Search

Background: There has been growing interest in using theory-driven research to develop and evaluate continuing medical education (CME) activities. Within health professions education, testing has been shown to promote learning in a variety of different contexts, an effect referred to as test-enhanced learning (TEL). However, the extent to which TEL generalizes to CME remains unclear. The purpose of this study was to investigate whether physicians who received two intervening tests following a CME event would experience a TEL effect relative to physicians who received additional study material to review without testing. Methods: Forty-nine physicians were recruited during a local CME activity. Physicians were randomized to either a) the test group (n=26), where participants completed two 20 multiple-choice question (MCQ) quizzes related to the lecture content or b) the study group (n=23), where participants studied the same information without testing. Testing and studying occurred independently during the CME activity, and then four weeks later online. At eight weeks, participants completed a final 20-item MCQ online test. A between-subjects t-test was used to compare performance on the final test as a function of the initial educational activity (test group vs. study group).Results: Performance on the final MCQ test was equivalent for both test (Mean (SD): 75% (9.9)) and study-only (77% (7.3)) conditions (t(47) = 0.94, p=0.35). Conclusion: The null findings in the present study are contrary to previous findings demonstrating TEL among novice learner populations. The lack of TEL highlights several programmatic considerations that should be factored in before implementing TEL as a part of CME.

Background and Purpose— Central poststroke pain is a chronic neuropathic disorder that follows a stroke. Current research on its management is limited, and no review has evaluated all therapies for central poststroke pain. Methods— We conducted a systematic review of randomized controlled trials to evaluate therapies for central poststroke pain. We identified eligible trials, in any language, by systematic searches of AMED, CENTRAL, CINAHL, DARE, EMBASE, HealthSTAR, MEDLINE, and PsychINFO. Eligible trials (1) enrolled ≥10 patients with central poststroke pain; (2) randomly assigned them to an active therapy or a control arm; and (3) collected outcome data ≥14 days after treatment. Pairs of reviewers, independently and in duplicate, screened titles and abstracts of identified citations, reviewed full texts of potentially eligible trials, and extracted information from eligible studies. We used a modified Cochrane tool to evaluate risk of bias of eligible studies, and collected patient-important outcomes according to recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. We conducted, when possible, random effects meta-analyses, and evaluated our certainty in treatment effects using the Grading of Recommendations Assessment, Development, and Evaluation System. Results— Eight eligible English language randomized controlled trials (459 patients) tested anticonvulsants, an antidepressant, an opioid antagonist, repetitive transcranial magnetic stimulation, and acupuncture. Results suggested that all therapies had little to no effect on pain and other patient-important outcomes. Our certainty in the treatment estimates ranged from very low to low. Conclusions— Our findings are inconsistent with major clinical practice guidelines; the available evidence suggests no beneficial effects of any therapies that researchers have evaluated in randomized controlled trials.

The majority of time in a core General Internal Medicine (GIM) residency is spent focusing on inpatient medicine, with relatively little time devoted to ambulatory medicine. The Royal College of Physicians and Surgeons of Canada has mandated an improvement in ambulatory exposure. Unfortunately, most ambulatory experiences tend to lack formal structure, a dedicated educational curriculum, and graduated learner-specific responsibilities. The recent Royal College recognition of GIM as a subspecialty places renewed emphasis on core IM training providing a more comprehensive exposure to outpatient medicine as management of patients with multiple complex conditions may be best managed by a general internist. In July 2015, McMaster University opened an outpatient medicine clinic which is designed to be an Ambulatory Clinical Teaching Unit (A-CTU). The A-CTU provides a structured clinical environment which is focused on the management of medically-complex patients. It uses a multidisciplinary model, graded learner levels of responsibility and a dedicated educational curriculum. The unique structure of the A-CTU allows for the assessment of milestones and EPAs (entrustable professional activities) pertaining to consultation skills and chronic disease management, in keeping with competence by design.

Background Venous thromboembolism (VTE) prophylaxis in acutely ill medical patients has been shown to be safe and effective. Underutilization of this patient safety practice may result in avoidable mortality and morbidity. Objectives We aimed to determine the proportion of hospitalized, acutely ill medical patients across Canada who were eligible to receive thromboprophylaxis and to evaluate the frequency, determinants and appropriateness of its use. Patients/Methods CURVE is a national, multicenter chart audit of 29 Canadian hospitals. Data were collected on consecutive patients admitted to hospital for an acute medical illness during a defined 3-week study period. Information on demographic and clinical characteristics, risk factors for VTE and bleeding and use of VTE prophylaxis were recorded. The indications for and appropriateness of VTE prophylaxis were assessed using pre-specified criteria based on international consensus guidelines. Multivariable analyses were performed to identify determinants of prophylaxis use. Results Of the 4124 medical admissions screened over the study period, 1894 patients (46%) were eligible for study inclusion. The most common specified admitting diagnoses were severe infection (28%), COPD exacerbation or respiratory failure (12%), malignancy (9%) and congestive heart failure (8%). Thromboprophylaxis was indicated in 1702 (90%) study patients. Overall, some form of prophylaxis was administered to 23% of all patients. However, only 16% received appropriate thromboprophylaxis. Factors independently associated with greater use of prophylaxis included internist (vs. other specialty) as attending physician (OR 1.33, 95% confidence interval (CI) [1.03, 1.71]), university-associated (vs. community) hospital (OR 1.46, 95% CI [1.03, 2.07]), immobilization (per day) (OR 1.60, 95% CI [1.45, 1.77]), presence of ≥ 1 VTE risk factors (OR = 1.78, 95% CI [1.35, 2.34]) and duration of hospitalization (per day of stay) (OR 1.05, 95% CI [1.03, 1.07]), however, use of prophylaxis was unacceptably low in all groups. Patients with cancer had a significantly reduced likelihood of receiving prophylaxis (OR = 0.40, 95% CI [0.24, 0.68]). Presence of risk factors for bleeding did not influence the use or choice of prophylaxis. Conclusion Most patients hospitalized for medical illness had indications for thromboprophylaxis, yet only 16% received appropriate prophylaxis. Efforts should be made to elucidate the reasons that underlie the very low rate of thromboprophylaxis in medical patients and to develop and test strategies to improve implementation of this patient safety practice.

