Abstracts from Medical Literature for the Geriatrics Practitioner

Management of Neuropathic Pain
Patients with neuropathic pain (NP) are challenging to manage, and evidence-based clinical recommendations for pharmacologic management are needed. Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated at a consensus meeting. Medications were considered for recommendation if their efficacy was supported by at least one methodologically-sound, randomized clinical trial (RCT) demonstrating superiority to placebo or a relevant comparison treatment. Recommendations were based on the amount and consistency of evidence, degree of efficacy, safety, and clinical experience of the authors. Available RCTs typically evaluated chronic NP of moderate to severe intensity. Recommended first-line treatments include certain antidepressants (ie, tricyclic antidepressants and dual reuptake inhibitors of both serotonin and norepinephrine), calcium channel alpha2-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine. Opioid analgesics and tramadol are recommended as generally second-line treatments that can be considered for first-line use in select clinical circumstances. Other medications that would generally be used as third-line treatments but that could also be used as second-line treatments in some circumstances include certain antiepileptic and antidepressant medications, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin. Medication selection should be individualized, considering side effects, potential beneficial or deleterious effects on comorbidities, and whether prompt onset of pain relief is necessary. To date, no medications have demonstrated efficacy in lumbosacral radiculopathy, which is probably the most common type of NP. Long-term studies, head-to-head comparisons between medications, studies involving combinations of medications, and RCTs examining treatment of central NP are lacking and should be a priority for future research.

Pain 2007; Dec 5;132(3):237-251

RH Dworkin, AB O’Connor, M Backonja, JT Farrar, NB Finnerup, TS Jensen, EA Kalso, JD Loeser, C Miaskowski, TJ Nurmikko, RK Portenoy, AS Rice, BR Stacey, RD Treede, DC Turk, MS Wallace

Risperidone for Treatment-Refractory Major Depressive Disorder
Major depressive disorder has high prevalence, mor¬bidity, and mortality. Inadequate results with antidepressants prompts addition of a nonstandard treatment (augmentation ther¬apy). The objective of this study was to assess whether augmentation therapy with risperi¬done reduces symptoms and increases response to antidepressant therapy and remission of depression in adults. This multicenter, double-blind, placebo-controlled, randomized trial was conducted from October 19, 2004 to November 17, 2005 at 75 primary care and psychiatric centers. Patients were 274 outpatient adults with major depressive disorder that was suboptimally responsive to antidepressant therapy. After a 4-week run-in period to ensure insufficient response to standard antidepressants, patients were randomly as¬signed to receive risperidone, 1 mg/day or placebo for 6 weeks. After 4 weeks, the dosage of risperidone was increased to 2 mg/day in some cases. Symptoms were measured by using the 17-item Hamilton Rating Scale for Depression (HRSD-17). Other outcomes were response to therapy, remission of depression, and various c1inician- and patient-rated assessments. Results showed that of the intention-to-treat population (268 patients), 81 % (111 of 137) who received risperidone and 87.8% (115 of 131) who received placebo completed 6 weeks of double-blind treat¬ment. Mean (+/- SE) HRSD-17 scores improved more in the risperi¬done augmentation group than in the placebo group (13.4 +/- 0.54 vs. 16.2 +/- 0.53; difference, -2.8 +/- 0.72 [95% CI, -4.2 to -1.4]; P < 0.001). More risperidone recipients than placebo recipients ex¬perienced remission of depression (24.5% [26 of 106] vs. 10.7% [12 of 112]; P = 0.004) and had a response (46.2% [49 of 106] vs 29.5% [33 of 112]; P = 0.004). Headache (8.8% of risperidone recipients vs 14.5% of placebo recipients), somnolence (5.1 % vs 1.5%), and dry mouth (5.1% vs 0.8%) were the most frequently reported adverse events. A limitation was that patients were receiving many different antidepres¬sants, and the duration of augmentation therapy was limited. Authors concluded that risperidone augmentation produced a statistically sig¬nificant mean reduction in depression symptoms, substantially in¬creased remission and response, and improved other patient- and clinician-rated measures.

Ann Intern Med 2007;147:593-602.

