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.

A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer.

BACKGROUND: Cancer patients receiving chemotherapy are at increased risk for thrombosis. Apixaban, a factor Xa inhibitor, is oral and does not require laboratory monitoring. OBJECTIVES: A pilot study was conducted to evaluate whether apixaban would be well tolerated and acceptable in cancer patients receiving chemotherapy. PATIENTS/METHODS: Subjects receiving either first-line or second-line chemotherapy for advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian or prostate cancers, cancer of unknown origin, myeloma or selected lymphomas were randomized to 5 mg, 10 mg or 20 mg once daily of apixaban or placebo in a double-blind manner for 12 weeks. Use of the study drug began within 4 weeks of the start of chemotherapy. The primary outcome was either major bleeding or clinically relevant non-major (CRNM) bleeding. Secondary outcomes included venous thromboembolism (VTE) and grade III or higher adverse events related to the study drug. Thirty-two patients received 5 mg, 30 patients 10 mg, 33 patients 20 mg, and 30 patients placebo. In these groups, there were 0, 0, 2 and 1 major bleeds, respectively. The corresponding data for CRNM bleeds were 1, 1, 2, and 0. The rate of major bleeding in the 93 apixaban patients was 2.2% (95% confidence interval 0.26-7.5%). There were no fatal bleeds. Three placebo patients had symptomatic VTE. CONCLUSIONS: Apixaban was well tolerated in our study population. These results support further study of apixaban in phase III trials to prevent VTE in cancer patients receiving chemotherapy.

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

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 $5180 (95% CI $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.

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.

Acute liver failure because of chronic lymphocytic leukemia: case report and review of the literature.

Infiltration of the liver by hematologic malignancies is an uncommon cause of liver failure. B-Cell chronic lymphocytic leukemia (cll) is a usually indolent disease that may infiltrate the liver, but based on a review of the literature, has never been reported to induce acute liver failure. Here, we describe the case of a 78-year-old woman with acute liver failure secondary to infiltration with cll being unresponsive to chemotherapy and causing death. This case is notable because of its atypical presentation and ultimate poor prognosis.

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

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 24months. D-dimer was measured at 4months. A standardized ultrasound assessment for popliteal valvular reflux was performed at 12months. 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. 444.0µgL(-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 4months after DVT in patients not on warfarin, are associated with subsequent development of PTS. Venous valvular reflux is associated with moderate-to-severe PTS.

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.

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.

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.

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

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.

The persistence of anticardiolipin antibodies is associated with an increased risk of the presence of lupus anticoagulant and anti-beta2-glycoprotein I antibodies.

OBJECTIVE: We studied antiphospholipid antibodies (aPL) in blood samples from a cohort of individuals followed for thrombosis to determine whether the persistent presence of anticardiolipin antibodies (aCL) is associated with a greater likelihood of having lupus anticoagulant and/or anti-beta2-glycoprotein I antibodies (LA/abeta2GPI). METHODS: Blood samples from 353 individuals who had been tested for aCL on at least two occasions were tested for abeta2GPI and LA. Two groups were defined: aCL-persistent, who tested aCL-positive on at least two occasions, and aCL non-persistent, who tested aCL-positive on fewer than two occasions. Multivariate logistic regressions were performed using LA/abeta2GPI, LA and abeta2GPI as outcome variables and the percentage of aCL-positive tests as the predictor variable, adjusted for age, gender, family history of cardiovascular disease (CVD), systemic lupus erythematosus (SLE), smoking and number of venous (VT) and arterial thromboses (AT). RESULTS: Sixty-eight (19%) individuals were aCL persistent and 285 (81%) were aCL non-persistent. LA/abeta2GPI was found in 36 (53%) of the aCL persistent group and 38 (13%) of the aCL non-persistent group. The two groups were similar for age, gender and smoking. Family history of CVD, SLE, VT and AT were more frequent in the aCL persistent group. Multivariate analyses revealed that odds ratios for LA/abeta2GPI, LA and abeta2GPI were 1.34 [95% confidence interval (CI) = 1.22-1.47], 1.36 (95% CI = 1.24-1.50) and 1.47 (95% CI = 1.31-1.65) respectively for each 10% increase in aCL-positive tests vs 0% positive tests. CONCLUSION: Persistence of aCL positivity is associated with an increased risk of LA/abeta2GPI.

Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis.

