Anthonie W. A. Lensing

The Long-Term Clinical Course of Acute Deep Venous Thrombosis

Deep venous thrombosis of the lower extremity is a serious disorder; the estimated incidence is 1 per 1000 persons per year [1-3]. The disease can occur after surgical procedures and trauma and in the presence of cancer or inherited coagulation disorders; it can also develop without any of these factors [3]. The clinical course of deep venous thrombosis might be complicated by pulmonary embolism, recurrent episodes of deep venous thrombosis, and the development of serious post-thrombotic sequelae, such as venous ulceration, debilitating pain, and intractable edema [3]. Patients with deep venous thrombosis are usually treated with an initial course of heparin (5 to 10 days) followed by 3 to 6 months of oral anticoagulant therapy. This treatment regimen reduces the risk for short-term thromboembolic complications to approximately 5% [4, 5]. The long-term risk for recurrent venous thromboembolism and the incidence and severity of post-thrombotic sequelae in patients with symptomatic deep venous thrombosis have not been well documented. In a recent large randomized, clinical trial comparing 6 weeks of oral anticoagulant therapy with 6 months of therapy [6], patients with symptomatic deep venous thrombosis were followed for 2 years for recurrences and death. This trial showed a substantial reduction in the risk for recurrent venous thromboembolism among patients in the 6-month oral anticoagulant group, but the investigators did not report on the occurrence of the post-thrombotic syndrome. Another recent study [7] reported the 8-year incidence of recurrences and post-thrombotic manifestations in patients with confirmed symptomatic deep venous thrombosis. However, only a few patients were included in this study, and data were collected retrospectively. We assessed the clinical course of a first episode of symptomatic deep venous thrombosis in a large consecutive series of patients who had long-term follow-up. We assessed mortality and the long-term incidences of recurrent venous thromboembolism and the post-thrombotic syndrome. We also evaluated the potential risk factors for these three outcomes. Methods Identification of Inception Cohort The Department of Internal Medicine of the University of Padua, Padua, Italy, is a diagnostic facility for outpatients with clinically suspected venous thromboembolism in a community of approximately 350 000 persons. All consecutive outpatients with a first episode of clinically suspected deep venous thrombosis who were referred by their general practitioners between January 1986 and December 1991 had noninvasive testing [8]. Patients were potentially eligible for the study if confirmatory venography showed deep venous thrombosis. Patients were excluded from the study if they had been referred because of recurrent venous thrombosis, were geographically inaccessible for follow-up, or refused to give informed consent. The Institutional Review Board of the hospital of the University of Padua approved the study. Baseline Assessment At the time of referral, demographic characteristics were recorded and a medical history was taken; information was elicited on the period between the onset of symptoms and presentation to the thrombosis service (patientphysician delay), the presence of risk factors for thrombosis (that is, cancer, surgery, trauma or fracture, immobilization for more than 7 days, pregnancy or childbirth, or estrogen use), and symptoms of pulmonary embolism. Information was also obtained on the history of venous thromboembolism in first-degree relatives. Antithrombin, protein C and S, and lupus-like anticoagulant levels were subsequently measured. Assays were done, and previously described criteria for abnormality and deficiency were used [9]. The venograms obtained at baseline were divided into those representing proximal venous thrombosis (with or without concurrent venous thrombosis of the calf) and those indicating isolated venous thrombosis of the calf. Proximal venous thrombosis was defined as thrombosis located above the trifurcation of the calf veins that involved at least the popliteal vein, superficial femoral vein, common femoral vein, or iliac vein. The location and occlusiveness of proximal thrombi were also determined. A patient was considered to have nonocclusive deep venous thrombosis if contrast material was seen between the thrombus and the vessel wall along the entire thrombus. Treatment Patients were admitted to the hospital and treated with an initial course of high-dose intravenous standard heparin (a bolus of 5000 U followed by continuous infusion of 30 000 U/d, subsequently adjusted to maintain an activated partial thromboplastin time between 1.5 and 2.5 times the normal value) or subcutaneous low-molecular-weight heparin (90 U of anti-factor Xa/kg of body weight twice daily). Therapy with oral anticoagulant agents (warfarin) was started on day 5 to 7 of treatment and was continued for 3 months. The oral