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Growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (hs-TnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are associated with increased risk of venous thromboembolism (VTE) in noncancer patients. However, the performance of these biomarkers in cancer patients is unknown. Our objective was to assess performance of these biomarkers in predicting VTE in cancer patients at intermediate to high risk for VTE (Khorana Score ≥ 2). We used 1-month plasma samples from AVERT trial patients to determine if GDF-15, NT-proBNP, and hs-TnT levels are associated with VTE incidence between 1 and 7 months from the start of chemotherapy. The minimal Euclidean distance of the receiver operating characteristic curve was used to derive optimal cut-offs for GDF-15 and NT-proBNP given there was no evidence of a commonly used cut-off. Logistic and Fine and Gray competing risk regression analyses were used to calculate odds ratios (ORs) and subdistribution hazard ratios, respectively, while adjusting for age, sex, anticoagulation, and antiplatelet therapy. We tested in two groups: all patients (n = 476, Model 1) and all patients with nonprimary brain cancers (n = 454, Model 2). In models 1 and 2, GDF-15 ≥2,290.9 pg/mL had adjusted ORs for VTE of 1.65 (95% confidence interval [CI]: 0.89–3.08), and 2.28 (95% CI: 1.28–4.09), respectively. hs-TnT ≥14.0 pg/mL was associated with higher odds of VTE in models 1 and 2 (adjusted ORs: 2.26 [95% CI: 1.40–3.65] and 2.03 [95% CI: 1.07–3.84], respectively). For NT-proBNP, levels ≥183.5 pg/mL were not associated with VTE. Similar results were observed in the Fine and Gray analysis. Our results indicate that increased GDF-15 and hs-TnT levels predicted increased VTE risk.

Purpose Tube perforations are a common method of achieving early intraocular pressure control with ligated glaucoma drainage devices (GDDs). Our purpose was to investigate how bending GDD tubes affects the performance of needle perforations. Design Experimental report. Participants Twenty silicone GDD tubes attached to 27 G Rycroft cannulae tied with 7-0 Vicryl 10 mm from the cannulae tips. Methods Silicone GDD tubing was fitted over a 27 G Rycroft cannula and tied with a 7-0 suture 10 mm from the cannula tip. The tube was perforated 4 mm from the cannula tip with a 25 G needle (tube was kept straight). The tube was secured in a 50-mm water bath. Aqueous food dye was infused through the cannula from an adjustable height. The tube was observed under magnification while the height of the fluid column was adjusted to establish the pressure gradient at which the tube leaked dye (opening pressure) and ceased to leak (closing pressure), while the tube was held straight and bent 90 degrees. Measurements were repeated after a second perforation and a third perforation. Ten tubes were tested this way with 3 sequential slits. The entire experiment was repeated with another 10 tubes, but this time the tube was allowed to bend within the 3.5-mm open prongs of a needle holder during needle perforation. Main Outcome Measures Opening and closing pressures. Results For each tube, the opening and closing pressures were similar and highly reproducible, but there was wide variation between tubes. In the tubes kept straight when perforated, the opening/closing pressure ranged from 5 to 25 cmH2O. The opening and closing pressures of slits made in the bent tube were significantly lower, frequently leaking at Conclusions Tube perforations behave like pressure-sensitive valves, opening whenever intraluminal pressure increases above a specific value. However, we found a large variation in the performance of fenestrations made with a 25-G hypodermic needle. Allowing the GDD tube to bend during needle perforation increases the risk of very low opening and closing pressures.

