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Background Women with a history of venous thromboembolism may be at increased risk for venous thromboembolic events during pregnancy. In these women, the decision to give or withhold heparin in the antepartum period is controversial, because accurate estimates of the frequency of recurrent thromboembolic events if antepartum heparin is withheld are not available. Methods We prospectively studied 125 pregnant women with a single previous episode of venous thromboembolism. Antepartum heparin was withheld, but anticoagulant therapy was given for four to six weeks post partum. Our primary objective was to determine the rate of antepartum recurrence of venous thromboembolism. Laboratory studies were performed to identify thrombophilia in 95 women. Results Three of the 125 women (2.4 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 0.2 to 6.9 percent). There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episod...

Educators have devoted little attention to formal evaluation of educational administrative personnel. The authors surveyed the educational administrators working in McMaster University’s Department of Medicine residency program and found they felt they were receiving little useful feedback. The authors also surveyed the colleagues, residents, and administrative staff with whom the administrators worked and found they felt they had inadequate input into the administrators’ evaluation. In response to these results, a measurement instrument was developed based on existing job descriptions and feedback was obtained on administrators’ performance from relevant individuals. After three yearly evaluations, administrators and evaluators acknowledged much broader input into evaluation but saw little evaluation related improvement in performance. Of the administrators, 85% felt the process should continue as did 91% of the evaluators. An evaluation process may not alter perceived performance when it is already good but there may be other benefits to rigorous evaluation.

Patients with acute VTE require clinical assessment and objective testing to be accurately diagnosed. Almost all patients with acute VTE have an elevated D-dimer level. An elevated D-dimer is associated with many illnesses, and therefore, is not specific for VTE. D-dimer tests can have a high sensitivity, however, which is useful because a normal test excludes the diagnosis of VTE. D-dimer testing is most appropriate in the assessment of outpatients because the prevalence of disease and the likelihood of comorbid conditions are lower than in inpatient populations, making a test of exclusion particularly valuable. Accuracy studies using conventional ELISA assays have confirmed that a test with a high sensitivity can be used to exclude a diagnosis of VTE, but conventional ELISA testing is not practical. Studies of more practical D-dimer testing indicate that, for patients with suspected DVT or PE, the need for serial testing or further investigation can be reduced if normal results are obtained using assays with a high sensitivity. There are, however, many sources of variation in the test characteristics of D-dimer assays. Therefore there is no reassurance that results from one manufacturer's test are applicable to other tests and different investigators may obtain varied results when using the same manufacturer's product. In addition, the results of D-dimer accuracy studies lack generalizability. This lack of generalizability has led to the recommendation that clinicians await the results of management studies before adopting the routine use of D-dimer assays in the diagnosis of VTE. Further, it may be reasonable to perform an accuracy study when planning to adopt a specific D-dimer assay from a published management trial, to be confident of its characteristics can be reproduced. In the management of patients with suspected DVT, rapid ELISA tests show promise as a practical D-dimer test, in that they have a sensitivity similar to that of the conventional ELISA assay. Two management studies have recently confirmed that a normal D-dimer result (using the SimpliRED whole-blood assay or the Instant IA rapid ELISA) in combination with a noninvasive test or a clinical model can reliably exclude DVT in outpatients. Use of a clinical model can reduce the need for VU, and the combination of a clinical model and D-dimer testing could further reduce the number of VU procedures required. As noted by Wells et al, who recently published a clinical model, however, a normal D-dimer result was most accurate in the patients with a low pretest likelihood (NPV = 99.5%) and least accurate in patients with a high pretest likelihood (NPV = 85.7%) Patients with a low pretest likelihood and a normal D-dimer are the largest proportion of outpatients referred for testing, and considerable resources may be saved if additional management studies confirm the usefulness of D-dimer testing in such patients. In patients with suspected PE, there is a lack of published management trials despite a number of accuracy studies indicating that D-dimer testing may be useful as a method of PE diagnosis exclusion. Recent results, however, from an accuracy study of patients with suspected PE who had D-dimer testing complement the findings of Wells et al in patients with suspected DVT. Using a standardized clinical model of PE in combination with a SimpliRED D-dimer assay, Ginsberg and colleagues found that the combination of a low pretest likelihood and a normal D-dimer had a negative predictive value of 99%, whereas the negative predictive value was only 78% in patients with a high pretest likelihood and a normal D-dimer. Similar to the findings in DVT, these results indicate that D-dimer testing is most useful in patients with a low pretest likelihood for PE and raise the possibility that such patients may not require lung scans. This finding is currently being evaluated in a prospective management trial.

