A prospective study of Rivaroxaban for central venous catheter associated upper extremity deep vein thrombosis in cancer patients (Catheter 2).

INTRODUCTION: Patients with cancer are at increased risk of thrombosis, particularly those with central venous catheter (CVC) placement, which may predispose to the development of upper extremity deep vein thrombosis (UEDVT). Standard treatment includes low molecular weight heparin (LMWH) or LMWH bridged to warfarin. The direct oral anticoagulants (DOACs) have become standard of care for uncomplicated venous thromboembolism (VTE), but research in patients with cancer is ongoing. OBJECTIVES: To assess rivaroxaban monotherapy in patients with cancer who develop UEDVT due to CVC for preservation of line function, and safety outcomes of VTE recurrence, bleeding risk and death. MATERIALS AND METHODS: Patients ≥18years of age with active malignancy and symptomatic proximal UEDVT with or without pulmonary embolism (PE), associated with a CVC, were eligible. Treatment included rivaroxaban 15mg oral twice daily for 3weeks, followed by 20mg oral daily for 9weeks. Patients were followed clinically for 12weeks to assess for line function, recurrent VTE and bleeding. RESULTS: Seventy patients (47 women) were included, with mean age 54.1years. The most common malignancy was breast cancer (41%). Preservation of line function was 100% at 12weeks. The risk of recurrent VTE at 12weeks was 1.43%, with one episode of fatal PE. 9 patients (12.9%) experienced 11 total bleeding episodes. CONCLUSIONS: Rivaroxaban showed promise in treating CVC-UEDVT in cancer patients, resulting in preserved line function. However, bleeding rates and a fatal pulmonary embolism on treatment are concerning safety outcomes necessitating further study before rivaroxaban can be recommended.

Association between remote major venous thromboembolism risk factors and the risk of recurrence after a first unprovoked episode.

Essentials Is remote exposure to major venous thromboembolism (VTE) risk factor related to lower recurrence? We analyzed data from the REVERSE study, a cohort of patients with no recent major risk factor. We found no association between remote risk factors and the risk of recurrence. Patients with remote VTE risk factor should be managed as having had an unprovoked VTE. SUMMARY: Background It has been shown that the risk of recurrence of venous thromboembolism (VTE) is significantly lower when provoked by a major risk factor such as surgery or trauma compared with an event that was unprovoked. Objectives In this study we aimed to assess the association between remote exposure (3-12 months prior to VTE) to major VTE risk factors and the risk of recurrent VTE. Methods This was a post-hoc analysis of the REVERSE study, a prospective cohort of 646 patients with a first VTE, not provoked by a recent (< 3 months) major risk factor. Results We found no difference in the recurrence rate in patients with or without remote exposure to major VTE risk factors, including immobilization (hazard-ratio [HR], 1.4; 95% confidence interval, 0.7-2.6), surgery (HR, 0.8; 0.3-1.9) and trauma (HR, 1.3; 0.5-3.6). Conclusion None of the tested risk factors were associated with a lower risk of recurrence during follow-up. Patients with remote exposure to major risk factors at the time of a first VTE should not be managed differently from patients with no VTE risk factors.

Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study.

BACKGROUND: Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE. METHODS: Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12. FINDINGS: Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding. CONCLUSION: Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months.

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.

Conservative perioperative anticoagulation management in patients with chronic venous thromboembolic disease: a cohort study.

BACKGROUND: Guidelines for perioperative warfarin management in patients with venous thromboembolic disease (VTE) are largely based on expert opinion. OBJECTIVES: To assess the effectiveness and safety of a conservative perioperative anticoagulation strategy in patients with VTE on chronic warfarin therapy. Our center uses a conservative bridging approach for chronic VTE patients consisting of withholding warfarin for 5 days preoperatively, with prophylactic low-molecular-weight heparin (LMWH) post-procedure only if patients are admitted to hospital. PATIENTS/METHODS: We performed a single-center retrospective cohort study. During the study period (1997-2011) there were 634 procedures in 416 patients that were reviewed for postoperative outcomes at 30 and 90 days. RESULTS: Of the 634 procedures, 156 procedures (24.6%) were completed as inpatients. Pre- and post-procedure LMWH bridging was used in 15 (2.4%) and 152 (24.0%) of all procedures, respectively. The 30-day VTE incidence was 0.32% (95% confidence interval [CI] 0.087-1.14), all non-fatal DVTs. The 30-day incidence of major and total bleeding events was 1.26% (95% CI 0.64-2.47) and 3.00% (95% CI 1.93-4.63), respectively. The all-cause mortality rate was 0.32% (95% CI 0.087-1.14) at 30 days; two patients died from arterial thrombosis events. CONCLUSIONS: A randomized controlled trial is needed to provide definitive conclusions but a conservative bridging approach appears promising.

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.

Baseline imaging after therapy for unprovoked venous thromboembolism: a randomized controlled comparison of baseline imaging for diagnosis of suspected recurrence.

