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Essentials Long-term recurrence risk after a first unprovoked VTE with negative d-dimer levels is uncertain. Anticoagulation was stopped if d-dimer was negative, and was continued if d-dimer was positive. Five years after stopping anticoagulants, recurrent VTE was 30% in men and 17% in women. Negative d-dimers do not justify stopping anticoagulants in most men but appear to in most women. BACKGROUND The long-term risk of recurrence in patients with a first unprovoked venous thromboembolism (VTE) who have negative d-dimer results is uncertain. OBJECTIVES To determine this risk, including in subgroups based on sex. PATIENTS AND METHODS ln a prospective interventional cohort study of 410 patients with a first unprovoked VTE, anticoagulants were stopped if d-dimer was negative on therapy and 1 month after stopping therapy. Other patients remained on anticoagulant therapy. We previously reported findings after a mean of 2.2 years. The current report includes 3 years of additional follow-up in 293 of these patients. RESULTS During a median follow-up of 5.0 years, recurrent VTE after stopping therapy in response to negative d-dimer testing was 5.1% (95% confidence interval [CI], 3.6-6.5) per patient-year overall, 7.5% (95% CI, 5.5-10.0) in men, 3.8% (95% CI, 2.0-6.6) in women with VTE not associated with estrogens, and 0.4% (95% CI, 0.0-2.3) in women with VTE associated with estrogens (P

Introduction Dose adjustment based on laboratory monitoring is not routinely recommended for patients treated with rivaroxaban but because an association has been reported between high drug level and bleeding, it would be of interest to know if measuring drug level once could identify patients at risk of bleeding who might benefit from a dose reduction. Objective This study was aimed to investigate the reliability of a single measurement of rivaroxaban level to identify clinic patients with persistently high levels, defined as levels that remained in the upper quintile of drug-level distribution. Methods In this prospective cohort study of 100 patients with atrial fibrillation or venous thromboembolism, peak and trough rivaroxaban levels were measured using the STA-Liquid Anti-Xa assay at baseline and after 2 months. Values of 395.8 and 60.2 ng/mL corresponded to the 80th percentile for peak and trough levels, respectively, and levels above these cut-offs were categorized as high for our analyses. Results Among patients with a peak or trough level in the upper quintile at baseline, only 26.7% (95% confidence interval [CI]: 10.9–52.0%), and 13.3% (95% CI: 2.4–37.9%), respectively, remained above these thresholds. Conclusion Our findings do not support the use of a single rivaroxaban level measurement to identify patients who would benefit from a dose reduction because such an approach is unable to reliably identify patients with high levels.

Venous thromboembolism (VTE) is the third most common cause of vascular mortality worldwide and comprises deep-vein thrombosis (DVT) and pulmonary embolism (PE). In this review, we discuss how an understanding of VTE epidemiology and the results of thromboprophylaxis trials have shaped the current approach to VTE prevention. We will discuss modern thromboprophylaxis as it pertains to genetic risk factors, exogenous hormonal therapies, pregnancy, surgery, medical hospitalization, cancer, and what is known thus far about VTE in COVID-19 infection.

Background Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients.Objectives To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis.Results and Discussion We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs.Conclusion The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

Until recently, attempts to improve the benefit of aspirin by adding another antithrombotic agent have not resulted in a mortality reduction in patients with chronic symptomatic atherosclerosis. In this population, COMPASS is the only one among six trials to show a significant mortality reduction, thereby providing evidence of a clear net clinical benefit with the combination of low-dose rivaroxaban plus aspirin. In this systematic review, we sought to determine whether the mortality benefit of the combination arm in COMPASS is best explained by greater statistical power or by a more favorable efficacy–safety profile than the other regimens evaluated in patients with chronic symptomatic atherosclerosis.

Background Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined. Methods and Results Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and > 90% reversal at 24 hours. Conclusion Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.

Canadian guidelines recommend non vitamin K antagonists (NOACs) in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF), but NOACs are more expensive than VKAs. Canada has a universal healthcare system that covers the cost of NOACs for select patient groups. Ability to pay for NOACs may influence their use. We reviewed medical charts of Hamilton General Hospital outpatients under the age of 65 with a new diagnosis of AF who were referred for initiation of OAC therapy. We contacted these patients by phone and asked them to complete a questionnaire regarding their OAC choice, economic factors that may have influenced this choice (income, insurance) and the financial burden of OAC therapy. We included 110 patients, mean age 56 years, and 26.4% females. NOAC users had a higher median neighborhood income than VKA users (p = 0.0144, n = 110). 73 patients responded to the questionnaire. NOAC users reported higher annual household income (p = 0.0038, n = 73). Patients with private insurance were more likely to use NOACs than those without insurance (p = 0.0496, n = 73). The cost of NOACs and ability to pay is a determinant of their use Ontario patients under the age of 65. This two tiered provision of care appears to contradict the values of Canada's universal healthcare system.