Background Low-molecular-weight heparin is known to be safe and effective for the initial Treatment of patients with proximal deep-vein thrombosis. However, its application to patients with pulmonary embolism or previous episodes of thromboembolism has not been studied.Methods We randomly assigned 1021 patients with symptomatic venous thromboembolism to fixed-dose, subcutaneous low-molecular-weight heparin (reviparin sodium) or adjusted-dose, intravenous unfractionated heparin. Oral anticoagulant therapy with a coumarin derivative was started concomitantly and continued for 12 weeks, Approximately one third of the patients had associated pulmonary embolism, The outcome events studied over the 12 weeks were symptomatic recurrent venous thromboembolism, major bleeding, and death. We sought to determine whether low-molecular-weight heparin is at least equivalent to unfractionated heparin in patients with venous thromboembolism.Results Twenty-seven of the 510 patients assigned to low-molecular-weight heparin (5.3 percent) had recurrent thromboembolic events, as compared with 25 of the 511 patients assigned to unfractionated heparin (4.9 percent). The difference of 0.4 percentage point indicates that the two therapies have equivalent value according to our predetermined definition of equivalence. Sixteen patients assigned to low-molecular-weight heparin (3.1 percent) and 12 patients assigned to unfractionated heparin (2.3 percent) had episodes of major bleeding (P=0.63), and the mortality rates in the two groups were 7.1 percent and 7.6 percent, respectively (P=0.89).Conclusions Fixed-dose, subcutaneous low-molecular-weight heparin is as effective and safe as adjusted-dose, intravenous unfractionated heparin for the initial management of venous thromboembolism, regardless of whether the patient has pulmonary embolism or a history of venous thromboembolism. (C) 1997, Massachusetts Medical Society.

SummaryWe performed a prospective matched cohort study to investigate the effects of long-term (>1 month) heparin therapy on lumbar spine bone density. Twenty-five women who received heparin during pregnancy, and 25 matched controls underwent dual photon absorptiometry of the lumbar spine in the post-partum period. Zero of 25 heparin-treated patients developed fractures. Heparin-treated patients had a 0.082 g/cm2 lower bone density compared to untreated controls, which is clinically and statistically significant (p = 0.0077). There were 6 matched pairs in which only the heparin-treated patient had a bone density below 1.0 g/ cm2, compared to only one pair in which only the control patient had a bone density below this level (p = 0.089). The correlation coefficients of the difference .in bone density in each matched pair, and the duration of heparin therapy, the mean daily dose, and the total dose of heparin were 0.042, -0.015, and 0.021, respectively; none of these values is statistically significant. We conclude: 1) long-term heparin therapy was associated with a significant reduction in bone density, although fractures are uncommon, 2) there was no significant correlation between lumbar bone density and the dose or duration of heparin.

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.

The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus erythematosus who have venous thromboembolism (VTE) in unknown. Limited evidence suggests that there is an association between the presence of APLA and both initial and recurrent episodes of VTE and that patients with APLA and VTE are resistant to warfarin therapy. Unselected patients with a first episode of clinically suspected deep vein thrombosis or pulmonary embolism were evaluated with objective tests for VTE and with laboratory tests for APLA; the latter included tests for the lupus anticoagulant (LA) and anticardiolipin antibodies (ACLA). Patients with VTE were treated with anticoagulant therapy and observed during and after discontinuation of anticoagulants for symptomatic recurrence of VTE. There was a strong association between LA and VTE (odds ratio, 9.4; 95% confidence interval [CI], 2.1 to 46.2) and 9 to 65 (14%; 95% CI, 7% to 25%) patients with VTE had LA. There was no association between the presence of ACLA and VTE (odds ratio, 0.7; 95%CI, 0.3 to 1.7) because of the high frequency of positive ACLA assays in patients without VTE. None of the 16 patients with VTE and APLA developed recurrent VTE while receiving warfarin therapy. There was no difference in rates of recurrent VTE in patients with or without APLA after anticoagulant therapy was discontinued. The strong association between LA and VTE suggests that testing for LA in patients with VTE is useful. The measurement of ACLA in patients with VTE has no clinical usefulness because the results are abnormal in a high proportion of patients without VTE. Although the presence of APLA in patients with VTE was not associated with resistance to a conventional intensity of warfarin or an increased risk of recurrent VTE after discontinuation of warfarin, a larger study should address these issues in a subgroup of patients with VTE and LA.

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.

