Old antithrombotics: ready to retire?
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Biomedical subjects
Publications and source records attributed to A W Lensing.
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Carriers of a mutation in the prothrombin (clotting factor II) or factor V gene have a 2- to 4-fold greater risk for venous thromboembolism than subjects without the mutations. Whether both mutations also predispose to recurrent venous thromboembolism is unclear. Outpatients who had a first episode of proven symptomatic deep-vein thrombosis and a long-term follow-up were studied. The outcome measure was the cumulative incidence of confirmed venous thromboembolic complications. Two hundred fifty-one patients were enrolled in the study. Mean duration of follow-up was 8.3 years. The prothrombin gene mutation was demonstrated in 27 patients (prevalence, 10.8%; 95% CI, 6.9 to 14.6), and the factor V gene mutation was demonstrated in 41 patients (prevalence, 16.3%; 95% CI, 11.8 to 20.9). The cumulative incidence of venous thromboembolic complications after 10 years was 61.3% (95% CI, 35.7 to 87.9), and the hazard ratio was 2.4 (95% CI, 1.3 to 4.7; P =.004) in patients with the prothrombin gene mutation); the cumulative incidence of venous thromboembolic complications after 10 years was 55.2% (95% CI, 36.4 to 74.0), and the hazard ratio was 2.4 (95% CI, 1.4 to 4.1; P =.001) in patients with the factor V gene mutation. In comparison, the cumulative incidence of venous thromboembolic complications after 10 years was 23.1% (95% CI, 16.2 to 30.1) in patients without the mutations. Prothrombin and factor V gene mutations occur frequently in patients with venous thrombosis and are associated with an increased risk for recurrent venous thromboembolic complications.
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BACKGROUND: Low molecular weight heparins have been shown to be effective and safe for prevention of venous thromboembolism. There is accumulating evidence that these new anticoagulants are also effective and safe for treatment of venous thromboembolism. OBJECTIVES: The objective of this review was to determine the effect of fixed-dose, subcutaneous low molecular weight heparins compared with adjusted-dose, intravenous or subcutaneous, unfractionated heparin for initial treatment of acute deep venous thrombosis or pulmonary embolism. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group trials register and LILACS. The reviewers contacted colleagues and representatives of pharmaceutical companies for additional information about trials. SELECTION CRITERIA: Randomised trials comparing fixed-dose, subcutaneous low molecular weight heparin with adjusted-dose, intravenous or subcutaneous, unfractionated heparin in patients with venous thromboembolism. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trials for inclusion and quality, and extracted data independently. MAIN RESULTS: Fourteen studies with a total of 4754 patients were included. By the end of follow up in ten trials, thrombotic complications occurred in 86 (4.3%) of the 1998 patients treated with low molecular weight heparin, compared with 113 (5.6%) of the 2021 patients treated with unfractionated heparin (odds ratio 0.76, 95% confidence interval 0.57 to 1.01). In eight trials a reduction in thrombus size was shown by 60% treated with low molecular weight heparin and 54% treated with unfractionated heparin (odds ratio 0.77, 95% confidence interval 0.61 to 0.97). At the end of the initial treatment period, in all 14 of the trials, major haemorrhages occurred in 30 (1.3%) of the 2353 patients treated with low molecular weight heparin, compared with 51 (2.1%) of the 2401 patients treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0.39 to 0.93). By the end of follow up in 11 trials, 135 (6.4%) of the 2108 patients treated with low molecular weight heparin had died, compared with 172 (8.0%) of the 2137 patients treated with unfractionated heparin (odds ratio 0.78, 95% confidence interval 0.62 to 0.99). Five studies with a total of 1636 patients examined proximal (above the knee) thrombosis; 814 treated with low molecular weight heparin and 822 with unfractionated heparin. A sub-analysis of these trials showed statistically significant reductions favouring the action of low molecular weight heparin in three areas: thrombotic complications; major haemorrhages; and overall mortality. By the end of follow up 39 (4. 8%) patients treated with low molecular weight heparin had thrombotic complications, compared with 64 (7.8%) treated with unfractionated heparin (odds ratio 0.60, 95% confidence interval 0. 40 to 0.89). Major haemorrhages occurred in 8 (1.0%) treated with low molecular weight heparin, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.44, 95% confidence interval 0. 21 to 0.95). By the end of follow up, 44 (5.4%) treated with low molecular weight heparin had died, compared with 68 (8.3%) treated with unfractionated heparin (odds ratio 0.64, 95% confidence interval 0.43 to 0.93). REVIEWER'S CONCLUSIONS: Low molecular weight heparin is at least as effective as unfractionated heparin in preventing recurrent venous thromboembolism, and significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at the end of follow-up. It can be adopted safely as the standard therapy for deep venous thrombosis, and studies comparing individual low molecular weight heparins are merited.
