Sylvie Desmarais

NON-INVASIVE DIAGNOSIS OF VENOUS THROMBOEMBOLISM IN OUTPATIENTS

BACKGROUND We designed a simple and integrated diagnostic algorithm for acute venous thromboembolism based on clinical probability assessment of deep-vein thrombosis (DVT) or pulmonary embolism (PE), plasma D-dimer measurement, lower-limb venous compression ultrasonography, and lung scan to reduce the need for phlebography and pulmonary angiography. METHODS 918 consecutive patients presenting at the emergency ward of the Geneva University Hospital, Geneva, Switzerland, and Hôpital Saint-Luc, Montreal, Canada, with clinically suspected venous thromboembolism were entered into a sequential diagnostic protocol. Patients in whom venous thromboembolism was deemed absent were not given anticoagulants and were followed up for 3 months. FINDINGS A normal D-dimer concentration (<500 microg/L by a rapid ELISA) ruled out venous thromboembolism in 286 (31%) members of the study cohort, whereas DVT by ultrasonography established the diagnosis in 157 (17%). Lung scan was diagnostic in 80 (9%) of the remaining patients. Venous thromboembolism was also deemed absent in patients with low to intermediate clinical probability of DVT and a normal venous ultrasonography (236 [26%] patients), and in patients with a low clinical probability of PE and a non-diagnostic result on lung scan (107 [12%] patients). Pulmonary angiography and phlebography were done in only 50 (5%) and 2 (<1%) of the patients, respectively. Hence, a non-invasive diagnosis was possible in 866 (94%) members of the entire cohort. The 3-month thromboembolic risk in patients not given anticoagulants, based on the results of the diagnostic protocol, was 1.8% (95% CI 0.9-3.1). INTERPRETATION A diagnostic strategy combining clinical assessment, D-dimer, ultrasonography, and lung scan gave a non-invasive diagnosis in the vast majority of outpatients with suspected venous thromboembolism, and appeared to be safe.

Determinants and Time Course of the Postthrombotic Syndrome after Acute Deep Venous Thrombosis

BACKGROUND The reason some patients with deep venous thrombosis (DVT) develop the postthrombotic syndrome is not well understood. OBJECTIVE To determine the frequency, time course, and predictors of the postthrombotic syndrome after acute DVT. DESIGN Prospective, multicenter cohort study. SETTING 8 Canadian hospital centers. PATIENTS 387 outpatients and inpatients who received an objective diagnosis of acute symptomatic DVT were recruited from 2001 to 2004. MEASUREMENTS Standardized assessments for the postthrombotic syndrome using the Villalta scale at 1, 4, 8, 12, and 24 months after enrollment. Mean postthrombotic score and severity category at each interval was calculated. Predictors of postthrombotic score profiles over time since diagnosis of DVT were identified by using linear mixed modeling. RESULTS At all study intervals, about 30% of patients had mild (score, 5 to 9), 10% had moderate (score, 10 to 14), and 3% had severe (score >14 or ulcer) postthrombotic syndrome. Greater postthrombotic severity category at the 1-month visit strongly predicted higher mean postthrombotic scores throughout 24 months of follow-up (1.97, 5.03, and 7.00 increase in Villalta score for mild, moderate, and severe 1-month severity categories, respectively, vs. none; P < 0.001). Additional predictors of higher scores over time were venous thrombosis of the common femoral or iliac vein (2.23 increase in score vs. distal [calf] venous thrombosis; P < 0.001), higher body mass index (0.14 increase in score per kg/m(2); P < 0.001), previous ipsilateral venous thrombosis (1.78 increase in score; P = 0.001), older age (0.30 increase in score per 10-year age increase; P = 0.011), and female sex (0.79 increase in score; P = 0.020). LIMITATIONS Decisions to prescribe compression stockings were left to treating physicians rather than by protocol. Because international normalized ratio data were unavailable, the relationship between anticoagulation quality and Villalta scores could not be assessed. CONCLUSION The postthrombotic syndrome occurs frequently after DVT. Patients with extensive DVT and those with more severe postthrombotic manifestations 1 month after DVT have poorer long-term outcomes.

Determinants of health-related quality of life during the 2 years following deep vein thrombosis.