To determine whether an association exists between the presence of antiphospholipid antibodies and pregnancy loss, a cross-sectional study was performed. Consecutive women who were referred to three outpatient rheumatology clinics and who had systemic lupus erythematosus (SLE) and a history of one or more pregnancies were evaluated. Patients were interviewed to determine outcomes of all previous pregnancies. Blood was taken on two separate occasions at least 3 months apart to test for the presence of the lupus anticoagulant and anticardiolipin antibodies; on both occasions, five tests of the lupus anticoagulant, with well- defined normal ranges, and an enzyme-linked immunosorbent assay to measure IgG anticardiolipin antibodies were performed. Patients were considered to be positive for the lupus anticoagulant if one or more tests was abnormal on both occasions and positive for anticardiolipin antibodies if the test was abnormal on both occasions. Forty-two women were studied. Statistically significant associations were shown between lupus anticoagulant positivity and previous pregnancy loss (odds ratio [OR], 4.8; 95% confidence intervals [CI], 1.0 to 23.6; P = .05) and between anticardiolipin antibody positivity and previous pregnancy loss (OR, 20.0; 95% CI, 1.3 to 97.0; P = .01). All seven women with multiple episodes of pregnancy loss were lupus anticoagulant positive and four of these were also anticardiolipin antibody positive. If patients who are transiently positive for lupus anticoagulant and/or anticardiolipin antibodies are considered to be test positive, the associations with pregnancy loss are no longer statistically significant. Within the group of lupus anticoagulant-positive patients, we observed stronger associations between the presence of six or more positive tests and pregnancy loss than between the presence of two to five positive tests and pregnancy loss. No single test for the lupus anticoagulant provides a statistically significant association with pregnancy loss. The results of our study show that by performing multiple lupus anticoagulant tests and by repeating testing for lupus anticoagulant and anticardiolipin antibodies on more than one occasion, significant associations between the presence of antiphospholipid antibodies and previous pregnancy loss can be shown in patients with SLE.

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.

SummaryWe compared the abilities of heparin and two direct thrombin inhibitors to prevent fibrin accretion onto pre-existing thrombi in rabbits. Inhibition of thrombus growth was measured as the ability of each test compound to inhibit the accretion of 125I-fibrin onto thrombi pre-formed in jugular veins of rabbits. When administered as a continuous infusion, the two direct (i. e. antithrombin III-independent) thrombin inhibitors, r-hirudin and a tripeptide, Ac(D)-Phe-Pro-bor-Arg (P-8714) inhibited fibrin accretion as effectively as heparin, but did so in doses which generated little systemic anticoagulation, as compared to the marked anticoagulation associated with the heparin effect. However, both r-hirudin and P-8714 were more effective when they were administered as a single bolus injection than as a continuous infusion. Under the former conditions, there was only a transient systemic anticoagulant effect. We conclude that direct or antithrombin III-independent thrombin inhibitors are more effective than heparin in preventing thrombus growth. The limited effect of heparin is likely due to fibrin impairing the ability of heparin/antithrombin III to inactivate thrombin.

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.

SummaryIn order to determine whether an association exists between antiphospholipid antibodies (APLA) and thromboembolic events in patients with systemic lupus erythematosus (SLE), we performed a cross-sectional study of consecutive unselected SLE patients. The occurrence of previous thromboembolic events was determined by investigators blinded to the APLA status of the patients by critical review of objective tests that had been performed at the time of symptomatic presentation and by performing venous Doppler ultrasound of the legs to elicit venous reflux as an indication of previous venous thrombosis. The presence of APLA was determined by coagulation assays for the lupus anticoagulant (LA) using five tests with well-defined control ranges and by ELISA assay for anticardiolipin antibodies (ACLA). These tests were measured on two separate occasions. The results of the study demonstrate a statistically significant association between persistently abnormal ACLA assays and thromboembolic events and a non-significant trend between persistently abnormal LA and thromboembolic events. Transient abnormalities of LA and ACLA were less strongly associated with thromboembolic events. We conclude that in patients with SLE, there is a significant association between thromboembolism and APLA.

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.

SummaryIn order to provide estimates of the risks of symptomatic osteoporosis and reduced bone density in premenopausal women treated with long-term (greater than 1 month) heparin therapy, we evaluated a cohort of 61 consecutive premenopausal women previously treated with long-term heparin (cases) and a group of controls matched for age, parity and duration between the last pregnancy and evaluation. All patients underwent dual photon absorptiometry of the lumbar spine and single photon absorptiometry of the wrist and most cases underwent plain lateral radiography of the thoracolumbar spine in order to exclude silent fractures. Although none of the cases suffered symptomatic fractures (0 of 61, 95% confidence intervals 0.0 to 5.9%), there was a significantly greater proportion of cases than controls with bone density below our pre-defined levels. The long-term implications of our findings are uncertain but because it is possible that the reduction in bone density predisposes women to fractures, this potential risk should be considered when treating women with long-term heparin.