Background: Transfer of young adults (YAs) with chronic diseases from pediatric- to adult hospital-based care is a major life event for this vulnerable group of patients. Inadequate preparation of the YAs and poorly planned transition of care are associated with subsequent treatment non-adherence, discontinuity of care and poor long-term outcomes. A formalized structured process for HCT has been demonstrated to improve patient experience and optimize subsequent engagement with adult healthcare and is now recommended as standard of care. Implementation of this approach is however suboptimal at a global level and practices vary within institutes and between specialties. We recognized this issue at the Ottawa Hospital (TOH) and sought to explore the impact of differences in approaches to HCT from the YA’s perspective. We assessed and compared patient experience of HCT in specialties with and without a structured HCT program with the aim of gaining insight into gaps in care to facilitate reforming current practices and optimizing care. Methods: YAs aged 18 to 25 years (n=175) who had transitioned into five adult specialties at TOH volunteered for this study. A self-care assessment survey and two feedback surveys were customized from the Got TransitionTM HCT measurement resources. Responses of those YAs attending clinics with (n=93) and without (n=82) a structured HCT program were assessed and compared.Results: YAs who transitioned into clinics with structured HCT reported better medical knowledge and practical skills for independent use of the healthcare system compared to YAs who attended clinics without a formal HCT process. This group reported a greater level of involvement in preparation for HCT by their pediatric health-care providers and better education and provision of practical information by their adult healthcare team compared to the YAs attending clinics without a formal HCT process. Conclusions: Results demonstrate superior health knowledge and healthcare usage skills in YAs attending clinics with structured HCT programs and support the benefit of establishing a structured approach to HCT across all specialties caring for transitioned YAs at TOH. By identifying strengths and gaps in current practices, this study has provided a basis to drive institutional reform to improve quality of care for this vulnerable patient population.

BackgroundThere is widespread concern across the clinical and research communities that clinical trials, powered for patient-reported outcomes, testing new surgical procedures are often expensive and time-consuming, particularly when the new intervention is shown to be no better than the standard. Conventional (non-adaptive) randomised controlled trials (RCTs) are perceived as being particularly inefficient in this setting. Therefore, we have developed an adaptive group sequential design that allows early endpoints to inform decision making and show, through simulations and a worked example, that these designs are feasible and often preferable to conventional non-adaptive designs. The methodology is motivated by an ongoing clinical trial investigating a saline-filled balloon, inserted above the main joint of the shoulder at the end of arthroscopic debridement, for treatment of tears of rotor cuff tendons. This research question and setting is typical of many studies undertaken to assess new surgical procedures.MethodsTest statistics are presented based on the setting of two early outcomes, and methods for estimation of sequential stopping boundaries are described. A framework for the implementation of simulations to evaluate design characteristics is also described.ResultsSimulations show that designs with one, two and three early looks are feasible and, with appropriately chosen futility stopping boundaries, have appealing design characteristics. A number of possible design options are described that have good power and a high probability of stopping for futility if there is no evidence of a treatment effect at early looks. A worked example, with code in R, provides a practical demonstration of how the design might work in a real study.ConclusionsIn summary, we show that adaptive designs are feasible and could work in practice. We describe the operating characteristics of the designs and provide guidelines for appropriate values for the stopping boundaries for the START:REACTS (Sub-acromial spacer for Tears Affecting Rotator cuff Tendons: a Randomised, Efficient, Adaptive Clinical Trial in Surgery) study.Trial registrationISRCTN Registry, ISRCTN17825590. Registered on 5 March 2018.

IntroductionEach year in the UK over 120 000 people fracture their ankle. It is not known what the best rehabilitation strategy is for these people. Traditionally standard care has involved immobilisation in a plaster cast but an alternative is a functional brace, which can be removed to allow early movement. This paper details the protocol for a multicentre randomised trial of plaster cast immobilisation versus functional bracing for patients with an ankle fracture.Methods and analysisWe will recruit adults with a fractured ankle, for which the treating clinician would consider plaster cast to be a reasonable management option. Randomisation will be on a 1:1 basis, stratified by centre, operative or non-operative management and age. Participants will be allocated to either plaster cast or a functional brace, both treatments are widely used. To have 90% power to detect a difference of 10 points on the primary outcome (Olerud and Molander Ankle Score) at the primary outcome time point (16 weeks), we need to randomise a minimum of 478 people. Quality of life and resource use will be collected at 6, 10, 16, 24 weeks and 12, 18, 24 months. The differences between treatment groups will be assessed on an intention-to-treat basis. The economic evaluation will adhere to the recommendations of the National Institute for Health and Care Excellence reference case.Ethics, registration and disseminationNational Research Ethic Committee approved this study on 4 July 2017 (17/WM/0239). The first site opened to recruitment 9 October 2017. The results of this trial will be submitted to a peer-reviewed journal and will inform clinical practice.Trial registration numberISRCTN15537280; Pre-results.