anticoagulant dose was adjusted daily to maintain an international normalized ratio between 2.0 and 3.0. Treatment with low-molecular-weight heparin was discontinued on day 10 or later if the international normalized ratio was less than 2.0. This treatment strategy deviated in the following groups of patients: those with cancer, protein deficiencies, or lupus anticoagulant, in whom oral anticoagulation therapy was prolonged; those with small isolated venous thrombosis of the calf, who received oral anticoagulation alone; those with contraindications to anticoagulant treatment, who received no treatment or an inferior caval-vein filter; those who refused to be hospitalized, who received low-dose heparin and oral anticoagulant agents; and those with threatened viability of the leg, who received thrombolytic therapy. The actual type and duration of treatments were recorded. All patients were instructed to wear elastic graduated compression stockings (providing 40 mm Hg of pressure at the ankle) for at least 2 years. Follow-up All patients were seen 3 and 6 months after the initial referral and thereafter returned to the study center every 6 months for follow-up assessments. Patients were asked to return to the thrombosis center immediately if symptoms suggestive of recurrent venous thromboembolism developed. Follow-up was continued for as long as 8 years or until July 1995. To avoid diagnostic suspicion bias, the medical history on general health, symptoms of recurrent venous thromboembolism, and the post-thrombotic syndrome was obtained by using a standardized form. Patients who could not attend the follow-up sessions were visited at home. For all patients who died during follow-up, the date and cause of death were documented. Diagnosis of Recurrent Venous Thromboembolism and Hemorrhage Contrast venography of the symptomatic leg or legs was done as described previously [10]. The criteria for deep venous thrombosis were a constant intraluminal filling defect confirmed in at least two different projections or nonvisualization of a vein or a segment thereof, despite adequate technique and repeated injections with contrast material. The presence or absence of venous thrombosis was assessed by a panel of independent observers who were unaware of the patients other clinical features or previous test results. If a patient presented with clinically suspected recurrent venous thrombosis of the leg, venography was done. The criterion for recurrent venous thrombosis of the leg was a new intraluminal filling defect on the venogram. If the venogram was not diagnostic, recurrent venous thrombosis was diagnosed on the basis of an abnormal 125I-fibrinogen leg scan or results of noninvasive tests that had changed from normal to abnormal [11, 12]. Patients with suspected pulmonary embolism had venography if they had concurrent leg symptoms or perfusion lung scanning in the absence of leg symptoms. Pulmonary embolism was excluded if the perfusion scan was normal. Because ventilation lung scanning was not available during the first years of the study and because pulmonary angiography could not routinely be done, we could not definitively diagnose pulmonary embolism in some patients. If a definitive diagnosis could not be made, patients were classified as not having recurrent venous thromboembolism. Perfusion lung scanning and pulmonary angiography were done and their results were interpreted according to standard procedures [13]. Hemorrhagic episodes were classified as major or minor, as reported previously [14]. The documentation of all patients suspected of having a recurrent venous thromboembolic or bleeding event was reviewed by a three-member adjudication committee that was unaware of further clinical details of the patient. Criteria for the Post-Thrombotic Syndrome Presence of the post-thrombotic syndrome was assessed by investigators who were unaware of previous post-thrombotic manifestations and further clinical details of the patient. The presence of leg symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and signs (pretibial edema, induration of the skin, hyperpigmentation, new venous ectasia, redness, and pain during calf compression) was scored. For each item, the investigators assigned a score of 0 (not present or minimal) to 3 (severe). The presence of a venous ulcer of the lower limb was recorded. In patients with bilateral thrombosis, the higher score was used. A total score of 15 or more on two consecutive visits or the presence of a venous ulcer indicated severe post-thrombotic syndrome, and a total score of 5 to 14 on two consecutive visits indicated mild post-thrombotic syndrome. This score has been shown to have good reproducibility, and it correlates well with the patients perception of the interference of leg symptoms with daily life [15]. Statistical Analysis We calculated Kaplan-Meier estimates and 95% CIs for a visual assessment of survival and calculated the risk for recurrent venous thromboembolism and mild and severe post-thrombotic

