Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry1

Summary. Background: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. Objectives: We assessed the incidence, risk factors and prognosis of heparin‐associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Patients/Methods: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25 369 patients with confirmed VTE until February 2009. Among them, 24 401 patients were treated either with UFH or with LMWH, and had available information about the 6‐month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150 000 mm^–3. Results: One hundred and forty‐one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6‐month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79–2.17) than in the LMWH group (0.54%, 95% CI 0.44–0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58–9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64–3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH‐associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. Conclusions: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non‐cancerous patients.     

Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study

Summary. Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non‐randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. Patients and Methods: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24 h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow‐up. Results: Of 297 included patients, who all completed the follow‐up, six (2.0%; 95% confidence interval [CI] 0.8–4.3) had recurrent VTE (five PE [1.7%] and one DVT [0.3%]). Three patients (1.0%, 95% CI 0.2–2.9) died during the 3 months of follow‐up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08–2.4). Conclusion: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319; http://www.trialregister.nl/trialreg/index.asp ).     

Prophylaxis with low‐dose low‐molecular‐weight heparin during pregnancy and postpartum: is it effective?

Summary. Background: The optimal approach for venous thrombosis (VTE) prophylaxis during pregnancy and postpartum in women with an increased risk of VTE is not established. Objectives: To evaluate the effectiveness, represented as the incidence of pregnancy‐related VTE, and safety, represented as incidence of postpartum hemorrhage (PPH), of a protocol recommending prophylaxis with low‐dose low‐molecular‐weight heparin (LMWH) in women at intermediate to high risk of VTE. Patients/methods: In this retrospective cohort study, we analyzed 34 women (44 pregnancies) with intermediate risk of VTE who received low‐dose LMWH for 6 weeks postpartum and 57 women (82 pregnancies) with high risk of VTE who received low‐dose LMWH during pregnancy and for 6 weeks postpartum. Pregnancy‐related VTE was defined as VTE during pregnancy or ≤ 3 months postpartum. PPH was defined as blood loss > 500 mL and severe PPH as blood loss > 1000 mL. Results: The incidence of pregnancy‐related VTE was 5.5% (95% CI, 2.4–12.3) despite prophylaxis with low‐dose LMWH. All events occurred in women at high risk, with a postpartum incidence of 7.0% (95% CI, 2.9–16.7) and antepartum incidence of 1.8% (95% CI, 0.4–9.2). The risk of PPH was 21.6% (95% CI, 14.3–31.3) and severe PPH 9.1% (95% CI, 4.7–16.9), which was not different in women who started LMWH postpartum and those who used LMWH during pregnancy. Conclusions: Although prophylaxis with low‐dose LMWH during pregnancy and postpartum proved to be safe, the risk of pregnancy‐related VTE is considerable in women with a high risk of VTE. VTE prophylaxis with low‐dose LMWH may not be sufficiently effective in these women.     

Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta‐analysis

Summary. Background: Whether patients with unprovoked venous thromboembolism (VTE) have a higher risk of arterial cardiovascular events than the general population and patients with provoked VTE is a matter of debate. Objective: To perform a systematic review and a meta‐analysis aimed at assessing the risk of arterial cardiovascular events in patients with unprovoked VTE as compared with both patients with provoked VTE and controls. Methods: A systematic search was performed. Studies reporting on (i) patients with confirmed VTE, (ii) a follow‐up of at least 6 months and (iii) the incidence of arterial cardiovascular events (acute myocardial infarction and ischemic stroke) were included in the systematic review. Those studies reporting separate incidences of cardiovascular events in patients with unprovoked and provoked VTE or patients with unprovoked VTE and controls were included in the incidence rate meta‐analysis. Results: Overall, 17 studies were included in the systematic review. The weighted mean incidence of arterial cardiovascular events was 0.46% [95% confidence interval (CI) 0.34–0.59] and 0.35% (95% CI 0.24–0.49) per patient‐year in patients with unprovoked and provoked VTE, respectively. Six studies were included in the meta‐analysis. The risk of arterial cardiovascular events appeared to be higher in patients with unprovoked VTE than in controls [incidence rate ratio (IRR) 1.87, 95% CI 1.32–2.65] and than in patients with provoked VTE (IRR 1.86, 95% CI 1.19–2.89). Conclusions: Patients with unprovoked VTE have a higher risk of arterial cardiovascular events than patients with provoked VTE over long‐term follow‐up.     

