Factor Xa is a superior target to factor IIa for antithrombotic therapies.
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Anticoagulants↗
Biomedical subjects
Harry R Büller
Publications and source records attributed to Harry R Büller.
Ruling out clinically suspected pulmonary embolism by assessment of clinical probability and D-dimer levels: a management study.
D-dimer test combined with clinical probability assessment has been proposed as the first step in the diagnostic work-up of patients with suspected pulmonary embolism (PE). In a prospective management study we investigated the safety and efficiency of excluding PE by a normal D-dimer combined with a low or moderate clinical probability. Of the 202 study patients this combination ruled out PE in 64 (32%) patients. The 3-month thromboembolic risk in these patients was 0% (95% CI, 0.0-5.6%). The prevalence of PE in the entire cohort was 29% (59 patients), whereas in the low, moderate and high clinical probability groups this was 25%, 26% and 50%, respectively. We conclude that ruling out suspected PE by a normal D-dimer combined with a low or moderate clinical probability appears to be a safe and efficient strategy. The accuracy of the clinical probability assessment is modest.
Adult↗
Travel and the risk of symptomatic venous thromboembolism.
Whether long-distance travel and symptomatic venous thromboembolism (VTE) are associated is debated. On the basis of the available literature a fair risk estimate cannot be obtained. We estimated an accurate odds ratio for the relationship between recent travelling and symptomatic VTE. From three case-control studies consisting of 788 and 170 patients with clinically suspected deep vein thrombosis (DVT) and 989 patients with clinically suspected pulmonary embolism (PE) referred for diagnostic work-up, a pooled odds ratio for the relation between travel and symptomatic VTE was calculated. Cases were patients in whom the diagnosis was confirmed according to a diagnostic management strategy, whereas controls were patients in whom the diagnosis was excluded and who had an uneventful clinical follow-up. Patients were seen in the period April 1997 to September 2000. Travel history was recorded prior to diagnostic work-up. The pooled odds ratio for the association between any travel and symptomatic venous thromboembolism was 0.9 (95% CI: 0.6-1.4). The median travel time was 7 h (quartile range 4 to 10 h). Separate analyses performed for different types of transport (plane, car, bus or train) yielded comparable odds ratios. The analysis for duration of travelling showed an increased odds ratio of 2.5 (95% CI: 1.0-6.2) in the category of 10-15 h of travelling. This study shows that the average traveller does not have an increased risk for symptomatic venous thromboembolism. Only very long travelling (more than 10 h) may be associated with venous thromboembolic disease.
Adolescent↗
Quality of life and the duration of treatment with vitamin K antagonists in patients with deep venous thrombosis.
In clinical practice, decisions on the duration of treatment with vitamin K antagonists are usually based on the presence of persistent risk factors, the risk of bleeding and centre policy. Little is known about the influence of patients' experienced quality of life. The objectives of this study were: 1). to explore the course of quality of life in patients with venous thrombosis treated for 3 months versus patients treated for 6 months with vitamin K antagonists; 2). to investigate the factors that were associated with the duration of treatment with vitamin K antagonists. The study sample comprised patients participating in a multi-centre clinical trial. Quality of life was assessed at study entry, after 10-14 days, 3 and 6 months in 360 patients. Overall, no differences in quality of life were found between the 2 patient groups. An interaction effect between group and time was found for physical functioning. Regression analyses indicated that the presence of one or more permanent risk factors, duration of hospitalisation, mobility prior to deep-vein thrombosis and study centre were associated with the duration of treatment with vitamin K antagonists. Interestingly, quality of life was not associated with treatment duration. Since study centre was the most important factor associated with treatment duration, local policy appears to have a great influence on decisions regarding the duration of treatment with vitamin K antagonists.
Activities of Daily Living↗
Comparison of six-month outcome of patients initially treated for acute deep vein thrombosis with a low molecular weight heparin Certoparin at a fixed, body-weight-independent dosage or unfractionated heparin.