Detection of Deep-Vein Thrombosis by Real-Time B-Mode Ultrasonography

In 220 consecutive outpatients with clinically suspected deep-vein thrombosis of the leg, we compared contrast venography with real-time B-mode ultrasonography, using the single criterion of vein compressibility with the ultrasound transducer probe. The common femoral and popliteal veins were evaluated for full compressibility (no thrombosis) and noncompressibility (thrombosis). Both veins were fully compressible in 142 of the 143 patients with normal venograms (specificity, 99 percent; 95 percent confidence interval, 97 to 100). All 66 patients with proximal-vein thrombosis had noncompressible femoral veins, popliteal veins, or both (sensitivity, 100 percent; 95 percent confidence interval, 95 to 100). For all patients (including 11 with calf-vein thrombi), sensitivity and specificity were 91 (95 percent confidence interval, 82 to 96) and 99 percent, respectively. The sensitivity for isolated calf-vein thrombosis was only 36 percent. The compression ultrasound test was repeated in a subset of 45 consecutive patients by a second examiner, unaware of the results of the first test, whose results agreed in all patients with those of the first examiner (kappa = 1). We conclude that ultrasonography with the single criterion of vein compressibility is a highly accurate, simple, objective, and reproducible noninvasive method for detecting proximal-vein thrombosis in outpatients with clinically suspected deep-venous thrombosis.

Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.

Abstract Objective To determine the efficacy and safety of the anticoagulant fondaparinux in older acute medical inpatients at moderate to high risk of venous thromboembolism. Design Double blind randomised placebo controlled trial. Setting 35 centres in eight countries. Participants 849 medical patients aged 60 or more admitted to hospital for congestive heart failure, acute respiratory illness in the presence of chronic lung disease, or acute infectious or inflammatory disease and expected to remain in bed for at least four days. Interventions 2.5 mg fondaparinux or placebo subcutaneously once daily for six to 14 days. Outcome measure The primary efficacy outcome was venous thromboembolism detected by routine bilateral venography along with symptomatic venous thromboembolism up to day 15. Secondary outcomes were bleeding and death. Patients were followed up at one month. Results 425 patients in the fondaparinux group and 414 patients in the placebo group were evaluable for safety analysis (10 were not treated). 644 patients (75.9%) were available for the primary efficacy analysis. Venous thrombembolism was detected in 5.6% (18/321) of patients treated with fondaparinux and 10.5% (34/323) of patients given placebo, a relative risk reduction of 46.7% (95% confidence interval 7.7% to 69.3%). Symptomatic venous thromboembolism occurred in five patients in the placebo group and none in the fondaparinux group (P = 0.029). Major bleeding occurred in one patient (0.2%) in each group. At the end of follow-up, 14 patients in the fondaparinux group (3.3%) and 25 in the placebo group (6.0%) had died. Conclusion Fondaparinux is effective in the prevention of asymptomatic and symptomatic venous thromboembolic events in older acute medical patients. The frequency of major bleeding was similar for both fondaparinux and placebo treated patients.

Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial

Context Are selective inhibitors of factor Xa as good as low-molecular-weight heparin in treating deep venous thrombosis? Contribution In this large, multicenter, double-blind trial, patients with symptomatic deep venous thrombosis were randomly assigned to receive either fondaparinux ( a selective inhibitor of factor Xa) or enoxaparin given subcutaneously for at least 5 days plus an oral vitamin K antagonist for 3 months. In both groups, about 1% of the patients experienced major bleeding during initial treatment and about 4% had recurrent thromboembolic events within 3 months. Implications Fondaparinux and enoxaparin have similar safety and efficacy for initial treatment of symptomatic deep venous thrombosis. The Editors Low-molecular-weight heparin (LMWH) therapy has expanded the options for initial management of patients presenting with deep venous thrombosis (1, 2). Low-molecular-weight heparin treatment is simple and consists of once- or twice-daily subcutaneous injection of a dose adjusted only for body weight. Treating suitable patients at home, often with self-injection, is effective and safe and has become standard practice in many settings (2-4). Clinically relevant aspects of LMWH treatment of venous thromboembolism remain uncertain, which may influence usage and recurrence or bleeding. First, LMWHs differ among themselves. Second, data on whether once- or twice-daily LMWH may be superior are conflicting (5, 6), suggesting that a once-daily regimen of enoxaparin may be less effective in patients with higher body mass index and patients with cancer (7). Third, since LMWHs are eliminated in the urine and plasma levels are higher in patients with even modest renal insufficiency (8), some clinicians administer lower dosages when the patients creatinine clearance is less than 0.84 mL/s (9), despite few outcome data to guide such alterations. Finally, in addition to the clinical and economic circumstances, practical issues surround drug administration, including the patients capacity to administer the desired dosage from a fixed-volume syringe or multidose vial; these issues can affect the feasibility of early discharge and home treatment. Fondaparinux is a synthetic and selective inhibitor of factor Xa that has proven efficacy and safety for preventing venous thromboembolism in orthopedic surgery. Although laboratory observations and theory suggested that such a compound might not be effective for treating established thrombosis (10), a dose-ranging study of deep venous thrombosis treatment found that a once-daily subcutaneous injection of fondaparinux, 7.5 mg, may be effective and safe across a broad range of body weights (50 kg and 100 kg) (11). Pharmacokinetic analyses suggested that daily doses of 5 mg and 10 mg are appropriate for patients less than and more than that weight range, respectively. Moreover, the predictable and sustained anticoagulant effect of fondaparinux for 24 hours allows once-daily injection, and since fondaparinux does not cross-react with heparin-induced antibodies, platelet count monitoring may no longer be needed (12). This may further simplify treatment. Therefore, we designed this randomized, double-blind study of 2205 symptomatic patients to determine whether the efficacy and safety of a once-daily subcutaneous fixed-dose regimen of fondaparinux are similar to those of the standard therapy of a twice-daily, subcutaneous, body weightadjusted regimen of enoxaparin. Early discharge was encouraged in both treatment groups. The large sample size allowed outcome assessment in patients with a broad range of body weights and renal function. Methods Patients Consecutive patients (>18 years of age) who presented with acute symptomatic deep venous thrombosis involving the popliteal, femoral, or iliac veins or the trifurcation of the calf veins and who required antithrombotic therapy were eligible for the study. Diagnostic criteria for deep venous thrombosis were a noncompressible vein found on ultrasonography or an intraluminal filling defect found on venography (11, 13). Patients were ineligible for the study if they had symptomatic pulmonary embolism; received therapeutic doses of anticoagulants or oral anticoagulant therapy for more than 24 hours; required thrombolysis, thrombectomy, or a vena cava filter; had contraindication to anticoagulant therapy (for example, active bleeding, thrombocytopenia [platelet count < 100 109 cells/L]); had elevated serum creatinine levels (>177 mol/L [>2 mg/dL]); had contraindication to contrast medium; had uncontrolled hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg); were pregnant; or had a life expectancy of less than 3 months. After giving informed consent, patients were randomly assigned by a computerized interactive voice response system that recorded information about patients before treatment assignment. Randomization was stratified by center in balanced blocks of 4 patients. The