Requirements for appropriate evaluation of diagnostic tests in suspected pulmonary embolism.
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Angiography↗
Biomedical subjects
H R Büller
Publications and source records attributed to H R Büller.
Randomised evaluation of treatment modalities in thromboembolic disorders.
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Ambulatory Care↗
Undiagnosed malignancy in patients with deep vein thrombosis: incidence, risk indicators, and diagnosis.
BACKGROUND: The reported incidence of a subsequent diagnosis of malignancy in patients presenting with deep vein thrombosis (DVT) varies from 2-25%. Risk indicators and diagnostic procedures to be performed in these patients are controversial. METHODS: Four hundred consecutive patients with confirmed DVT included in a randomized clinical trial were followed prospectively for 6 months. The incidence of a subsequent diagnosis of malignancy was calculated and compared between patients with unexplained DVT and patients with secondary DVT. Potential risk indicators for subsequent malignant disease were evaluated. RESULTS: Of the 400 patients, 70 already had been diagnosed with malignancy; another four patients were lost to follow-up. Of the remaining 326 patients, 10 new malignancies were diagnosed among 137 patients with unexplained DVT (7.3%) and 3 new malignancies were diagnosed in 189 patients with secondary DVT (1.6%). The relative risk was 4.6 (95% confidence interval, 1.3-16; P=0.009). Age, gender, or location of the DVT had no significant effect on the incidence of diagnosis when adjusted for unexplained DVT. Ten of these 13 patients (77%) had abnormal clinical findings suggestive of malignancy at the time of presentation with DVT. CONCLUSIONS: Unexplained DVT is a significant risk indicator of underlying malignancy. The majority of patients with undiagnosed malignancy have some clinical abnormality suggestive of underlying malignancy at the time of presentation with unexplained DVT. A simple clinical evaluation comprised of medical history, physical examination, routine laboratory tests, and chest X-ray can detect such patients. Extensive screening of all patients presenting with unexplained DVT does not appear to be justified.
Adult↗
Low-molecular-weight heparins in the treatment of venous thromboembolism.
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Anticoagulants↗
Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study.
OBJECTIVE: To evaluate the safety of withholding anticoagulant treatment from patients with clinically suspected deep vein thrombosis but normal findings on compression ultrasonography. DESIGN: Compression ultrasonography was done with a simplified diagnostic procedure limited to the common femoral vein in the groin and the popliteal vein extending down to the trifurcation of the calf veins. Patients with normal ultrasonography findings at presentation were retested 1 week later. MAIN OUTCOME MEASURE: The incidence of venous thromboembolic complications during follow up for 6 months in patients in whom anticoagulant treatment was withheld on the basis of normal results on two ultrasonography tests 1 week apart. SETTING: University research centres in four hospitals. RESULTS: A total of 1702 patients were included in the study. Abnormal results on compression ultrasonography at presentation or at 1 week were found in 400 and 12 patients, respectively, for a prevalence of deep vein thrombosis of 24%. None of the patients were lost to follow up. Venous thromboembolic complications during the week of serial testing occurred in a single patient and in eight patients during 6 months' follow up, resulting in a cumulative rate of venous thromboembolic complications of 0.7% (95% confidence interval 0.3% to 1.2%). The mean number of extra hospital visits and additional tests required per initially referred patient was 0.8. CONCLUSION: It is safe to withhold anticoagulant treatment from patients with clinically suspected deep vein thrombosis who have a normal result on compression ultrasonography at the time of presentation and at 1 week.
Adolescent↗
The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.