Purpose Women with a history of prior venous thromboembolism have an increased risk for recurrence during pregnancy. Although thromboprophylaxis reduces this risk, recent evidence suggests that, in many cases, prophylaxis can be safely withheld because the estimated recurrence risk is very low. The balance of risks and benefits in women with different recurrence risks has not been examined. Methods We developed a Markov state transition decision analytic model to compare prophylactic low molecular weight heparin to expectant management for pregnant women with a single prior venous thromboembolism. A lifetime time horizon and societal perspective were assumed. Input data were obtained by literature review. Outcomes were expressed as U.S. dollars per quality-adjusted life-year (QALY). Results For "low-risk" women with a prior venous thromboembolism associated with a transient risk factor and no known thrombophilic condition (recurrence risk 0.5%), expectant management was both more effective and less costly than prophylaxis. For "high-risk" women with prior idiopathic venous thromboembolism or known thrombophilic condition (recurrence risk 5.9%), prophylaxis was associated with a reasonable cost-effectiveness ratio ($38,700 per QALY) given a risk of bleeding complications Conclusion For low-risk women with prior venous thromboembolism, expectant management during pregnancy leads to better outcomes than administration of prophylactic low molecular weight heparin. For high-risk women, antepartum thromboprophylaxis is a cost-effective use of resources.

When deep venous thrombosis is suspected, objective testing is required to confirm or refute the diagnosis.To determine whether the combination of a low clinical suspicion and a normal D -dimer result rules out deep venous thrombosis.Prospective cohort study.Three tertiary care hospitals in Canada.445 outpatients with a suspected first episode of deep venous thrombosis.Patients were categorized as having low, moderate, or high pretest probability of thrombosis and underwent whole-blood D -dimer testing. Patients with a low pretest probability and a negative result on the D -dimer test had no further diagnostic testing and received no anticoagulant therapy. Additional diagnostic testing was done in all other patients.Venous thromboembolic events during 3-month follow-up.177 (40%) patients had both a low pretest probability and a negative D -dimer result. One of these patients had deep venous thrombosis during follow-up (negative predictive value, 99.4% [95% CI, 96.9% to 100%]).The combination of a low pretest probability of deep venous thrombosis and a negative result on a whole-blood D -dimer test rules out deep venous thrombosis in a large proportion of symptomatic outpatients.

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.

In order to determine whether there is a relationship between acquired free protein S deficiency and increased thrombin generation, we performed a cross-sectional study of patients with systemic lupus erythematosus (SLE). Plasma samples were assayed for free protein S and were correlated to levels of prothrombin fragments (F1 + 2); an elevated level of F1 + 2 was used as a surrogate marker for a prothrombotic state. Assays for anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) were performed on two separate blood samples taken at least 3 months apart in order to detect the presence of antiphospholipid antibodies. Of the 36 subjects, 9 had reduced free protein S levels compared to 0 of 21 controls (P = 0.01) and the mean free protein S level was significantly lower in the SLE population than in controls (0.30 +/- 0.08 U/mL versus 0.43 +/- 0.10 U/mL, P0.001). Of the 24 subjects with antiphospholipid antibodies, 9 had reduced free protein S levels, compared to 0 of 12 subjects without antiphospholipid antibodies (P = .01). The mean F1 + 2 level was significantly higher in study subjects with reduced free protein S levels than in those with normal free protein S levels (1.22 +/- 0.50 nmol/L versus 0.78 +/- 0.27 nmol/L, P = 0.05). This study confirms an association between antiphospholipid antibodies and reduced free protein S levels and demonstrates that patients with SLE and acquired free protein S deficiency generate more thrombin than patients with SLE and normal free protein S levels. Further studies are needed to determine whether the thrombotic diathesis associated with the presence of antiphospholipid antibodies is directly caused by the concomitant presence of acquired free protein S deficiency.