BACKGROUND AND OBJECTIVES: Body weight-adjusted subcutaneous low molecular weight heparin (LMWH) has been proven to be more effective and safer than aPTT-adjusted intravenous unfractionated heparin (UFH) for the initial treatment of patients with acute symptomatic deep venous thrombosis (DVT) based on analyses pooling the results of studies with different LMWHs. We investigated whether these findings hold for a particular LMWH by pooling the results of two independent studies. DESIGN AND METHODS: Patients with acute symptomatic proximal DVT (n=1758), proven by ascending phlebography or compression ultrasound, received either a fixed, body weight independent dose of 8,000 IU Certoparin b.i.d. (n=893) for 8.6 days or intravenous UFH (n=865) adjusted to an 1.5 to 3.0-fold prolongation of the aPTT for 12.0 days both followed by vitamin K-antagonists for 6 months. RESULTS: Venous thromboembolism (VTE) re-occurred in 5.1% and 3.1% (RRR 0.62, CI 0.39-0.98, 2p=0.04), major bleeding in 3.5% and 1.9% (RRR 0.55, CI 0.31-0.99, 2p=0.05), mortality in 3.6% and 2.1% (RRR 0.59, CI 0.34-1.04, 2p=0.08), and the composite outcome of all three events in 10.3% and 6.3% (RRR 0.61, CI 0.44 to 0.84, 2p=0.002) of patients at 6 months initially randomised to UFH and LMWH, respectively. INTERPRETATION AND CONCLUSIONS: The initial treatment of acute DVT with a fixed dose of the LMWH, certoparin, is more effective in reducing, over 6 months, the re-occurrence of VTE and the composite outcome of recurrent VTE, major bleeding, and mortality without any relation of the bodyweight of the patients to recurrent venous thromboembolism or major bleeding complications.
Anticoagulants↗
Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers.
BACKGROUND: The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. METHODS AND RESULTS: In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 microg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1+2 (F(1+2)), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection. CONCLUSIONS: rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.
Adolescent↗
The performance of two rapid quantitative D-dimer assays in 287 patients with clinically suspected pulmonary embolism.
CONTEXT: Objective tests are necessary for the diagnosis of pulmonary embolism (PE). D-dimer assays have been suggested as useful screening tests to exclude this diagnosis. OBJECTIVE: To compare the diagnostic accuracy of two rapid quantitative D-dimers in patients with suspected pulmonary embolism. DESIGN: Plasma D-dimer levels were measured using two commercially available assays (Tinaquant and Vidas). A strict imaging protocol was used to arrive at a final diagnosis of PE or deep venous thrombosis (DVT). SETTING: Multicenter study in six Dutch referral centers. PATIENTS: A total of 287 in- and outpatients with clinically suspected pulmonary embolism. MAIN OUTCOME MEASURES: Diagnostic accuracy indices for the two assays were calculated and additional receiver-operated characteristics (ROC) analysis was performed. RESULTS: Using the manufacturer's advised cutoff values, the sensitivity and specificity were 88% and 52% for Vidas and 82% and 61% for Tinaquant, respectively. These differences were statistically significant (McNemar, P < 0.0001). However, no statistical differences were found between the two assays using ROC analysis (AUC = 0.78 for both assays). CONCLUSIONS: Both quantitative D-dimer tests had similar diagnostic accuracy; however, at the manufacturer's advised cutoff level, Vidas performed significantly better. Nevertheless, to safely exclude pulmonary embolism, D-dimer assays should be combined with other diagnostic tests.
Adult↗
The clinical usefulness of D-dimer testing in cancer patients with suspected deep venous thrombosis.