Background Increasing concerns over the effectiveness and quality of continuing medical education (CME) programs has encouraged educators to use theoretically driven empirical research to improve the educational value of these activities. Within cognitive psychology, theories of learning and knowledge acquisition, such as test-enhanced learning (TEL), may be used to enhance the effectiveness of CME protocols and delivery. The present study examined whether the pedagogical benefits of testing can be observed in practicing physicians. Methods A total of 83 physicians were recruited following an education session on constipation management and were randomized to either (a) the test condition (n = 43), where learners wrote a short test consisting of 10 short-answer questions (SAQs), or (b) the study condition (n = 40), where learners studied the same information. Four weeks later, 56 (68%) physicians completed a final test with 10 new SAQs, with 27 being from the initial test condition and 29 belonging to the initial study condition. Results Performance on the final SAQ test was equivalent for both test (42.5%) and study-only (41.2%) conditions (p = .71). Discussion The null findings in the present study are inconsistent with previous research showing the pedagogical benefits of testing relative to studying. Given that most TEL research focuses on novice learners, who lack strong associative memory networks, it is possible that TEL is specific to novices and not generalizable to experts. Alternative explanations focus on the importance of repeated, distributed testing with feedback.

OBJECTIVESWe sought to evaluate whether oral anticoagulant (AC) therapy given for five months was superior to standard (control) therapy in patients with unstable angina receiving aspirin.BACKGROUNDThe long-term risk of myocardial infarction (MI) or death remains high in patients with unstable angina, despite the use of aspirin. Therefore, additional treatments are necessary.METHODSOf the 10,141 patients entering the main trial, 3,712 were randomized 12 to 48 h later to receive oral AC therapy (n = 1,848) or standard therapy (n = 1,864).RESULTSOne-hundred forty patients (7.6%) suffered from cardiovascular death, MI or stroke while receiving oral AC, compared with 155 patients (8.3%) on standard therapy (relative risk [RR] 0.90, 95% confidence interval [CI] 0.72 to 1.14; p = 0.40). The rates of the primary outcomes plus refractory angina were 16.7% (n = 308) versus 17.5% (n = 327) (RR 0.95, 95% CI 0.81 to 1.11; p = 0.53). Countries were divided into good or poor compliers (based on the use of oral AC above or below 70% at 35 days), without knowledge of results by country. In good-complier countries, oral AC was discontinued in only 10.4% of patients at seven days and in 23.6% by five months, compared with 27.6% and 44.9%, respectively, in poor complier countries. There were significant reductions in the risks of both the primary (6.1% vs. 8.9%; RR 0.68, 95% CI 0.48 to 0.95; p = 0.02) and secondary outcomes (11.9% vs. 16.5%; RR 0.70, 95% CI 0.55 to 0.90; p = 0.005) with oral AC in the good-complier countries. There was little difference in the poor-complier countries (9.0% vs. 7.8% for the primary and 21.3% vs. 18.5% for the secondary outcomes, tests for interactions comparing the RRs for the primary and secondary outcomes were p < 0.02 and p = 0.002, respectively, between the two sets of countries). In the overall study, there was an excess of major bleeding (2.7% vs. 1.3%; p = 0.004), which was larger in the good-complier countries (RR 2.71) compared with the poor-complier countries (RR 1.58). There were also reductions in cardiac catheterization (RR 0.80; p = 0.004) and coronary revascularization procedures (RR 0.82; p = 0.06) in the good-complier countries, but not in the poor-complier countries (RR 0.98 and 1.06, respectively, p for interaction of 0.06 and 0.04, respectively).CONCLUSIONSOverall, oral AC led to a small, nonsignificant reduction in the risk of the primary and secondary outcomes. Stratifying the countries or centers by their rates of compliance to oral AC suggested that good compliance to oral AC could potentially lead to clinically important reductions in major ischemic cardiovascular events.

Background Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease. Methods and Results Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0.71, 95% CI 0.58-0.86, P=0.0006) and a 10% reduction in vascular events when compared with aspirin (n=22 254) (OR 0.91, 95% Cl 0.84-0.99, P=0.039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001) or aspirin plus warfarin (OR 0.51, 95% CI 0.33-0.78, P=0.002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3-12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12 500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80-90%, while maintaining an overall type I error (a) of 0.05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome. Conclusions Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and longterm treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome. (C) 2000 The European Society of Cardiology.

Background and Purpose— Chronic pain syndromes are reported to be common after stroke, but most previous epidemiological studies have generally included small cohorts of patients with relatively short-term follow-up. In a large cohort with ischemic stroke (Prevention Regimen for Effectively avoiding Second Stroke [PRoFESS] trial), we determined the prevalence, risk factors, and clinical consequence of new poststroke pain syndromes. Methods— Within the PRoFESS trial (mean follow-up 2.5 years), a standardized chronic pain questionnaire was administered (at the penultimate follow-up visit) to all participants who reported chronic pain since their stroke and did not have a history of chronic pain before their index stroke. Multivariable logistic regression analyses were used to determine risk factors for poststroke pain (and pain subtypes), and the association between poststroke pain and cognitive (≥3 reduction in Mini-Mental State Examination score) and functional decline (≥1 increase in m-Rankin). Results— In total, 15 754 participants were included; of which 1665 participants (10.6%) reported new chronic poststroke pain, and included 431 participants (2.7%) with central poststroke pain, 238 (1.5%) with peripheral neuropathic pain, 208 (1.3%) with pain from spasticity, and 136 participants (0.9%) with pain from shoulder subluxation. More than 1 pain subtype was reported in 86 participants (0.6%). Predictors of poststroke pain included increased stroke severity, female sex, alcohol intake, statin use, depressive symptoms, diabetes mellitus, antithrombotic regimen, and peripheral vascular disease. A new chronic pain syndrome was associated with greater dependence (odds ratio, 2.16; 95% confidence interval, 1.82–2.56). Peripheral neuropathy and pain from spasticity/shoulder subluxation were associated with cognitive decline. Conclusions— Chronic pain syndromes are common after ischemic stroke and are associated with increased functional dependence and cognitive decline.

SummaryIn order to determine the clinical utility of an enzyme immunoassay (EIA) for soluble fibrin in patients with suspected pulmonary embolism (PE), 195 unselected patients with suspected PE underwent blood sampling for measurement of plasma levels of soluble fibrin, and objective testing for PE. A soluble fibrin result of ≤ 0.75 Μg/ml showed a sensitivity of 100% for PE and a specificity of 12.8%, whereas a soluble fibrin result of ≤ 1.35 Μg/ml showed a sensitivity of 90.3% and a specificity of 49.4% for PE. The soluble fibrin assay has potential clinical utility in excluding PE.