Study objective To determine whether measurement of D-dimer, using an enzyme-linked immunosorbent assay (ELISA) with a cutoff of 300 ng/ml, and a latex agglutination assay with a cutoff of 500 ng/ml, is clinically useful in patients with suspected pulmonary embolism (PE). Design Prospective cohort. Setting Tertiary care referral center, university-affiliated hospital. Patients Two hundred twenty-one consecutive patients with clinically suspected PE. Intervention All patients had blood drawn to measure levels of D-dimer and underwent ventilation/perfusion (V/Q) lung scanning and bilateral impedance plethysmography (IPG); pulmonary angiography was performed in nine patients. Patients were classified as follows: (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 on serial testing and confirmed by contrast venography) or symptomatic thromboembolic event within 3 months of presentation; or (2) PE-negative; normal V/Q scan or normal pulmonary angiography or non-high-probability V/Q scan and either normal serial IPG or abnormal IPG with normal venography and absence of symptomatic venous thromboembolism within 3 months of followup. Forty-three patients were classified as PE positive and 178 patients were classified as PE negative. Measurements and results The sensitivities, specificities, positive predictive values, and negative predictive values of the ELISA and latex agglutination assay were calculated for all patients and for the subgroup of patients with non-high-probability V/Q scans. The ELISA D-dimer, using a cutoff of 300 ng/ml, showed a sensitivity and negative predictive value of 100 percent in all patients and patients with non-high-probability V/Q scans, but the corresponding specificities were only 26 percent and 13 percent, respectively. The latex agglutination assay for D-dimer using a cutoff of 500 ng/ml showed the following: sensitivities of 84 percent in all patients and 90 percent in patients with non-high-probability scans, negative predictive values of 93 percent in all patients, and 98 percent in patients with non-high-probability scans and specificities of 56 percent in all patients and 55 percent in patients with non-high-probability scans. Conclusions This study demonstrates that an ELISA D-dimer result of less than 300 ng/ml excludes PE but occurs in a small proportion of patients with clinically suspected PE. The latex agglutination assay, using a cutoff of 500 ng/ml, has potential clinical utility in excluding PE in the subgroup of patients with clinically suspected PE and non-high-probability V/Q scans. However, the 95 percent confidence interval on the observed sensitivity of the latex agglutination assay in patients with non-high-probability V/Q scans is wide. Therefore, these promising results should be confirmed in a large clinical trial before the latex agglutination assay is used to make management decisions.

To compare two methods of determining a therapeutic range of activated partial thromboplastin time (aPTT) results.Cohort studies.Referral teaching hospital.Inpatients who received unfractionated heparin intravenously for venous thromboembolic disease.A therapeutic range determined by aPTT ratios of 1.5 to 2.5 times the control value as compared with a therapeutic range determined by protamine titration heparin levels of 0.2 to 0.4 U/mL.For all aPTT reagents studied, a ratio of 1.5 times the control value is much less than a minimum protamine titration heparin level of 0.2 U/mL. Various manufacturers' aPTT reagents and reagent lots from the same manufacturer show considerable variation in response to heparin and therefore have different therapeutic ranges.A different dose of heparin would be required to produce an aPTT ratio of 1.5 times the control value, depending on the reagent used. Establishing a therapeutic range for aPTT results using protamine titration heparin levels of 0.2 to 0.4 U/mL as a reference standard is practical and compensates for the variable response of aPTT reagents to heparin.

Warfarin-induced skin necrosis is a rare but serious complication of oral anticoagulant therapy. This condition has been associated with protein C deficiency but only rarely reported in patients with a deficiency of protein S. We have managed 2 patients with a history of warfarin-induced skin necrosis who were diagnosed as being protein-S-deficient. Since both patients were candidates for long-term anticoagulant therapy we elected to reintroduce warfarin using a regimen designed to minimize the risk of recurrent skin necrosis. While they were therapeutically anticoagulated with heparin, warfarin was started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued until the prothrombin times were in the therapeutic range for at least 72 h. Both patients tolerated the reinstitution of warfarin without difficulty and they have now been followed for over 2 years on oral anticoagulants without complication.

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.