Essentials Coronary artery bypass graft (CABG) failure is associated with myocardial infarction and death. We tested whether more frequent dosing improves aspirin (ASA) response following CABG surgery. Twice-daily compared with once-daily dosing reduces ASA hyporesponsiveness after CABG surgery. The efficacy of twice-daily ASA needs to be tested in a trial powered for clinical outcomes. SummaryBackground Acetyl-salicylic acid (ASA) hyporesponsiveness occurs transiently after coronary artery bypass graft (CABG) surgery and may compromise the effectiveness of ASA in reducing thrombotic graft failure. A reduced response to ASA 81 mg once-daily after CABG surgery is overcome by four times daily ASA dosing. Objectives To determine whether ASA 325 mg once-daily or 162 mg twice-daily overcomes a reduced response to ASA 81 mg once-daily after CABG surgery. Methods Adults undergoing CABG surgery were randomized to ASA 81 mg once-daily, 325 mg once-daily or 162 mg twice-daily. The primary outcome was median serum thromboxane B2 (TXB2) level on postoperative day 4. We pooled the results with those of our earlier study to obtain better estimates of the effect of ASA 325 mg once-daily or in divided doses over 24 h. Results We randomized 68 patients undergoing CABG surgery. On postoperative day 4, patients randomized to receive ASA 81 mg once-daily had a median day 4 TXB2 level of 4.2 ng mL−1 (Q1, Q3: 1.5, 7.5 ng mL−1), which was higher than in those randomized to ASA 162 mg twice-daily (1.1 ng mL−1; Q1, Q3: 0.7, 2.7 ng mL−1) and similar to those randomized to ASA 325 mg once-daily (1.9 ng mL−1; Q1, Q3: 0.9, 4.7 ng mL−1). Pooled data showed that the median TXB2 level on day 4 in groups receiving ASA 162 mg twice-daily or 81 mg four times daily was 1.1 ng mL−1 compared with 2.2 ng mL−1 in those receiving ASA 325 mg once-daily. Conclusions Multiple daily dosing of ASA is more effective than ASA 81 mg once-daily or 325 mg once-daily at suppressing serum TXB2 formation after CABG surgery. A twice-daily treatment regimen needs to be tested in a clinical outcome study.

Background Systematic reviews reporting time trends in mortality following major orthopaedic surgery are few and have limitations. They reported on only a fraction (< 15%) of the available data and did not investigate potential causes of the reduction in mortality. Methods We searched PubMed for randomized trials and observational studies, published between 1950 and 2016, reporting on mortality within 3 months of elective total hip and knee replacement (THR/TKR). Mortality risks were estimated for each 5-year interval using a Poisson regression model and presented by study design and mode of prophylaxis. To estimate the mortality reduction unrelated to anti-thrombotic use, we performed a pooled analysis of four thromboprophylaxis strategies for which data spanned five decades. Results We identified 255 eligible studies, which documented 31,604 deaths among 6,293,954 patients, and found a consistent decline in mortality irrespective of study design and mode of prophylaxis. Mortality declined from 1.15% pre-1980 to 0.24% post-2000, a 78.7% relative risk reduction (95% confidence interval [CI]: 74.7–82.1%) in randomized and cohort studies. Furthermore, our data showed a 74.4% (95% CI: 68.7–79.0%) relative reduction in mortality independent of the methods of prophylaxis, thereby indicating that improvements in peri-operative care unrelated to anti-thrombotic prophylaxis played a major role in such reduction. Conclusion Mortality following elective THR/TKR has markedly declined over the past 50 years and is now low irrespective of which prophylactic agent is being used. Although anti-thrombotic prophylaxis may have contributed, other improvements in peri-operative care played a major role in the mortality reduction.