SummaryBackground. The objective of this study was to determine the clinical utility of an enzyme immunoassay (HIA) for soluble fibrin in patients with clinically suspected deep vein thrombosis (DVT).Methods and Results. 101 unselected patients with clinically suspected DVT underwent blood sampling for measurement of plasma levels of soluble fibrin, and objective testing for DVT. According to results of the objective tests, patients were classified as DVT-positive (n = 34) or DVT-negative (n = 67). Using different cut-points of soluble fibrin results, the sensitivities, specificities, positive and negative predictive values of the soluble fibrin assay were calculated. A soluble fibrin result of ≤0.75 mg/ml showed a sensitivity and negative predictive value of 100%, and a specificity of 17.9% for DVT, a soluble fibrin result of ≤ 1.40 mg/ml showed a sensitivity of 91.2% and a negative predictive value of 93.6%, and a specificity of 65.7% for DVT, whereas a soluble fibrin result of ≤ 8.0 mg/ml showed a specificity and positive predicive value of 100% for DVT.Conclusions. This study demonstrates that the soluble fibrin assay used in the study has potential clinical utility as a diagnostic test in patients with clinically suspected DVT and supports further evaluation of this assay.

SummaryStudy Objective: To determine the clinical utility of a novel whole blood assay for D-dimer (SimpliRED™) in patients with clinically suspected pulmonary embolism (PE).Design: Prospective cohort.Patients: Eighty-six consecutive patients with clinically suspected PE.Intervention: All patients had the SimpliRED D-dimer assay performed and underwent ventilation/perfusion (V/Q) lung scanning and bilateral impedance plethysmography (IPG); pulmonary angiography was performed in two patients. Patients were classified as: 1) PE-positive; positive pulmonary angiography or high probability V/Q scan or non-high probability V/Q scan and either abnormal IPG (either at presentation or upon serial testing and confirmed by contrast venography) or symptomatic thromboembolic event within three months of presentation or 2) PE-negative; normal V/Q scan or normal pulmonary angiography or non-high probability V/Q scan and normal serial IPG and absence of symptomatic venous thromboembolism within three months of follow up. Sixteen (19%) patients were classified as PE-positive and 70 (81%) patients were classified as PE-negative.Measurements and Result: The sensitivities, specificities, positive predictive values, and negative predictive values of the D-dimer assay were calculated for all patients and for the subgroup of patients without comorbid conditions that independently can cause elevated D-dimer levels. The D-dimer showed a sensitivity of 94%, a negative predictive value of 98%, a specificity of 66%, and a positive predictive value of 38%. In the subgroup of patients without comorbid conditions, the specificity increased to 98% and the positive predictive value to 83%, but because only six patients had an abnormal D-dimer level, the 95% confidence interval on the observed positive predictive value is wide (36-100%).Conclusions: This study demonstrates that the SimpliRED D-dimer assay, which can be performed and interpreted at the bedside within five minutes, has potential clinical utility as an exclusionary test in patients with clinically suspected PE. The assay should be evaluated in large clinical management studies.

Background: Venous thromboembolism (VTE) prophylaxis is effective in the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in medical patients. Methods: A retrospective chart review was performed on medical inpatients at two academic hospitals in Hamilton, Ontario to investigate if patients received VTE prophylaxis as per current guidelines. Results: An analysis was performed on 762 patient charts and 170 met inclusion criteria for use of pharmacological VTE prophylaxis. Of these, 91 (54%) received pharmacological VTE prophylaxis. In 63 patients with a contraindication to pharmacological VTE prophylaxis, 16 (25%) received non-pharmacological VTE prophylaxis. Conclusion: The provision rate of pharmacological VTE prophylaxis in hospitalised medical patients who met pre-defined clinical criteria for prophylaxis was 54%. The rate of prophylaxis increased with additional VTE risk factors to a peak rate of 67%. There is room for the development of strategies to improve the use of VTE prophylaxis in hospitalised medical patients.

Context Diabetic peripheral neuropathy predisposes patients to foot ulceration that heals poorly and too often leads to amputation. Large-fiber peripheral neuropathy (LFPN), one common form of diabetic neuropathy, when detected early prompts aggressive measures to prevent progression to foot ulceration and its associated morbidity and mortality. Objective To systematically review the literature to determine the clinical examination findings predictive of asymptomatic LFPN before foot ulceration develops. Data Sources, Study Selection, and Data Extraction MEDLINE (January 1966–November 2009) and EMBASE (1980-2009 [week 50]) databases were searched for articles on bedside diagnosis of diabetic peripheral neuropathy. Included studies compared elements of history or physical examination with nerve conduction testing as the reference standard. Data Synthesis Of 1388 articles, 9 on diagnostic accuracy and 3 on precision met inclusion criteria. The prevalence of diabetic LFPN ranged from 23% to 79%. A score greater than 4 on a symptom questionnaire developed by the Italian Society of Diabetology increases the likelihood of LFPN (likelihood ratio [LR], 4.0; 95% confidence interval [CI], 2.9-5.6; negative LR, 0.19; 95% CI, 0.10-0.38). The most useful examination findings were vibration perception with a 128-Hz tuning fork (LR range, 16-35) and pressure sensation with a 5.07 Semmes-Weinstein monofilament (LR range, 11-16). Normal results on vibration testing (LR range, 0.33-0.51) or monofilament (LR range, 0.09-0.54) make LFPN less likely. Combinations of signs did not perform better than these 2 individual findings. Conclusions Physical examination is most useful in evaluating for LFPN in patients with diabetes. Abnormal results on monofilament testing and vibratory perception (alone or in combination with the appearance of the feet, ulceration, and ankle reflexes) are the most helpful signs.

SummaryOne hundred and fifty-six consecutive patients with clinically suspected pulmonary embolism (PE) had blood drawn to measure levels of D-dimer and thrombin-antithrombin (TAT) complexes and underwent ventilation/perfusion (V/Q) lung scanning and bilateral impedance plethysmography (IPG); pulmonary angiography was performed in 10 patients. Patients were classified as: PE-positive (positive pulmonary angiography or high probability lung scan or non-high probability lung scan and abnormal IPG) or, PE-negative (normal lung scan or normal pulmonary angiography) or PE-unlikely (non-high probability lung scan and normal serial IPG and absence of venous thromboembolism in follow-up). Thirty patients were classified as PE-positive, 64 as PE-negative and 62 patients as PE-unlikely. PE-positive patients were treated with anticoagulants, whereas PE-negative and PE-unlikely patients were not. PE-unlikely patients were followed for 3 months with repeat IPG and clinical evaluation for the occurrence of venous thromboembolism. The sensitivities, specificities, positive predictive values and negative predictive values of the D-dimer and TAT complex assays were calculated for patients classified as PE-positive and PE-negative. In addition, the prevalences of normal D-dimer and TAT complex assays were calculated for PE-unlikely patients.Cutoffs of 300 ng/ml for D-dimer and 3.5 μg/ml for TAT complexes provided sensitivities of 96% for both assays, negative predictive values of 97% for D-dimer and 96% for TAT complexes and specificities of 52% for D-dimer and 51% for TAT complexes. The specificities of the assays were higher in patients without comorbid conditions and in outpatients. Among PE-unlikely patients, 14 had normal D-dimer levels and 5 had normal levels of TAT complexes. None of these patients developed venous thromboembolism in follow-up.Our study indicates that: 1) PE is highly unlikely in patients who have D-dimer levels of less than 300 ng/ml and/or levels of TAT complexes below 3.5 μg/ml, and 2), because of their relatively low positive predictive values, further investigation is required if levels of D-dimer and/or TAT complexes are above these cutoffs. These results should be confirmed in future clinical management trials.

