Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study

Summary. Background: It remains unclear whether a single complete ultrasound examination, which detects calf vein thrombosis, is as safe as a baseline rapid ultrasound examination, repeated after 1 week when negative, which examines the veins in the groin and the knee. Therefore, we compared the safety and feasibility of two diagnostic ultrasound strategies, involving rapid and complete compression ultrasound (CUS) examination. Methods: Consecutive patients with suspected deep vein thrombosis (DVT) underwent clinical probability assessment. In patients with an unlikely clinical probability and a normal D‐dimer finding, DVT was considered to be excluded. All others were randomized to undergo a rapid or a single complete CUS examination. Patients in whom DVT was excluded were followed for 3 months to assess the incidence of venous thromboembolism (VTE). Results: A total of 1002 patients were included. A clinical decision rule indicating DVT to be unlikely and a normal D‐dimer finding occurred in 481 patients (48%), with a VTE incidence of 0.4% [95% confidence interval (CI) 0.05–1.5%] during follow‐up. DVT was confirmed in 59 of the 257 patients (23%) who underwent rapid CUS examination, and in 99 of the 264 patients (38%) who underwent complete CUS examination. VTE during follow‐up occurred in four patients (2.0%; 95% CI 0.6–5.1%) in the rapid CUS arm, and in two patients (1.2%; 95% CI 0.2–4.3%) in the complete CUS arm. Conclusions: A diagnostic strategy with a clinical decision rule, a D‐dimer test and a CUS examination is safe and efficient. Both the rapid and the complete CUS test are comparable and efficient strategies, with differing advantages and disadvantages.     

D‐dimer testing in pregnant patients: towards determining the next ‘level’ in the diagnosis of deep vein thrombosis

Summary. Background: The role of D‐dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. We hypothesized that the specificity of sensitive D‐dimer assays could be improved without compromising sensitivity by using higher D‐dimer cut‐off values. Objective: To determine the test characteristics of two rapid enzyme‐linked immunosorbent assays and three latex agglutination assays in pregnancy. Method: We recruited consecutive pregnant women who presented to participating centers with suspected DVT for the study. Symptomatic women were investigated with compression ultrasonography, and received 3 months of clinical follow‐up to assess for the presence of venous thrombosis. Plasma samples for D‐dimer were collected and frozen at the time of presentation. The median and mean D‐dimer values for respective trimesters of pregnancy in patients with and without DVT were calculated. Receiver operating curves (ROCs) were plotted for respective assays to establish the best cut‐points. The test characteristics corresponding to standard cut‐points and these ‘pregnancy’ cut‐points are presented. Results: The prevalence of DVT in our cohort was 6.6% (95% confidence interval 4.0–10.6%). The mean and median D‐dimer values were significantly increased throughout pregnancy. Overall, women with confirmed DVT had higher D‐dimer levels than women without DVT (P < 0.0001). Improved specificities (62–79%) were observed with the use of higher cut‐points obtained from ROCs for all five assays, and high sensitivities were manintained (80–100%) for DVT diagnosis. Conclusion: Using higher cut‐points than those used in non‐pregnant patients, the specificity of D‐dimer assays for the diagnosis of DVT in pregnancy can be improved without compromising sensitivity. Validation in prospective management studies is needed.     

D‐dimer testing in the diagnosis of cerebral vein thrombosis: a systematic review and a meta‐analysis of the literature

Summary. Background: Quantitative measurement of circulating D‐dimer, a product of fibrin degradation, has been shown to be a very useful diagnostic tool in the management of patients with suspected deep vein thrombosis and/or pulmonary embolism. Whether D‐dimer can play a similar role in the diagnostic approach to patients with suspected cerebral vein thrombosis (CVT) remains controversial.Methods: Studies evaluating the diagnostic accuracy of the D‐dimer test in the diagnosis of CVT were systematically searched for in the MEDLINE and EMBASE databases (up to July 2011). Weighted mean sensitivity and specificity with 95% confidence intervals (CIs) were calculated with a bivariate random‐effects regression approach.Results: Fourteen studies, for a total of 1134 patients, were included. D‐dimer accuracy was good, with a resulting weighted mean sensitivity of 93.9% (95% CI 87.5–97.1) and weighted mean specificity of 89.7% (95% CI 86.5–92.2), calculated with a bivariate approach. Potential risk factors for false‐negative D‐dimer results included isolated headache, longer duration of symptoms, and limited sinus involvement.Conclusions: Our findings suggest that D‐dimer may be a useful diagnostic tool in the management of patients with suspected CVT. Future prospective studies are warranted to confirm our preliminary findings.     