Essentials Recent randomized trials suggested fewer bleeding events in fragile patients with VTE receiving DOACs.The frequency, clinical characteristics and outcome of these patients have not been reported in real life.Fragile patients with VTE had a higher risk for major bleeding or death and a lower risk for recurrences than non‐fragile. Background Subgroup analyses from randomized trials suggested favorable results for the direct oral anticoagulants in fragile patients with venous thromboembolism (VTE). The frequency and natural history of fragile patients with VTE have not been studied yet. Objectives To compare the clinical characteristics, treatment and outcomes during the first 3 months of anticoagulation in fragile vs non‐fragile patients with VTE. Methods Retrospective study using consecutive patients enrolled in the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry. Fragile patients were defined as those having age ≥75 years, creatinine clearance (CrCl) levels ≤50 mL/min, and/or body weight ≤50 kg. Results From January 2013 to October 2016, 15 079 patients were recruited. Of these, 6260 (42%) were fragile: 37% were aged ≥75 years, 20% had CrCl levels ≤50 mL/min, and 3.6% weighed ≤50 kg. During the first 3 months of anticoagulant therapy, fragile patients had a lower risk of VTE recurrences (0.78% vs 1.4%; adjusted odds ratio [OR]: 0.52; 95% confidence intervals [CI]: 0.37‐0.74) and a higher risk of major bleeding (2.6% vs 1.4%; adjusted OR: 1.41; 95% CI: 1.10‐1.80), gastrointestinal bleeding (0.86% vs 0.35%; adjusted OR: 1.84; 95% CI: 1.16‐2.92), haematoma (0.51% vs 0.07%; adjusted OR: 5.05; 95% CI: 2.05‐12.4), all‐cause death (9.2% vs 3.5%; adjusted OR: 2.02; 95% CI: 1.75‐2.33), or fatal PE (0.85% vs 0.35%; adjusted OR: 1.77; 95% CI: 1.10‐2.85) than the non‐fragile. Conclusions In real life, 42% of VTE patients were fragile. During anticoagulation, they had fewer VTE recurrences and more major bleeding events than the non‐fragile.

Background Evidence-based recommendations do not adequately address the treatment of right heart thrombi in patients who present with acute symptomatic pulmonary embolism. Methods This study included patients who had acute pulmonary embolism associated with right heart thrombi and participated in the Registro Informatizado de la Enfermedad TromboEmbolica registry. We assessed the effectiveness of anticoagulation versus reperfusion treatment for the outcomes of all-cause mortality, pulmonary embolism–related mortality, recurrent venous thromboembolism, and major bleeding rates through 30 days after initiation of pulmonary embolism treatment. We used propensity score matching to adjust for the likelihood of receiving reperfusion treatment. Results Of 325 patients with pulmonary embolism and right heart thrombi, 255 (78%; 95% confidence interval, 74-83) received anticoagulation and 70 (22%; 95% confidence interval, 17-26) also received reperfusion treatment. Propensity score–matched pairs analyses did not detect a statistically lower risk of all-cause death (6.2% vs 14%, P = .15) or pulmonary embolism–related mortality (4.7% vs 7.8%; P = .47) for reperfusion compared with anticoagulation. Of the patients who received reperfusion treatment, 6.2% had a recurrence during the study follow-up period, compared with 0% of those who received anticoagulation ( P = .049). The incidence of major bleeding events was not statistically different between the 2 treatment groups (3.1% vs 3.1%; P = 1.00). Conclusions In patients with pulmonary embolism and right heart thrombi, no significant difference was found between reperfusion therapy and anticoagulant therapy for mortality and bleeding. The risk of recurrences was significantly higher for reperfusion therapy compared with anticoagulation. Right heart thrombi may not warrant riskier interventions than standard anticoagulation.

Background The benefits of a diagnostic workup for occult cancer in patients with VTE are controversial. Our aim was to provide and validate a risk score for occult cancer in patients with VTE. Methods We designed a nested case-control study in a cohort of patients with VTE included in the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry from 2001 to 2014. Cases included cancer detected beyond the first 30 days and up to 24 months after VTE. Control subjects were defined as patients with VTE with no cancer in the same period. Results Of 5,863 eligible patients, 444 (7.6%; 95% CI, 6.8%-8.2%) were diagnosed with occult cancer. On multivariable analysis, variables selected were male sex, age > 70 years, chronic lung disease, anemia, elevated platelet count, prior VTE, and recent surgery. We built a risk score assigning points to each variable. Internal validity was confirmed using bootstrap analysis. The proportion of patients with cancer who scored ≤ 2 points was 5.8% (241 of 4,150) and that proportion in those who scored ≥ 3 points was 12% (203 of 1,713). We also identified scores divided by sex and age subgroups. Conclusions This is the first risk score that has identified patients with VTE who are at increased risk for occult cancer. Our score needs to be externally validated.