Background It may be safe to omit additional diagnostic testing in selected patients with suspected pulmonary embolism (PE) who have a negative D-dimer test, but this approach has never been evaluated in a randomized, controlled trial. Objective To determine if additional diagnostic testing can be safely withheld in patients with suspected PE who have negative erythrocyte agglutination D-dimer test results. Design Randomized comparisons in 2 subgroups of a prospective multicenter study. Setting 7 university hospitals. Patients 1126 outpatients or inpatients with suspected PE; of these, 456 patients with negative erythrocyte agglutination D-dimer test results were randomly assigned to the intervention groups. Patients were classified into 2 clinical probability groups: those with a low clinical probability of PE (low-probability group) and those with a moderate or high clinical probability of PE, a nondiagnostic ventilation-perfusion lung scan, and no evidence of proximal deep venous thrombosis on bilateral ultrasonography (moderate- or high-probability group). Interventions The experimental intervention for both probability groups was no further diagnostic testing for PE. The control intervention for the low-probability group was a ventilation-perfusion lung scan followed by ultrasonography of the proximal deep veins of the legs on the same day. If the lung scan was nondiagnostic, ultrasonography of the legs was repeated 7 and 14 days later. The control intervention for the moderate- or high-probability group was ultrasonography of the proximal deep veins of the legs after 7 and 14 days. In the control and experimental groups, anticoagulation was withheld or withdrawn if PE was not diagnosed. Measurements Symptomatic venous thromboembolism (VTE) during 6 months of follow-up. Results Prevalence of VTE was 15.2% in the 1126 enrolled patients. In the low-probability group, VTE occurred during follow-up in 0 of 182 patients who had no additional diagnostic testing and in 1 of 185 patients who had additional testing (difference, -0.5 percentage point [95% CI, -3.0 to 1.6 percentage points]). In the moderate- or high-probability group, VTE occurred during follow-up in 1 of 41 patients who had no additional diagnostic testing and in 0 of 41 patients who had additional testing (difference, 2.4 percentage points [CI, -6.4 to 12.6 percentage points]). Limitations The authors could not enroll 2000 patients as originally planned; 3 randomly assigned patients did not receive the allocated intervention, and 7 received inadequate follow-up. Personnel who performed follow-up evaluations were not blinded to the results of diagnostic testing at enrollment or to allocation group assignments. Conclusion In patients with a low probability of PE who have negative D-dimer results, additional diagnostic testing can be withheld without increasing the frequency of VTE during follow-up. Low clinical probability and negative D-dimer results occur in 50% of outpatients and in 20% of inpatients with suspected PE.

Background Studies evaluating the accuracy of the SimpliRED D-dimer assay for venous thromboembolism (VTE) have used a capillary fingerstick blood sample, which requires the test to be performed immediately at the bedside. Initial studies showed a sensitivity for VTE of 90% to 95% when the assay was performed by a finite number of experienced health care workers. However, because of the test's subjectivity, misinterpretation of the result is possible when performed by inexperienced staff. Recent reports by other investigators indicated a low sensitivity of this assay for VTE and noted a reduction in sensitivity (84%) for pulmonary embolism. Objective To determine the sensitivity and specificity of the D-dimer test performed in the laboratory by experienced technologists on venous whole-blood samples in routine collection tubes. If D-dimer testing results accurately detect VTE when performed in this manner, concerns about the sensitivity of this assay would be solved. Methods One hundred forty-eight consecutive patients with suspected VTE underwent D-dimer testing at the bedside using a fingerstick sample and venous blood collected into a plain tube. Venous blood was also collected into tubes containing tri-potassium EDTA, sodium citrate, or a combination of lithium and heparin for D-dimer testing in the laboratory. In addition, the EDTA tube was refrigerated overnight at 4°C for retesting at approximately 24 hours. The presence or absence of VTE was determined by means of objective results of testing and a 3-month follow-up. Results Thirty-four subjects (23%) had confirmed VTE (25 with deep vein thrombosis; 9 with pulmonary embolism). All laboratory venous blood D-dimer results showed sensitivities of 97%, specificities of 61% to 64%, and negative predictive values of 99%, compared with 88%, 71%, and 95%, respectively, when the results were obtained by means of fingerstick at the bedside. Conclusions The SimpliRED D-dimer assay performed in the laboratory on venous blood, collected into any of 3 routine laboratory tubes, is sensitive and moderately specific for VTE. Based on this study, immediate bedside testing (particularly by inexperienced personnel) under suboptimal conditions is unnecessary. Furthermore, the high sensitivity of refrigerated EDTA samples allows specimens to be stored or transported (on ice at 4°C) for testing for 24 hours after collection.

ContextThe long-term effect of policies restricting contact between residents and pharmaceutical company representatives (PCRs) during internal medicine training is unknown. The McMaster University Department of Medicine in Hamilton, Ontario, implemented a policy restricting PCR contact with trainees in 1992, whereas the Department of Medicine at the University of Toronto, Toronto, Ontario, has no such policy.ObjectiveTo determine if the presence of a restrictive policy and the frequency of contact with PCRs during internal medicine training predict attitudes and behavior several years after completion of training.Design, Setting, and ParticipantsRetrospective analysis of the attitudes and behavior of 3 cohorts of physicians: University of Toronto trainees, prepolicy McMaster trainees, and postpolicy McMaster trainees. Surveys were mailed to 242 former University of Toronto and 57 former McMaster trainees who completed their internal medicine training between 1990 and 1996, with response rates of 163 (67%) and 42 (74%), respectively.Main Outcome MeasuresPhysician attitude, assessed by a question about the perceived helpfulness of PCR information, and behavior, assessed by whether physicians met with PCRs in the office and the frequency of contacts with PCRs (current contact score, consisting of conversations with PCRs, PCR-sponsored events attended, gifts, honoraria, and consulting fees received).ResultsIn both the unadjusted and multiple regression analyses, postpolicy McMaster trainees were less likely to find information from PCRs beneficial in guiding their practice compared with Toronto and prepolicy McMaster trainees, with unadjusted odds ratios (ORs) of 0.44 (95% confidence interval [CI], 0.20-0.94) and 0.39 (95% CI, 0.13-1.22), respectively. All 3 groups were equally likely to report that they met with PCRs in their office in the past year (88%). Postpolicy McMaster trainees had a lower current contact score compared with Toronto (9.3 vs 10.9; P = .04) and prepolicy McMaster trainees (9.3 vs 10.8; P = .18). In multiple regression models, greater frequency of contact with PCRs during training was a predictor of increased perceived benefit of PCR information (OR, 1.29; 95% CI, 1.13-1.47) and was positively correlated with the current contact score (partial r = 0.49; P

