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

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

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

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.

Predictors of post-thrombotic syndrome in a population with a first deep vein thrombosis and no primary venous insufficiency.

BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis (DVT). Its diagnosis is based on clinical characteristics. However, symptoms and signs of PTS are non-specific, and could result from concomitant primary venous insufficiency (PVI) rather than DVT. This could bias evaluation of PTS. METHODS: Using data from the REVERSE multicenter study, we assessed risk factors for PTS in patients with a first unprovoked unilateral proximal DVT 5-7 months earlier who were free of clinically significant PVI (defined as absence of moderate or severe venous ectasia in the contralateral leg). RESULTS: Among the 328 patients considered, the prevalence of PTS was 27.1%. Obesity (odds ratio [OR] 2.6 [95% confidence interval (CI) 1.5-4.7]), mild contralateral venous ectasia (OR 2.2 [95% CI 1.1-4.3]), poor International Normalized Ratio (INR) control (OR per additional 1% of time with INR < 2 during anticoagulant treatment of 1.018 [95% CI 1.003-1.034]) and the presence of residual venous obstruction on ultrasound (OR 2.1 [95% CI 1.1-3.7]) significantly increased the risk for PTS in multivariable analyses. When we restricted our analysis to patients without any signs, even mild, of contralateral venous insufficiency (n = 244), the prevalence of PTS decreased slightly to 24.6%. Only obesity remained an independent predictor of PTS (OR 2.6 [95% CI 1.3-5.0]). Poor INR control and residual venous obstruction also increased the risk, but the results were no longer statistically significant (OR 1.017 [95% CI 0.999-1.035] and OR 1.7 [95% CI 0.9-3.3], respectively). CONCLUSIONS: After a first unprovoked proximal DVT, obese patients and patients with even mild PVI constitute a group at increased risk of developing PTS for whom particular attention should be paid with respect to PTS prevention. Careful monitoring of anticoagulant treatment may prevent PTS.

Risk of post-thrombotic syndrome after subtherapeutic warfarin anticoagulation for a first unprovoked deep vein thrombosis: results from the REVERSE study.

BACKGROUND: Risk factors for post-thrombotic syndrome (PTS) remain poorly understood. OBJECTIVES: In this multinational multicenter study, we evaluated whether subtherapeutic warfarin anticoagulation was associated with the development of PTS. METHODS: Patients with a first unprovoked deep venous thrombosis (DVT) received standard anticoagulation for 5-7 months and were then assessed for PTS. The time in the therapeutic range was calculated from the international normalized ratio (INR) data. An INR below 2, more than 20% of the time, was considered as subtherapeutic anticoagulation. RESULTS: Of the 349 patients enrolled, 97 (28%) developed PTS. The overall frequency of PTS in patients with subtherapeutic anticoagulation was 33.5%, compared with 21.6% in those with an INR below two for ≤ 20% of the time (P = 0.01). During the first 3 months of therapy, the odds ratio (OR) for developing PTS if a patient had subtherapeutic anticoagulation was 1.78 (95% confidence interval [CI] 1.10-2.87). After adjusting for confounding variables, the OR was 1.84 (95% CI 1.13-3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14-3.00) [crude] and 1.88 (95% CI 1.15-3.07) [adjusted]. CONCLUSION: Subtherapeutic warfarin anticoagulation after a first unprovoked DVT was significantly associated with the development of PTS.

Comparison of the Villalta post-thrombotic syndrome score in the ipsilateral vs. contralateral leg after a first unprovoked deep vein thrombosis.

BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent complication of a deep vein thrombosis (DVT). International guidelines recommend assessing PTS with the Villalta scale, a clinical measure that incorporates venous symptoms and signs in the leg ipsilateral to a DVT. However, these signs and symptoms are not specific for PTS and their prevalence and relevance in the contralateral leg have not previously been studied. METHODS: Using data from the REVERSE prospective multicentre cohort study, we compared the Villalta total score and prevalence of venous signs and symptoms in the ipsilateral vs. contralateral leg in patients with a first, unilateral DVT 5 to 7 months previously. RESULTS: Among the 367 patients analyzed, the mean Villalta score was higher in the ipsilateral than in the contralateral leg (mean ± standard deviation [SD] 3.7 [3.4] vs. 1.9 [2.5], respectively; P<0.0001). Villalta scores in the ipsilateral and contralateral legs were strongly correlated (r=0.68; P<0.0001). Ipsilateral PTS (defined by a Villalta total score >4) was present in 31.6% (n=116) of patients. Among these, 39.7% (n=46) of patients had a Villalta score >4 in the contralateral leg, and the distribution of Villalta symptoms and signs components was similar between the legs. CONCLUSIONS: Villalta scores in the ipsilateral and contralateral legs are strongly correlated. Almost half of cases considered to be PTS might reflect pre-existing symptomatic chronic venous disease. Alternatively, patients with pre-existing chronic venous disease might be more prone to developing PTS after a DVT. Performing a bilateral assessment of Villalta scores at the acute phase of DVT could be of clinical interest from a diagnostic, prognostic and therapeutic point of view.

Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study.

OBJECTIVES: There is growing interest in using residual vein obstruction (RVO) to guide the duration of oral anticoagulant therapy (OAT) for unprovoked deep vein thrombosis (DVT). We sought to determine if RVO as determined by compression ultrasonography (CUS) after completion of 5-7 months of anticoagulation for unprovoked DVT is associated with an increased risk of recurrent venous thromboembolism (VTE). MATERIALS AND METHODS: This was a multicentre multinational prospective cohort study undertaken in tertiary care centers. Patients with a first 'unprovoked' major VTE were enrolled over a 4-year period and completed a mean 18-month follow-up in September 2006. All 452 patients with DVT had baseline CUS at inclusion to assess any RVO before stopping OAT at 5-7 months. During follow-up off OAT, all episodes of suspected recurrent VTE were independently adjudicated with reference to baseline imaging. RESULTS: Forty-five out of 231 patients with abnormal CUS (19.5%) had recurrent VTE during follow-up, as compared with 32 out of 220 patients with normal CUS (14.6%), and one patient had inadequate CUS. There was no significant association between an abnormal CUS at inclusion and the risk of recurrent VTE: hazard ratio 1.4 (95% confidence interval, 0.9-2.1), P=0.19. None of the different degrees of clot resolution on baseline CUS was statistically significantly associated with the risk of recurrent VTE. CONCLUSION: In our study, the presence of RVO at the time of OAT withdrawal was not associated with a statistically significant higher risk of recurrent VTE. RVO assessment may not be useful to guide duration of anticoagulation.

Patients with a first symptomatic unprovoked deep vein thrombosis are at higher risk of recurrent venous thromboembolism than patients with a first unprovoked pulmonary embolism.

BACKGROUND: Previous studies are mixed as to whether patients with unprovoked pulmonary embolism (PE) have a higher rate of venous thromboembolism (VTE) recurrence after anticoagulation is discontinued than patients with unprovoked deep vein thrombosis (DVT). OBJECTIVES: To determine whether patients with unprovoked PE have a higher rate of VTE recurrence than patients with unprovoked DVT in a prospective multicenter cohort study. PATIENTS/METHODS: Six hundred and forty-six patients with a first episode of symptomatic unprovoked VTE were treated with heparin and subsequent oral anticoagulation for 5-7 months, and were followed every 6 months for recurrent VTE after their anticoagulant therapy was discontinued. RESULTS: Of 646 patients, 194 had isolated PE, 339 had isolated DVT, and 113 had both DVT and PE. After a mean of 18 months of follow-up, there were 91 recurrent VTE events (9.5% annualized risk of recurrent VTE in the total population). The crude recurrent VTE rate for the isolated PE, isolated DVT and DVT and PE groups were 7.7%, 16.5% and 17.7%, respectively. The relative risk of recurrent VTE for isolated DVT vs. isolated PE was 2.1 (95% confidence interval 1.2-3.7). CONCLUSIONS: This study has demonstrated that patients with a first episode of unprovoked isolated DVT are 2.1 times more likely to have a recurrent VTE episode than patients with a first episode of unprovoked isolated PE. These findings need to be considered when determining the optimal duration of anticoagulant therapy for patients with unprovoked VTE.