The Wells rule and D‐dimer for the diagnosis of isolated distal deep vein thrombosis

Summary. Background: Pretest clinical probability with the Wells rule and D‐dimer have been widely investigated for the diagnosis of symptomatic proximal deep vein thrombosis (DVT) of the lower limbs, but they have not been formally tested for symptomatic isolated distal DVT diagnosis. Objective: To evaluate the diagnostic accuracy of the Wells rule and D‐dimer for isolated distal DVT. Design, Setting, and Patients: This was a single‐center, cross‐sectional study including 873 consecutive outpatients with suspected DVT, in whom pretest clinical probability determination, D‐dimer determination (STA Liatest; cut‐off of < 500 ng mL^?1) and complete compression ultrasonography of both lower limbs were performed. Results: The isolated distal DVT prevalence was 12.4% (90/725). The sensitivity of the Wells rule for isolated distal DVT was 47% (95% confidence interval [CI] 36–57%), the specificity was 74% (95% CI 70–77%), and the negative and positive predictive values were 91% (95% CI 88–93%) and 20% (95% CI 15–26%), respectively. Patients with isolated distal DVT had higher D‐dimer levels than patients without DVT (1759 ± 1576 vs. 862 ± 1079 ng mL^?1, P = 0.0001). D‐dimer was negative in 13 patients with isolated distal DVT. D‐dimer sensitivity and specificity for isolated distal DVT were 84% (95% CI 75–91%) and 50% (95% CI 46–54%), respectively, with a negative predictive value of 96% (95% CI 93–98%). In patients with low pretest clinical probability, the D‐dimer negative predictive value was 99% (95% CI 95–100%). Conclusion: In clinically suspected DVT with negative proximal compression ultrasonography, pretest clinical probability with the Wells rule has a low diagnostic accuracy for isolated distal DVT. D‐dimer has a better negative predictive value, but alone it does not exclude isolated distal DVT. In patients with low pretest clinical probability, D‐dimer had a negative predictive value of > 95% for isolated distal DVT.     

Relation between D‐dimer level,venous valvular reflux and the development of post‐thrombotic syndrome after deep vein thrombosis

Summary. Background: The pathophysiology of post‐thrombotic syndrome (PTS) is postulated to involve persistent venous obstruction and venous valvular reflux. Objective: To study the association between D‐dimer level, valvular reflux and the PTS in a well‐defined cohort of deep vein thrombosis (DVT) patients. Methods: Consecutive patients with acute symptomatic DVT were recruited at eight centers and were followed for 24 months. D‐dimer was measured at 4 months. A standardized ultrasound assessment for popliteal valvular reflux was performed at 12 months. Using the Villalta scale, patients were assessed for PTS during follow‐up by evaluators who were unaware of D‐dimer or reflux results. Results: Three hundred and eighty‐seven patients were recruited; of these, 305 provided blood samples for D‐dimer and 233 had a 12‐month reflux assessment. PTS developed in 45.1% of subjects. Mean D‐dimer was significantly higher in patients with vs. without PTS (712.0 vs. 444.0 μg L^?1; P = 0.02). In logistic regression analyses adjusted for warfarin use at the time of D‐dimer determination and risk factors for PTS, D‐dimer level significantly predicted PTS (P = 0.03); when stratifying for warfarin use at the time of blood draw, adjusted odds ratio (OR) for developing PTS per unit difference in log D‐dimer was 2.33 (95% CI 0.89, 6.10) in those not on warfarin vs. 1.25 (95% CI 0.87, 1.79) in those on warfarin. Ipsilateral reflux was more frequent in patients with moderate‐to‐severe PTS than in patients with mild PTS (65% vs. 40%, respectively; P = 0.01) and was independently associated with moderate‐to‐severe PTS in logistic regression analyses (P = 0.01). Conclusion: D‐dimer levels, measured 4 months after DVT in patients not on warfarin, are associated with subsequent development of PTS. Venous valvular reflux is associated with moderate‐to‐severe PTS.     