SummaryIn order to determine the relative frequencies of left and right leg venous thrombosis during pregnancy and the frequencies of venous thrombosis during the three trimesters, a cohort study of 60 consecutive patients with a first episode of venous thrombosis during pregnancy was performed. Fifty-eight women had isolated left leg thrombosis, two patients had bilateral venous thrombosis and no patient had isolated right leg venous thrombosis. Thirteen patients had venous thrombosis during the first trimester (21.7%), 28 during the second trimester (46.7%) and 19 during the third trimester (31.7%). These findings indicate that patients with symptoms in the right leg rarely have venous thrombosis. Because leg pain and swelling occur most frequently during the third trimester but venous thrombosis is relatively equally distributed during all three trimesters, patients presenting earlier during pregnancy are more likely to have venous thrombosis than patients presenting later during pregnancy.

Patients with suspected pulmonary embolism often have nondiagnostic lung scans and may present in circumstances where lung scanning is unavailable. Levels of D-dimer, a fibrin-specific product, are increased in patients with acute thrombosis; this may simplify the diagnosis of pulmonary embolism.To determine the sensitivity and specificity of a whole-blood D-dimer assay in patients with suspected pulmonary embolism and in subgroups of patients with low pretest probability of pulmonary embolism or nondiagnostic lung scans.Prospective cohort.Four tertiary care hospitals.1177 consecutive patients with suspected pulmonary embolism.All patients underwent an assessment of pretest probability by use of a standardized clinical model, a D-dimer assay, ventilation-perfusion lung scanning, and bilateral compression ultrasonography. Patients in whom pulmonary embolism was not initially diagnosed were followed for 3 months. Accordingly, patients were categorized as positive or negative for pulmonary embolism.Of the 1177 patients, 197 (17%) were classified as positive for pulmonary embolism. Overall, the D-dimer assay showed a sensitivity of 84.8% and a specificity of 68.4%. In 703 patients (3.4%) with a low pretest probability of pulmonary embolism, the likelihood ratio associated with a negative D-dimer test result was 0.27, resulting in a posterior probability of 1.0% (95% CI, 0.3% to 2.2%). In 698 patients with nondiagnostic lung scans (previous probability, 7.4%), the likelihood ratio associated with a negative D-dimer test result was 0.36, resulting in a posterior probability of 2.8% (CI, 1.4% to 4.8%).A normal D-dimer test result is useful in excluding pulmonary embolism in patients with a low pretest probability of pulmonary embolism or a nondiagnostic lung scan.

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

CLINICAL SCENARIO A 55-year-old man had his serum cholesterol level measured at a shopping mall 2 months ago. His cholesterol level was elevated and he comes to you, his primary care physician, for advice. He does not smoke, is not obese, and does not have hypertension, diabetes mellitus, or any first-order relatives with premature coronary heart disease (CHD). You repeat his cholesterol test and schedule a follow-up appointment. The test confirms an elevated cholesterol level (7.9 mmol/L [305 mg/dL]), but before deciding on a treatment recommendation, you elect to find out just how big a reduction in the risk of CHD this patient could expect from a cholesterollowering diet or drug therapy. THE SEARCH There are a number of cholesterol-lowering trials, and instead of trying to find and review all of the original studies yourself, you use Grateful Med to find a recent overview. On the first subject line you

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)