Ramy A. Mahmoud. MD, MPH; Gahan J. Pandin, PhD; Ibrahim Turkoz, MS; Colette Kosik-Gonzalez, MS; Carla M. Canuso, MD; Mary J. Kujawa, MD, PhD; and Georges M. Gharabawi-Garibaldi, MD

Aspirin in Alzheimer’s Disease (AD2000)
AD2000 Collaborative Group
Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer’s disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. The investigators assessed the benefits of aspirin in patients with AD. 310 community-resident patients who had AD and no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n = 154). Primary outcome measures were cognition (assessed with the Mini-Mental State Examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioraI symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0.10 points higher (95% CI, -0.37 to 0.57; P = 0.7) and mean BADLS score was 0.62 points lower (-1.37 to 0.13; P = 0.11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1 %) patients in the control group had bleeds that led to admission to hospital (relative risk = 4.4, 95% CI, 1.5-12.8; P = 0.007); three (2%) patients in the aspirin group had fatal cerebral bleeds. The authors concluded that although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.

Lancet Neurol 2008;Jan;7(1):41-49.

Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis
The comparative effectiveness of rheumatoid arthritis therapies is uncertain. The purpose of this systematic review was to compare the benefits and harms of disease-modifying antirheumatic drugs (DMARDs) for adults with rheumatoid arthritis. Data sources were records limited to the English language, and studies of adults were identified by using MEDLlNE, EMBASE, The Coch¬rane Library, and International Pharmaceutical Abstracts from 1980 to September 2007. Two persons independently selected relevant head- to-head trials and prospective cohort studies with at least 100 participants, and 12-week follow-up and relevant good- or fair-quality meta-analyses that compared benefits or harms of 11 drug therapies. For harms, they included retrospective cohort studies. Data were extracted on study design, interventions, out¬comes, and quality, according to a standard protocol. Head-to-head trials (n = 23), mostly examining synthetic DMARDs, showed no clinically important differences in efficacy among synthetic DMARDs (limited to methotrexate, le¬flunomide, and sulfasalazine) or among anti-tumor necrosis factor drugs (adalimumab, etanercept, and infliximab). Monotherapy with anti-tumor necrosis factor drugs resulted in better radiographic outcomes than did methotrexate but no important differences in clinical outcomes (for example, 20%, 50%, or 70% improvement according to American College of Rheumatology response criteria). Various combinations of biological DMARDs plus methotrexate im¬proved clinical response rates and functional outcomes more than monotherapy with either methotrexate or biological DMARDs. In patients whose monotherapy failed, combination therapy with syn¬thetic DMARDs improved response rates. Numbers and types of short-term adverse events were similar for biological and synthetic DMARDs. The evidence was insufficient to draw conclusions about differences for rare but serious adverse events for biological DMARDs. A limitation was that most studies were short-term efficacy trials conducted in selected populations with few comorbid conditions. Authors concluded that limited available comparative evidence does not sup¬port one monotherapy over another for adults with rheumatoid arthritis. Although combination therapy is more effective for pa¬tients whose monotherapy fails, the evidence is insufficient to draw firm conclusions about whether one combination or treatment strategy is better than another or is the best treatment for early rheumatoid arthritis.

Ann Intern Med 2008;148:124-134.

Katona E. Donahue, MD, MPH; Gerald Gartlehner, MD, MPH; Daniel E. Jonas, MD, MPH; Linda J. Lux, MPA; Patricia Thieda, MA; Beth L. Jonas, MD; Richard A. Hansen, PhD; Laura C. Morgan, MA; and Kathleen N. Lohr, PhD