BACKGROUND: After a first unprovoked venous thromboembolism (VTE), many patients have residual pulmonary and/or lower limb vascular obstruction following completion of short-term anticoagulation. Residual vascular obstruction may complicate the diagnosis of recurrent VTE. Whether baseline imaging, conducted after completion of anticoagulation, helps in interpreting diagnostic testing in patients who subsequently have suspected recurrent VTE is unknown. STUDY DESIGN: The REVERSE study is a cohort study whose primary aim was to derive a clinical decision rule to guide the duration of anticoagulation after a first unprovoked VTE. All patients underwent baseline imaging after completing 5-7 months of anticoagulant therapy. We performed a post hoc randomized controlled comparison among 121 patients investigated for a suspected recurrent VTE during follow-up: the decision on recurrent VTE with or without baseline imaging was made available to two independent adjudicators. RESULTS: The proportion of patients not classifiable for recurrent VTE was statistically significantly higher in the group with no baseline imaging than in the group with baseline imaging: one in five as compared with one in 25. The interobserver agreement between the two adjudicators was better in the group with baseline imaging than in the group with no baseline imaging: κ-values were 0.78 and 0.54, respectively. CONCLUSIONS: In patients with a first unprovoked VTE, baseline imaging at completion of anticoagulant therapy helps in interpreting diagnostic tests performed in cases of suspected recurrent VTE.

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.

Ambulatory management of pulmonary embolism: a pragmatic evaluation.

BACKGROUND: Patients diagnosed with pulmonary embolism should be considered for treatment on an outpatient basis; however, this practise is not accepted in many centers. OBJECTIVES: Review the safety and efficacy of ambulatory management of patients with pulmonary embolism at our institution. PATIENTS/METHODS: This was a retrospective single center cohort study of consecutive patients diagnosed with idiopathic or secondary pulmonary embolism between January 2003 and January 2008 at the London Health Sciences Centre in London, Ontario, Canada. Patients were eligible for outpatient management of pulmonary embolism if they were hemodynamically stable, did not require oxygen therapy, did not require parenteral narcotics for pain management, and were not felt to be high risk for a major hemorrhage. Patients were assessed at 3 months for thrombosis recurrence and major bleeding episodes. RESULTS: Six hundred and thirty-nine patients were included in the study, of which 314 (49.1%; 95% CI 45.2, 53.1) were managed as outpatients; among these there were three (0.95%; 95% CI, 0.25, 3) thrombotic recurrences and three hemorrhagic events. There were nine deaths (2.9%; 95% CI, 1.4, 5.6), all due to underlying cancer and all occurring after the first 7 days of treatment. CONCLUSIONS: Outpatient management of uncomplicated pulmonary embolism seems safe and effective in the absence of other indications for hospital admission.

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.

Predicting warfarin maintenance dose in patients with venous thromboembolism based on the response to a standardized warfarin initiation nomogram.

BACKGROUND: Polymorphisms in the VKORC1 and CYP2C9 genes influence warfarin requirements. It has been suggested that dosing algorithms incorporating them might outperform usual care. Standardized warfarin initiation nomograms are safe and effective and patients' responses to them could be used to predict warfarin requirements without the need for genetic testing. OBJECTIVES: To develop a model to predict warfarin dose requirements based on the response to a standard nomogram without using genetic testing. PATIENTS/METHODS: We included 363 outpatients with acute venous thromboembolism who were started on treatment using a standardized warfarin nomogram and achieved a stable maintenance warfarin dose defined as a dose prescribed twice consecutively after two consecutive INR measurements between 2.0 and 3.0. Linear regression was used to derive equations predicting the maintenance dose and models were validated using non-parametric bootstrapping and tested in an independent cohort. RESULTS: Three models were constructed for patients completing the nomogram until day 3 (warfarin dose (mg week(-1)) = Exp [2.737 + 1.896(INR(3)(-1))-0.008(Age)]; R2adj = 0.462), day 5 (warfarin dose (mg week(-1)) = Exp[2.261 + 2.412(INR(3)(-1)) -0.285(DeltaINR(5-3))]; R2adj = 0.603) and day 8 (warfarin dose (mg week(-1)) = Exp[1.574 + 1.788(INR(8)(-1)) + 0.024(cumulated warfarin dose until nomogram day 7)]; R2adj = 0.643), where Exp is the exponential function; INR3 and INR8 are the INR on days 3 or 8 of the nomogram, and DeltaINR(5-3) is the difference in the INR on days 5 and 3. All models were internally and externally validated and were accurate to within 25% of the actual dose in >60% of patients. CONCLUSION: Maintenance warfarin dose can be accurately predicted using individual response to a standard warfarin initiation nomogram without the need for costly genetic testing.

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.

Increased mortality in hemodialysis patients having specific antibodies to the platelet factor 4-heparin complex.

Heparin-induced thrombocytopenia is a serious complication of heparin therapy that can lead to thromboembolism, cardiovascular events, and death. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing antibodies to the platelet factor 4-heparin (PF4-H) complex. We sought to determine the association between PF4-H antibodies and mortality in a prospective cohort of 419 asymptomatic hemodialysis patients. Pre-dialysis blood samples were screened for nonspecific PF4-H antibodies, and all positive and indeterminate samples were subsequently tested using immunoglobulin (Ig)G-specific PF4-H and platelet serotonin-release assays. During a median follow-up of 2.5 years there were 129 all-cause deaths. After controlling for potential confounding variables, the relative risk of death was significantly increased for patients with IgG-specific PF4-H antibodies and further elevated with an indeterminate serotonin-release assay. Our study suggests that IgG-specific PF4-H antibody formation is associated with increased mortality in hemodialysis patients.