BACKGROUND: The post-thrombotic syndrome is a chronic, poorly understood complication of deep venous thrombosis (DVT). OBJECTIVES: To evaluate predictors of the post-thrombotic syndrome, including intensity of long-term anticoagulation, and to assess the impact of the post-thrombotic syndrome on quality of life. PATIENTS AND METHODS: The setting was 13 Canadian hospitals and one US hospital. One hundred and forty-five patients with an unprovoked episode of proximal DVT who were initially treated with 3 months of conventional-intensity warfarin [target International Normalized Ratio (INR) of 2.5] then participated in a trial comparing two intensities of long-term warfarin therapy (target INR 2.5 vs. INR 1.7). Post-thrombotic syndrome was assessed at the end of the trial using a validated clinical scale. Generic and venous disease-specific quality of life was compared in patients with and without the post-thrombotic syndrome. Multivariable regression analyses were performed to identify predictors of the post-thrombotic syndrome and of its severity. RESULTS: After an average follow-up of 2.2 years, the prevalence of post-thrombotic syndrome was 37% and of severe post-thrombotic syndrome was 4%. Quality of life was worse in patients with the post-thrombotic syndrome compared with patients who did not have it. The presence of factor (F)V Leiden or the prothrombin gene mutation was an independent predictor of both a lower risk (P = 0.006) and reduced severity (P = 0.045) of the post-thrombotic syndrome. Intensity of anticoagulation did not influence the risk of developing the post-thrombotic syndrome. CONCLUSIONS: The post-thrombotic syndrome is a frequent and burdensome complication of proximal DVT, even among patients maintained on long-term oral anticoagulation. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of post-thrombotic syndrome, this finding requires further evaluation in prospective studies.

Single-arm study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin.

BACKGROUND: When warfarin is interrupted for surgery, low-molecular-weight heparin is often used as bridging therapy. However, this practice has never been evaluated in a large prospective study. This study was designed to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital. METHODS AND RESULTS: This was a prospective, multicenter, single-arm cohort study of patients at high risk of arterial embolism (prosthetic valves and atrial fibrillation with a major risk factor). Warfarin was held for 5 days preoperatively. Low-molecular-weight heparin was given 3 days preoperatively and at least 4 days postoperatively. Patients were followed up for 3 months for thromboembolism and bleeding. Eleven Canadian tertiary care academic centers participated; 224 patients were enrolled. Eight patients (3.6%; 95% CI, 1.8 to 6.9) had an episode of thromboembolism, of which 2 (0.9%; 95% CI, 0.2 to 3.2) were judged to be due to cardioembolism. Of these 8 episodes of thromboembolism, 6 occurred in patients who had warfarin deferred or withdrawn because of bleeding. There were 15 episodes of major bleeding (6.7%; 95% CI, 4.1 to 10.8): 8 occurred intraoperatively or early postoperatively before low-molecular-weight heparin was restarted, 5 occurred in the first postoperative week after low-molecular-weight heparin was restarted, and 2 occurred well after low-molecular-weight heparin was stopped. There were no deaths. CONCLUSIONS: Bridging therapy with subcutaneous low-molecular-weight heparin is feasible; however, the optimal approach for the management of patients who require temporary interruption of warfarin to have invasive procedures is uncertain.

Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.

BACKGROUND: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. METHODS: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. RESULTS: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) - 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI - 3.8, 11.0). There were no major bleeds in either group. CONCLUSION: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Biological profiles in subjects with recurrent acute coronary events compared with subjects with long-standing stable angina.

BACKGROUND: At one end of the clinical spectrum of coronary artery disease (CAD) are subjects who have had repeated acute ischemic events, and at the other end are those with long-standing angina who have never been unstable. This study tests the hypothesis that a specific biological profile can distinguish these 2 extreme groups and predict acute coronary events. METHODS AND RESULTS: Blood levels of lipoprotein(a), homocysteine, tissue plasminogen activator, plasminogen activator inhibitor-1, C-reactive protein (CRP), fibrinogen, and von Willebrand factor were compared in 3 groups of 50 subjects each: (1) those with previous multiple acute coronary events, (2) age-matched subjects with >/=3 years of stable angina and no prior acute coronary events, and (3) matched controls without evidence of atherosclerotic disease and a normal coronary angiogram. All subjects were followed for 4.0 years. Lipoprotein(a), homocysteine, tissue plasminogen activator, and plasminogen activator inhibitor-1 were similar in both CAD groups and significantly higher than in the control group. However, compared with subjects with long-standing stable angina, those with previous multiple coronary events had higher values of CRP (5.7+/-5.4 versus 3.0+/-5.2 mg/L, P=0.012), fibrinogen (3.38+/-0.75 versus 2.92+/-0.64 g/L, P=0.001), and von Willebrand factor (1.60+/-0.55 versus 1.25+/-0.36 U/mL, P=0.0003). On follow-up, myocardial infarction and unstable angina occurred in 42% of the group with multiple events, 4% of the stable angina group (P<0.0001), and none of the control subjects. In the 100 patients with CAD, CRP was 4.9 mg/L in those with and 1.8 mg/L in those without new instability (P<0.0001). In a multivariate analysis, only CRP distinguished those with follow-up acute coronary events (adjusted odds ratio 5.9, 95% CI 2.0 to 17.9; P=0.002). A baseline CRP >3.5 mg/L had a relative risk of 7.6 (2.6 to 21.7, P=0.0002) for subsequent acute events. CONCLUSIONS: An inflammatory biological profile distinguished patients with previous multiple acute coronary events from those with long-standing stable angina and predicted acute coronary instability.