Summary 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 Ginsberg's 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.
The reason some patients with deep venous thrombosis (DVT) develop the postthrombotic syndrome is not well understood.
To determine the frequency, time course, and predictors of the postthrombotic ...syndrome after acute DVT.
Prospective, multicenter cohort study.
8 Canadian hospital centers.
387 outpatients and inpatients who received an objective diagnosis of acute symptomatic DVT were recruited from 2001 to 2004.
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.
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).
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.
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.
Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing ...venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.
Documenting patterns and outcomes of venous thromboembolism (VTE) management and degree of adherence by clinicians to treatment guidelines could help identify remediable gaps in patient care. ...Prospective, clinical practice-based data from Canadian outpatient settings on management of VTE, degree of adherence with treatment guidelines and frequency of recurrent VTE and bleeding during follow-up was obtained in a multicentre, prospective observational study. From 12 Canadian centres, we assessed 868 outpatients with acute symptomatic VTE who received the low-molecular-weight heparin (LMWH) enoxaparin alone or with vitamin K antagonists (VKA), at baseline and at six months (or at the end of treatment, whichever came first). Index VTE was limb deep venous thrombosis (DVT) in 583 (67.2%) patients, pulmonary embolism (PE) with or without DVT in 262 (30.2%) patients, and unusual site DVT in 23 (2.6%) patients. VTE was unprovoked in 399 (46.0%) patients, associated with cancer in 74 (8.5%) patients, transient risk factors in 327 (37.7%) patients and hormonal factors in 68 (7.8%) patients.With regard to guideline adherence, 58 (7.3%) patients received <5 days LMWH and 114 (14.5%) had overlap <1 day. Among patients with cancer-related VTE, 59.5% were prescribed LMWH monotherapy and 43.2% received such treatment for >3 months. Only 38.1% of patients with transient VTE risk factors had received thromboprophylaxis. Our study provides useful information on clinical presentation, management and related outcomes in Canadian outpatients with VTE. Our results suggest there may be important gaps in use of thromboprophylaxis to prevent VTE and use of LMWH monotherapy to treat cancer-related VTE.
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.
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.
A normal D-dimer concentration (<500 μg/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).
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.
Objective Inflammation may play a role in pathogenesis of venous thromboembolism, but the nature of this relationship is not yet understood. The objective of this study was to assess whether ...inflammation marker levels measured at diagnosis of deep venous thrombosis (DVT) and change in levels during the first month after DVT are associated with anatomic extent of DVT and severity of venous signs and symptoms at baseline and 1 month. Methods The BioSOX study is a biomarker substudy of the Compression Stockings to Prevent the Post-Thrombotic Syndrome (SOX) trial, a multicenter, randomized controlled trial that included patients with a first, acute, symptomatic, proximal DVT. Blood samples were collected from participants at baseline and 1 month, and C-reactive protein (CRP), intercellular adhesion molecule 1, interleukin (IL)-6, and IL-10 were measured by established assays. Linear regression was used to assess the association between continuous log-transformed baseline biomarker levels and anatomic extent of DVT, classified as iliac or common femoral DVT vs femoral or popliteal DVT (reference). Proportional odds ordinal logistic regression models were used to analyze the association between biomarker level and Villalta score (as a measure of severity of venous signs and symptoms) at baseline and 1 month. Results Among 717 patients, 60.2% were male, and the mean age was 55.2 years. There was a significant association between more extensive DVT (common femoral or iliac) and levels of CRP and IL-6 at DVT diagnosis. Median (interquartile range) CRP level was 11.6 mg/L (3.84-39.5) in patients with common femoral or iliac DVT vs 6.86 mg/L (3.11-22) in patients with popliteal or femoral DVT, and median IL-6 level was 6.36 pg/mL (1.09-14.37) vs 4.40 pg/mL (2.35-8.27), respectively. These differences were statistically significant in linear regression analyses. In addition, compared with those in the lowest quartile, each higher quartile of baseline CRP concentration was associated with an odds ratio of 2.89 (1.93-4.33) for having a more severe Villalta category at baseline and 1.98 (1.28-3.08) for having a more severe Villalta category 1 month after DVT. Higher baseline levels of IL-6 were associated with Villalta severity category at baseline (odds ratio, 2.40 1.61-3.59). Change in biomarker levels during the first month after DVT was not strongly associated with the 1-month Villalta score. Conclusions Levels of CRP and IL-6 at DVT diagnosis were associated with thrombotic disease burden, as measured by DVT extent, and severity of DVT symptoms and signs. Further studies are required to more fully elucidate the role of inflammation in DVT and its clinical course.