Objectives: An increased rate of platelet production is a possible cause of reduced antithrombotic response to once-daily aspirin. Markers of immature platelets (IPs),such as immature platelet count (IPC), immature platelet fraction (IPF), and mean platelet volume (MPV) might be useful for identifying patients who have an increase in their rate of platelet production. However, their potential as markers of platelet production has not been rigorously evaluated. We aimed to investigate the utility of the IPC, IPF, and MPV as surrogates for increased platelet production using coronary artery bypass grafting (CABG) as a model of enhanced thrombopoiesis. Methods: Daily changes in platelet count, IPC, IPF, and MPV were followed in 45 patients undergoing CABG. Results: The rise in IP markers preceded that in the platelet count. IPC (16% per day increase from nadir) but not IPF or MPV showed a significant and sustained rise,which paralleled the pattern observed with platelet count (18% per day increase from nadir).Conclusions: Of the 3 markers, IPC was the most promising as surrogates for platelet production. Future studies should evaluate the utility of the IPC to identify patientswith cardiovascular disease with reduced response to aspirin who might benefit fromtwice-dailyaspirin. Refereed/Peer-reviewed

Cancer is a strong risk factor for venous thromboembolism.1 For decades, standard treatment for all patients with venous thromboembolism consisted of heparin followed by warfarin. The rate of recur...

The non-vitamin K antagonist oral anticoagulants (NOACs), rivaroxaban, apixaban, and dabigatran, have been shown in phase 3 trials to be effective for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Results from prior studies suggested that the safety of anticoagulants in such patients was improved if the first postoperative dose was delayed for at least 6 h after surgery. The timing of the first postoperative dose of the NOACs tested in phase 2 studies differed among the three NOACs: dabigatran was started 1 to 4 h postoperatively, whereas rivaroxaban and apixaban were started at least 6 and 12 h, postoperatively, respectively. Our review of the timing of initiation of thromboprophylaxis in randomized trials provides three related lessons. First, clinical trials performed before the NOACs were evaluated demonstrated that delaying the first dose of prophylactic anticoagulation until after major surgery is effective and safe. Second, the optimal timing of the first dose of prophylactic anticoagulation after surgery depends on the dose that is selected. Third, the results of the phase 3 trials with NOACs for thromboprophylaxis support the concept that acceptable efficacy and safety can be achieved when the appropriate first postoperative dose of anticoagulant is delayed for at least 6 h after surgery.

Summary 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.

Summary Background The efficacy of ASA for prevention of graft failure following CABG surgery may be limited by incomplete platelet inhibition due to increased post-operative platelet turnover. Objectives To determine whether acetyl-salicylic acid (ASA) 325 mg once-daily or 81 mg four-times daily overcomes the impaired response to ASA 81 mg once-daily in post-operative coronary artery bypass graft (CABG) patients. Methods We randomized 110 patients undergoing CABG surgery to either ASA 81 mg once-daily, 81 mg four times daily or 325 mg once-daily and compared their effects on serum thromboxane B2 (TXB2) suppression and arachidonate-induced platelet aggregation. Results One hundred patients were included in the final analysis. Platelet counts fell after surgery, reached a nadir on day 2, and then gradually increased. Although there was near complete suppression of TXB2 on the second or third post-operative day, TXB2 levels increased in parallel with the rise in platelet count on subsequent days. This increase was most marked in patients receiving ASA 81 mg once-daily and less evident in those receiving ASA four times daily. On post-operative day 4, (i) median TXB2 levels were lower with four times daily ASA than with either ASA 81 mg once-daily (1.1 ng/mL; Quartile(Q) Q1,Q3: 0.5, 2.4 and 13.3 ng/mL; Q1,Q3: 7.8, 30.8 ng/mL, respectively; P

Background Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment. Objective To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence. Design Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915). Setting 13 university-affiliated clinical centers. Patients 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy. Intervention Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month. Measurements Recurrent VTE during an average follow-up of 2.2 years. Results In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison). Limitations Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study. Conclusion The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women. Primary funding source Canadian Institutes of Health Research.

SummaryAsymptomatic deep-vein thrombosis (DVT) detected by mandatory venography, a surrogate outcome, comprises most of the efficacy outcome events in recent thromboprophylaxis trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in these clinical trials requires a consistent relationship between asymptomatic DVT and symptomatic venous thromboembolism (VTE). In this systematic review of high quality VTE prevention trials, we examined the consistency of the ratios of asymptomatic DVT to symptomatic VTE across a broad range of indications. Studies were identified from citations listed in the chapters on VTE prevention in the antithrombotic guidelines by the American College of Chest Physicians, 2012. A study was eligible if it: 1) was a randomised trial comparing an anticoagulant with standard of care; 2) included at least 500 participants; 3) reported asymptomatic or all DVT rates; and 4) re ported symptomatic VTE rates. Of the 26 eligible trials, 19 trials were conducted in orthopaedic patients, five in general surgery patients and two in general medical patients. The overall median rates (ranges) for asymptomatic DVT and symptomatic VTE were 9.11% (0.75 to 54.87%) and 0.49% (0.00 to 3.10%), respectively. The median ratio was 14.53, with a wide range (2.75 to 103.86). Wide variability in the ratios persisted despite indication- and anticoagulant-specific analyses. In VTE prevention trials of alternative anticoagulants, the wide variability in the ratios of asymptomatic DVT to symptomatic VTE precludes judging the trade-off between thrombotic and bleeding events on the basis of composite outcomes dominated by venographic DVT.

