on the Neuropsychiatric
Inventory—a scale from 1 to 120—averaged 1.72
points (95% confidence interval [CI], 0.87–2.57
points); improvement on the Alzheimer Disease
Assessment Scale—a scale from 1 to 50—averaged
0.03 points (95% CI, 0.00–0.05 points). Similar small
beneficial effects on activities of daily living were
found, but were of questionable clinical significance.1
The second review considered 16 RCTs of
anticholinesterase inhibitor vs placebo, and showed
that 12 patients would need to be treated for 1
patient to show minimal improvement.
Importantly, this same review determined that for
every 12 patients treated, 1 would experience an
adverse event; for every 16 patients treated, 1 would
discontinue treatment because of adverse events.2
Thus, although cholinesterase inhibitors have
shown to benefit some patients with Alzheimer’s, the
effect size is small and adverse events are common.
Memantine: Firm evidence of effectiveness
It is now known that the excitatory activity of
L-glutamate plays a role in the pathogenesis of
Alzheimer’s disease. NMDAs are believed to act by
partially blocking glutamate activity. A systematic
review of studies involving the NMDA memantine
hydrochloride found it to have beneficial effects in
patients with moderate-to-severe disease.
IMPROVED COGNITION AND FUNCTIONAL STATUS
Patients taking memantine, 20mg/d for 28 weeks,
showed statistically significant improvement in cognition. When evaluated with the Severe Impairment
Battery (SIB) at 28 weeks, patients taking memantine
exhibited a mean difference from baseline score of 6.1
points (95% CI, 2.99–9.21; P=.0001), compared with
those receiving placebo. The SIB is a 51-item scale
used to evaluate cognition in advanced Alzheimer’s,
with a range of 0 (greatest impairment) to 100.
Decline in functional status also slowed for
patients taking memantine over the course of the
study. A mean difference of 0.32 points (95% CI,
0.07–0.73; P=.01) was found favoring memantine
on a modified Alzheimer’s Disease Cooperative
Study–Activities of Daily Living assessment
(ADCS-ADL). This instrument assesses functional
capacity over a broad range of severity in patients
with Alzheimer’s, with a total score of 54 signifying
optimal performance in all areas. However, these
beneficial effects were too small to be clinically discernable. The review also concluded that the incidence of side effects and adverse events was low.3
Evidence-Based Practice
9
DRUG PROFILE
CONTINUED
drug in patients with advanced disease, consider
using it in this population. The cost of a 30-day supply at a local pharmacy (20 mg/d) was $144.75. EBP
CONFIRMATION WITH OTHER ASSESSMENT TOOLS
In a subsequent trial, patients with moderate-to-severe
Alzheimer’s disease who took memantine, 20 mg/d for
28 weeks, showed similar improvement in cognition
based on the Clinician’s Interview-Based Impression
of Change Plus Caregiver Input (CIBIC-Plus). This
assessment tool measures overall global change relative
to base line, and is scored from 1 (markedly improved)
to 7 (markedly worse). The mean difference in scores
between patients receiving memantine and placebo
was 0.3 (95% CI, 0.03–0.69; P=.03) at 28 weeks.
Decreased deterioration in activities of daily living was also found (mean difference in ADCS-ADL
scores=3.4 favoring memantine [95% CI, 1.45–5.28;
P=.003]). Furthermore, this study found that caregiver time decreased (mean difference between
groups=45.8 hours per month; (95% CI,
10.37–81.27 hours; P=.01) with patients receiving
memantine versus those receiving placebo.4
REFERENCES
1.
Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase
inhibitors in the treatment of neuropsychiatric symptoms and functional
impairment in Alzheimer disease: a meta-analysis. JAMA 2003;
289:210–216.
2.
Lanctot KL, Herrmann N, Yau KK, Khan LR, Liu BA, LouLou MM,
Einarson TR. Efficacy and safety of cholinesterase inhibitors in
Alzheimer's disease: a meta-analysis. CMAJ 2003; 169:557–564.
3.