Parental history and venous thromboembolism: a nationwide study of age‐specific and sex‐specific familial risks in Sweden

Summary. Background: The value of parental history as a risk indicator for venous thromboembolism (VTE) has not been determined in a nationwide setting. Objectives: To perform the first nationwide study of age‐specific and sex‐specific familial VTE risks in offspring of parents hospitalized for VTE. Patients/Methods: The Swedish Multigeneration Register of 0–75‐year‐old subjects was linked to the Hospital Discharge Register for 1987–2007. Standardized incidence ratios (SIRs) were calculated for individuals whose parents were hospitalized for VTE as compared with those whose parents were unaffected. Results: Among 45 362 hospitalized offspring cases with VTE, 4865 offspring of affected parents were identified with a familial SIR of 2.00 (95% confidence interval [CI] 1.94–2.05). Familial SIR was slightly higher for male offspring than for female offspring (2.08, 95% CI 2.00–2.16 vs. 1.91, 95% CI 1.84–1.99). The risk in offspring was further increased when both parents were affected (3.97, 95% CI 3.40–4.61), with high familial risks at ages 20–29 years (10.00, 95% CI 5.91–15.84). The familial risks for VTE among offspring were increased from the age of 10 years up to 75 years, with familial SIRs of 3.96 (95% CI 3.13–4.94) at age 10–19 years and 1.48 (95% CI 1.17–1.84) at ages 70–75 years. However, the absolute incidence rate increased with age. Conclusions: Parental history is potentially useful for risk assessments of VTE, although age needs to be considered. Our results support the use of an age‐dependent multicausal model to estimate the risk of VTE.     

Incidence and cumulative recurrence rates of venous thromboembolism in the Taiwanese population

Summary. Background: Little information is available on the epidemiology of venous thromboembolism (VTE) in Asian populations. Objectives: To investigate VTE incidence, VTE cumulative recurrence rates and risk factors for VTE recurrence among the adult Taiwanese population. Methods: This population‐based cohort study used the Taiwanese National Health Insurance claims databases to identify 5347 adult patients (2463 men, 46.1%) with VTE diagnosed in 2001 and 2002. We calculated the crude incidence of VTE and its recurrence. We also conducted a nested case–control study (n = 3576) among this population to estimate the association between VTE recurrence and exposure to potential VTE risk factors by conditional logistic regression. Results: The crude incidence of VTE was 15.9 per 100 000 person‐years, and its recurrence rate was 5.1% per person‐year. During 11 566 person‐years of follow‐up, the cumulative rates of VTE recurrence at 6, 12, 24, 36 and 47 months were 6.7%, 9.4%, 12.4%, 13.9%, and 14.4%, respectively. By conditional logistic regression, histories of VTE [adjusted odds ratio (OR) 1.71, 95% confidence interval (CI) 1.32–2.16] or malignant neoplasm (adjusted OR 1.64, 95% CI 1.26–1.99), major extremity trauma (adjusted OR 2.76, 95% CI 1.82–4.52), serious neurologic diseases (adjusted OR 1.43, 95% CI 1.12–1.84) or undergoing major surgery (adjusted OR 4.57, 95% CI 1.72–12.50) were associated with higher risks of VTE recurrence. Conclusions: The incidence of VTE is lower in the Taiwanese population than in Caucasians. Most VTE recurrences occur within 12 months, but they continue to occur beyond 1 year. The VTE recurrences are associated with malignancy, history of VTE, and major surgery after a previous VTE.     