Comparison of the clinical history of symptomatic isolated distal deep‐vein thrombosis vs. proximal deep vein thrombosis in 11 086 patients

Background: The clinical significance of symptomatic isolated distal deep vein thrombosis (DVT) is uncertain. Consequently, this leads to important disparities in its management. Objective: To examine the clinical history of isolated distal DVT and to compare it with that of proximal DVT. Methods: Using data from the international, prospective, RIETE registry on patients with confirmed symptomatic venous thromboembolism (VTE), we compared the risk factors and 3‐month outcome in patients with isolated distal DVT vs. proximal DVT. Results: Eleven thousand and eighty‐six patients with symptomatic DVT, but without pulmonary embolism, were included between 2001 and 2008; 1921 (17.3%) exhibited isolated distal DVT. Anticoagulant treatment was received by 89.1% (1680/1885) of isolated distal DVT and 91.8% (7911/8613) of proximal DVT patients for the entire follow‐up period. Isolated distal DVTs were more associated with transient risk factors (i.e. recent travel, hospitalization, recent surgery), whereas proximal DVTs were more associated with chronic states (i.e. ≥75 years or with active cancer). At 3 months, major bleeding rate was lower in patients with isolated distal DVT (1.0% vs. 2.2%, P < 0.01), whereas VTE recurrence rate was equivalent (2.0% vs. 2.7%, P = 0.07). The mortality rate was lower in patients with isolated distal DVT (2.7% vs. 7.5%; P < 0.001); this was mainly due to a lower rate of non‐VTE‐related deaths (2.2% vs. 6.3%; P < 0.001). Active cancer was the main predictive factor of death in patients with isolated distal DVT. Conclusions: Proximal and isolated distal DVT patients differ in terms of risk factors and clinical outcomes, suggesting different populations. In the short term, the life expectancy of patients with isolated distal DVT depended chiefly on their cancer status.     

Management of primary care patients with suspected deep vein thrombosis: use of a therapeutic dose of low-molecular-weight heparin to avoid urgent ultrasonographic evaluation

BACKGROUND: Out of hospital management of patients with suspected deep vein thrombosis (DVT) can be problematic. The accuracy of clinical prediction rules in the primary care setting may be inadequate, D-dimer testing may not be available, and the cost-effectiveness of urgent ultrasonographic evaluation is uncertain. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of an empiric single therapeutic dose of low-molecular weight heparin (LMWH) in the time interval preceding ultrasound investigation in patients presenting to primary care physicians (PCPs) for suspicion of DVT. METHODS: Consecutive patients with suspected DVT who presented to the office of a PCP outside regular thrombosis center working hours were enrolled. All eligible patients received a single therapeutic dose of LMWH (100 anti-Xa IU kg(-1) weight) and were scheduled to undergo clinical and instrumental evaluation at the thrombosis center the morning after. Clinical events were documented after a 3-month follow-up. RESULTS: A total of 534 consecutive patients with suspected DVT were included in this study; of these 102 patients had subsequent diagnosis of DVT. We detected no episodes of pulmonary embolism, major bleeding, or death during the 18-h window between the administration of LMWH and objective evaluation. Of the 432 patients in whom diagnosis of DVT was subsequently excluded, only three (0.7%; CI: 0.2-2.0%) developed venous thromboembolic events during the 3-month follow-up period. CONCLUSIONS: Empiric treatment with a single therapeutic dose of LMWH is effective and safe for outpatients with suspected DVT initially managed in a primary care setting. This strategy has the potential to reduce the need for urgent diagnostic imaging.     

The pulmonary embolism rule‐out criteria (PERC) rule does not safely exclude pulmonary embolism

Summary. Background: The Pulmonary Embolism Rule‐out Criteria (PERC) rule is a clinical diagnostic rule designed to exclude pulmonary embolism (PE) without further testing. We sought to externally validate the diagnostic performance of the PERC rule alone and combined with clinical probability assessment based on the revised Geneva score. Methods: The PERC rule was applied retrospectively to consecutive patients who presented with a clinical suspicion of PE to six emergency departments, and who were enrolled in a randomized trial of PE diagnosis. Patients who met all eight PERC criteria [PERC_(?)] were considered to be at a very low risk for PE. We calculated the prevalence of PE among PERC_(?) patients according to their clinical pretest probability of PE. We estimated the negative likelihood ratio of the PERC rule to predict PE. Results: Among 1675 patients, the prevalence of PE was 21.3%. Overall, 13.2% of patients were PERC_(?). The prevalence of PE was 5.4% [95% confidence interval (CI): 3.1–9.3%] among PERC_(?) patients overall and 6.4% (95% CI: 3.7–10.8%) among those PERC_(?) patients with a low clinical pretest probability of PE. The PERC rule had a negative likelihood ratio of 0.70 (95% CI: 0.67–0.73) for predicting PE overall, and 0.63 (95% CI: 0.38–1.06) in low‐risk patients. Conclusions: Our results suggest that the PERC rule alone or even when combined with the revised Geneva score cannot safely identify very low risk patients in whom PE can be ruled out without additional testing, at least in populations with a relatively high prevalence of PE.     