respective institutional review boards approved the study protocol, and an independent data safety monitoring board monitored the study. We assessed 5141 patients for eligibility: 2205 patients were randomly assigned to study groups, 2416 patients were excluded, and 520 patients declined to participate (Figure). The most common reasons for exclusion were the use of therapeutic anticoagulation for more than 24 hours, thrombolytic therapy, or vena cava filter (580 patients); contraindication to anticoagulant therapy (395 patients); symptomatic pulmonary embolism (387 patients); and a life expectancy of less than 3 months (228 patients). Figure. Flow of patients through the study. Treatment Regimens The patients allocated to fondaparinux (Arixtra, NV Organon, Oss, the Netherlands, and Sanofi-Synthlabo, Paris, France) received a once-daily subcutaneous injection of 5.0 mg if they weighed less than 50 kg, 7.5 mg if they weighed between 50 and 100 kg, or 10.0 mg if they weighed more than 100 kg. They also received twice-daily subcutaneous injections of placebo that appeared identical to enoxaparin. The patients allocated to enoxaparin (Lovenox, Clexane, Aventis Pharmaceuticals, Bridgewater, New Jersey) received a twice-daily subcutaneous dose of 1 mg/kg of body weight and a once-daily subcutaneous injection of placebo that appeared identical to fondaparinux. Although home treatment with the study drug was allowed, the treating physician made this decision and the drug had to be administered by a home care service. In both groups, vitamin K antagonist therapy was started as soon as possible but within 72 hours of initiation of fondaparinux or enoxaparin therapy. The investigator chose the type of vitamin K antagonist therapy according to local hospital practice. The same type of vitamin K antagonist was recommended for all patients in a particular center. During initial treatment, prothrombin times were measured at least every other day and the dose of vitamin K antagonist was adjusted to maintain the international normalized ratio between 2.0 and 3.0. Double-blind, initial treatment was continued for at least 5 days and until the international normalized ratio was greater than 2.0 for 2 consecutive days. Treatment with vitamin K antagonists was continued for 3 months, and the international normalized ratio was determined at least once per month. Surveillance and Follow-up All patients were contacted daily during initial treatment and at 1 and 3 months. At each contact, patients were evaluated for symptomatic recurrence of deep venous thrombosis or pulmonary embolism and bleeding and were informed about the symptoms and signs of these conditions. They were instructed to report to the study center on an emergency basis if any of these conditions occurred. If recurrent deep venous thrombosis or pulmonary embolism was suspected, the protocol required objective testing for confirmation. Outcome Assessment The primary efficacy outcome was the incidence of symptomatic recurrent venous thromboembolism during the 3-month study period. Symptomatic recurrent venous thromboembolism was defined as objectively documented recurrent deep venous thrombosis or pulmonary embolism or death in which pulmonary embolism was a contributing cause or could not be excluded. Without objective test results to adequately confirm or exclude recurrent venous thromboembolism, this diagnosis was accepted if the physician managed the patient with therapeutic doses of LMWH for more than 2 days, thrombolysis, a vena cava filter, or thrombectomy (3, 13). The criteria for the objective diagnosis of recurrent deep venous thrombosis were a new noncompressible venous segment or a substantial increase ( 4 mm) in diameter of the thrombus during full compression in a previously abnormal segment on ultrasonography (14, 15) or a new intraluminal filling defect found on venography. The criteria for the objective diagnosis of pulmonary embolism were an intraluminal filling defect on spiral computed tomography or pulmonary angiography, cut-off of a vessel of more than 2.5 mm in diameter on pulmonary angiography, perfusion defect of at least 75% of a segment with corresponding normal ventilation (high-probability lung scan), nondiagnostic lung scan associated with new deep venous thrombosis documented by ultrasonography or venography, or pulmonary embolism confirmed by autopsy. The main safety outcomes were major bleeding during the initial treatment period and 3-month mortality. Bleeding was defined as major if it was clinically overt and associated with a decrease in the hemoglobin level of 20 g/L or more, led to transfusion of 2 or more units of red blood cells or whole blood cells, was retroperitoneal or intracranial, occurred in a critical organ, or contributed to death. Bleeding episodes that were clinically relevant but not major (for example, epistaxis that required intervention or spontaneous macroscopic hematuria) were an additional safety outcome. The cause of deat