CLINICAL SCENARIO You are about to see a 76-year-old retired schoolteacher for the second time. You first saw her in the clinic a month ago because of cognitive problems. Your evaluation at that time included a Standardized Mini-Mental State Examination,1on which she scored 18 out of a possible 30 points, and a physical examination that was normal including no focal neurological signs. You arranged investigations for the treatable causes of dementia that were negative, and you thus feel she has probable Alzheimer's disease. The patient has lived with her son since her husband died 6 years ago. Her son thinks that she first developed significant problems with her memory about 3 years ago. However, she has become increasingly agitated and paranoid during the last year. She has refused to allow him to look after her financial affairs, despite the fact that she owns three pieces of property and

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)

CLINICAL SCENARIO You are a medical consultant asked by a surgical colleague to see a 78-year-old woman, now 10 days after abdominal surgery, who has become increasingly short of breath over the last 24 hours. She has also been experiencing what she describes as chest discomfort, which is sometimes made worse by taking a deep breath (but sometimes not). Abnormal findings on physical examination are restricted to residual tenderness in the abdomen and scattered crackles at both lung bases. Chest roentgenogram reveals a small right pleural effusion, but this is the first roentgenogram since the operation. Arterial blood gases show a Po 2 of 70 mm Hg, with a saturation of 92%. The electrocardiogram shows only nonspecific changes. You suspect that the patient, despite receiving 5000 U of heparin twice a day

CLINICAL SCENARIO You are a general internist who is asked to see a 65-year-old man with controlled hypertension and a 6-month history of atrial fibrillation resistant to cardioversion. Although he has no evidence for valvular or coronary heart disease, the family physician who referred him to you wants your advice on whether the benefits of long-term anticoagulants (to reduce the risk of embolic stroke) outweigh their risks (of hemorrhage from anticoagulant therapy). The patient shares these concerns and doesn't want to receive a treatment that would do more harm than good. You know that there have been randomized trials of warfarin for nonvalvular atrial fibrillation and decide that you'd better review one of them.

Background: The use of subcutaneous heparin, the therapy of choice for women requiring anticoagulant prophylaxis during pregnancy, is problematic because of the discomfort produced by repeated injections. An indwelling subcutaneous Teflon catheter that can be left in place for 1 week recently became available for use as an entry port for parenteral therapy. Since the use of this catheter has the potential to overcome some of the problems of long-term heparin therapy, we decided to compare this Teflon catheter with twice-daily subcutaneous injections in women requiring heparin during pregnancy. Methods: In a randomized, multiple-crossover study, patients alternated every 2 weeks between having heparin administered through the indwelling Teflon catheter and receiving heparin via subcutaneous injections. After each 4-week cycle, patients completed a questionnaire designed to determine their preferred method of heparin administration. The side effects, doses, and anticoagulant activity of heparin with the two delivery systems were also compared. Results: Twelve patients completed one to five 4-week cycles of heparin therapy. Ten of the patients selected the Teflon catheter as the preferred route of heparin administration (P=.04) and 11 patients reported that the catheter caused less pain and bruising than twice-daily subcutaneous injections (P Conclusions: Most pregnant women in our study preferred to have subcutaneous heparin administered through an indwelling Teflon catheter rather than by twice-daily injections. Heparin given through the Teflon catheter was bioavailable and caused less local bruising than twice-daily injections. Urticarial reactions to heparin tended to be more severe with the use of the Teflon catheter and resulted in the discontinuation of the device's use in two of 12 patients. (Arch Intern Med. 1993;153:841-844)

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)

• The postphlebitic syndrome is a common affliction with limited therapeutic options. Patients who fail to respond to treatment with graded elastic compression stockings often develop a chronic pain syndrome manifested by intractable pain and swelling. Because lymphedema, a condition also associated with leg pain and swelling, has been successfully treated by intermittent compressive therapy with an extremity pump, we conducted a pilot study of compressive therapy in patients with severe postphlebitic syndrome. All five patients studied had dramatic improvement in symptoms and functional status without side effects. Although a large randomized trial is needed to properly evaluate compressive therapy, it appears to be very effective in selected patients. ( Arch Intern Med. 1989;149:1651-1652)

The true maternal and fetal risks of heparin therapy during pregnancy are unknown, because most published studies are small and do not report consecutively treated patients. In order to address these issues, we performed a retrospective cohort study of 100 pregnancies in 77 women treated with heparin during pregnancy. In 98 pregnancies heparin therapy was given for the prevention or treatment of venous thromboembolism; in the remaining 2, because of prosthetic heart valves. The rates of prematurity, abortions, stillbirths, neonatal deaths, and congenital abnormalities were similar to those in the normal population. There were two bleeding episodes and no symptomatic thrombotic episodes associated with heparin therapy. We conclude that maternal heparin therapy is safe for the fetus and is associated with an acceptable bleeding rate and a low rate of thrombotic recurrence in the mother.