Serum lipoprotein (a) levels in patients with first unprovoked venous thromboembolism is not associated with subsequent risk of recurrent VTE.

INTRODUCTION: Case-control studies suggest that elevated lipoprotein (a) (Lp(a)) is a risk factor for first venous thromboembolism (VTE). Lp(a) has not been prospectively investigated as a possible risk factor for recurrent VTE in first unprovoked VTE patients. We sought to determine if serum Lp(a) levels in patients with unprovoked VTE who discontinue anticoagulants after 5 to 7 months of therapy predict VTE recurrence in a prospective cohort study. MATERIALS AND METHODS: Serum Lp(a) measurements were obtained from 510 first unprovoked VTE patients treated for 5 -7 months with anticoagulants in a 12 center study. Patients were subsequently followed for a mean of 16.9 months (SD+/-11.2) for symptomatic VTE recurrence which was independently adjudicated with reference to baseline imaging. RESULTS: There was no significant association between Lp(a) as a continuous variable and recurrent VTE nor in gender stratified subgroups. No statistically significant differences were observed in the median Lp(a) concentrations between patients who recurred and those who did not recur (median (interquartile range): 0.09 g/L (0.17) versus 0.06 g/L (0.11) respectively; p=0.15). The Lp(a) cut-off point of 0.3g/L was not significantly associated with recurrent VTE for the overall population nor in gender stratified subgroups. CONCLUSIONS: Elevated serum Lp(a) does not appear to be associated with recurrent VTE in patients with history of first unprovoked VTE and may not play a role in identifying patients with unprovoked VTE at high risk of recurrence. There was no optimal predictive threshold for the overall population or for sex sub-groups and Lp(a)>or=0.3 g/L was not a significant predictor of recurrent VTE.

Validation of a diagnostic approach to exclude recurrent venous thromboembolism.

SUMMARY INTRODUCTION: The diagnosis of recurrent venous thromboembolism (VTE) is a challenge in clinical practice. Our objective was to evaluate the safety of a diagnostic strategy utilizing comparison of diagnostic test results with baseline imaging results to rule out suspected recurrent VTE. METHODS: The REVERSE study was a prospective cohort study whose primary aim was to develop a clinical prediction rule for recurrent VTE. We included and followed patients who completed 5-7 months of anticoagulant therapy after a first unprovoked VTE. Suspected cases of recurrent VTE were assessed according to standardized diagnostic criteria based on comparison of diagnostic test results with those obtained at the time of anticoagulant treatment withdrawal. RESULTS: Out of the 398 suspected events, a recurrent VTE was diagnosed in 106 cases (26.6%) and excluded in 292 cases. In 76 cases (19%), the diagnosis of recurrent VTE was excluded on the basis of the fact that no significant change on diagnostic imaging was detected when compared to baseline imaging. During the ensuing 3 months, six patients received anticoagulant therapy after recurrent VTE was excluded, and two were lost to follow-up. Eight of 284 remaining patients in whom recurrent VTE had been excluded, who were not treated and who were not lost to follow-up were diagnosed with subsequent VTE (3-month risk, 2.8%; 95% confidence interval, 1.4-5.5%). Six of these eight patients with subsequent recurrent VTE had a known superficial or distal thrombosis at the time of initial suspected recurrent VTE. CONCLUSION: A diagnostic strategy comparing diagnostic test results obtained at the time of the suspected recurrent event with those obtained at baseline can safely and effectively rule out recurrent VTE in a significant proportion of patients. Registered at http://www.clinicaltrials.gov identifier: NCT00261014.