The Risk of Recurrent Venous Thromboembolism in Patients with an Arg506→Gln Mutation in the Gene for Factor V (Factor V Leiden)

BACKGROUND A recently discovered mutation in coagulation factor V (Arg506-->Gln, referred to as factor V Leiden), which results in resistance to activated protein C, is found in approximately one fifth of patients with venous thromboembolism. However, the risk of recurrent thromboembolism in heterozygous carriers of this genetic abnormality is unknown. METHODS We searched for factor V Leiden in 251 unselected patients with a first episode of symptomatic deep-vein thrombosis diagnosed by venography. The patients were followed prospectively for a mean of 3.9 years to determine the frequency of recurrent venous thrombosis and pulmonary embolism. RESULTS Factor V Leiden was found in 41 of the patients (16.3 percent; 95 percent confidence interval, 11.8 to 20.9 percent). The cumulative incidence of recurrent venous thromboembolism after follow-up of up to eight years was 39.7 percent (95 percent confidence interval, 22.8 to 56.5 percent) among carriers of the mutation, as compared with 18.3 percent (95 percent confidence interval, 12.3 to 24.3 percent) among patients without the mutation (hazard ratio, 2.4; 95 percent confidence interval, 1.3 to 4.5; P<0.01). CONCLUSIONS The risk of recurrent thromboembolic events is significantly higher in carriers of factor V Leiden than in patients without this abnormality. Large trials assessing the risk-benefit ratio of long-term anticoagulation in carriers of the mutation who have had a first episode of venous thromboembolism are indicated.

A Comparison of Real-Time Compression Ultrasonography with Impedance Plethysmography for the Diagnosis of Deep-Vein Thrombosis in Symptomatic Outpatients

BACKGROUND Impedance plethysmography performed serially over a one-week period has been shown to be an effective diagnostic strategy for patients with clinically suspected acute deep-vein thrombosis. Compression ultrasonography has a high sensitivity and specificity for the detection of proximal-vein thrombosis. The clinical value of repeated ultrasonography in the management of symptomatic deep-vein thrombosis is unknown. METHODS We conducted a randomized trial in 985 consecutive outpatients with clinically suspected deep-vein thrombosis to compare the diagnostic value of serial impedance plethysmography (494 patients) and serial compression ultrasonography (491 patients). We compared the positive predictive values of both tests for the diagnosis of venous thrombosis, using contrast venography as a reference. The frequencies of venous thromboembolism during a six-month follow-up period were also compared in patients with repeatedly normal results in order to evaluate the safety of withholding anticoagulant therapy from such patients. RESULTS The positive predictive value of an abnormal ultrasonogram was 94 percent (95 percent confidence interval, 87 to 98 percent), whereas the predictive value of impedance plethysmography was 83 percent (95 percent confidence interval, 75 to 90 percent) (P = 0.02). In patients with repeatedly normal results, the incidence of venous thromboembolism during the six-month follow-up period was 1.5 percent (95 percent confidence interval, 0.5 to 3.3 percent) for serial compression ultrasonography, as compared with 2.5 percent (95 percent confidence interval, 1.2 to 4.6 percent) for serial impedance plethysmography. CONCLUSIONS In making the diagnosis of deep-vein thrombosis in symptomatic outpatients, serial compression ultrasonography is preferable to impedance plethysmography, in view of its superior performance in detecting venous thrombosis.

Accuracy of Ultrasound for the Diagnosis of Deep Venous Thrombosis in Asymptomatic Patients after Orthopedic Surgery: A Meta-Analysis