Over- and undercoagulation with warfarin are associated with hemorrhagic and thromboembolic events, respectively. Genetic and clinical factors affect warfarin response, and the causes of this variability remain unclear. We present descriptive statistics and test for predictors of poor anticoagulation control. The Quebec Warfarin Cohort (QWC) comprises 1059 new warfarin users, with prospective follow-up using telephone questionnaires every 3 months for 1 year, and using healthcare administrative databases (RAMQ and Med-Echo) for 5 years prior to cohort entry and up to 10 years following active patient participation. Genetic material was collected, and genotyping of CYP2C9 and VKORC1 genes was conducted. Measured outcomes included the percentage of time patients spent within therapeutic range, anticoagulation control, warfarin dose, bleeding, and thromboembolic events. We report baseline characteristics and outcomes after 1 year of follow-up. Poor anticoagulation control was defined as time in therapeutic range

It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-β2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915.

Background In patients with nonvalvular atrial fibrillation (AF), apixaban is given in doses of 5 or 2.5 mg twice daily, according to clinical characteristics. The usual on-treatment range of apixaban drug levels, as determined by apixaban-calibrated anti-factor Xa (anti-Xa) activity, has previously been measured in small cohorts; however, the association between anti-Xa activity and clinical outcomes and the predictors of variability in anti-Xa activity have not been well studied in the AF population. Methods and Results Anti-Xa activity was measured before taking the morning dose, 3 months after enrollment in the AVERROES study using a calibrated anti-Xa assay (Rotachrom). Patients with two of the following criteria—age >80; weight 133 μg/L—received 2.5 mg twice daily (n = 145), while all others received 5 mg twice daily (n = 2,247). A total of 2,392 patients were included, with median follow-up of 1.1 years. Median apixaban anti-Xa activity was 122 ng/mL (interquartile range [IQR]: 63–198 ng/mL) for the entire group; 99 ng/mL (IQR: 60–146 ng/mL) for the 2.5-mg group; and 125 ng/mL (IQR: 64–202 ng/mL) for the 5-mg group (p = 0.003). A relationship was evident between bleeding and anti-Xa activity (p = 0.01), which was driven by minor bleeding. No relationship was evident between major bleeding or stroke/systemic embolism and anti-Xa activity. In those receiving the 5-mg dose, estimated glomerular filtration rate, sex, and age had the strongest association with anti-Xa activity. Conclusion There is considerable variability in anti-Xa activity among AF patients receiving apixaban. Rates of major bleeding and stroke/systemic embolism were low irrespective of anti-Xa activity. Clinical Trial Registration ClinicalTrials.gov NCT00496769; https://clinicaltrials.gov/ct2/show/NCT00496769.

Background The media serves as an important link between medical research, as reported in scholarly sources, and the public and has the potential to act as a powerful tool to improve public health. However, concerns about the reliability of health research reports have been raised. Tools to monitor the quality of health research reporting in the media are needed to identify areas of weakness in health research reporting and to subsequently work towards the efficient use of the lay media as a public health tool through which the public’s health behaviors can be improved. Methods We developed the Quality Index for health-related Media Reports (QIMR) as a tool to monitor the quality of health research reports in the lay media. The tool was developed according to themes generated from interviews with health journalists and researchers. Item and domain characteristics and scale reliability were assessed. The scale was correlated with a global quality assessment score and media report word count to provide evidence towards its construct validity. Results The items and domains of the QIMR demonstrated acceptable validity and reliability. Items from the ‘validity’ domain were negatively skewed, suggesting possible floor effect. These items were not eliminated due to acceptable content and face validity. QIMR total scores produced a strong correlation with raters’ global assessment and a moderate correlation with media report word count, providing evidence towards the construct validity of the instrument. Conclusions The results of this investigation indicate that QIMR can adequately measure the quality of health research reports, with acceptable reliability and validity. Electronic supplementary material The online version of this article (doi:10.1186/s12889-017-4259-y) contains supplementary material, which is available to authorized users.