BACKGROUND: Little is known about the diagnostic value of a D-dimer test in cancer patients with clinically suspected deep venous thrombosis (DVT). OBJECTIVE: To evaluate the clinical utility of a whole blood rapid D-dimer test (SimpliRED) in cancer patients compared with noncancer patients. METHODS: In consecutive patients with suspected lower limb DVT, a D-dimer test and ultrasonogram were performed. Cancer status was recorded at presentation. If the D-dimer test and ultrasonogram results were normal, DVT was considered absent. If the D-dimer result was abnormal, ultrasonography was performed again 1 week later. Anticoagulant therapy was only instituted in those patients with an abnormal ultrasonography result. All patients were followed up for 3 months to record subsequent thromboembolic events. The accuracy of the D-dimer test was assessed, and the efficiency and safety of withholding additional ultrasonography in cancer patients with normal results on both D-dimer and ultrasonography was compared with noncancer patients. RESULTS: A total of 1739 consecutive patients were studied, 217 (12%) of whom had cancer. The negative predictive value of the D-dimer test was 97% in both cancer and noncancer patients. In 63 (29%) of all 217 cancer patients, the D-dimer and ultrasonography results were normal at referral; therefore, the diagnosis of DVT was refuted and anticoagulant treatment was withheld. In these 63 patients, one thromboembolic event occurred during follow-up (1.6%; 95% confidence interval, 0.04%-8.53%). CONCLUSIONS: The negative predictive value of a whole blood D-dimer test in cancer patients seems as high as in noncancer patients. In a substantial proportion of cancer patients, the diagnosis can likely be refuted at referral, based on normal D-dimer test and ultrasonogram results. Furthermore, it seems safe to withhold anticoagulant therapy in these patients.
Adult↗
Use of a clinical decision rule in combination with D-dimer concentration in diagnostic workup of patients with suspected pulmonary embolism: a prospective management study.
BACKGROUND: We designed a diagnostic strategy, based on clinical probability and D-dimer concentration, to select patients who were unlikely to have pulmonary embolism (PE), before further diagnostic workup was performed. The utility and safety of this strategy were evaluated in a prospective management study. METHODS: Consecutive patients with suspected PE had D-dimer testing and clinical probability assessment with a clinical decision rule. Patients with a low probability and a normal D-dimer concentration (<500 ng/mL) were considered not to have PE, and further diagnostic testing and anticoagulant therapy were withheld. In patients with a low probability and elevated D-dimer level or with a moderate or high probability, bilateral compression ultrasonography of the legs was performed. If deep venous thrombosis was detected, venous thromboembolism was diagnosed. If compression ultrasonography was normal, pulmonary angiography was performed. All patients were followed up for 3 months. RESULTS: Of the 234 consecutive patients, 26% had the combination of a low probability and normal D-dimer level. During the follow-up period, none of these patients died and 3 patients had recurrent complaints of PE. In these 3 patients, PE was excluded by objective testing. The 3-month thromboembolic risk was therefore 0% (95% confidence interval, 0%-6%). The prevalence of PE in the entire population was 22%. CONCLUSIONS: The combination of a low clinical probability and a normal D-dimer concentration appears to be a safe method to exclude PE, with a high clinical utility, and is readily accepted by clinicians.
Adult↗
Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery?