Summary.  Background/objectives: We prospectively measured change in quality of life (QOL) during the 2 years after a diagnosis of deep vein thrombosis (DVT) and evaluated determinants of QOL, including development of the post‐thrombotic syndrome (PTS). Patients/methods: Consecutive patients with acute DVT were recruited from 2001 to 2004 at eight hospitals in Canada. At study visits at baseline, and 1, 4, 8, 12 and 24 months, clinical data were collected, standardized PTS assessments were performed, and QOL questionnaires were self‐completed. Generic QOL was measured using the Short‐Form Health Survey‐36 (SF‐36) questionnaire. Venous disease‐specific QOL was measured using the Venous Insufficiency Epidemiological and Economic Study (VEINES)‐QOL/Sym questionnaire. The change in QOL scores over a 2‐year follow‐up was assessed. The influence of PTS and other characteristics on QOL at 2 years was evaluated using multivariable regression analyses. Results: Among the 387 patients recruited, the average age was 56 years, two‐thirds were outpatients, and 60% had proximal DVT. The cumulative incidence of PTS was 47%. On average, QOL scores improved during follow‐up. However, patients who developed PTS had lower scores at all visits and significantly less improvement in QOL over time (P‐values for PTS*time interaction were 0.001, 0.012, 0.014 and 0.006 for PCS, MCS, VEINES‐QOL and VEINES‐Sym). Multivariable regression analyses showed that PTS (P < 0.0001), age (P = 0.0009), proximal DVT (P = 0.01) and inpatient status (P = 0.04) independently predicted 2‐year SF‐36 PCS scores. PTS alone independently predicted 2‐year VEINES‐QOL (P < 0.0001) and VEINES‐Sym (P < 0.0001) scores. Conclusions: Development of PTS is the principal determinant of health‐related QOL 2 years after DVT. Our study provides prognostic information on patient‐reported outcomes after DVT and emphasizes the need for effective prevention and treatment of the PTS.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsbergs criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING Canadian Institutes of Health Research.

Economic burden and cost determinants of deep vein thrombosis during 2 years following diagnosis: a prospective evaluation

Summary.  Background: Few studies have evaluated the long‐term economic consequences of deep vein thrombosis (DVT). None of them have incorporated prospectively collected clinical data to ensure accurate identification of incident cases of DVT and DVT‐related health outcomes of interest, such as post‐thrombotic syndrome (PTS). Objectives: To prospectively quantify medical and non‐medical resource use and costs related to DVT during 2 years following diagnosis, and to identify clinical determinants of costs. Methods: Three hundred and fifty‐five consecutive patients with acute DVT were recruited at seven Canadian hospital centers. Resource use and cost information were retrieved from three sources: weekly patient‐completed cost diaries, nurse‐completed case report forms, and the Quebec provincial administrative healthcare database (RAMQ). Results: The rate of DVT‐related hospitalization was 3.5 per 100 patient‐years (95% confidence interval [CI] 2.2–4.9). Patients reported a mean (standard deviation) of 15.0 (14.5) physician visits and 0.7 (1.2) other healthcare professional visits. The average cost of DVT was

Comparison of the Villalta and Ginsberg clinical scales to diagnose the post-thrombotic syndrome: correlation with patient-reported disease burden and venous valvular reflux.

5180 (95% CI

Seasonal variation in deep vein thrombosis

4344–6017) in Canadian dollars, with 51.6% of costs being attributable to non‐medical resource use. Multivariate analysis identified four independent predictors of costs: concomitant pulmonary embolism (relative increase in cost [RIC] 3.16; 95% CI 2.18–4.58), unprovoked DVT (RIC 1.65; 95% CI 1.28–2.13), development of PTS during follow‐up (RIC 1.35; 95% CI 1.05–1.74), and management of DVT in the inpatient setting (RIC 1.79; 95% CI 1.33–2.40). Conclusions: The economic burden of DVT is substantial. The use of measures to prevent the occurrence of PTS and favoring outpatient care of DVT has the potential to diminish costs.