Predictors of the post‐thrombotic syndrome with non‐invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis

Summary. Background: Post‐thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) affecting a large number of patients. Because of its potential debilitating effects, identification of patients at high risk for the development of this syndrome is relevant, and only a few predictors are known. Objectives: To assess the incidence and potential predictors of PTS. Methods: We prospectively followed 111 consecutive patients for 2 years after a first episode of objectively documented DVT of the leg. With non‐invasive venous examinations, residual thrombosis, valvular reflux, calf muscle pump function and venous outflow resistance were assessed at 6 weeks, 3 months, 6 months, 1 year, and 2 years. The Clinical, Etiologic, Anatomic, and Pathophysiologi classification was used to record the occurrence and severity of PTS. Regression analysis with area under the receiver operating characteristic (ROC) curve was performed to identify potential predictors. Results: The cumulative incidence of PTS was 46% after 3 months, and the incidence and severity did not increase further. Men appeared to be at increased risk as compared with women (risk ratio [RR] 1.4, 95% confidence interval [CI] 0.9–2.2), as were patients over 50 years as compared with younger patients (RR 1.4%, 95% CI 0.9–2.1). Patients with thrombosis localized in the proximal veins at diagnosis had an increased risk of PTS as compared with patients with distal thrombosis (RR 2.3%, 95% CI 1.0–5.6). PTS developed in 32 of 52 patients (62%) with residual thrombosis in the proximal veins 6 weeks after diagnosis, as compared with 17 of 45 patients (38%) without residual proximal thrombosis, leading to a 1.6‐fold increased risk (95% CI 1.0–2.5). The presence of valvular reflux in the superficial veins was also a predictor at 6 weeks, with a 1.6‐fold increased risk as compared with patients without superficial reflux (95% CI 1.1–2.3). A multivariate analysis of these predictors yielded an area under the ROC curve of 0.72 (95% CI 0.62–0.82). Conclusions: PTS develops in half of all patients within 3 months, with no further increase being seen up to 2 years of follow‐up. Male sex, age over 50 years, proximal localization of the thrombus at entry, residual proximal thrombosis and superficial valvular reflux at 6 weeks seem to be the most important predictors of PTS in patients with a first episode of DVT. Duplex scanning 6 weeks after diagnosis appears to be clinically useful for the identification of patients at risk of PTS.     

Differences in clinical presentation of deep vein thrombosis in men and women

Summary. Background: As assessment of clinical pretest probability is the first step in the diagnostic evaluation of deep vein thrombosis (DVT), it is important to know if the clinical features of DVT are the same in men and women. Objectives: To compare the prevalence and clinical characteristics of DVT, and the accuracy of clinical pretest probability assessment, between men and women with suspected DVT. Methods: A retrospective analysis of individual patient data from three prospective studies by our group that evaluated diagnostic tests for a suspected first episode of DVT. Clinical characteristics, clinical pretest probability for DVT, and prevalence and extent of DVT was assessed in a total of 1838 outpatients. Results: The overall prevalence of DVT was higher in men than in women (14.4% vs. 9.4%) (P = 0.001). The prevalence of DVT was higher in men than in women who were categorized as having a clinical pretest probability that was low (6.9% vs. 3.5%; P = 0.025) or moderate (16.9% vs. 8.7%; P = 0.04), but similar in patients in the high category (40.2% vs. 44.0%; P = 0.6). In patients diagnosed with DVT, swelling of the entire leg occurred more often (41.5% vs. 15.7%; P < 0.001), and thrombosis was more extensive (involvement of both popliteal and common femoral veins in 47.9% vs. 21.6%), in women than in men. Conclusions: In outpatients with suspected DVT, the overall prevalence of thrombosis and the prevalence of thrombosis in those with a low or a moderate clinical pretest probability were higher in men than in women.     