BACKGROUND: Prophylaxis of venous thromboembolism with low-molecular-weight heparins in patients undergoing major orthopedic surgery is currently initiated according to at least 3 different regimens. In Europe, traditionally, prophylaxis is started 12 hours before surgery, whereas in North America it is initiated 12 to 48 hours postoperatively. The third regimen (perioperative) begins prophylaxis either earlier than 12 hours before or 12 hours after surgery. Unfortunately, the optimal regimen is uncertain because direct comparisons among these regimens with sufficiently large sample sizes are not available. OBJECTIVE: To assess, in a systematic review, the relative efficacy and safety of the 3 low-molecular-weight heparin regimens used to prevent thrombosis after total hip replacement. The incidence of postoperative thrombosis detected by contrast venography was used as the measure of efficacy and the rate of major bleeding was used as the measure of safety. METHODS: We pooled the results of all published studies, which met the following criteria: (1) inclusion of in at least 1 arm of the study of a dose of low-molecular-weight heparin that is approved for both preoperative and postoperative initiation of prophylaxis; (2) the use of mandatory bilateral contrast venography, performed between days 6 and 15 postoperatively; (3) thromboprophylaxis continued until venography; (4) independent reading of venograms; and (5) assessment of clinically overt major bleeding by predefined criteria. Articles were excluded if no separate data could be obtained for patients undergoing elective hip surgery (in case of patient mix), or if they were reported more than once. RESULTS: In the 1926 patients who used a preoperative regimen, the incidence of postoperative deep vein thrombosis was 19.2% (95% confidence interval [CI], 17%-21%). In the cohort of 925 patients who received a perioperative regimen, the rate of deep vein thrombosis was 12.4% (95% CI, 10%-14%), whereas in the group of 694 patients who received a postoperative regimen, it was 14.4% (95% CI, 12%-17%). The rate of major bleeding was 1.4% (95% CI, 1%-2%) in the preoperative group, 6.3% (95% CI, 5%-7%) in the perioperative group, and 2.5% (95% CI, 1%-3%) in the postoperative group. CONCLUSIONS: We find no convincing evidence that starting prophylaxis preoperatively is associated with a lower incidence of venous thromboembolism than starting postoperatively. Perioperative regimens may lower the risk of postoperative thrombosis, but if so, this positive effect is offset by an increase in postoperative major bleeding.
Anticoagulants↗
Simplification of the diagnostic management of suspected deep vein thrombosis.
BACKGROUND: The standard diagnostic approach in patients with suspected deep vein thrombosis is to repeat the compression ultrasonography after 1 week in all patients with an initial normal result. We hypothesized that a normal finding of a D-dimer assay safely obviates the need for repeated ultrasonography. In addition, we evaluated the potential value of a pretest probability assessment for this purpose. METHODS: At presentation, consecutive outpatients with suspected thrombosis underwent independent assessment by means of ultrasonography of the proximal veins, a whole-blood D-dimer assay, and a pretest clinical model. Patients with normal ultrasonographic findings and an abnormal D-dimer assay result were scheduled for repeated ultrasonography. We evaluated the incidence of symptomatic venous thromboembolic complications during a 3-month follow-up, and the value of clinical pretest probability with ultrasonography or D-dimer assay in scenario analyses. RESULTS: We studied 1756 patients with prevalence of thrombosis of 22%. At entry, results of the D-dimer assay and ultrasonography were normal in 828 patients (47%). Of these, 6 returned with confirmed symptomatic venous thromboembolism (complication rate, 0.7%; 95% confidence interval [CI], 0.3%-1.6%). Repeated ultrasonography was avoided in 61% of the patients with an initial normal test result. Scenario analyses disclosed that the complication rate was 1.6% (95% CI, 0.8%-2.6%) in those with a low clinical pretest probability and a normal result of ultrasonography at referral, whereas this figure was 1.8% (95% CI, 0.9%-3.3%) in patients with a low clinical probability result and a normal result of the D-dimer assay at referral. CONCLUSIONS: It is safe to withhold repeated ultrasonography in patients with suspected deep vein thrombosis who have normal results of ultrasonograpy and the SimpliRED D-dimer assay at presentation. The combination of a low clinical pretest probability with a normal result of compression ultrasonography or the D-dimer assay appears to be equally safe in refuting the diagnosis of deep vein thrombosis.
Adolescent↗
Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors.