BACKGROUND: The factor V Leiden mutation is a genetic defect associated with an increased incidence of venous thromboembolism. When the incidence of venous thromboembolism in relatives of patients known to have the mutation outweighs the disadvantages of prophylactic strategies, family screening may be necessary. OBJECTIVE: To determine the incidence of venous thromboembolism in first-degree relatives of symptomatic carriers of the factor V Leiden mutation. DESIGN: Retrospective blinded study. SETTING: University hospitals. PARTICIPANTS: 437 first-degree relatives of 112 heterozygous propositi and 30 relatives of 6 homozygous propositi. MEASUREMENTS: Before DNA testing, information on previous venous thromboembolism and concomitant risk factors was obtained. Relatives with and without the FV: Q506 mutation were compared. RESULTS: The annual incidence of thromboembolism in relatives of heterozygous propositi was 0.45% (95% CI, 0.28% to 0.61%) in those with the mutation and 0.10% (CI, 0.02% to 0.19%) in those without the mutation (relative risk, 4.2 [CI, 1.8 to 9.9]). Among carriers, the incidence increased from 0.25% (CI, 0.12% to 0.49%) in the 15- to 30-year-old age group to 1.1% (CI, 0.24% to 3.33%) in persons older than 60 years of age. Half of the episodes of venous thromboembolism occurred spontaneously, 20% were related to surgery, and 30% were associated with pregnancy or use of oral contraceptives. CONCLUSIONS: The observed low annual risk for venous thromboembolism in persons carrying the factor V Leiden mutation does not seem to outweigh the risks for bleeding associated with coumarin prophylaxis or justify discouragement of the use of oral contraceptives. A general policy of screening the families of all patients with the factor V Leiden mutation does not seem to be indicated. The observations in this moderate-size, retrospective study need to be confirmed by prospective follow-up studies.
Adolescent↗
Weight watching in cardiology: low molecular weight heparin for acute coronary syndromes.
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Acute Disease↗
Diagnostic management of venous thromboembolism.
The accuracy of diagnostic methods for the diagnosis of deep vein thrombosis and pulmonary embolism in symptomatic patients is critically reviewed. In addition, the safety of withholding anticoagulant therapy from patients with suspected deep vein thrombosis or pulmonary embolism in whom the qualified diagnostic strategy was normal is evaluated by determining the frequency of venous thromboembolic complications during 3 months of follow-up. It is shown that the currently used available diagnostic techniques for deep vein thrombosis are all able to identify the majority of patients who indeed have venous thrombosis. However, as result of its accuracy and practical advantages, compression ultrasound is the test of choice in the evaluation of symptomatic patients. Patients with a normal test outcome should be re-tested to detect the small proportion of patients with proximally extending calf vein thrombosis. In the strategy of repeated diagnostic testing, impedance plethysmography could be used as an alternative to ultrasonography. To obtain a reduction in repeat tests various diagnostic strategies have been evaluated and it was shown that these strategies, using non-invasive tests, can be as accurate and safe as the invasive reference strategy. The safeties of the various strategies were very similar; however, important differences were observed with respect to the practical implementation of the various diagnostic strategies. Simplification of the repeated testing strategy by using a D-dimer assay and/or a clinical decision rule seems to be promising. The reference standard for the diagnosis of pulmonary embolism remains pulmonary angiography. Several strategies based on non-invasive diagnostic methods have been evaluated for their safety and complexability. Perfusion-ventilation lung scanning is the most thoroughly evaluated non-invasive technique so far. It seems safe to withhold anticoagulant therapy in patients suspected of pulmonary embolism with a normal perfusion lung scan result; however, further testing is needed in the case of a non-diagnostic perfusion-ventilation lung scan result. At this moment angiography is the method of choice in this category of patients. D-dimer assays, clinical decision rules and ultrasound examinations of the legs seem to have a high potential to limit the need for angiography. Also, spiral computerized tomography and magnetic resonance imaging are promising techniques, but their role in the diagnostic management of pulmonary embolism is still uncertain.
Diagnostic Techniques and Procedures↗
Low molecular weight heparin as an adjunct to thrombolysis for acute myocardial infarction: the FATIMA study. Fraxiparin Anticoagulant Therapy in Myocardial Infarction Study Amsterdam (FATIMA) Study Group.