To assess the validity of VEINES-QOL/Sym, a patient-reported questionnaire to evaluate quality of life and symptoms in patients with deep venous thrombosis (DVT).
Psychometric study within the Venous ...Thrombosis Outcomes (VETO) Study, a prospective cohort study of long-term outcomes after DVT. A total of 359 English- and French-speaking patients with acute, objectively diagnosed DVT were recruited at seven hospitals in Quebec, Canada. The VEINES-QOL/Sym questionnaire, a 26-item patient-reported measure that generates separate summary scores for symptoms (VEINES-Sym) and quality of life (VEINES-QOL) was evaluated for acceptability, reliability, validity, and responsiveness in VETO Study subjects.
Standard psychometric tests confirmed the acceptability (missing data, item endorsement frequencies, floor and ceiling effects), reliability (internal consistency, item–total and inter-item correlations, test–retest), validity (content, construct, convergent, discriminant, known groups), and responsiveness to clinical change of the VEINES-QOL/Sym in patients with DVT.
The VEINES-QOL/Sym is a practical and scientifically sound patient-reported measure of outcomes that was developed using gold-standard methods. VEINES-QOL/Sym is valid and reliable for use as a measure of quality of life and symptoms in patients with acute DVT and provides a rigorous tool to allow more comprehensive evaluation of outcomes in clinical trials and epidemiological studies of patients with DVT.
Abstract ▪393▪This icon denotes a clinically relevant abstract
The post-thrombotic syndrome (PTS) is a burdensome, costly complication of deep venous thrombosis (DVT). Investigating strategies to ...prevent PTS is important, as treatments for PTS are limited. To date, randomized trials of elastic compression stockings (ECS) to prevent PTS were small, single-center, none used a placebo control and results are conflicting.
To determine whether ECS, compared with inactive (placebo) stockings, are effective to prevent PTS in patients with proximal DVT.
We conducted a multicenter (24 centres, Canada and U.S.) randomized placebo controlled trial of active ECS (A-ECS) vs. placebo ECS (P-ECS) to prevent PTS after a first, symptomatic proximal DVT. A-ECS were knee length 30–40 mm Hg (Class II) graduated ECS. P-ECS were manufactured to look identical to A-ECS but lacked therapeutic compression. Stockings were mailed directly to patients and worn on the DVT-affected leg daily for up to 2 years. Patients did not wear their stockings at study follow-up visits (1, 6, 12, 18 and 24 months) to maintain study personnel blinding.
The primary study outcome, PTS, was diagnosed at or after the 6 month visit using the Ginsberg measure (leg pain and swelling of 3 1 month duration and typical in character: worse end of day or after prolonged sitting/standing and improved after rest/leg elevation). All PTS diagnoses were confirmed by the local study physicians. Secondary outcomes were incidence and severity of PTS using the Villalta scale, venous ulcers, VTE recurrence and death from VTE. A sample size of 800 patients was targeted based on a hypothesized cumulative incidence of the primary outcome of 30% in P-ECS vs. 20% in A-ECS, 2-tailed a of 0.05 and 80% power, and anticipated 25% rate of death/withdrawal/lost-to-follow-up. Using a modified intent to treat approach, we performed a time-to-event analysis using a Cox proportional hazards model adjusted for center to calculate hazard ratios (HR) and 95% confidence intervals (CI) to compare rates of the primary outcome in A-ECS vs. P-ECS. A similar time-to-event analysis was performed for Villalta PTS (Villalta score ≥ 5 at or after the 6 month visit).