Severe stroke: patient profile and predictors of favorable outcome

Summary. Background: Severe stroke carries high rates of mortality and morbidity. The aims of this study were to determine the characteristics of patients who initially presented with severe ischemic stroke, and to identify acute and subacute predictors of favorable clinical outcome in these patients. Methods: An observational cohort study, Acute Stroke Registry and Analysis of Lausanne (ASTRAL), was analyzed, and all patients presenting with severe stroke – defined as a National Institute of Health Stroke Scale score of ≥ 20 on admission – were compared with all other patients. In a multivariate analysis, associations with demographic, clinical, pathophysiologic, metabolic and neuroimaging factors were determined. Furthermore, we analyzed predictors of favorable outcome (modified Rankin scale score of ≤ 3 at 3 months) in the subgroup of severe stroke patients. Results: Of 1915 consecutive patients, 243 (12.7%) presented with severe stroke. This was significantly associated with cardio‐embolic stroke mechanism (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.19–2.54), unknown stroke onset (OR 2.35, 95% CI 1.14–4.83), more neuroimaging signs of early ischemia (mostly computed tomography; OR 2.65, 95% CI 1.79–3.92), arterial occlusions on acute imaging (OR 27.01, 95% CI 11.5–62.9), fewer chronic radiologic infarcts (OR 0.43, 95% CI 0.26–0.72), lower hemoglobin concentration (OR 0.97, 95% CI 0.96–0.99), and higher white cell count (OR 1.05, 95% CI 1.00–1.11). In the 68 (28%) patients with favorable outcomes despite presenting with severe stroke, this was predicted by lower age (OR 0.94, 95% CI 0.92–0.97), preceding cerebrovascular events (OR 3.00, 95% CI 1.01–8.97), hypolipemic pretreatment (OR 3.82, 95% CI 1.34–10.90), lower acute temperature (OR 0.43, 95% CI 0.23–0.78), lower subacute glucose concentration (OR 0.74, 95% CI 0.56–0.97), and spontaneous or treatment‐induced recanalization (OR 4.51, 95% CI 1.96–10.41). Conclusions: Severe stroke presentation is predicted by multiple clinical, radiologic and metabolic variables, several of which are modifiable. Predictors in the 28% of patients with favorable outcome despite presenting with severe stroke include hypolipemic pretreatment, lower acute temperature, lower glucose levels at 24 h, and arterial recanalization.     

Clinical implications of clopidogrel non‐response in cardiovascular patients: a systematic review and meta‐analysis

Summary. Background: Previous studies have shown an important risk of cardiovascular events in patients with clopidogrel biological non‐response, and data have shown considerable, unexplored heterogeneity. Objectives: To evaluate the magnitude of cardiovascular risk associated with clopidogrel non‐response and to explore heterogeneity. Methods: This was a systematic review and meta‐analysis of prospective studies of patients treated with clopidogrel for symptomatic atherothrombosis, evaluated by light transmission aggregometry with ADP and monitored prospectively for clinical ischemic events. Results: Fifteen studies were included, totaling 3960 patients, of whom 25% were considered to be clopidogrel non‐responders. The global relative risk (RR) for recurrent ischemic events in clopidogrel non‐responders was 3.5 [95% confidence interval (CI) 2.4–5.2, P < 0.0001]. The results of the different studies were heterogeneous (Cochran P = 0.01 and I² = 52%). The most recent studies yielded lower RRs [global RR = 2.9 (95% CI 2.3–3.8) after 2007, and global RR = 6.6 (95% CI 3.7–11.9) before 2007, P = 0.01]. Heterogeneity was present in the group of studies in which more than 10% of patients took glycoprotein (GP)IIb–IIIa inhibitors [Cochran P = 0.003 and I² = 70%; RR = 3.8 (95% CI 2.9–5.1)] and was absent in the other studies [Cochran P = 0.88 and I² = 0; RR = 2.5 (95% CI 1.7–3.6)]. The RR was significantly higher in studies using higher ADP maximal aggregation cut‐offs (> 65%) for clopidogrel non‐response than in studies using lower cut‐offs [RR = 5.8 (95% CI 3.2–10.3) and RR = 2.9 (95% CI 2.2–3.7), respectively, P = 0.03]. Conclusions: The risk of ischemic events associated with clopidogrel non‐response is now more precisely defined. The risk is heterogeneous across studies, possibly because of an interaction with GPIIb–IIIa inhibitors and the use of different cut‐offs to identify non‐responders.     

Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta‐analysis

Summary. Background: Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease.Objectives: To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence‐based guidelines.Patients/Methods: Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0–3.5, and ASA, 50–650 mg daily, with at least 3 months of follow‐up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model.Results: Four thousand four hundred and forty‐two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83–1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71–3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61–1.75). Minor bleeding, from a 1748‐patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13–2.00).Conclusions: This meta‐analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0–3.5, and ASA, 50–650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.     

Safety and efficacy of protease‐activated receptor‐1 antagonists in patients with coronary artery disease: a meta‐analysis of randomized clinical trials

Summary. Background: Thrombin receptor antagonists blocking protease‐activated receptor‐1 (PAR‐1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. Objectives: We investigated the safety and efficacy of PAR‐1 antagonists in patients with coronary artery disease (CAD). Patients/Methods: Randomized, placebo‐controlled trials of the PAR‐1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. Results: A total of 41 647 patients from eight trials were included. PAR‐1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39–1.57, P < 0.001), major (OR 1.46, 95% CI 1.28–1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40–2.00, P < 0.001) bleeding than placebo in the fixed‐effects model. PAR‐1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81–0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78–0.92, P < 0.001). Conversely, PAR‐1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90–1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84–1.10, P = 0.59). Conclusions: PAR‐1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.     

Clinical predictors of prophylaxis use prior to the onset of acute venous thromboembolism in hospitalized patients SWIss Venous ThromboEmbolism Registry (SWIVTER)

Summary. Background: We investigated clinical predictors of appropriate prophylaxis prior to the onset of venous thromboembolism (VTE). Methods: In 14 Swiss hospitals, 567 consecutive patients (306 medical, 261 surgical) with acute VTE and hospitalization < 30 days prior to the VTE event were enrolled. Results: Prophylaxis was used in 329 (58%) patients within 30 days prior to the VTE event. Among the medical patients, 146 (48%) received prophylaxis, and among the surgical patients, 183 (70%) received prophylaxis (P < 0.001). The indication for prophylaxis was present in 262 (86%) medical patients and in 217 (83%) surgical patients. Among the patients with an indication for prophylaxis, 135 (52%) of the medical patients and 165 (76%) of the surgical patients received prophylaxis (P < 0.001). Admission to the intensive care unit [odds ratio (OR) 3.28, 95% confidence interval (CI) 1.94–5.57], recent surgery (OR 2.28, 95% CI  1.51–3.44), bed rest > 3 days (OR 2.12, 95% CI  1.45–3.09), obesity (OR 2.01, 95% CI  1.03–3.90), prior deep vein thrombosis (OR 1.71, 95% CI  1.31–2.24) and prior pulmonary embolism (OR 1.54, 95% CI  1.05–2.26) were independent predictors of prophylaxis. In contrast, cancer (OR 1.06, 95% CI  0.89–1.25), age (OR 0.99, 95% CI  0.98–1.01), acute heart failure (OR 1.13, 95% CI  0.79–1.63) and acute respiratory failure (OR 1.19, 95% CI  0.89–1.59) were not predictive of prophylaxis. Conclusions: Although an indication for prophylaxis was present in most patients who suffered acute VTE, almost half did not receive any form of prophylaxis. Future efforts should focus on the improvement of prophylaxis for hospitalized patients, particularly in patients with cancer, acute heart or respiratory failure, and in the elderly.     

Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study

Summary. Background: It remains unclear whether a single complete ultrasound examination, which detects calf vein thrombosis, is as safe as a baseline rapid ultrasound examination, repeated after 1 week when negative, which examines the veins in the groin and the knee. Therefore, we compared the safety and feasibility of two diagnostic ultrasound strategies, involving rapid and complete compression ultrasound (CUS) examination. Methods: Consecutive patients with suspected deep vein thrombosis (DVT) underwent clinical probability assessment. In patients with an unlikely clinical probability and a normal D‐dimer finding, DVT was considered to be excluded. All others were randomized to undergo a rapid or a single complete CUS examination. Patients in whom DVT was excluded were followed for 3 months to assess the incidence of venous thromboembolism (VTE). Results: A total of 1002 patients were included. A clinical decision rule indicating DVT to be unlikely and a normal D‐dimer finding occurred in 481 patients (48%), with a VTE incidence of 0.4% [95% confidence interval (CI) 0.05–1.5%] during follow‐up. DVT was confirmed in 59 of the 257 patients (23%) who underwent rapid CUS examination, and in 99 of the 264 patients (38%) who underwent complete CUS examination. VTE during follow‐up occurred in four patients (2.0%; 95% CI 0.6–5.1%) in the rapid CUS arm, and in two patients (1.2%; 95% CI 0.2–4.3%) in the complete CUS arm. Conclusions: A diagnostic strategy with a clinical decision rule, a D‐dimer test and a CUS examination is safe and efficient. Both the rapid and the complete CUS test are comparable and efficient strategies, with differing advantages and disadvantages.     

Individual patient data meta‐analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients

Summary. Background: Unfractionated heparin (UFH) and low‐molecular‐weight heparin (LMWH) are both recommended for venous thromboembolism (VTE) prophylaxis in hospitalized medical patients. Objective: To perform an individual patient data meta‐analysis to evaluate the relative efficacy and safety of the LMWH enoxaparin and UFH in preventing VTE in hospitalized medical patients. Methods: Randomized clinical trials comparing subcutaneous enoxaparin (4000 IU once‐daily) and UFH (5000 IU subcutaneous two‐ or three‐times daily) for VTE prevention were identified by a systematic search. Individual patient data were obtained from each eligible trial. Results: Overall, four trials were eligible, including 3600 patients randomized to receive enoxaparin (n = 1799) or UFH (n = 1801). Median patient age was 71 years, and 49.3% were female. Compared with UFH, enoxaparin was associated with risk reductions of 37% for total VTE [relative risk (RR) 0.63, 95% confidence interval (CI) 0.51–0.77] and 62% for symptomatic VTE (RR 0.38, 95% CI 0.17–0.85) at day 15. RR for total VTE in stroke and non‐stroke patients was 0.59 (95% CI 0.47–0.74) and 0.87 (95% CI 0.51–1.50), respectively. Major bleeding rates were consistently low and similar between treatment groups at day 15 (RR 1.13, 95% CI 0.53–2.44). There was a trend towards reduced risk for mortality in patients receiving enoxaparin (RR 0.83, 95% CI 0.64–1.08), compared with UFH. Conclusions: Enoxaparin significantly reduces VTE in hospitalized medical patients, compared with UFH, without increasing the risk for major bleeding, and was associated with a trend towards reduced all‐cause mortality.     

Prevention of venous thromboembolism in the cancer surgery patient

Cancer patients, especially those undergoing surgery for cancer, are at extremely high risk for developing venous thromboembolism (VTE), even with appropriate thromboprophylaxis. Anticoagulant prophylaxis in cancer surgery patients has reduced the incidence of VTE events by approximately one-half in placebo-controlled trials, and extended prophylaxis (for up to 1 month) has also significantly reduced out-of-hospital VTE events in clinical trials in this population. Clinical trials show no difference between low-molecular-weight heparin (LMWH) and unfractionated heparin in VTE prophylaxis efficacy or bleeding risk in this population, although the incidence of heparin-induced thrombocytopenia is lower with LMWH. The risk-benefit profile of low-dose anticoagulant prophylaxis appears to be favorable even in many cancer patients undergoing neurosurgery, for whom pharmacologic VTE prophylaxis has been controversial because of bleeding risks.     

PRODIGE: a randomized placebo‐controlled trial of dalteparin low‐molecular‐weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma

Summary. Background and objectives: Venous thromboembolism (VTE) occurs in 20–30% of patients with malignant glioma per year of survival. We tested the efficacy of long‐term dalteparin low‐molecular‐weight heparin (LMWH) for prevention of VTE in these patients. Patients/methods: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti‐Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. Results: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety‐nine patients were randomized to LMWH and 87 to placebo. Twenty‐two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19–1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48–36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12‐month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73–2.0, P = 0.48). Conclusions: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long‐term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.     