Patients who have major orthopedic operations have an increased risk for deep venous thrombosis; without prophylaxis, the incidence of deep venous thrombosis is about 50% after hip replacement and about 65% after major knee surgery [1]. In both of these groups, the incidence of the more dangerous proximal venous thrombosis (thrombosis in the popliteal or more proximal veins) is approximately 20%. Most of these thrombi are asymptomatic. Nevertheless, the risk for pulmonary embolism from asymptomatic proximal venous thrombosis is substantial, about 25%, and fatal pulmonary embolism occurs in 1% to 2% of this group [2]. Several effective prophylactic methods are available. However, even with the most effective methods, the incidence of postoperative thrombosis is 15% to 20% for elective hip surgery and the incidence of thrombosis is 20% to 30% for major knee surgery detected by routine venography done at the time of discharge from hospital [1]. Because of this relatively high incidence of thrombosis despite primary prophylaxis, some authorities [3] advocate routine venography before hospital discharge in addition to primary prophylaxis to detect silent deep venous thrombosis in patients who have major orthopedic procedures. Thrombi that are detected are usually treated with anticoagulant agents. Venography is expensive, can be painful, and can produce other side effects [4]; it is therefore not an ideal screening test. Radioactive fibrinogen leg scanning and impedance plethysmography have been used as screening tests but are much less sensitive than venography [5-7]. More recently, venous ultrasound imaging has been evaluated as a screening test after hip surgery and has been recommended as a substitute for venography [8]. The initial studies with venous ultrasound used real-time B-mode imaging and lack of venous compressibility with gentle probe pressure as the diagnostic criterion for venous thrombosis [9-11]. Subsequently, a Doppler component (duplex) and then a color Doppler component were added as adjuncts to the original B-mode imaging. These modifications facilitate the identification of veins, but the definitive diagnostic criterion with both of these newer techniques is generally considered to be noncompressibility of the vein under gentle probe pressure. Studies [9-17] in symptomatic patients have consistently shown a high sensitivity and specificity (97% and 97%, respectively) for all three methods of ultrasound imaging. In contrast, studies evaluating the sensitivity of venous ultrasound imaging for detecting thrombi in asymptomatic patients after surgery have produced inconsistent results, with reported sensitivities ranging from 38% to 100%. The reason for the marked differences in the sensitivity among studies evaluating venous ultrasound imaging for asymptomatic proximal venous thrombosis is uncertain. Possible explanations for the observed differences in sensitivity among studies include 1) falsely high estimates of sensitivity because of bias resulting from shortcomings in the study design, 2) falsely low estimates of accuracy because of background noise caused by inadequate technique, 3) dependence of accuracy on the type of ultrasound method used, and 4) chance. In a previous study [5] addressing the variation in the sensitivity of radioactive fibrinogen leg scanning as a screening test for postoperative deep venous thrombosis, we provided evidence that wide differences were probably caused by bias in study design. Bias can result either from inappropriate patient selection or from diagnostic suspicion bias. To avoid a biased selection of patients, a study should include consecutive patients. To avoid diagnostic suspicion bias, the diagnostic tests should be done and their results interpreted by blinded observers using validated and explicit diagnostic criteria to ensure that the results can be reproduced by other investigators [18]. To critically evaluate the accuracy of ultrasound screening for deep venous thrombosis, we did a systematic overview of the literature. Studies in which the potential for bias was minimized were evaluated separately from those in which bias was not minimized. We determined the accuracy for detecting asymptomatic proximal venous thrombosis of each of the three ultrasound imaging methods (real-time B-mode, duplex, and color Doppler ultrasonography) by doing a meta-analysis (combining the results of studies regardless of the modality used and then analyzing the results separately for each of the three modalities). We also examined the accuracy of ultrasound as a screening test for isolated calf venous thrombosis. Methods The review was initiated by a computer search of the English-language medical literature using the MEDLINE database from January 1982 to October 1993. We used combinations of the medical subject headings ultrasound, orthopedics, postoperative period, and thrombophlebitis to identify all articles that evaluated screening with venous ultrasound imaging. Bibliographies of retrieved articles were checked for any additional studies. Recent journals were searched independently and using Current Contents to find new reports that were not identified in the computer search. Early reports of data that were later published in full were excluded from the analysis. Abstracts were also excluded because it