Background A comprehensive evaluation of temporal trends in the treatment of patients who have DVT may assist with identification of modifiable factors that contribute to short-term outcomes. Methods We assessed temporal trends in length of hospital stay and use of pharmacological and interventional therapies among 26,695 adults with DVT enrolled in the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2014. We also examined temporal trends in risk-adjusted rates of all-cause, pulmonary embolism-related, and bleeding-related death to 30 days after diagnosis. Results The mean length of hospital stay decreased from 9.0 days in 2001 to 2005 to 7.6 days in 2010 to 2014 (P

SummaryGenetic factors are thought to contribute to the pathogenesis of acute myocardial infarction (AMI).A common variant of factor XIII (FXIII), FXIII Val34Leu, may be protective against developing an AMI, but various studies show conflicting results. We performed a meta-analysis to determine whether the FXIII Val34Leu variant is associated with a decreased risk of AMI. One hundred ninety-five articles were reviewed and 12 case-control studies were selected. We included studies involving patients with objectively diagnosed AMIs (WHO criteria), provided that FXIII Val34Leu genotyping data were available. Inclusion decisions, quality assessment, and data extraction were conducted by two reviewers. Hypothesizing that the Leu allele was protective, we performed three analyses with the Val/Val genotype as the reference group. Pooled odds ratios (OR) and their 95% confidence intervals (95% CI) were determined. Prior to pooling, heterogeneity testing was performed using the I 2 statistic. These studies included a total of 8,743 patients, of which 3,663 were AMI patients and 5,080 were healthy controls. Using the random effects methods, protective effects were seen with the Leu/Val genotype alone (OR 0.79, 95% CI 0.68–0.93) and with Leu/Val and Leu/Leu genotypes combined (OR 0.79, 95% CI 0.66–0.93).There was also a protective effect with the Leu/Leu genotype alone, (not statistically significant: OR 0.83, 95% CI 0.61–1.12), likely due to the low frequency of this genotype. These results suggest that there is an association between the factor XIII Leu allele and a modest protective effect against AMI and may provide useful information in profiling susceptibility to myocardial infarction.

Introduction The aim of this study was to investigate the recurrence rate of venous thromboembolism (VTE) and the prevalence of major bleeding or death in patients with previous VTE in pregnancy and puerperium. Risk factors for VTE recurrence were also assessed. Materials and methods We evaluated a cohort of patients enrolled in the international, multicenter, prospective Registro Informatizado de la Enfermedad Trombo-Embolica (RIETE) registry with objectively confirmed VTE. Results In the registry, 607 women were presenting with VTE that occurred during pregnancy or puerperium. The 2-year VTE recurrence rate was 3.3% (CI: 95 1.5–5.0%) and the recurrent VTE incidence rate was 2.28 events/100 patients-year. Among the 16 cases of VTE recurrence 11 cases appeared during drug treatment while only five cases were diagnosed after therapy discontinuation. No significant difference was found in treatment duration among these two subgroups of VTE recurrence cases and women without recurrence. Furthermore, the use of thrombolytics and inferior vena cava filter in initial treatment was associated to an increased risk of VTE recurrence. Conclusions The current study provides new insights on VTE recurrence rate in patients with deep vein thrombosis (DVT) or pulmonary embolism (PE) that occurred in pregnancy or postpartum period. These findings can contribute to risk assessment of thrombotic burden, thereby allowing for better decision making regarding antithrombotic management in this clinical setting.

We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics.We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence.For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C).Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.