International audience; When counseling first-degree relatives of patients with venous thromboembolism (VTE), it is important to know whether factors other than thrombophilia influence their risk for thrombosis. We assessed the risk for VTE in 915 first-degree relatives of patients with provoked VTE, compared this with the risk in 1752 first-degree relatives of patients with unprovoked VTE, and then combined data from the 2 groups of relatives to identify predictors of thrombosis. There had been 123 VTEs in 2617 first-degree relatives (0.12 per 100 person-years). The risk for VTE in first-degree relatives was higher if the index cases had an unprovoked compared with a provoked VTE (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.43-3.85), if the index case was younger (OR, 0.97 per year older; 95% CI, 0.96-0.99), and if an additional family member had VTE (OR, 2.71; 95% CI, 2.22-3.31). Among first-degree relatives of an index case with factor V Leiden or the prothrombin 20210A gene variant, the presence of these abnormalities also predicted thrombosis (OR, 4.42; 95% CI, 1.35-14.38). We conclude that thrombosis at a young age and unprovoked VTE predict VTE in first-degree relatives, and that the influence of these 2 factors is additive.

Summary Background Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. Methods We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. Findings From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73–1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. Interpretation ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. Funding Canadian Institutes of Health Research.

SummaryAnticoagulants are effective at preventing and treating thrombosis, but can cause bleeding. For decades, vitamin K antagonists (VKAs) have been the only available oral anticoagulants. The development of non-VKA oral anticoagulants (NOACs), which inhibit either factor Xa or thrombin stoichiometrically, has provided alternatives to VKAs for several indications. The results of recent large-scale randomised controlled trials comparing NOACs with VKAs for the prevention of stroke in patients with non-valvular atrial fibrillation (AF) have produced some unexpected results. As a group, NOACs showed similar efficacy as warfarin, but a reduced risk of major bleeding. The reduction in bleeding with NOACs was greatest with intracranial hemorrhage. In contrast, the relative risk of gastro-intestinal bleeding was increased with some NOACs. In this review, we explore the potential mechanisms as well as the implications of these organ-specific bleeding patterns.

SummaryFour recently introduced new oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban) have been shown to be at least as efficacious and safe as warfarin for stroke prevention in patients with atrial fibrillation in their respective trials. The first three have been approved, while edoxaban is awaiting regulatory approval. Several guidelines have endorsed the approved new oral anticoagulants over warfarin because of their favourable risk-benefit ratio, low propensity for food and drug interactions, and lack of requirement for routine coagulation monitoring. In this invited review, we summarise the results of the four studies and discuss widely held conclusions. We take a step further and discuss how differences in study design, analysis plan, and unexpected events affect the interpretation of the study results. Finally, we take our re-interpretation of study results and discuss how they might impact clinical practice and anticoagulant choice for patients.

SummaryAcute 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.

The P2Y12 inhibitors, clopidogrel, prasugrel, and ticagrelor, are administered in fixed doses without laboratory monitoring. Randomized trials in acute coronary syndrome have shown that prasugrel and ticagrelor are more effective than standard-dose clopidogrel. Nonetheless, standard-dose clopidogrel remains widely used because it causes less bleeding and is less expensive. Patients treated with standard-dose clopidogrel have substantial variability in platelet inhibition, which is partly explained by genetic polymorphisms encoding CYP2C19, the hepatic enzyme involved in biotransformation of clopidogrel to its active metabolite. Some advocate tailoring P2Y12 inhibitor therapy according to the results of routine laboratory testing. Although there is good evidence for analytic, biological, and clinical validity of several phenotypic and genotypic biomarkers, the benefit of a management strategy that incorporates routine biomarker testing over standard of care without such testing remains unproven. Appropriately designed, adequately powered trials are needed but face the challenges of feasibility, cost, and the progressive switch from clopidogrel to prasugrel or ticagrelor.