In order to determine the efficacy and safety of ancrod, a rapid acting defibrinogenating drug, for patients with heparin-induced thrombocytopenia, 11 consecutive patients who required anticoagulant therapy because of venous thromboembolism and who developed acute heparin-induced thrombocytopenia or had a history of heparin-induced thrombocytopenia were treated with ancrod. Heparin therapy was discontinued (in patients receiving heparin) and ancrod started at a dose of 1 to 2 U/kg every 24 hours with subsequent daily doses adjusted to maintain fibrinogen levels between 0.5 and 1.0 g/L. Ancrod was continued until warfarin had become effective. The platelet count increased to more than 150 x 10(9)/L within 2 to 10 days in all thrombocytopenic patients. Two patients with a history of heparin- induced thrombocytopenia maintained normal platelet counts while receiving ancrod. Two patients had recurrent venous thrombosis while receiving warfarin, 10 days after ancrod was discontinued: one of these patients had metastatic pancreatic carcinoma and developed phlegmasia cerulea dolens and the other patient developed a venographically proven extension of her deep venous thrombosis. One patient suffered a bleeding episode into the thigh with a 16-g/L decrease in her hemoglobin level while receiving ancrod therapy. No other side effects were noted. Our experience indicates that ancrod therapy is a reasonable approach for patients with heparin-induced thrombocytopenia who require anticoagulant therapy.

It is common practice to begin anticoagulant treatment of deep-vein thrombosis with a 10-day course of intravenous heparin, with warfarin added on day 5 to 10 and continued for several months. We performed a randomized, double-blind trial comparing a shorter course of continuous intravenous heparin (5 days, with warfarin sodium begun on the first day) with the conventional 10-day course of heparin (with warfarin sodium begun on the fifth day) in the initial treatment of 199 patients with acute proximal venous thrombosis documented by venography. The frequency of objectively documented recurrent venous thromboembolism was low and essentially the same in the two groups (7.1 percent in the short-course group vs. 7.0 percent in the long-course group). Because the observed difference between the groups was 0.1 percent in favor of the long-course group, it is unlikely (P less than 0.05) that a true difference in favor of this group would be greater than 7.5 percent; the difference could be as much as 7.3 percent in favor of the short-course group. Major bleeding episodes were infrequent, and the rate was similar in both groups. We conclude that a five-day course of heparin is as effective as a 10-day course in treating deep venous thrombosis. Furthermore, using the shorter course would permit earlier discharge from the hospital and thus offer substantial cost savings.

The objective of this study was to test the safety of withholding anticoagulant therapy in patients with clinically suspected pulmonary embolism who have normal perfusion lung scans, regardless of the clinical manifestations. Anticoagulant therapy was withheld or withdrawn in 515 consecutive patients except in patients in whom deep-vein thrombosis was detected. Only three of the 515 patients had symptomatic venous thromboembolism on follow-up. The frequency of symptomatic pulmonary embolism on follow-up was one of 515 patients. With knowledge of the normal findings by perfusion scanning, an alternative diagnosis was established in 367 of the 515 patients. Cause of symptoms remained uncertain in 148 patients. It is safe to withhold anticoagulant therapy in patients with suspected pulmonary embolism and normal perfusion scans, regardless of the clinical manifestations. The finding of a normal perfusion scan excludes the presence of clinically important pulmonary embolism and makes pulmonary angiography unnecessary. (Chest 1990; 97:23-26)

Objective:To determine the ability of troponin I (TnI) measurement to predict the likelihood of a serious cardiac outcome over the subsequent 72 hours in patients presenting to the emergency department (ED) with symptoms suggestive of an acute coronary syndrome.Methods:This prospective observational study enrolled consecutive patients presenting to 2 urban tertiary care hospital EDs over a 5-week period. Eligible patients included those for whom a TnI test was ordered within 24 hours of arrival and in whom no serious cardiac outcome occurred before the test result was available. Patients were followed for 72 hours and serious cardiac outcomes documented; these included cardiovascular death, myocardial infarction, congestive heart failure, serious arrhythmia and refractory pain. We calculated likelihood ratios (LRs) to describe the association of the TnI result with serious cardiac outcomes.Results:Of the 352 enrolled patients, 20 had a serious cardiac outcome within 72 hours of ED presentation. The derived LRs (and 95% confidence interval [CI]) were 0.5 (0.3–0.9) for TnI values 2.0 to 10.0 µg/L and 14.4 (4.8–42.9) for TnI values >10.0 µg/L.Conclusions:TnI values >2.0 µg/L are associated with an increased probability of serious cardiac outcomes within 72 hours. TnI values between 0.5 and 2.0 µg/L are weakly positive predictors. TnI values

ContextLower extremity peripheral arterial disease (PAD) is common and associated with significant increases in morbidity and mortality. Physicians typically depend on the clinical examination to identify patients who need further diagnostic testing.ObjectiveTo systematically review the accuracy and precision of the clinical examination for PAD.Data Sources, Study Selection, and Data ExtractionMEDLINE (January 1966 to March 2005) and Cochrane databases were searched for articles on the diagnosis of PAD based on physical examination published in the English language. Included studies compared an element of the history or physical examination with a reference standard of ankle-brachial index, duplex sonography, or angiogram. Seventeen of the 51 potential articles identified met inclusion criteria. Two of the authors independently extracted data, performed quality review, and used consensus to resolve any discrepancies.Data SynthesisFor asymptomatic patients, the most useful clinical findings to diagnose PAD are the presence of claudication (likelihood ratio [LR], 3.30; 95% confidence interval [CI], 2.30-4.80), femoral bruit (LR, 4.80; 95% CI, 2.40-9.50), or any pulse abnormality (LR, 3.10; 95% CI, 1.40-6.60). While none of the clinical examination features help to lower the likelihood of any degree of PAD, the absence of claudication or the presence of normal pulses decreases the likelihood of moderate to severe disease. When considering patients who are symptomatic with leg complaints, the most useful clinical findings are the presence of cool skin (LR, 5.90; 95% CI, 4.10-8.60), the presence of at least 1 bruit (LR, 5.60; 95% CI, 4.70-6.70), or any palpable pulse abnormality (LR, 4.70; 95% CI, 2.20-9.90). The absence of any bruits (iliac, femoral, or popliteal) (LR, 0.39; 95% CI, 0.34-0.45) or pulse abnormality (LR, 0.38; 95% CI, 0.23-0.64) reduces the likelihood of PAD. Combinations of physical examination findings do not increase the likelihood of PAD beyond that of individual clinical findings. However, when combinations of clinical findings are all normal, the likelihood of disease is lower than when individual symptoms or signs are normal. A PAD scoring system, which includes auscultation of arterial components by handheld Doppler, provides greater diagnostic accuracy.ConclusionsClinical examination findings must be used in the context of the pretest probability because they are not independently sufficient to include or exclude a diagnosis of PAD with certainty. The PAD screening score using the hand-held Doppler has the greatest diagnostic accuracy.