SummaryClinical equipoise exists regarding whether relatives of individuals with venous thromboembolism (VTE) and thrombophilia should be screened for thrombophilia. There have been no systematic attempts to summarize studies that have assessed the incidence of VTE in relatives. The purpose of this review was to systematically identify and review observational studies with thrombophilic relatives and to summarize their findings with respect to their risk of VTE.We conducted a systematic literature review and included nine observational studies meeting a priori inclusion criteria. Potentially eligible studies evaluated VTE incidence in relatives of index patients (probands) with symptomatic thrombophilia. In the four prospective studies, the incidence of VTE for asymptomatic family members with factor V Leiden ranged from 0.58-0.67% per year, 1.0-2.5% for protein C deficiency, 0.7-2.2% for protein S deficiency, and 4% for antithrombin deficiency. About half of all VTEs occurred during well-known risk periods but incidence rates were decreased by use of prophylaxis. No deaths from pulmonary embolism or fatal hemorrhages from anticoagulants were reported. The incidence of VTE was generally lower in the retrospective studies. The pooled relative risk from four retrospective studies for factor V Leiden carriers was 3.69 (CI 2.27, 6.00) and from two studies the pooled relative risk for deficiencies of protein C, protein S, and antithrombin was 10.58 (CI 5.38, 20.81).In conclusion, the risk of VTE events in asymptomatic relatives is low, but this may be an underestimate. Anticoagulant prophylaxis during risk periods appears to be of benefit but further research in this area is required.

Background Individuals with factor V Leiden or prothrombin G20210A mutations are at a higher risk to develop venous thromboembolism. However, the influence of these polymorphisms on patient outcome during anticoagulant therapy has not been consistently explored. Methods We used the Registro Informatizado de Enfermedad TromboEmbolica database to compare rates of venous thromboembolism recurrence and bleeding events occurring during the anticoagulation course in factor V Leiden carriers, prothrombin mutation carriers, and noncarriers. Results Between March 2001 and December 2015, 10,139 patients underwent thrombophilia testing. Of these, 1384 were factor V Leiden carriers, 1115 were prothrombin mutation carriers, and 7640 were noncarriers. During the anticoagulation course, 160 patients developed recurrent deep vein thrombosis and 94 patients developed pulmonary embolism (16 died); 154 patients had major bleeding (10 died), and 291 patients had nonmajor bleeding. On multivariable analysis, factor V Leiden carriers had a similar rate of venous thromboembolism recurrence (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.82-1.64), half the rate of major bleeding (adjusted HR, 0.50; 95% CI, 0.25-0.99) and a nonsignificantly lower rate of nonmajor bleeding (adjusted HR, 0.66; 95% CI, 0.43-1.01) than noncarriers. Prothrombin mutation carriers and noncarriers had a comparable rate of venous thromboembolism recurrence (adjusted HR, 1.00; 95% CI, 0.68-1.48), major bleeding (adjusted HR, 0.75; 95% CI, 0.42-1.34), and nonmajor bleeding events (adjusted HR, 1.10; 95% CI, 0.77-1.57). Conclusions During the anticoagulation course, factor V Leiden carriers had a similar risk for venous thromboembolism recurrence and half the risk for major bleeding compared with noncarriers. This finding may contribute to decision-making regarding anticoagulation duration in selected factor V Leiden carriers with venous thromboembolism.

Background Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. Methods In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. Results A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months....

A variety of types of fossil evidence — pollen, macrofossils, and snails — document the occurrence of boreal forest species at low latitudes of eastern North America duringthe last full glacial (18,000 yr B.P.). Both the northern and southern boundaries of boreal coniferous forest are determined by limiting values of summer warmth. Knowledge of these limiting factors permits construction of a gradient of Wisconsinan summer temperatures. The reconstructed temperature departures are 5–12°C for the eastern part of the continent south of the ice, with temperature departures of no less than 5–6°C along the Gulf coast. Information regarding occurrence of tundra and depression of treeline in the Appalachian mountains provides another estimate of summer temperature depression that is in agreement with these results. Comparison with proxy data from other parts of the world shows that the degree of temperature depression is of about the same degree as that postulated for the tropics (Rind and Peteet, 1985; Lui and Colinvaux, 1985) on the basis of the elevational shifts in vegetational zones and snowline. Quantitative estimates of past temperatures (or temperature departures) of the type produced here are valuable because they permit comparison with model simulations of the full-glacial climate. The depression in summer temperatures indicated is lower than most recent modeling results using CLIMAP boundary conditions and adds to suggestions that the reconstructed sea-surface temperatures used as boundary conditions in simulations of glacial and Holocene climates may be in error.