Deep-vein thrombosis is an important complication of several inherited and acquired disorders, but may also occur spontaneously. Prevention of recurrent venous thrombosis and pulmonary embolism is the main reason for accurate diagnosis and adequate treatment. This seminar discusses only symptomatic deep-vein thrombosis. The diagnosis can be confirmed by objective tests in only about 30% of patients with symptoms. Venous thromboembolic complications happen in less than 1% of untreated patients in whom the presence of venous thrombosis is rejected on the basis of serial ultrasonography or ultrasonography plus either D-dimer or clinical score. Initial anticoagulant treatment (intravenous or subcutaneous heparin) should continue until oral anticoagulant treatment, started concurrently, increases the international normalised ratio above 2.0 for more than 24 h. The optimum duration of oral anticoagulant treatment is unresolved, but may be guided by the presence of temporary or persistent risk factors or presentation with recurrent venous thromboembolism.
Oral anticoagulants have documented efficacy for many indications and are widely used in elderly patients. However, there is concern about whether this treatment induces an excess of major bleeding in elderly patients. In this systematic review, the incidence of oral anticoagulant-related major bleeding among elderly patients was determined. A total of 58 reports were identified that evaluated an oral anticoagulant, included patients with a mean age of at least 60 years, and provided data on the occurrence of major bleeding or provided separate data on the occurrence of major bleeding in elderly versus younger patients. In 50 studies no age differentiation was given. Although the incidence of bleeding complications varied, a trend towards increased bleeding with increasing age was shown in patients with major orthopaedic surgery and cardiac diseases. In the 8 articles that provided separate data on the occurrence of bleeding in different age categories, there was a clear tendency towards a 2-fold increase in bleeding in elderly patients. These findings emphasise the need for caution in the use of oral anticoagulants in elderly patients. However, the decision to start oral anticoagulant treatment should be based on an evaluation of the risk/benefit balance on a careful patient-by-patient basis. In general, if oral anticoagulant treatment is started, the lowest possible effective International Normalised Ratios (INR) should be selected and regular monitoring should be done to avoid over-anticoagulation.
Consecutive patients undergoing total hip replacement in 43 centres were randomly assigned to receive blindly either enoxaparin (40 mg) or tinzaparin (4,500 anti-Factor IU Xa), as once daily subcutaneous injections. The first injection was administered 12 h preoperatively. Efficacy was assessed by bilateral venography performed 12-14 days postoperatively. Efficacy and safety were blindly and centrally adjudicated. Among the 499 patients included, 440 had a venogram. The total incidence of DVTs was 44 (20.1%) of the 219 patients of the enoxaparin group and 48 (21.7%) of the 221 patients of the tinzaparin group. The upper limit of the 80% confidence interval of the difference between the two treatment groups was less than 5.0%. Therefore according to the protocol's specifications equivalence was shown. Proximal DVTs occurred in 10.5% of the enoxaparin group (23 patients) and in 9.5% (21 patients) of the tinzaparin group. No overt major bleeding was observed. One patient in the enoxaparin group developed severe thrombocytopenia and died. The LMWH tinzaparin appears clinically to be as effective and safe as enoxaparin in the prophylaxis of deep vein thrombosis after total hip replacement, at the doses used and under the conditions of this study.