Venous thromboembolism is a frequent complication in patients admitted to intensive care units (ICU), despite prophylactic treatment with subcutaneous low-molecular-weight (LMW) heparin. We postulated that poor efficacy of subcutaneous heparin might be due to administration of vasopressors, which could cause impaired peripheral circulation and inadequate systemic bioavailability of the anticoagulant. We compared concentrations of factor Xa activity in three groups of 15 patients: individuals in ICU who had and had not received vasopressors, and general surgery patients. Those who received vasopressors had lower plasma concentrations of factor-Xa activity than patients in ICU not on vasopressors and postoperative controls. Patients in ICU who take vasopressors could need higher doses of LMW heparin, or a different mode of administration of the drug, to attain adequate thrombosis prophylaxis.
Anticoagulants↗
Rebound thrombin generation after heparin therapy in unstable angina. A randomized comparison between unfractionated and low-molecular-weight heparin.
OBJECTIVES: This study compared rebound coagulation in patients with acute coronary syndrome patients after discontinuation of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). BACKGROUND: Up to a quarter of patients hospitalized for unstable angina experience recurrent ischemia after discontinuation of UFH or LMWH therapy, which may be the result of rebound coagulation activation and subsequent thrombosis. It is unknown whether UFH and LMWH differ in this respect. METHODS: We randomized 71 patients admitted with unstable angina to intravenous UFH or subcutaneous LMWH (dalteparin) and measured plasma markers of coagulation before, during, and after treatment. RESULTS: A complete series of measurements was obtained in 59 patients. Plasma prothrombin fragment 1+2 (F(1+2)) levels decreased in both groups during treatment. After loss of therapeutic plasma drug levels, F(1+2) increased (within 3 h) to a maximum level at 12 to 24 h that was higher than before or during treatment in both groups (p < 0.0001). In both groups, F(1+2) levels remained higher than pretreatment up to 24 h after discontinuation. Similarly, thrombin-antithrombin (TAT) levels exceeded treatment and pretreatment levels, at a slower rate after dalteparin than after UFH. However, after dalteparin a higher peak value of TAT was observed. CONCLUSIONS: Rebound coagulation activation occurs within hours after discontinuation of both UFH and dalteparin. With both drugs, thrombin generation is significantly greater after treatment than before or during treatment. A longer duration or weaning of treatment, or continuation with another anticoagulant treatment, may reduce rebound coagulation activation and ischemic events.
Angina, Unstable↗
Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism.
D-dimer blood tests have been suggested to rule out pulmonary embolism. Despite evidence of the safety of withholding anticoagulant treatment in patients with suspected pulmonary embolism and a normal D-dimer assay result, clinicians remain reluctant to use a D-dimer assay as a sole diagnostic test. This prospective study in 314 consecutive inpatients and outpatients investigates the relation between the diagnostic accuracy of D-dimer plasma concentration and pulmonary embolus location. Plasma D-dimer levels were measured using a quantitative immunoturbidimetric method. A strict protocol of ventilation-perfusion scintigraphy, pulmonary angiography, and spiral computed tomography was used to arrive at a final diagnosis and to assess the largest pulmonary artery in which embolus was visible. The influence of embolus location on the diagnostic accuracy was evaluated using the Kruskal-Wallis test and receiver operator characteristics (ROC) analysis. There was a strong correlation between plasma D-dimer concentration and embolus location (Kruskal-Wallis, p < 0.001). Thus, the assay showed greater accuracy in excluding segmental or larger emboli (sensitivity = 93%) than subsegmental emboli (sensitivity = 50%). D-dimer concentration and the accuracy of D-dimer assays are clearly dependent on embolus location and smaller, subsegmental emboli may be missed when D-dimer assays are used as a sole test to exclude pulmonary embolism.
Dimerization↗
Arterial wall thickness and the risk of recurrent ischemic events in carriers of the prothrombin G20210A mutation with clinical manifestations of atherosclerosis.