Low-molecular-weight heparin (LMWH) is increasingly being used for prophylaxis of venous thromboembolism (VTE) and prevention of pregnancy associated morbidity in pregnant women with thrombophilia. We sought to determine if the administration of prophylactic doses of LMWH downregulates coagulation activation in high risk pregnant women with thrombophilia. This sub-study was planned as part of a randomized open label controlled trial (Thrombophilia in Pregnancy Prophylaxis Study [TIPPS]) in which patients at high risk of pregnancy complications with confirmed thrombophilia are randomized to receive either dalteparin (5,000 units/day until 20 weeks then 5,000 units q12h until 37 weeks or onset of labor) or no treatment. Blood samples were collected at baseline, day 7-9 (after starting study drug), week 20 (before increasing study drug), week 36 (prior to stopping study drug) and at the time of admission to the labor and delivery unit. Samples were not drawn at fixed times in relation to drug injection. These samples were analyzed for levels of thrombin-antithrombin complexes (TAT), prothrombin fragments 1 + 2 (F1.2), D-dimer and anti-Xa activity. Generalized linear mixed models were used for statistical analysis and model results were controlled for age, smoking status, type of thrombophilia and predisposing risk factors. The effect of dalteparin on TAT levels was defined as the primary outcome. Of 198 patients eligible, 114 were enrolled in TIPPS. Ninety-one were eligible for the TIPPS coagulation activation sub-study and randomized. Thirty-nine patients were analyzed in the treatment group (dalteparin) and 46 patients in the control group (no intervention). Levels of coagulation activation factors F1.2, TAT and D-dimer increased significantly throughout pregnancy in both groups (p0.0001). Dalteparin prophylaxis resulted in a significant increase in anti-Xa activity through pregnancy (p0.0001) compared to controls. Dalteparin had no significant effects on the levels of TAT, F1.2 and D-dimer throughout pregnancy in thrombophilic women. A post-hoc Monte Carlo power analysis revealed that our study had 100% and 88% power to detect reductions in TAT values on treatment of 50% and 25%, respectively. Prophylaxis with dalteparin at doses used in this study did not reduce coagulation activation in high risk thrombophilic women during pregnancy.

It is possible to delimit the areas of the North, Central, and South America that are most susceptible to fire and would have been most affected by burning practices of early Americans. Areas amounting to approximately 155 x 10(5) km2 are here designated as the most burnable part of the New World. Using estimates of burnable biomass, burning frequency, and burning efficiency, the authors determine the amount of biomass burned annually in an environment in which anthropogenic fires were at a hypothesized maximum. The amount of carbon released annually approximates estimates for present-day burning. Changes in carbon sinks may have been the most significant aspect of a shift to a low-biomass state. Decreases in stored biomass, soil carbon, and charcoal production may have had effects on a global scale. Likewise, the shift to a higher biomass/lower fire-frequency state over the last 400-500 years may be one component of an increased mid- to high-latitude carbon sink. The assessment made here is preliminary but may aid in clarifying the state of the climate system during the pre-industrial period.

Abstract 4209 Background: The risk of recurrent venous thromboembolism (VTE) in patients with cancer-associated VTE, remains high even with the use of low molecular weight heparin (LMWH). However, due to the heterogeneity of the disease it is probable that recurrence risk varies widely. We have developed a prediction rule to classify risk of recurrence in the first 6 months of treatment: + 1 is scored for each of female gender, lung cancer and prior VTE and – 1 is scored for breast cancer and – 2 for TNM stage 1 disease. With a score of ≤ 0, 4.5% of patients recur (this represented 48% of the patient populations), and > 0, 19.7% recur. The rule was derived in a retrospective cohort study of patients followed at the Thrombosis unit of the Ottawa hospital and requires validation. Methods: We applied our rule in a new set of 819 consecutive patients with cancer-associated VTE from 2 multicentre randomized controlled trials comparing LMWH with vitamin K antagonists (VKA) (ClotCant group). In these studies the stage of disease was not separated by exact TNM classification, rather patients were classified as stage I, II (no metastasis) versus III, IV (metastasis). As such, we redid our derivation model with stage I and II grouped together, which gave this variable a score of – 1. This resulted in a prediction rule which gave a recurrence risk that no longer clearly dichotomized risk; rather gave a low, intermediate, and high risk groups. As in our derivation study, we evaluated patients' risk of recurrence regardless of type of anticoagulant use (VKA or LMWH). Results: Of 819 patients, 86 (10.5%) presented with a VTE recurrence during the anticoagulation period. When we applied our derivation rule in this population, we were able to demonstrate a significant difference in VTE recurrence risk dependent on gender, primary tumour site, stage and history of prior VTE. Patients with a score < 0 have low risk (5.1%) for VTE recurrence and this represented 19% of the patient population; patients with a score of 0 had a intermediate risk (9.8%) and this represented 42% of patients; a score ≥ 1 was high risk (13.9%), occurring in 38% of the population. Dichotomizing the results gave a recurrence risk of 8% in patients with a score ≤ 0 and a 15.2% recurrence risk with a score > 0. Conclusion: the validation dataset suggests reproducibility of our model. The dichotomized score is less discriminatory than our original model suggesting an advantage to classifying patients tumour stage as TNM stage I versus stage II, III and IV. Unfortunately, we could not test this hypothesis with the ClotCant dataset. Our model appears to differentiate risk for recurrence and should be utilized in treatment trials: attempting novel treatment strategies in high risk patients since LMWH alone does not seem to be enough; and using the less costly typical “LMWH followed by oral anticoagulants” in the low risk population to evaluate whether VKA can be as safe and effective as long term LMWH. Disclosures: Lee: Eisai: Research Funding; Sanofi Aventis: Consultancy, Honoraria; Leo Pharma: Consultancy; Pfizer: Consultancy, Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Speakers Bureau.