Unfractionated heparin (UFH) remains the anticoagulant of choice during pregnancy. Low-molecular-weight heparins (LMWH) are an attractive alternative to UFH due to their logistic advantages and their association with a lower incidence of osteoporosis and HIT. We reviewed all published clinical reports concerning the use of LMWH during pregnancy. In addition, participants of an international interest group contributed a cohort of pregnant women treated with LMWH. Pregnancies were divided into two groups; those with and those without maternal comorbid conditions. The number of adverse fetal outcomes and the occurrence of maternal complications were evaluated in the two groups. In the group of women with comorbid conditions (n = 290), 13.4% of the pregnancies were associated with an adverse fetal outcome. In contrast, in the group of women without comorbid conditions (n = 196), 3.1% were associated with an adverse outcome, which is comparable to that seen in the normal population. We conclude that LMWH appear to be a safe alternative to unfractionated heparin as an anticoagulant during pregnancy.
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Ischaemic stroke accounts for 70-85% of stroke incidence worldwide, causing substantial morbidity and mortality. Antiplatelet agents and carotid endarterectomy are effective in stroke prevention but active therapy for acute stroke is limited at present. Treatments investigated to date include thrombolysis and antiplatelet agents, both of which have been shown to modify the effects of stroke and provide a small long-term benefit in selected patients, and anticoagulation with heparin derivatives and oral agents. The value of unfractionated heparin (UFH) in modifying the acute effects of stroke has never been clearly established, and the risk of intracranial bleeding has limited its clinical application. However, disability and death following stroke stem from both the acute cerebral event and the secondary development of venous thromboembolism (VTE). Antithrombotic therapy may therefore, in principle, provide the dual benefit of retarding ongoing cerebral thrombosis and preventing secondary VTE. Low-molecular-weight heparins (LMWHs) and one heparinoid may have an improved ratio of antithrombotic action to haemorrhagic effect compared with UFH. Recent trials with these agents demonstrated a significant reduction in deep vein thrombosis and pulmonary embolism. Evidence has also emerged of improved long-term outcomes in terms of combined rates of death and residual disability, but data from different studies are conflicting. The potential role of LMWHs and heparinoids in acute stroke remains to be clarified.
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OBJECTIVE: To investigate the efficacy of using a rapid plasma D-dimer test as an adjunct to compression ultrasound for diagnosing clinically suspected deep vein thrombosis. DESIGN: D-dimer concentrations were determined in all patients with a normal ultrasonogram at presentation. Repeat ultrasonography was performed 1 week later only in patients with abnormal D-dimer test results. MAIN OUTCOME AND MEASURES: Patients with normal ultrasonograms were not treated with anticoagulants and were followed for 3 months for thromboembolic complications. SETTING: University research and affiliated centres. SUBJECTS: 946 patients with clinically suspected deep vein thrombosis. RESULTS: Ultrasonograms were abnormal at presentation in 260 (27.5%) patients. Of the remaining 686 patients tested for D-dimer, 88 (12.8%) had abnormal concentrations. During follow up venous thromboembolic complications occurred in one of the 598 patients who were not treated with anticoagulants and who had an initial normal ultrasonogram and D-dimer concentration, whereas thromboembolic complications occurred in two of the 83 untreated patients who had abnormal D-dimer concentrations but a normal repeat ultrasonogram. The cumulative incidence of venous thromboembolic complications during follow up was 0.4% (95% confidence interval 0% to 0.9%). The rapid plasma D-dimer test used as an adjunct to compression ultrasonography resulted in a reduction in the mean number of repeat ultrasound examinations and additional hospital visits from 0.7 to 0.1 per patient. CONCLUSIONS: Testing for D-dimer as an adjunct to a normal baseline ultrasound examination decreased the number of subsequent ultrasound examinations considerably without any increased risk of venous thromboembolic complications in patients not receiving anticoagulants. The use of ultrasound and testing for D-dimer enabled treatment decisions to be made at the time of presentation in most patients.
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Current drug treatment of Bell's palsy often consists of prednisone for patients with a complete paralysis. Since it was demonstrated that herpes simplex plays a role in the pathogenesis of Bell's palsy, antiviral therapy may become the treatment of choice. Six randomized controlled trials comparing prednisone with placebo have been performed: four of them did not conform to the criteria for good clinical trials. The remaining two trials did not demonstrate therapeutic efficacy of prednisone. A recently published randomized controlled trial comparing prednisone and acyclovir with prednisone and placebo showed a statistically significant and clinically important superiority of the combination therapy. This trial, however, also had methodological flaws and its results should be interpreted with caution. In our opinion, further evidence is needed before acyclovir should be given routinely to patients with Bell's palsy.
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.
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.