Risk factors for post‐thrombotic syndrome in patients with a first deep venous thrombosis

Summary. Background: Post‐thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). Objectives: To determine the risk of PTS after DVT and to assess risk factors for PTS. Methods: Patients were recruited from the Multiple Environmental and Genetic Assessment (MEGA) study of risk factors for venous thrombosis. Consecutive patients who suffered a first DVT of the leg were included in a follow‐up study. All patients completed a questionnaire and DNA was obtained. PTS was ascertained in a structured interview using a clinical classification score. Results: The 1‐year cumulative incidence of PTS was 25% and 7% for severe PTS. Elastic compression stockings were prescribed in 1412 (85%) patients. The majority used their stockings every day. Women were at an increased risk compared with men [risk ratio (RR) 1.5, 95% confidence interval (CI) 1.3–1.8]. Similarly, obese patients had a 1.5‐fold increased risk of PTS compared with normal weight patients (RR 1.5, 95% CI 1.2–1.9), with a 1‐year cumulative incidence of 34% compared with 22%. Patients who already had varicose veins had an increased risk (RR 1.5, 95% CI 1.2–1.8) of PTS. DVT in the femoral and iliac vein was associated with a 1.3‐fold increased risk of PTS compared with popliteal vein thrombosis (RR 1.3, 95% CI 1.1–1.6). Patients over 60 years were less likely to develop PTS than patients below the age of 30 (RR 0.6, 95% CI 0.4–0.9). Malignancy, surgery, minor injury, plaster cast, pregnancy or hormone use did not influence the risk of PTS neither did factor (F)V Leiden nor the prothrombin 20210A mutation. Conclusions: PTS is a frequent complication of DVT, despite the widespread use of elastic compression stockings. Women, obese patients, patients with proximal DVT and those with varicose veins have an increased risk of PTS, whereas the elderly appeared to have a decreased risk.     

Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta‐analysis

See also Watson HG. RVO – Real value obscure. This issue, pp 1116–8; Le Gal G, Carrier M, Kovacs MJ, Betancourt MT, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Delluc A, White RH, Vickars L, Rodger M. Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study. This issue, pp 1126–32. Summary. Background: Residual vein obstruction (RVO) detected on compression ultrasonography of the leg after a few months of anticoagulation therapy might be able to identify patients with deep vein thrombosis (DVT) at high risk of having a recurrent venous thromboembolism (VTE). Aim: To determine whether RVO is associated with an increased risk of recurrent events in patients with DVT. Patients and Methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. We selected 14 articles (nine prospective cohort studies and five randomized controlled trials) that included patients with DVT who had an assessment for RVO with the use of compression ultrasonography. Two reviewers independently extracted data onto standardized forms. Results: Overall, the presence of RVO was not associated with an increased risk of recurrent VTE (odds ratio [OR] 1.24, 95% confidence interval [CI] 0.9–1.7) in patients with unprovoked DVT who stopped oral anticoagulation therapy at the time of RVO assessment. However, RVO was significantly associated with recurrent VTE in patients with any (unprovoked or provoked) DVT (OR 1.5, 95% CI 1.1–2.0). Conclusions: RVO was associated with a modestly increased risk of recurrent VTE in patients with DVT (unprovoked and provoked). However, RVO did not seem to be a predictor of recurrent VTE in patients with unprovoked DVT following anticoagulation discontinuation. Further prospective studies are needed to assess the role of RVO in patients with unprovoked DVT.     

血浆D-二聚体结合Wells临床评估量表对下肢深静脉血栓形成的诊断价值

目的：评价血浆D-二聚体结合Wells临床评估量表对下肢深静脉血栓形成的早期诊断价值.方法：344例疑似下肢深静脉血栓形成患者（398条下肢）进行回顾性分析,用D-二聚体、Wells临床评估量表及两者结合方法作为诊断标准对下肢深静脉血栓形成进行诊断,并与彩色多普勒的诊断结果进行比较分析.结果：D-二聚体对近端和远端深静脉血栓灵敏度分别为88.7%,80.9%;阴性预测值分别为96.3%,97.9%;Youden指数分别为0.43,0.31.Wells临床估价量表对近端和远端深静脉血栓灵敏度分别为83.9%,66.7%,阴性预测值分别为94.9%,96.5%;Youden指数分别为0.40,0.08.两者结合对近端和远端深静脉血栓灵敏度为98.4%,90.5%;阴性预测值分别为99.3%,98.6%;Youden指数分别为0.42,0.29.结论：D-二聚体和Wells临床评估量表作为下肢深静脉血栓形成常规检查,对下肢深静脉血栓形成的诊断具有筛检价值,便于快速普查,有利于降低医疗费用;两者结合起互补作用,可以增加诊断的准确性.