Background: Venous thromboembolic disease (VTE) is a major cause of morbidity and mortality in hospitalized patients. Most hospitalized patients with a fatal pulmonary embolism are medical patients who do not have a history of recent surgery [BMJ 302 (1991) 709; J. R. Soc. Med. 82 (1989) 198]. There is evidence suggesting that VTE prophylaxis is indicated in many high risk medical patients [Chest 119 (2001) 132S; NEJM 341 (1999) 793]. However, previous studies have shown that only about one third of high risk medical patients receive VTE prophylaxis [Ann. Intern. Med. 115 (1991) 591; Chest 106 (1994) 13; Chest 107 (1995) 296]. The objective of this study was to determine the frequency of use of VTE prophylaxis in medical inpatients at two teaching hospitals in Hamilton, Ontario. Methods: A retrospective chart review of consecutive patients admitted to medical wards at two acute care sites of McMaster University affiliated teaching hospitals between October 10, 2001 and December 11, 2001 was performed. For each patient, demographic data, risk factors for VTE, method of VTE prophylaxis and contraindications to VTE prophylaxis were recorded. Results: 756 patient charts were reviewed and 310 (41%) were excluded because the primary diagnosis required anticoagulation, the patients were being treated with anticoagulation (warfarin or heparin) before admission or the patient was admitted to the intensive care unit. Of the remaining 446 patients, 146 (33%) received some form of VTE prophylaxis. Of the patients receiving prophylaxis, 4% had early ambulation, 9% wore anti-embolic stockings (AES), 1% used intermittent pneumatic compression, 23% used unfractionated heparin and 3% used low molecular weight heparin. Two hundred five (46%) patients had one identifiable VTE risk factor and 63 (14%) had two or more risk factors. Patients with more VTE risk factors were more likely to receive prophylaxis. Interpretation: One third of medical inpatients at two teaching hospitals in Hamilton received some form of VTE prophylaxis.

Introduction Chronic neuropathic pain is associated with reduced health-related quality of life and substantial socioeconomic costs. Current research addressing management of chronic neuropathic pain is limited. No review has evaluated all interventional studies for chronic neuropathic pain, which limits attempts to make inferences regarding the relative effectiveness of treatments. Methods and analysis We will conduct a systematic review of all randomised controlled trials evaluating therapies for chronic neuropathic pain. We will identify eligible trials, in any language, by a systematic search of CINAHL, EMBASE, MEDLINE, AMED, HealthSTAR, DARE, PsychINFO and the Cochrane Central Registry of Controlled Trials. Eligible trials will be: (1) enrol patients presenting with chronic neuropathic pain, and (2) randomise patients to alternative interventions (pharmacological or non-pharmacological) or an intervention and a control arm. Pairs of reviewers will, independently and in duplicate, screen titles and abstracts of identified citations, review the full texts of potentially eligible trials and extract information from eligible trials. We will use a modified Cochrane instrument to evaluate risk of bias of eligible studies, recommendations from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to inform the outcomes we will collect, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to evaluate our confidence in treatment effects. When possible, we will conduct: (1) in direct comparisons, a random-effects meta-analysis to establish the effect of reported therapies on patient-important outcomes; and (2) a multiple treatment comparison meta-analysis within a Bayesian framework to assess the relative effects of treatments. We will define a priori hypotheses to explain heterogeneity between studies, and conduct meta-regression and subgroup analyses consistent with the current best practices. Ethics and Dissemination We do not require ethics approval for our proposed review. We will disseminate our findings through peer-reviewed publications and conference presentations. Trial registration number PROSPERO (CRD42014009212).

SummaryStudy objective. To determine whether levels of thrombin-antithrombin III (TAT) in plasma, taken two weeks pre-operatively, predict the development of deep vein thrombosis (DVT) in patients undergoing major hip or knee surgery.Design. Prospective cohort.Setting. Tertiary-care referral centre, university-affiliated hospital.Patients. Ninety eight consecutive patients undergoing elective hip or knee surgery.Intervention. All eligible consenting patients were seen in a preoperative clinic two weeks prior to surgery and had blood taken for measurement of plasma TAT level. After surgery, they received a combination of unfractionated heparin 5000 Units 12-hourly subcutaneously, and antiembolism stockings (TEDS), as prophylaxis against DVT. Contrast venography was performed prior to discharge, and according to the results, patients were classified as having proximal (popliteal and/or more proximal) DVT (n = 12), calf DVT (n = 7) or no DVT (n = 79).Measurements and Results. The mean TAT level was significantly higher in patients who developed DVT (5.7 μg/l) than in those who did not (4.1 μg/l), p = 0.035. Using cut-points of 3.5 and 5.5 μg/l for the TAT level, patients could be categorized as high, intermediate, and low risk for the development of DVT. The proportion of patients with TAT levels of ≥3.5μg/l who developed calf or proximal DVT was significantly higher than the proportion of patients with TAT levels of 5.5 μg/l who developed proximal DVT was significantly higher than the proportion of patients with TAT levels of ≤5.5 μg/l who developed proximal DVT (p = 0.03).Conclusions. This study demonstrates that pre-operative TAT levels correlate with the risk of developing DVT after major orthopedic surgery. Further studies are needed to determine the reason(s) for this observation and whether rational recommendations about prophylaxis and screening for DVT can be made based on the results of a pre-operative TAT level.