OBJECTIVE: To investigate the feasibility of fixed dose, weight adjusted subcutaneous low molecular weight heparin (LMWH), with monitoring of anti-Xa levels and assessment of coronary patency rates after three to five days, thereby giving an initial indication of its safety and efficacy. DESIGN: In 30 patients with acute myocardial infarction, LMWH (nadroparine) was given as a body weight adjusted intravenous bolus with thrombolysis (rt-PA infusion) and in weight adjusted subcutaneous doses at six hours, and every 12 hours thereafter for 72 hours. The target range was defined prospectively as 0.35-0.70 anti-factor Xa activity (aXa) units. The aXa level was measured every six hours. Coronary angiography was performed in all patients within five days after the start of thrombolytic treatment to determine patency (TIMI 2 and 3 flow) of the infarct related artery. RESULTS: The mean (SEM) aXa level over 72 hours was 0.52 (0.08) U/ml; from 12 hours onwards 88% of all aXa measurements were within the target range. At angiography, a patent infarct related artery was present in 24 of the 30 patients. No major bleeding complications occurred, though minor bleeding complications were observed in two patients. CONCLUSIONS: This small study indicates that LMWH is feasible as an adjunct to thrombolysis in patients with acute myocardial infarction. The aXa levels were within the target range and patency rates at three to five days were around 80%, with no major bleeding complications.
Adult↗
Outpatient therapy with low-molecular-weight heparins: new perspectives for treatment of deep vein thrombosis.
Subcutaneous administration of low-molecular-weight heparin (LMWH) has been demonstrated to be as safe and effective for treatment of acute venous thrombosis as conventional treatment with unfractionated heparin, which requires intravenous infusion. In addition, LMWHs appear to provide an improved quality of life for patients with less impairment of physical activity. The ease of administration of LMWHs could be exploited in the clinical management of patients to increase the extent of LMWH outpatient therapy and reduce the number of hospitalizations for venous thrombosis, thus providing a more cost-effective therapy than conventional heparin. Efficient support services, patient education and careful follow up will be required for home treatment to be successful.
Anticoagulants↗
Early discharge strategies following venous thrombosis.
Low-molecular-weight heparin therapy is administered subcutaneously, not intravenously. This has made possible the management of selected patients who have acute deep venous thrombosis as outpatients. Others can be treated with an abbreviated several day hospitalization rather than the conventional 5 or more hospital days needed for administration of continuous intravenous unfractionated heparin. Two large studies, Tasman and a Canadian trial, have demonstrated the efficacy and safety of low-molecular-weight heparin in this setting. Now, the task is to develop guidelines for widespread application of these findings to daily clinical practice. However, successful home treatment will require intensive patient education as well as an extensive infrastructure of supportive nursing and physician services. Careful patient follow-up will be crucially important.
Adult↗
Observer and biological variation of a rapid whole blood D-dimer test.
In consecutive patients with suspected venous thromboembolism the interobserver variability of the SimpliRED D-dimer test was evaluated by two observers who independently scored one plate, the between assay variation was performed simultaneously by a third independent observer, who assessed a second plate. The biological variation was studied, 1-4 hours later by an independent evaluation. A total of 155 patients entered the study, venous thromboembolism was present in 42 patients (28%). The interobserver variability was 2/83 samples, with a kappa of 0.95 (95% confidence interval 0.88-1.0). The between assay variation was 2/98, with a kappa value of 0.96 (95% confidence interval 0.90-1.0). When testing the biological variation the observers disagreed in 2 of 69 patients (3%). The SimpliRED D-dimer assay has a good to excellent interobserver variability, between assay variation and reproducibility.
Adolescent↗
Replacing inpatient care by outpatient care in the treatment of deep venous thrombosis--an economic evaluation. TASMAN Study Group.
Two clinical trials in patients with acute deep venous thrombosis have indicated that the outpatient management with fixed-dose, subcutaneous low-molecular-weight heparin is at least as effective and safe as inpatient treatment with unfractionated intravenous heparin with respect to recurrent venous thromboembolism and major bleeding. We performed an economic evaluation alongside one of these trials to assess the cost consequences of the outpatient management strategy. Data were collected through case record forms, complemented by a prospective questionnaire in 78 consecutive patients, interviews with health care providers, and hospital data bases. Our study demonstrated that seventy-five percent of patients allocated to low-molecular-weight heparin received treatment either entirely at home or after a brief hospital stay. Fifteen percent of these patients required professional domiciliary care. Within-centre comparisons of resource utilisation in terms of natural units showed that outpatient management with low-molecular-weight heparin reduced the average number of hospital days in the initial treatment period in nine centres by 59 percent (95% CI: 43 to 71 percent) accompanied by a limited increase in outpatient and professional domiciliary care. The average reduction in hospital days at the end of follow up was 40 percent (95% CI: 25 to 54 percent). A cost-minimisation analysis, focusing on resource utilisation directly related to the treatment of deep venous thrombosis and associated costs in one centre demonstrated a cost reduction of 64 percent (95% CI: 56 to 72 percent) with the outpatient management with low-molecular-weight heparin. These data suggest that outpatient management of patients with proximal venous thrombosis using low-molecular-weight heparin reduces resource utilisation and total treatment cost. Implementation should be preceded by a cautious evaluation of a potential cost shifting and organisational prerequisites.