Areosa Sastre A, Sherriff F. Memantine for dementia (Cochrane Review). In:
The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons.
4.
Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ;
Memantine Study Group. Memantine in moderate-to-severe Alzheimer's
disease. N Engl J Med 2003; 348:1333–1341.
5.
Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I;
Memantine Study Group. Memantine treatment in patients with moderate
to severe Alzheimer disease already receiving donepezil: a randomized
controlled trial. JAMA 2004; 291:317–324.
MEMANTINE ADDITIVE TO DONEPEZIL
CME CREDIT
In a recently published RCT, 404 patients with moderate-to-severe Alzheimer’s who were already receiving the cholinesterase inhibitor donepezil were randomly assigned to have memantine (eventual dose
20 mg/d) or placebo added to their treatment regimen, and followed for 24 weeks. Improvement was
noted in cognition (SIB=0.9 [SE, 0.67] vs –2.5 [SE,
0.69], for memantine vs. placebo P<.001), activities
of daily living (modified ADCS-ADL= –2.0 [SE,
0.50] vs –3.4 [SE, 0.51]; P=.03); as well as in global
outcome, and behavior (CIBIC-Plus=4.41 [SE,
0.074] vs 4.66 [SE, 0.075]; P=.03). The drug was
well tolerated, and there was no increase in dropouts
due to adverse events in the memantine group compared with those receiving placebo.5
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 joint sponsorship of Michigan State University, College of
Human Medicine, and THE JOURNAL OF FAMILY PRACTICE. 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 Dowden
Health Media, Inc., 110 Summit Avenue, Montvale, N.J. 07645. Telephone 800-7077040, Fax 201-505-5890, E-mail: [email protected]. Subscription rates for
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Consider memantine for first-line therapy
In 2003, the FDA approved the use of memantine as
the first drug indicated for the treatment of patients
with moderate-to-severe Alzheimer’s. The most common side effects cited in this statement included dizziness (7%), headache (6%), and constipation (6%).
Evidence shows that memantine is likely to
have a small, but statistically significant, clinical benefit for patients, improving cognition and activities of
daily living, used alone or in addition to donepezil.
Given the relative effectiveness and safety of this
10 Evidence-Based Practice
EVIDENCE IN PERSPECTIVE
Primary care guidance on reports from other sources
How should we treat ulcers of aphthous stomatitis?
Chlorhexidine gel or mouthwash and sulfuric acid/phenolic solutions
are likely effective against aphthous ulcers. Consider patient preferences
when prescribing treatment
The goals of treatment for aphthous stomatitis are
reduction of the number of ulcers and duration of
ulceration, and relief from discomfort. Many traditional and pharmacologic interventions are used,
but evidence for the efficacy of these treatments is
insufficient, based on limited numbers of controlled
trials with inconsistent findings.
Clinical Evidence report
Based on a search done in December 2002, Clinical
Evidence states the effectiveness of topical steroids
is unknown, and that hexetidine is unlikely to be
effective.1 However, one agent, chlorhexidine
gluconate, appears to increase the number of ulcerfree days during attacks of aphthous stomatitis and
reduces the severity of symptoms.
Evidence reported elsewhere:
Sulfuric acid/phenolic solution effective
Another approach to the management of aphthous
stomatitis involves the use the cauterizing agent
Debacterol—a sulfuric acid/phenolic solution
applied once in the office to lesions with a cottontipped applicator.
In a nonrandomized trial, 60 patients with
recurrent aphthous stomatitis were assigned to use
topically applied Debacterol or Kenalog-in-Orabase,
or to apply no treatment; all were followed for 10
days.2 By the third day of treatment, a striking 70%
of patients receiving Debacterol were found to have
a significant decrease in their pain, compared with
less than 20% of patients in the other 2 groups.
EVIDENCE FOR CHLORHEXIDINE EFFECTIVENESS
Clinical Evidence reports on 5 randomized controlled trials that were designed to assess the efficacy
of chlorhexidine gluconate preparations.1 In these
studies, either chlorhexidine gel or chlorhexidine
mouthwash was used as the active treatment.