From 2004–2010, 398 patients were randomized to A-ECS and 408 to P-ECS. 3 patients found to be ineligible soon after randomization were excluded from the analysis. Median time from DVT diagnosis to randomization was 4 days. Baseline features were similar in the 2 groups; overall, 60% were male, mean age was 55 years, and most proximal extent of DVT was iliac or femoral vein in 70% and popliteal vein in 30% of patients. The cumulative incidence of PTS (primary outcome) by 750 days was 14.8% in A-ECS vs. 12.3% in P-ECS (Figure) (HRadj 1.17; 95% CI 0.75–1.81; p=0.49). The cumulative incidence of Villalta PTS (secondary outcome) was 52.1% in A-ECS vs. 52.2% in P-ECS (HRadj 0.96; 95% CI 0.78–1.19; p=0.69). Additional outcomes were also similar in the two intervention groups (Table). Rates of loss to follow-up (5.5% vs. 5.4%) and withdrawal (8.3% vs. 9.1%) were similar in A-ECS and P-ECS. Overall, ∼70% of patients in both groups continued the intervention throughout study follow-up, and of these, >80% of patients in both groups reported use for ≥ 3 days per week.
In a large randomized placebo-controlled trial, ECS did not prevent the occurrence of PTS after a first proximal DVT and did not influence the severity of PTS or rate of recurrent VTE. The reported benefits of ECS to prevent PTS in some prior studies could be due, at least in part, to bias from open-label design. Whether ECS may be of benefit to manage symptoms of established PTS should be evaluated in future studies.Active ECS (n = 397)Placebo ECS (n = 406)Villalta severity category*None (score <5)181 (51.9%)182 (50.8%)Mild (5-9)114 (32.6%)116 (32.4%)Moderate (10-14)30 (8.6%)37 (10.3%)Severe (>14 or ulcer)24 (6.9%)23 (6.4%)Ipsilateral leg ulcer16 ulcers in 16 patients17 ulcers in 16 patientsRecurrent VTE45 events in 33 patients44 events in 38 patientsRecurrent ipsilateral DVT18 events in 16 patients17 events in 17 patientsDeath36 (9.0%)36 (9.1%)Death due to PE00Serious adverse event due to ECS00Adverse event due to ECS#78*Highest Villalta score at or after 6-month visit. Missing for 48 patients in each group;#leg rash or itching. Display omitted
Kahn:NIH: Research Funding; Canadian Institutes for Health Research: Research Funding; Sigvaris: Research Funding.
Summary
Pulmonary embolism (PE) may encompass a wide spectrum of severity. To determine whether clinical findings, D-dimer (DD) concentration, and deep vein thrombosis (DVT) shown by lower-limb ...venous compression ultrasonography (US) might predict the scintigraphic extent of PE, we studied 104 hemodynamically stable consecutive outpatients with acute PE diagnosed by a high-probability ventilation-perfusion lung scan. Scintigraphic extent of PE was classified into three categories: perfusion defects corresponding to <30%, 30–50%, or >50% of the total lung area. Median respiratory and heart rates were found to be significantly related to the extent of PE. Higher median alveolar-arterial oxygen difference values were observed as the proportion of lung perfusion defects increased (>50% vs. <30%, 6.3 vs. 3.6 kPa, P <.0001). Median plasma DD concentration was 7950 g/L in patients with >50% perfusion defects compared to 2731 g/L in those with <30% defects (P = .0001). DD levels above 4000 g/L were associated to more extensive perfusion defects (>50% vs. <30% defects, OR 30; 95% CI 5.8–155). Finally, a proximal DVT was more likely among patients with larger perfusion defects (>50% vs. <30% defects, OR 4.5; 95% CI 1.5–13.6). In conclusion, clinical signs such as tachypnea and tachycardia, alveolar-arterial oxygen difference, plasma DD concentration, and presence of DVT on US are predictors of a larger PE, as assessed by the extent of perfusion defects on high probability lung scans.
Abstract 565
Little is known about patterns and quality of venous thromboembolism (VTE) management in Canadian outpatient settings, including how closely clinicians adhere to evidence based treatment ...guidelines. Such information could help identify gaps in patient care requiring attention.