Administration, Cutaneous↗
Use of a heparin nomogram for treatment of patients with venous thromboembolism in a community hospital.
BACKGROUND: The application of a heparin dosing nomogram in the treatment of patients with venous thromboembolism resulted in improvement of heparin therapy in clinical research settings. In 1992 a heparin nomogram was introduced in our hospital, which is a community hospital where anticoagulant therapy is supervised by the attending physicians. We studied whether comparable improvements were achieved in such a non-surveyed clinical setting. METHODS: Patients were identified from computerized discharge records, and classified into a pre-nomogram (discharged in 1990 or 1991) and a nomogram patient group (discharged in 1993 or 1994). The use of the nomogram was encouraged but the application remained on a voluntary basis. Since the definition of the target APTT range was different in the pre-nomogram period as compared to the nomogram period, a formal analysis of pre- and post-nomogram results was not considered justified. RESULTS: The APTT ratio, six hours after the start of heparin treatment, was below the predefined lower limit in 72% of 127 patients in the pre-nomogram group and in 13% of 127 patients in the nomogram group. During 1043 days heparin therapy in the nomogram group the morning APTT ratio was subtherapeutic in 8%. In 58% of all APTT results the physician responded according to the nomogram. The subsequent APTT was in the target range in 64% of the cases compared to 31% if the adjustement was not performed according to the nomogram (P<.0001). Major bleeding episodes occurred in 3.1% in the pre-nomogram period and in 0.7% in the nomogram period. CONCLUSION: The present study shows that the introduction of a heparin dosing nomogram in a non-research clinical setting results in more adequate heparin anticoagulation with low risks of bleeding.
Adult↗
Recurrence of venous thromboembolism in patients with familial thrombophilia.
BACKGROUND: Treatment of patients with deep vein thrombosis and an antithrombin or protein C or S deficiency is based on case reports and personal experience. OBJECTIVE: To systematically assess the risk for recurrence of venous thromboembolism after a first episode in patients with these deficiencies, a literature review and retrospective family cohort study were performed. METHODS: For the literature review, the annual incidence of a first recurrent venous thromboembolism was assessed for each deficiency by dividing the number of venous thromboembolic events by the number of years at risk. For the family cohort study, 1- and 5-year cumulative incidences of first recurrence were calculated based on medical histories taken in relatives of consecutive patients in whom venous thromboembolism and a deficiency were diagnosed. RESULTS: For the literature review, the annual incidence of a first recurrent venous thromboembolism in patients with antithrombin or protein S deficiency ranged from 13% to 17% and 14% to 16%, respectively. For the family cohort study, the 1- and 5-year cumulative incidences of recurrent venous thromboembolism were 10% (95% confidence interval, 1%-19%) and 23% (95% confidence interval, 10%-36%), respectively. Warfarin sodium (Coumadin) prophylaxis was associated with 2 venous thromboembolic events in 141 years at risk (1.4% per year), in contrast with 19 events in 709 years at risk (2.7% per year) without prophylaxis (difference, -1.3%; 95% confidence interval, -3.5% to 1.0%). CONCLUSIONS: The annual incidence of recurrent venous thromboembolism is high during the first years following a first episode, but seems to decline thereafter. Therefore, our results challenge current practice of prescribing lifelong warfarin therapy after a first or second episode of venous thromboembolism in patients with antithrombin or protein C or S deficiency.