Background The clinical utility of using a novel whole blood assay for D-dimer (SimpliRED), alone or in combination with impedance plethysmography (IPG), was investigated in a two-center, prospective cohort study of 214 consecutive patients with clinically suspected deep vein thrombosis (DVT). Methods and Results All patients underwent the SimpliRED D-dimer assay, contrast venography, and IPG. According to the results of venography, 43 patients had proximal DVT (popliteal and/or more proximal veins), 10 had isolated calf DVT, and 161 had DVT ruled out. The D-dimer had a sensitivity of 93% for proximal DVT and of 70% for calf DVT, an overall specificity of 77%, and a negative predictive value of 98% for proximal DVT. The sensitivity and specificity of IPG for proximal DVT were 67% and 96%, respectively. When analyzed in combination with the IPG results, it was determined that (1) the combination of a negative D-dimer and a normal IPG had a negative predictive value of 97% for all DVT and of 99% for proximal DVT and occurred in 58% of patients (likelihood ratio, 0.1) and (2) the combination of a positive D-dimer and an abnormal IPG had a positive predictive value of 93% for any DVT and of 90% for proximal DVT and occurred in 14% of patients (likelihood ratio, 42.6). When the D-dimer and IPG results were discordant, it was not possible to exclude or diagnose DVT reliably; discordant results occurred in 28% of patients. Conclusions The SimpliRED D-dimer assay, which can be performed and interpreted at the bedside within 5 minutes, has great potential in patients with clinically suspected DVT, especially for ruling out DVT, and is complementary to IPG. The assay should be evaluated in large clinical management studies.

To compare the sensitivity, specificity, and predictive values of compression ultrasonography (US) in postoperative orthopedic patients with those of (a) impedance plethysmography in postoperative patients and (b) compression US in symptomatic outpatients, the authors performed an investigator-blinded cohort study. One hundred thirty-four consecutive inpatients who had undergone elective knee-replacement surgery or surgery for a fractured hip and 65 consecutive outpatients with clinically suspected venous thrombosis who had undergone venography were evaluated. Compression US allowed detection of 11 of 21 (52.4%) proximal-vein thrombi but was insensitive to calf-vein thrombi in the orthopedic patients. Compression US had a significantly greater specificity and positive predictive value than impedance plethysmography for all thrombi in orthopedic patients; compression US also had greater sensitivity. The sensitivity of compression US for proximal-vein thrombi was significantly higher (92.1%) in symptomatic outpatients than in orthopedic patients. The authors conclude that compression US has significant advantages over impedance plethysmography in the detection of proximal-vein thrombi in patients who have undergone hip- or knee-replacement surgery.

Despite evidence that effective regimens are available for the prevention of venous thrombosis in fractured hip patients, many centers do not use prophylaxis. In order to evaluate the efficacy and safety of heparin and graduated compression stockings, we conducted a cohort study of 55 consecutive fractures hip patients treated postoperatively with heparin, 5,000 U every 12 h, and graduated compression stockings. The rates of venous thromboembolism and bleeding were compared with an historical cohort from Hamilton. Before discharge, 51 patients underwent bilateral venography. Deep venous thrombosis (DVT) occurred in 10 of the 51 patients (incidence of 20%); three had proximal DVT (incidence of proximal DVT was 6%). DVT was seen in 29 of the 63 control patients (incidence 46%); 19 had proximal DVT (incidence of proximal DVT was 30%). The differences in the rates of DVT and proximal DVT are statistically significant (p less than 0.01). Bleeding occurred in one patient in the treatment group (incidence 2%) and five patients in the control group (incidence 8%). This study confirms that therapy with heparin and graduated compression stockings is effective, inexpensive, and convenient for the prevention of venous thrombosis in fractured hip patients and is associated with a low bleeding risk.

Introduction: Fibrin D-dimer is the degradation products from cross-linked fibrin. It is a marker of intravascular thrombogenesis. Menstruation is associated with activation of coagulation and fibrinolytic pathways. To investigate the changes of plasma fibrin D-dimer level during menstruation cycle, we measure the D-dimer level on day 1, 3, 5, and 21 of the menstruation period for 5 consecutive female volunteers. MDA D-dimer assay is used because it is one of the most sensitive laboratory methods for quantitative measurement of D-dimer level. Methods: Normal female volunteers with normal regular menstruation cycle are recruited. To avoid other confronting factors, subjects with recent history of thromboembolic diseases; ischemic heart disease; pregnancy or child birth; active malignancy; active inflammatory or infectious disease; surgery or trauma; and/or use of birth control pills are excluded. All volunteers have the menstruating period identified. Day 1 of menstruating period is defined as the first day when menstruating flow occurs. On Day 1, 3, 5 and 21 of menstruating cycle, blood samples are collected in tubes precoated with 3.2% trisodium citrate-dihydrate. Specimens are centrifuged at 2500 g for 15 minutes. The MDA D-dimer assay is performed using a commercial kit as per manufacturer’s instructions. Plasma fibrin MDA D-dimer level is expressed in F.E.U./ml (normal range is Results: The results are summarized in table 1 and figure 1. There is no significant variation of D-dimer level measured on day 1, 3, 5, and 21 of menstruation cycle. (p = 0.382) Conclusion: The MDA D-dimer level does not have significant change during the menstruation period. The clotting process during menstruation may mainly be extravascular and, therefore, not affect the D-dimer level. Clinically, D-dimer test can still be used to rule out venous thromboembolism in a menstruating woman. D-dimer levels (F.E.U./ml) on various days of menstruation cycle for 5 volunteers Figure Figure Subject Number 2 3 4 5 6 Day 1 0.12 0.21 0.31 0.34 0.44 Day 3 0.10 0.18 0.23 0.13 0.31 Day 5 0.11 0.17 0.16 0.27 0.22 Day 21 0.21 0.10 0.17 0.39 0.29