To obtain prospective, clinical practice-based data from Canadian outpatient settings on 1) management of VTE; 2) determinants of patterns of VTE management; 3) degree of adherence with ACCP 2008 VTE treatment guidelines; and 4) frequency of bleeding and recurrent VTE during follow-up.
We performed a multi-centre prospective observational study to evaluate physician practice patterns and degree of adherence to ACCP consensus guidelines for VTE treatment. From 2007–2010, we enrolled 915 consecutive patients with objectively confirmed acute symptomatic VTE who received treatment with the low molecular weight heparin (LMWH) enoxaparin alone or with warfarin in the outpatient setting (mainly thrombosis clinics) in 12 Canadian centers. Patients attended an enrolment visit, where data on demographics, site(s) of VTE, VTE risk factors, bleeding risk factors, creatinine clearance and initial treatment were recorded. A follow-up visit occurred when anticoagulant treatment was stopped or at 6 months, whichever occurred first. Indicators of adherence to VTE treatment guidelines included: (1) having received any thromboprophylaxis for VTE associated with transient risk factors (recent medical admission, major surgery or leg immobilization); (2) use of LMWH monotherapy to treat cancer-associated VTE; (3) at least 5 days median duration of LMWH in patients treated with initial LMWH overlapped with warfarin; (4) at least 1 day overlap of LMWH and warfarin once INR was therapeutic. Recurrent VTE, bleeding and adverse events were recorded throughout study follow-up.
At the time of abstract submission, end of study data were available for 747 of 915 enrolled patients. Average age was 56 years, 54% were male and mean body mass index was 28.3 kg/m2. Index VTE was lower or upper extremity deep venous thrombosis (DVT) in 511 (68.4%) patients, pulmonary embolism (PE) with or without DVT in 218 (29.2%) patients, and unusual site DVT in 18 (2.4%) patients. VTE was associated with cancer in 70 (9.4%) patients, transient risk factors in 289 (38.7%) patients, hormonal risk factors in 55 (7.4%) patients and was deemed unprovoked in 331 (44.3%) patients. Overall, enoxaparin was prescribed at a dose/frequency of 1.5 mg/kg QD in 85.4% of patients, 1.0 mg/kg BID in 14.6% of patients and 1.0 mg/kg QD for one patient who had creatinine clearance <30ml/min. Among patients with VTE risk factors such as recent medical admission, recent surgery or paralysis, only 37.3% had been prescribed thromboprophylaxis. Among patients with cancer-related VTE (n=70), 61.4% were prescribed LMWH monotherapy, a majority received 1.5 mg/kg once daily, and 42.9% received such treatment for >3 months. Among patients treated with initial LMWH overlapped with warfarin (n= 667; 89.3%), median duration of LMWH was 8 days (IQR 6–10 days), median duration of warfarin was 182 days (IQR 115–190) and median overlap with LMWH once INR was therapeutic was 1 day (IQR 1–2 days). However, 48 (7.2%) patients received <5 days LMWH and 99 (15%) patients had overlap <1 day. During follow-up, 16 (2.1%) patients had recurrent VTE, at a median of 71 days follow-up; rate of recurrent VTE was highest (8.6%) and occurred earliest (median, 49 days) in cancer patients. Major bleeding events (primarily GI or GU) occurred in 10 (1.3%) patients at a median of 23 days; at the time of bleed, 2 patients were receiving LMWH alone, 3 patients, LMWH and warfarin, and 5 patients, warfarin alone.
Our study provides useful information on clinical features of patients, management of VTE and rates of recurrence and bleeding in Canadian outpatients. Our results suggest that there are important gaps in (1) use of thromboprophylaxis to prevent VTE and (2) use of LMWH monotherapy to treat VTE in cancer patients. Conversely, in patients treated with combination LMWH/warfarin therapy, adherence to recommendations regarding minimum duration of LMWH and minimum overlap of LMWH and warfarin once INR was therapeutic was quite good.
Kahn:Sigvaris: Research Funding; sanofi-aventis: Advisory Board, Research Funding; Boehringer Ingelheim:. Schulman:Sanofi Aventis: Honoraria.
