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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 ■ ■ What are the signs and symptoms of mesenteric artery occlusion and how do you test for it? 5 Is guaifenesin safe during pregnancy? ■ ■ 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 ■ ■ 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 ■ ■ ■ ■ 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 ■ 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 ■ ■ ■ 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) ■ ■ ■ ■ ■ ■ ■ ■ 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) ■ ■ 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 2004: 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 Montvale, NJ 07645. The GST number for Canadian subscribers is 124002536. Postmaster: Send address changes to Dowden Health Media, Inc., 110 Summit Avenue, Montvale, NJ 07645 Attn: Kathleen Wenzler. Copyright © 2004 by Dowden Health Media. 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.