Anticoagulants↗
Low-molecular-weight heparin in the treatment of patients with venous thromboembolism.
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 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.
Anticoagulants↗
Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo.
BACKGROUND: In many case-control as well as epidemiological studies, increased lipoprotein(a) [Lp(a)] levels are considered to constitute an independent risk factor for premature coronary artery and cerebrovascular disease. Lp(a) resembles an LDL particle with an additional linked protein [apolipoprotein(a), apo(a)], whose molecular structure has been demonstrated to be homologous to the fibrinolytic proenzyme plasminogen. Because of the high similarity between plasminogen and apo(a), apo(a) may potentially interfere in the fibrinolytic system by competing with plasminogen for fibrin binding sites. In vitro studies have demonstrated that Lp(a) indeed competes with plasminogen binding to fibrin and inhibits tissue plasminogen activator (TPA)-mediated activation of plasminogen. No direct in vivo studies to test this hypothesis have been performed. METHODS AND RESULTS: To test this hypothesis, we studied the effect of a recombinant form of apo(a) on endogenous and TPA-mediated thrombolysis in an in vivo model of experimental venous thrombosis. Thrombi containing either 16 microg r-apo(a), 8 microg r-apo(a), or vehicle (HEPES-buffered saline, control) were formed in the jugular veins of a rabbit and showed significantly reduced endogenous thrombolysis after 60 minutes in a dose-dependent fashion, ID 2.7+/-0.9% and 4.6+/-1.8%, respectively, versus 7.4+/-1.6% of that of the control. High concentrations of incorporated apo(a) significantly reduced TPA-induced thrombolysis (12.2+/-2.5% versus 22.2+/-2.6% in the control thrombi), but no effect of lower concentrations of incorporated r-apo(a) was demonstrated on the exogenous TPA-induced thrombolysis. CONCLUSIONS: The present study demonstrates the attenuation of endogenous fibrinolysis by apo(a) in an in vivo model of experimental venous thrombosis, lending support to the proposed mechanism of impaired fibrinolysis by which Lp(a) may contribute to atherothrombotic disorders.
Animals↗
Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism.
BACKGROUND: The standard diagnostic approach in patients suspected of having pulmonary embolism starts with perfusion-ventilation lung scanning. If the resulting scan is not diagnostic, pulmonary angiography should be done. The use of tests for deep venous thrombosis has been advocated as an adjunct to establishing the diagnosis of pulmonary embolism, but no prospective studies have provided adequate information about the value of these tests. OBJECTIVE: To determine the accuracy and potential clinical utility of compression ultrasonography in the diagnosis of pulmonary embolism. DESIGN: Prospective cohort study with blinded assessment of ultrasonographic results. SETTING: Teaching hospital. PATIENTS: 397 consecutive inpatients and outpatients in whom pulmonary embolism was clinically suspected. MEASUREMENTS: Sensitivity and specificity of compression ultrasonography. Perfusion-ventilation scanning and angiography were the conjoint gold standard for determining the presence or absence of pulmonary embolism. Also calculated were the number of angiograms and lung scans avoided and the number of patients unnecessarily treated when compression ultrasonography was included in the diagnostic strategy. RESULTS: The overall sensitivity of compression ultrasonography for deep venous thrombosis in patients with pulmonary embolism was 29% (95% CI 22% to 37%); the specificity was 97% (CI, 94% to 99%). Adding ultrasonography to the diagnostic approach before lung scanning would avoid approximately 14% of lung scans and 9% of angiograms but would lead to unnecessary treatment of 13% of patients who have an abnormal ultrasonographic result (2% to 4% of all those receiving anticoagulation). When compression ultrasonography is done only in patients with a nondiagnostic lung scan, 9% of angiographies are prevented at the cost of unnecessarily treating 26% of patients who have an abnormal ultrasonographic result (2% of all patients receiving anticoagulation). CONCLUSION: The diagnostic value of compression ultrasonography for the detection of deep venous thrombosis in patients suspected of having pulmonary embolism is limited; the gain in diagnostic efficiency obtained through the use of ultrasonography may be offset by a loss in diagnostic accuracy.
Adolescent↗