ContextExperienced clinicians' gestalt is useful in estimating the pretest probability for pulmonary embolism and is complementary to diagnostic testing, such as lung scanning. However, it is unclear whether recently developed clinical prediction rules, using explicit features of clinical examination, are comparable with clinicians' gestalt. If so, clinical prediction rules would be powerful tools because they could be used by less-experienced health care professionals to simplify the diagnosis of pulmonary embolism. Recent studies have shown that the combination of a low pretest probability (using a clinical prediction rule) and a normal result of a D-dimer test reliably excludes pulmonary embolism without the need for further testing.ObjectiveTo evaluate and demonstrate the accuracy of pretest probability assessment for pulmonary embolism using clinical gestalt vs clinical prediction rules.Data SourcesThe MEDLINE database was searched for relevant articles published between 1966 and March 2003. Bibliographies of pertinent articles also were scanned for suitable articles.Study SelectionTo be included in the analysis, studies were required to have consecutive, unselected patients enrolled; participating physicians in the studies, blinded to the results of diagnostic testing, had to estimate pretest probability of pulmonary embolism; and validated diagnostic methods had to be used to confirm or exclude pulmonary embolism.Data ExtractionThree reviewers independently scanned titles and abstracts for inclusion of studies. An initial MEDLINE search identified 1709 studies, of which 16 involving 8306 patients were included in the final analysis.Data SynthesisA clinical gestalt strategy was used in 7 studies, and in the low, moderate, and high pretest categories, the rates of pulmonary embolism ranged from 8% to 19%, 26% to 47%, and 46% to 91%, respectively. Clinical prediction rules were used in 10 studies, and 3% to 28%, 16% to 46%, and 38% to 98% in the low, moderate, and high pretest probability groups, respectively, had pulmonary embolism.ConclusionsThe clinical gestalt of experienced clinicians and the clinical prediction rules used by physicians of varying experience have shown similar accuracy in discriminating among patients who have a low, moderate, or high pretest probability of pulmonary embolism. We advocate the use of a clinical prediction rule because it has shown to be accurate and can be used by less-experienced clinicians.

When faced with a patient with acute chest pain, clinicians must distinguish myocardial infarction (MI) from all other causes of acute chest pain. If MI is suspected, current therapeutic practice includes deciding whether to administer thrombolysis or primary percutaneous transluminal coronary angioplasty and whether to admit patients to a coronary care unit. The former decision is based on electrocardiographic (ECG) changes, including ST-segment elevation or left bundle-branch block, the latter on the likelihood of the patient’s having unstable high-risk ischemia or MI without ECG changes. Despite advances in investigative modalities, a focused history and physical examination followed by an ECG remain the key tools for the diagnosis of MI. The most powerful features that increase the probability of MI, and their associated likelihood ratios (LRs), are new ST-segment elevation (LR range, 5.7-53.9); new Q wave (LR range, 5.3-24.8); chest pain radiating to both the left and right arm simultaneously (LR, 7.1); presence of a third heart sound (LR, 3.2); and hypotension (LR, 3.1). The most powerful features that decrease the probability of MI are a normal ECG result (LR range, 0.1-0.3), pleuritic chest pain (LR, 0.2), chest pain reproduced by palpation (LR range, 0.2-0.4), sharp or stabbing chest pain (LR, 0.3), and positional chest pain (LR, 0.3). Computer-derived algorithms that depend on clinical examination and ECG findings might improve the classification of patients according to the probability that an MI is causing their chest pain. JAMA. 1998;280:1256-1263

Objective: To prospectively test the hypothesis that a diagnosis of deep vein thrombosis can be excluded in outpatients who present with clinical indications of deep vein thrombosis and whose results of D-dimer testing and impedance plethysmographic examination on the day of presentation are normal. Design: Prospective cohort study. Setting: Four university-affiliated hospitals. Methods: Three hundred ninety-eight consecutive patients with clinical indications of deep vein thrombosis were included in the final analysis. All patients underwent an assessment of pretest probability, bedside D-dimer testing, and impedance plethysmographic examination. In most patients, if the results of D-dimer testing and impedance plethysmographic examination were negative for deep vein thrombosis, anticoagulants were withheld and patients were followed up for 3 months. If the results of one or both tests were abnormal, an examination using venous compression ultrasonography or phlebography was performed. Results: In the majority of patients (69%), the results of D-dimer testing and impedance plethysmographic examination were normal. This combination had a negative predictive value of 98.5% (95% confidence interval, 96.3-99.6) for deep vein thrombosis. Conclusion: The results of the D-dimer assay and impedance plethysmographic examination on the day of presentation can be used to treat the majority of outpatients who present with clinical indications of deep vein thrombosis without further testing. Arch Intern Med. 1997;157:1077-1081

Background: To reevaluate the sensitivity of impedance plethysmography (IPG) for proximal deep vein thrombosis (DVT) and to establish a relationship between the location and size of thrombi and the results of IPG. Design: Prospective cohort study. Methods: One hundred thirty-two consecutive patients with clinically suspected DVT underwent IPG testing and most (n=118) underwent contrast-enhanced venography; in 14 patients, venous ultrasonography was performed and demonstrated definitive proximal DVT in which the size and extent of the thrombus could be delineated. All patients with dubious or normal ultrasound results underwent contrast-enhanced venography. All tests were performed and test results were interpreted without knowledge of the results of the other tests. Patients were considered to have proximal DVT if this was demonstrated on venography or ultrasound, calf DVT if this was demonstrated on venography, or no DVT if venography yielded normal findings. The sensitivity and specificity of IPG for DVT were calculated. Results: Of the 132 patients, 40 (30%) had proximal DVT, seven (5%) had calf DVT, and 85 (64%) had no DVT. The sensitivity of IPG for proximal DVT was 65% and the specificity was 93%. Of the proximal vein thrombi, IPG detected three (23%) of 13 that involved the popliteal vein but not the superficial femoral vein and 23 (85%) of 27 proximal vein thrombi that involved the superficial femoral vein. Conclusions: Our study demonstrated that the sensitivity of IPG for proximal DVT at our center is only 65%, a figure that is much lower than those reported in earlier studies from our institution. We hypothesize that because of a change in referral practice, an increased proportion of patients with less severe symptoms are now referred to our center than in the past. These patients have thrombi that are smaller, less likely to be occlusive, and therefore less likely to yield abnormal IPG findings. (Arch Intern Med. 1994;154:1930-1933)

Background: Pulmonary embolism has historically presented a formidable diagnostic problem because of the nonspecificity of the clinical findings associated with this disorder and the diagnostic uncertainties and challenges presented by both ventilation-perfusion lung scanning and pulmonary angiography. We have reported previously that serial noninvasive leg testing provides a practical noninvasive alternative to pulmonary angiography in patients with nonhigh probability (nondiagnostic) lung scans and adequate cardiorespiratory reserve. We have reevaluated this observation prospectively to (1) confirm or refute our original observation in an independent cohort and (2) to increase the numbers sufficiently to provide narrow confidence limits for the observed outcomes. Methods: A prospective comparative study in 1564 consecutive patients with suspected pulmonary embolism who underwent ventilation-perfusion lung scanning and objective testing for proximal-vein thrombosis. Results: On long-term follow-up of 627 patients with the following characteristics: (1) abnormal, nondiagnostic lung scans, (2) not taking anticoagulant therapy, and (3) serial noninvasive test results negative for proximal-vein thrombosis, only 12 patients (1.9%; 95% confidence limits, 0.8% to 3.0%) had venous thromboembolism. By comparison, venous thromboembolism on follow-up occurred in four (0.7%) of 586 patients (95% confidence limits, 0.02% to 1.3%) with normal lung scans in whom anticoagulant therapy was withheld and in eight (5.5%) of 145 patients (95% confidence limits, 1.8% to 9.2%) with high probability lung scans who received anticoagulant therapy. Conclusions: Our findings indicate that the clinician has a practical noninvasive strategy in patients with adequate cardiorespiratory reserve and nondiagnostic lung scans that (1) avoids pulmonary angiography, (2) identifies patients with proximal-vein thrombosis who require treatment, and (3) avoids the need for treatment and further investigation in the majority of patients. (Arch Intern Med. 1994;154:289-297)