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

Post-thrombotic syndrome (PTS) is a frequent and burdensome complication of deep vein thrombosis (DVT). There is no objective, criterion standard test to diagnose PTS. However, two clinical scales have been developed to classifyDVTpatients as having or not having PTS: the Villalta scale [1] and the Ginsberg measure [2]. While both measures have been used in clinical studies of the incidence or prevention of PTS [3–6], none has undergone comprehensive validation and the performance of the two measures has not been directly compared. Differences in the test characteristics of these two measures could help explain the differing rates of PTS that have been reported in the long-term follow-up studies of patients with DVT. During a Canadian prospective multicenter cohort study of long-term outcomes after DVT (The Venous Thrombosis Outcomes [VETO] Study) [7], we carried out a substudy to compare the performance of the Villalta and Ginsberg PTS measures with regard to: (i) proportion of patients classified as having PTS; (ii) relation between PTS status and patientreported quality of life (QOL); and (iii) correlation of PTS status with venous valvular reflux, a physiological indicator of chronic venous disease. For this substudy, 259 VETO Study patients, all of whom had objectively diagnosed symptomatic DVT, were assessed for ipsilateral PTS by trained research personnel at the 1 year follow-up visit, using both the Villalta scale [1] [grades the severity, from 0 to 3 of five symptoms (pain, cramps, heaviness, pruritus, and paresthesia) and six signs (edema, skin induration, hyperpigmentation, venous ectasia, redness, and pain during calf compression); a summed total score of ‡5 indicates PTS, and >14 or presence of ulcer indicates severe PTS] and the Ginsberg measure [2] (PTS is defined by the presence of daily leg pain and swelling for 1 month, occurring 6 months or more after DVT, made worse by standing/walking, and relieved by rest/leg elevation). Study patients also selfcompleted the validated generic [MOS short form health survey (SF)-36] [8] and venous disease-specific (VEINES-QOL) [9,10] QOLquestionnaires, and underwent a standardized ultrasound assessment for ipsilateral popliteal venous valvular reflux. Sudden cessation of the venous Doppler signal following the Valsalva maneuver or after manual compression of the ipsilateral calf for a minimum of 10 s with sudden release was interpreted as venous valve competence (absence of reflux), whereas retrograde flow through the valve lasting ‡1.0 s was considered to indicate venous valve incompetence (presence of reflux). This technique has been shown by our group and by others to have high inter-rater and intra-rater reliability [6,11,12]. Approval to conduct this substudy was obtained from research ethics committees in each hospital center, and written informed consent was obtained from all participants. In our analysis, we compared the proportion of patients classified as having PTS with each measure and examined associations among PTS status, QOL, and valvular reflux. The mean (SD) age of the substudy sample was 58 (15) years, 50% were male, two of three were outpatients, 62% had proximal DVT and 20% had previous DVT. The proportion of patients classified as having PTSwith the Villalta scale was 37% (96 of 259) [5% (5 of 96) classified as severe PTS] and with the Ginsberg measure was 8.1% (21 of 259). Chancecorrected agreement (kappa [13]) between the two measures was poor (j 1⁄4 0.22; 95% CI 0.13, 0.32). Among 163 patients classified as not having PTS with the Villalta scale, 161 (99%) were also classified as not having PTS with the Ginsberg measure. However, among 91 patients classified as having mild PTS and five patients classified as having severe PTS with the Villalta scale, only 17 (19%) and two (40%), respectively, were classified as having PTS with the Ginsberg measure. The mean Villalta numeric score was higher in patients classified as having PTS with the Ginsberg measure than in those classified as having PTS with the Villalta scale (Table 1). For both measures, patients classified as having PTS had significantly lower generic and venous disease-specific QOL scores, indicating poorerQOL, comparedwith thosewithout PTS.However, QOL scores were lower, indicating worse QOL, in patients Correspondence: Susan R. Kahn, Center for Clinical Epidemiology and Community Studies, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste, Catherine Rm. A-127, Montreal, QC H3T 1E2, Canada. Tel.: +1 514 340 8222 #4667; fax: +1 514 340 7564; e-mail: susan. kahn@mcgill.ca

Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial.

In many temperate countries coronary events and stroke, as well as related deaths, are more common in winter than in summer.1 Fatal pulmonary embolism has also been reported more often in winter.2 3 This might be linked to changes in coagulation factors4 and to peripheral vasoconstriction, leading to reduced blood flow in the legs.5 Alternatively, venous stasis due to vasodilatation is greatest in summer. These uncertainties prompted us to study the seasonal distribution of deep vein thrombosis of the legs by reviewing the month of presentation of all patients with this diagnosis referred to our vascular laboratory over six years. All files coded as “suspected” deep vein thrombosis (n=7303, mean (SD) age 63 (19), 58% women, 85% medical patients) or “confirmed” deep vein …

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome

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.