Thalassemia trait and arterial thromboembolic events: a systematic review and a meta‐analysis of the literature

Summary. Background: An increased risk of venous thromboembolic events has been reported in thalassemic patients, in particular in patients with thalassemia intermedia. The association between β‐thalassemia trait and atherothrombotic cardiovascular events is not well established. Methods: In a systematic review and meta‐analysis of the literature, we evaluated the association between β‐thalassemia trait and arterial cardiovascular disease. Studies were identified from the MEDLINE and EMBASE (until July 2010) electronic databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random‐effects model. Statistical heterogeneity was evaluated with the I² statistic. Results: Of the 354 identified articles, eight case–control studies were eligible for the analysis. β‐Thalassemia trait was associated with a reduced risk of arterial cardiovascular disease (OR 0.45; 95% CI 0.45–0.60). Heterogeneity among studies was low (I² = 13%). The protective effect of β‐thalassemia trait was confined to male patients (OR 0.39; 95% CI 0.24–0.62), and was not observed in female subjects (OR 0.89; 95% CI 0.52–1.53). Conclusions: β‐Thalassemia trait may act as a protective factor against the development of arterial cardiovascular and cerebrovascular disease in male subjects. Larger prospective studies are necessary to confirm these preliminary findings and to further investigate the mechanisms underlying this protective effect.     

Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study

Summary. Background: Two recent case–control studies in Italy reported that long‐term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists on the possible association between long‐term traffic‐related air pollution and incident venous thromboembolism (VTE). Objectives: To examine the association between long‐term traffic exposure and incident VTE in a population‐based prospective cohort study. Methods: We studied 13 143 middle‐aged men and women in the Atherosclerosis Risk in Communities Study without a history of DVT or pulmonary embolism at baseline examination (1987–1989). The Geographical Information System‐mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE with proportional hazards regression models. Results: A total of 405 subjects developed VTE in 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95% confidence interval [CI] 0.88–1.57), 0.99 (95% CI 0.74–1.34) and 1.14 (95% CI 0.86–1.51) (P‐value for trend across quartiles = 0.64). For residents living within 150 m of major roads, as compared with subjects living further away, the adjusted hazard ratio was 1.16 (95% CI 0.95–1.42, P = 0.14). Conclusions: This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.     

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

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

Coffee consumption and the risk of venous thromboembolism: the Tromsø study

Summary. Background: Several studies have investigated the association between coffee consumption and cardiovascular disease, but little is known about coffee intake and the risk of venous thromboembolism (VTE). Objective: The aim of this prospective cohort study was to investigate the association between coffee consumption and the risk of incident VTE in a general population. Methods: Information about coffee consumption habits was obtained with a self‐administered questionnaire in 26 755 subjects, aged 25–97 years, who participated in the fourth survey of the Tromsø study (1994–1995). Incident VTE events were registered until the end of follow‐up, 1 September 2007. Results: There were 462 incident VTE events (1.60 per 1000 person‐years, 95% confidence interval [CI] 1.46–1.75) during a median of 12.5 years of follow‐up. A daily consumption of three to four cups was borderline associated (hazard ratio [HR] 0.70; 95% CI 0.48–1.02) and a daily consumption of five to six cups (HR 0.67; 95% CI 0.45–0.97) was significantly associated with reduced risk of VTE as compared with coffee abstainers in multivariable analysis adjusted for age, sex, body mass index (BMI), smoking status, physical activity, diabetes, history of cardiovascular disease and cancer. Similar risk estimates were found for provoked and unprovoked VTE, and in sex‐stratified analyses. Conclusion: Our findings suggest a possible U‐shaped relationship between coffee consumption and VTE, and that moderate coffee consumption may be associated with a reduced risk of VTE. However, more studies are needed to establish whether moderate coffee consumption is inversely associated with the risk of VTE.