CLINICAL GUIDELINES
Screening for Carotid Artery Stenosis: An Update of the Evidence for the U.S. Preventive Services Task Force
Cerebrovascular disease is the third leading cause of death in the United States. The proportion of all strokes attributable to previously asymptomatic carotid artery stenosis (CAS) is low. In 1996, the U.S. Preventive Services Task Force concluded that evi¬dence was insufficient to recommend for or against screening of asymptomatic persons for CAS by using physical examination or carotid ultrasonography. The purpose of this study was to examine the evidence of benefits and harms of screening asymptomatic patients with duplex ultrasonography and treatment with carotid endarterectomy for CAS. Data sources used were MEDLINE and Cochrane Library (search dates Jan¬uary 1994 to April 2007), recent systematic reviews, reference lists of retrieved articles, and suggestions from experts. English-language randomized, controlled trials (RCTs) of screening for CAS; RCTs of carotid endarterectomy ver¬sus medical treatment; systematic reviews of screening tests; and observational studies of harms from carotid endarterectomy were selected to answer the following questions: Is there direct evidence that screening with ultrasonography for asymptomatic CAS reduces strokes? What is the accuracy of ultrasonography to detect CAS? Does intervention with carotid endarterectomy reduce morbidity or mortality? Does screening or carotid endarterectomy result in harm? All studies were reviewed, abstracted, and rated for quality by using predefined Task Force criteria. No RCTs of screening for CAS have been done. According to systematic reviews, the sensitivity of ultrasonography is approximately 94% and the specificity is approximately 92 %. Treatment of CAS in selected patients by selected surgeons could lead to an approximately 5-percentage point absolute reduction in strokes over 5 years. Thirty-day stroke and death rates from carotid endarterectomy vary from 2.7% to 4.7% in RCTs; higher rates have been reported in observational studies (up to 6.7%). A limitation was that evidence is inadequate to stratify people into catego¬ries of risk for clinically important CAS. The RCTs of carotid end¬arterectomy versus medical treatment were conducted in selected populations with selected surgeons. The authors concluded that the actual stroke reduction from screening asymptom¬atic patients and treatment with carotid endarterectomy is un¬known; the benefit is limited by a low overall prevalence of treat¬able disease in the general asymptomatic population and harms from treatment.

Ann Intern Med 2007;147:860-870.

Tracy Wolff, MD, MPH; Janelle Guirguis-Blake, MD; Therese Miller, DrPH; Michael Gillespie, MD, MPH; and Russell Harris, MD, MPH

The Risk for Fatal Pulmonary Embolism after Discontinuing Anticoagulant Therapy for Venous Thromboembolism
The long-term risk for fatal pulmonary embolism (PE) after treatment of venous thromboembolism (VTE) may be an important factor in the decision to discontinue the treatment. The objective of this prospective cohort study conducted at academic medical centers was to provide reliable and precise estimates of the annual risk for fatal PE and the case-fatality rate of disease recurrence, and to assess these outcomes according to the initial presentation of VTE (deep venous thrombosis [DVT], PE, or both) and its etiology (secondary or idiopathic) in patients who have discontinued anti¬coagulant therapy. This was an inception cohort of patients with a first episode of symp¬tomatic VTE who discontinued anticoagulant therapy. Researchers measured incidence rates of any fatal PE (which included sudden death from possible fatal PE) and definite or probable PE per 100 person-years of follow-up and case-fatality rate of recur¬rent VTE. Results showed that of 2052 patients studied, 1450 had DVT, 310 had PE, and 292 had DVT and PE. The mean duration of previous anticoagulant therapy was 6 months (range, 3 to 39 mo), and the mean duration of follow-up after discontinuation of treatment was 54 months (range, 1 to 120 mo). The annual risk for any fatal PE and definite or probable fatal PE after discontinuation of anti¬coagulation was 0.49 events (95% CI, 0.36 to 0.64 events) per 100 person-years and 0.19 events (CI, 0.12 to 0.30 events) per 100 person-years, respectively. The case-fatality rate of recurrent disease was 9.0% (CI, 6.8% to 11.8%) for any fatal PE and 3.8% (CI, 2.4% to 5.9%) for definite or probable fatal PE. A limitation of the study was that the findings are less pertinent to patients with active cancer, permanent immobility, or high-risk thrombophilia. The authors concluded that the risk for fatal PE is 0.19 to 0.49 events per 100 person-years for patients who have finished a course of anticoagulant therapy for a first episode of symptomatic VTE. The case-fatality rate for death from recurrent PE is 4% to 9%. This infor¬mation helps to inform patient prognosis and may assist clinicians in deciding whether to discontinue anticoagulant therapy for VTE.

Ann Intern Med 2007;147:766-774.

James D. Douketis, MD; Chu Shu Gu, MSc; Sam Schulman, MD, PhD; Angelo Ghirarduzzi, MD; Vittorio Pengo, MD; and Paolo Prandoni, MD, PhD