The G20210A mutation in the prothrombin gene is an established risk factor for venous thrombosis. There is controversy about the role of this mutation in arterial thrombotic disease and atherosclerosis. We determined the presence of the prothrombin mutation and examined its influence on carotid and femoral artery intima-media thickness (IMT) and the occurrence of new ischemic events during follow-up in 277 patients with clinically manifest atherosclerotic disease: ischemic stroke, myocardial infarction or peripheral arterial disease. The mean age at entry was 63 years. Mean IMT was significantly higher in carriers of the prothrombin mutation (1.17 (SD 0.29) mm versus 0.97 (SD 0.25) mm: (delta)IMT=0.20, P=0.02). The increase in IMT was not attributable to differences in age, type of arterial disease or cardiovascular risk factors between carriers and non-carriers. During a mean follow-up of 3.5 years, a strong trend for more ischemic events was observed: 4 of the 11 carriers suffered from a recurrent ischemic event, compared with 30 of the 164 male non-carriers (36 versus 18%; P=0.06). These results suggest that the G20210A mutation contributes to the process of arterial wall thickening and is associated with the occurrence of ischemic events in a cohort of elderly persons with established atherosclerosis.
Aged↗
The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders.
The duration of anticoagulant treatment after a first episode of venous thromboembolism primarily depends on the risk of recurrence. Variability of recurrence rates in factor (F) V Leiden carriers may be due to concomitant thrombophilic disorders. A retrospective study was performed in 329 FV Leiden carriers with a history of venous thromboembolism (262 probands, 67 relatives). The annual rate of first recurrence was estimated in relatives. The contribution of concomitant thrombophilic disorders to the recurrence rate was evaluated in probands and relatives by a nested case--control analysis in 105 matched pairs of carriers either with or without recurrence. The overall annual recurrence rate was 2.3 per 100 patient-years. The adjusted risk of recurrence for concomitant thrombophilic disorders was: 9.1 (1.3-62.8) for the FII mutation; 1.0 (0.2-4.9) for homozygosity for FV Leiden; 1.5 (0.2-9.5) for inherited deficiencies of protein C or S; 1.8 (0.7-4.9) for FVIII coagulant activity (FVIII:C) levels >122%; 5.4 (1.6-18.6) for fasting homocysteine levels >15.2 micromol/l; and 4.4 (1.0-18.7) for loading homocysteine levels >45.8 micromol/l. Of these disorders, only the FII mutation and hyperhomocysteinaemia significantly increased the risk of recurrence in FV Leiden carriers. The estimated recurrence rate ranged from 0.45 per 100 patient--years after a secondary first event in the absence of concomitant disorders to 4.8 per 100 patient-years when a spontaneous first event was combined with concomitant disorders. Our study provides supportive evidence that the incidence of recurrent venous thromboembolism in heterozygous FV Leiden carriers depends on the concomitance of other thrombophilic disorders, in addition to whether the first thrombotic event occurred spontaneously.
Adolescent↗
Treatment of symptomatic venous thromboembolism: improving outcomes.
Antithrombotic therapy with unfractionated heparin (UFH) and warfarin for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) became widely accepted in the early 1960s. Subsequent clinical trials have focused on the importance of early intravenous UFH in the treatment of venous thromboembolic events, the method of heparin administration, the importance of rapid anticoagulation to prevent recurrent venous thromboembolism (VTE), and the optimal duration of UFH administration. Low-molecular-weight heparin (LMWH) represents a significant advance over UFH therapy for VTE. Developed in the late 1980s, LMWH has become an excellent alternative to UFH because it offers superior efficacy and safety, improved pharmacokinetics, longer half-life, and once- or twice-daily subcutaneous administration without the need for laboratory monitoring. Fondaparinux is the first of a new class of antithrombotic agents that targets factor Xa. Based on studies of the heparin binding site of antithrombin, this novel pentasaccharide has superior pharmacokinetics and bioavailability when compared with LMWH and can be administered once daily. Studies in patients undergoing major orthopedic surgery and in those with proximal DVT indicate that the efficacy and safety of fondaparinux may represent an improvement over those of LMWH.
Double-Blind Method↗
Benefit of selective factor inhibition.
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Antithrombin III↗