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor under regulatory review for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery. Two large, randomized controlled trials compared 10 mg rivaroxaban once daily (od) with subcutaneous (sc) enoxaparin 40 mg od (RECORD3) and enoxaparin 30 mg twice daily (bid)(RECORD4) in patients undergoing total knee replacement (TKR). Rivaroxaban and enoxaparin were administered for 12 ± 2 days in both trials. In RECORD3, rivaroxaban was associated with a relative risk reduction (RRR) of 49% in total VTE (composite of any deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality) and 66% in symptomatic VTE versus enoxaparin (p=0.005). In RECORD4, rivaroxaban reduced total VTE versus enoxaparin (RRR 32%, p=0.012). There was no statistical difference in major bleeding between rivaroxaban and enoxaparin in either study. Although the comparison between rivaroxaban and enoxaparin is important, there are alternative VTE prophylaxes such as warfarin, fondaparinux and dabigatran (which received EU marketing approval in March 2008) for which there are no direct comparisons with rivaroxaban. This analysis was designed to assess the relative efficacy and safety of rivaroxaban versus warfarin, fondaparinux and dabigatran. This is important for clinical decision makers, but also provides important inputs for cost-effectiveness analyses of rivaroxaban versus these comparators. Methods: The efficacy of rivaroxaban relative to warfarin, fondaparinux and dabigatran was assessed by comparing the occurrence of total VTE, total DVT (proximal and distal) and symptomatic DVT. Relative safety was assessed using rates of major bleeding. A systematic literature review identified randomised control trials (RCTs) comparing enoxaparin to warfarin, fondaparinux or dabigatran in TKR. Each of these publications was reviewed by independent analysts. Data for relevant efficacy and safety outcomes were taken from these studies, and from RECORD3 and 4 for rivaroxaban versus enoxaparin. If more than one set of RCTs were available for each comparator, a meta-analysis was undertaken to obtain the pooled results for efficacy and safety (Bucher et al., 1997). Indirect comparisons were conducted based on the summary statistics obtained in each meta-analysis. Results are presented for the indirect comparisons through enoxaparin 30 mg bid and enoxaparin 40 mg od separately. The results from such an analysis do not represent the same level of evidence as a comparative trial, but they provide a guide to potential relative efficacy and safety in the absence of a comparative trial and could be used by authorities to aid decision making (NICE, 2007). Results: Rivaroxaban significantly reduced the incidence of key outcomes. When enoxaparin 30 mg bid was used as the common comparator, rivaroxaban was associated with reductions in total VTE of 56% versus warfarin (p Conclusions: An indirect statistical comparison showed that rivaroxaban reduced the incidence of overall or symptomatic VTE events relative to alternative prophylaxes without increasing major bleeding following TKR. In the absence of direct comparisons, this is the best evidence regarding the relative efficacy and safety of these options.

Hogben was a brilliant biologist, a stimulating and indefatigable teacher, and a famous writer. More essentially, he was a dedicated socialist or scientific humanist— he used the former label in his youth and the latter in his maturity but the faith remained the same (1918a, 1939b). Professor Michael Abercrombie, who was in his Department at Birmingham, described him to me as a very moral man and Dr Sidney Truelove, his second-in-command at the War Office, as a puritan; not that he was particularly chaste or sober; they meant that he lived in strict conformity to his declared ethical creed.