is usually not possible to completely evaluate the methods and data. Remaining articles were then critically reviewed for the presence of three key methodologic criteria for the evaluation of the accuracy of diagnostic tests. Two of the authors independently checked the articles for the following methodologic standards: 1) previous establishment of objective criteria for normal and abnormal venographic and ultrasonographic results, 2) an independent comparison of the ultrasound result with contrast venography [the reference standard for diagnosis of venous thrombosis] by investigators blinded to the other test result, and 3) the prospective evaluation of consecutive eligible patients. A study was considered to have included consecutive patients if this was explicitly mentioned in the article or if the article stated that patients were excluded only if they refused consent or were allergic to contrast medium. Reports satisfying all three methodologic standards were classified as level 1 studies; otherwise, reports were classified as level 2 studies. Sensitivity, specificity, and positive predictive values for proximal and isolated calf venous thrombosis were calculated for the studies individually and were then calculated for the results of the pooled level 1 and pooled level 2 studies. Separate analyses were done for each of the three different ultrasound modalities (real-time B-mode, duplex, or color Doppler ultrasonography). A statistical test of homogeneity was calculated for the sensitivity and specificity of the three modalities in the pooled level 1 analysis. The 95% CIs for sensitivity and specificity were calculated according to the binomial distribution, adjusting for heterogeneity among studies using a random-effects model. The calculation of the 95% CIs for positive predictive value took into account sampling error in the sensitivities and specificities [19]. Likelihood ratios, and their 95% CIs, for abnormal ultrasound results were calculated for each study using the modification of adding 0.5 to each cell when zero entries occurred in the 2 2 table [20, 21]. Accuracy data were compared between level 1 and level 2 studies by using the normal approximation to the binomial distribution and by adjusting for between-study heterogeneity with a random-effects model [22]. Two-tailed P values are reported, and values of less than 0.05 were considered to be statistically significant. Results We identified 30 studies, all in patients who had had orthopedic surgery. Thirteen of these studies were excluded from analysis: Two studies were excluded because venography was not done or was done only in patients with abnormal ultrasound results [23, 24], 4 studies were excluded because it was impossible to distinguish the data on asymptomatic patients from those on symptomatic patients [25-28], and 7 studies were excluded because they were abstracts or early reports of studies later reported in full [29-35]. Sixteen of the remaining 17 reports evaluated proximal venous thrombi; real-time B-mode ultrasonography was evaluated in 7 reports [7, 36-41], duplex ultrasonography was evaluated in 7 reports [42-48], and color Doppler ultrasonography was evaluated in 2 reports [49, 50]. The last eligible report evaluated color Doppler ultrasonography only for the detection of isolated calf venous thrombosis, and, consequently, this report is included only in that analysis [51]. When level 1 and level 2 studies were combined, 2001 patients were studied. Two hundred seventeen proximal deep venous thrombi were detected by venography for an overall prevalence of no more than 10.8%. (Some studies reported deep venous thromboses by limbs only.) Table 1 shows the characteristics of the 16 analyzed studies, including documentation of the presence or absence of the three criteria necessary to minimize bias when evaluating the accuracy of diagnostic tests. In general, the timing of the ultrasound assessment, mean patient age, and prevalence of proximal venous thrombosis were similar. Studies with the highest rates of deep venous thrombosis did not provide information about whether or not prophylaxis was used or about the method of prophylaxis. Table 1. Summary of Trials Included in the Meta-Analysis* Accuracy of Ultrasonography for Proximal Venous Thrombosis In the level 1 studies Table 2, ultrasonography detected 95 of 153 proximal thrombi, for a sensitivity of 62% (95% CI, 54% to 70%). A falsely abnormal ultrasonographic result was found for 49 of 1463 venograms, for a specificity of 97% (CI, 96% to 98%). Accordingly, the positive predictive value was 66% (95 of 144; CI, 58% to 74%). Th

D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study

Abstract 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 measure 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.

Deep-vein thrombosis

Summary 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.

Erratum to: Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention

BACKGROUND AND OBJECTIVE Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population. METHODS A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described. RESULTS The pharmacokinetics of rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma rivaroxaban concentrations (≤500 μg/L). CONCLUSION Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.