A NEW paradigm for medical practice is emerging. Evidence-based medicine de-emphasizes intuition, unsystematic clinical experience, and pathophysiologic rationale as sufficient grounds for clinical decision making and stresses the examination of evidence from clinical research. Evidence-based medicine requires new skills of the physician, including efficient literature searching and the application of formal rules of evidence evaluating the clinical literature. An important goal of our medical residency program is to educate physicians in the practice of evidence-based medicine. Strategies include a weekly, formal academic half-day for residents, devoted to learning the necessary skills; recruitment into teaching roles of physicians who practice evidence-based medicine; sharing among faculty of approaches to teaching evidence-based medicine; and providing faculty with feedback on their performance as role models and teachers of evidence-based medicine. The influence of evidencebased medicine on clinical practice and medical education is increasing. CLINICAL SCENARIO A junior medical resident working in a teaching hospital

Background.— Audits of heparin sodium therapy suggest that heparin administration is fraught with difficulty. The literature indicates that the current clinical practice of intuitive ordering of heparin results in inadequate therapy because of fear of bleeding. The importance of exceeding the lower limit of the therapeutic range has been strongly supported by findings of prospective clinical trials. Firm evidence indicates that failure to exceed the lower limit is associated with unacceptably high rates of recurrent venous thromboembolism. By comparison, evidence supporting the risk of exceeding the upper limit of the therapeutic range is weak. Objectives.— The purposes of this study were (1) to validate prospectively an approach designed to minimize the proportion of patients receiving subtherapeutic doses of heparin and (2) to determine the effectiveness and safety of decreasing the heparin dosage infused on the basis of activated partial thromboplastin time (APTT) prolongation reflecting both heparin and warfarin sodium effects. Methods.— We performed a randomized double-blind study evaluating a prescriptive approach to heparin administration in patients receiving heparin or heparin with warfarin. Thromboembolic and bleeding complications were objectively documented. Results.— Only 1% and 2% of patients had subtherapeutic heparin levels for 24 hours or more in the heparin and combined groups, respectively. Recurrent venous thromboembolism occurred infrequently in both groups (7%). Sixty-nine (69%) of 99 patients receiving combined therapy had supratherapeutic values, compared with 24 (24%) of 100 receiving heparin; bleeding complications occurred in 9% and 12%, respectively. Conclusions.— Our findings demonstrate that no association exists between supratherapeutic APTT responses and bleeding, which is in direct contrast to the observed association between subtherapeutic APTT responses and recurrent venous thromboembolism. (Arch Intern Med.1992;152:1589-1595)

We report a patient with hereditary antithrombin III deficiency who was successfully treated with heparin throughout pregnancy. Functional antithrombin III levels fell to 0.32 U/ml during heparin treatment, but it was possible to achieve a heparin effect, measured by the activated partial thromboplastin time, thrombin clotting time and heparin assay with subcutaneous heparin in doses of 30,000 U to 35,000 U/24 hours. This achieve an long term heparin effect was obtained without the need for antithrombin III infusions.

Background Deep-vein thrombosis is a potentially life-threatening complication of total hip or knee replacement. There are few data on the effectiveness and safety of warfarin as compared with low-molecular-weight heparin as prophylaxis against this problem. Methods We therefore performed a randomized, double-blind trial in 1436 patients to evaluate the effectiveness and safety of low-molecular-weight heparin (given subcutaneously once daily) as compared with adjusted-dose warfarin to prevent venous thrombosis after hip or knee replacement. Treatment with the drugs was started postoperatively. The primary end point was deep-vein thrombosis as detected by contrast venography (performed a mean of 9.4 days after surgery in each group). Results Among the 1207 patients with interpretable venograms, 231 of 617 patients (37.4 percent) in the warfarin group and 185 of 590 patients (31.4 percent) in the low-molecular-weight-heparin group had deep-vein thrombosis (P = 0.03). The reduction in risk with low-molecular...

Neuropathic pain (NeP), generated by disorders of the peripheral and central nervous system, can be particularly severe and disabling. Prevalence estimates indicate that 2% to 3% of the population in the developed world suffer from NeP, which suggests that up to one million Canadians have this disabling condition. Evidence-based guidelines for the pharmacological management of NeP are therefore urgently needed. Randomized, controlled trials, systematic reviews and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting. Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one methodologically sound, randomized, controlled trial showing significant benefit relative to placebo or another relevant control group. Recommendations for treatment are based on degree of evidence of analgesic efficacy, safety, ease of use and cost-effectiveness. Analgesic agents recommended for first-line treatments are certain antidepressants (tricyclics) and anticonvulsants (gabapentin and pregabalin). Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine. Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain. Recommended fourth-line treatments include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy, such as lamotrigine, topiramate and valproic acid. Treatment must be individualized for each patient based on efficacy, side-effect profile and drug accessibility, including cost. Further studies are required to examine head-to-head comparisons among analgesics, combinations of analgesics, long-term outcomes, and treatment of pediatric and central NeP.

• Pulmonary embolism is associated strongly with proximalvein thrombosis. We tested the hypothesis that recurrent venous thromboembolism is unlikely in the absence of proximal-vein thrombosis. We performed a prospective cohort study in 874 patients with suspected pulmonary embolism. On long-term follow-up of 371 patients with the following characteristics: (1) abnormal, non–high-probability lung scans, (2) off anticoagulant therapy, and (3) serial noninvasive test results negative for proximal-vein thrombosis, only 10 (2.7%; 95% confidence limits, 1.3% to 4.9%) had venous thromboembolism. By comparison, venous thromboembolism on follow-up occurred in 3(1%) of 315 patients (95% confidence limits, 0.2% to 2.8%) with normal lung scans, and in 5(7%) of 66 patients (95% confidence limits, 2.5% to 16.8%) with high-probability lung scans. Patients whose serial noninvasive test results were negative for proximal-vein thrombosis have a good prognosis without anticoagulant therapy. ( Arch Intern Med . 1989;149:2549-2555)