In 3 of the trials, an ulcer-day index was used as
an outcome of interest. Two of the 3 studies showed
significant improvement in ulcer-free days for patients
receiving chlorhexidine compared with placebo; one
study reported an increase of 5.4 mean ulcer-free days
over a 6 week period from 17.5 days to 22.9 days. The
third study showed no benefit for patients receiving
chlorhexidine. This lack of benefit may have been due
to the use of a 1% chlorhexidine mouthwash preparation, whereas both studies reporting effectiveness used
either 2% gel, or 2% chlorhexidine mouthwash.
Two of the 5 randomized controlled trials
demonstrated a significant decrease in patient-reported pain scores for those receiving chlorhexidine.
Self-limiting condition,
but potentially disfiguring
Aphthous stomatitis (aphthous ulcers, canker sores) are the
most common cause of recurrent oral lesions.3 Affecting
10%–20% of the population, they most commonly occur in
children. The lesions associated with this condition are small
ulcers of the labial or buccal mucosa, and can also be found
on the floor of the mouth or the tongue. The soft palate,
pharynx, and tonsils are not typically affected. They most
commonly appear as 2–10 mm grey-yellow ulcerations, often
with a raised erythematous margin, and are exquisitely
painful. Most of these lesions resolve spontaneously within 2
weeks, but recurrence is common. Minor aphthous stomatitis involves 1–5 ulcers, <1 cm in diameter which resolve
within 14 days, with no scarring. This is the pattern seen in
80% of patients. Major aphthous stomatitis refers to lesions
>1 cm in diameter that take 2 weeks to several months to
resolve, and result in scarring. The cause of aphthous stomatitis remains unknown.
Evidence-Based Practice 11
DRUG PROFILE
continued
Additionally, by day 6, the ulcers had clinically
disappeared in 80% of the patients receiving
Debacterol and were no longer causing symptoms;
only 30% of patients in the other 2 groups had
similar outcomes.
number of patients. Several interventions traditionally offered to patients with aphthous stomatitis lack evidence in support of their effectiveness.
Despite this, individuals may find that specific
unproven therapies provide adequate relief of
symptoms, and such preferences should always be
taken into account.
Chlorhexidine and sulfuric acid/phenolic
solution probably effective. We would like to see
more well designed studies confirming the efficacy
of 2% chlorhexidine gel or mouthwash and sulfuric
acid/phenolic solutions. Nonetheless, studies to
date suggest these agents (TABLE) are likely beneficial, and, to our knowledge, these agents are the
only ones for which evidence supports efficacy in
EBP
the treatment of aphthous stomatitis.
A reasonable perspective
Aphthous stomatitis, although typically a benign
condition, causes significant discomfort for a large
TABLE
Agents likely effective against aphthous ulcers
Drug
Dosage / administration
Cost*
Chlorhexidine
gluconate
0.2% solution
Rinse mouth with 15 mL
3 times daily
(generic)
$14.65 for
450 mL
Debacterol**
Apply topically to
individual ulcers once
$26.99 for
individual
(1-mL) pkt
Evidence-Based Practice
*Cost approximate; prices from local pharmacy.
**Applied in ofice by physician. Available from dental suppliers only.
See www.debacterol.com/prof_ai.html for detailed instructions.
Dowden Health Media
110 Summit Avenue,
Montvale, NJ 07645
www.ebponline.net
REFERENCES
1.
Clinical Evidence 2003; 9:1499–1505.
2.
Rhodus NL, Bereuter J. An evaluation of a chemical cautery agent and
an anti-inflammatory ointment for the treatment of recurrent aphthous
stomatitis: a pilot study. Quintessence Int 1998; 29:769–773.
3.
Chow AW. Infections of the oral cavity, neck, and head. In Mandell GL,
Bennett JE, Dolin R, eds: Principles and Practice of Infectious
Diseases. 5th ed. 2 vols. Philadelphia, Pa: Churchill Livingstone;
2000:chap 53.