Background: Compression ultrasonography performed serially over a 7-day period is recommended for the diagnosis of deep vein thrombosis in symptomatic pregnant women, but whether this approach is safe is unknown. We evaluated the safety of withholding anticoagulation from pregnant women with suspected deep vein thrombosis following negative serial compression ultrasonography and iliac vein imaging. Methods: Consecutive pregnant women who presented with suspected deep vein thrombosis underwent compression ultrasonography and Doppler imaging of the iliac vein of the symptomatic leg(s). Women whose initial test results were negative underwent serial testing on 2 occasions over the next 7 days. Women not diagnosed with deep vein thrombosis were followed for a minimum of 3 months for the development of symptomatic deep vein thrombosis or pulmonary embolism. Results: In total, 221 pregnant women presented with suspected deep vein thrombosis. Deep vein thrombosis was diagnosed in 16 (7.2%) women by initial compression ultrasonography and Doppler studies; none were identified as having deep vein thrombosis on serial testing. One patient with normal serial testing had a pulmonary embolism diagnosed 7 weeks later. The overall prevalence of deep vein thrombosis was 7.7% (17/221); of these, 65% (11/17) of cases were isolated to the iliofemoral veins and 12% (2/17) were isolated iliac deep vein thromboses. The incidence of venous thromboembolism during follow-up was 0.49% (95% confidence interval [CI] 0.09%–2.71%). The sensitivity of serial compression ultrasonography with Doppler imaging was 94.1% (95% CI 69.2%–99.7%), the negative predictive value was 99.5% (95% CI 96.9%–100%), and the negative likelihood ratio was 0.068 (95% CI 0.01–0.39). Interpretation: Serial compression ultrasonography with Doppler imaging of the iliac vein performed over a 7-day period excludes deep-vein thrombosis in symptomatic pregnant women.

There is a demand for providing evidence on the effectiveness of research investments on the promotion of novice researchers’ scientific productivity and production of research with new initiatives and innovations. We used a mixed method approach to evaluate the funding effect of the New Investigator Fund (NIF) by comparing scientific productivity between award recipients and non-recipients. We reviewed NIF grant applications submitted from 2004 to 2013. Scientific productivity was assessed by confirming the publication of the NIF-submitted application. Online databases were searched, independently and in duplicate, to locate the publications. Applicants’ perceptions and experiences were collected through a short survey and categorized into specified themes. Multivariable logistic regression was performed. Odds ratios (OR) with 95 % confidence intervals (CI) are reported. Of 296 applicants, 163 (55 %) were awarded. Gender, affiliation, and field of expertise did not affect funding decisions. More physicians with graduate education (32.0 %) and applicants with a doctorate degree (21.5 %) were awarded than applicants without postgraduate education (9.8 %). Basic science research (28.8 %), randomized controlled trials (24.5 %), and feasibility/pilot trials (13.3 %) were awarded more than observational designs (p

The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS).To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE.D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds.The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels250μg/l at one month; 5.2% with D-dimer levels between 250 and 499μg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were500μg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment.Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence.

Backgound Randomized controlled trials (RCTs) have shown that dabigatran, rivaroxaban and warfarin cause similar bleeding rates. Methods We performed a retrospective population-based cohort study to determine the incidence of bleeding in patients with atrial fibrillation (AF) beginning dabigatran, rivaroxaban or warfarin. Consecutive patients initiating anticoagulation for AF during a 3 year period were identified using a computerized database. Patients who bled and required hospitalization underwent chart review. Bleeding incidences were calculated per 100 patient-years of treatment. Results 18,249 patients were included: 9564 (52.4%) received warfarin, 5976 (32.7%) dabigatran, and 2709 (14.8%) rivaroxaban. Bleeding incidences were 3.9 (95% CI, 3.6–4.4) in warfarin-treated patients, 4.2 (95% CI, 3.7–4.7) in dabigatran patients, and 4.1 (95% CI, 3.0–5.3) in rivaroxaban patients. Intracranial hemorrhage (ICH) rates were 0.71 (95% CI, 0.56–0.90) for warfarin, 0.4 (95% CI, 0.18–0.87) for dabigatran, and 0.27 (95%CI, 0.10–0.80) for rivaroxaban. GI hemorrhage rates were 1.88 (95%CI, 1.62–2.20) for warfarin, 2.98 (95% CI, 2.4–3.5) for dabigatran and 2.39 (95%CI, 1.6–3.5) for rivaroxaban. Conclusions We demonstrate similar bleeding rates with both dabigatran 150 mg and 110 mg and rivaroxaban compared to warfarin.

International audience; The post-thrombotic syndrome (PTS) is a frequent, potentially disabling complication of deep vein thrombosis (DVT) that reduces quality of life and is costly. Clinical manifestations include symptoms and signs such as leg pain and heaviness, edema, redness, telangiectasia, new varicose veins, hyperpigmentation, skin thickening and in severe cases, leg ulcers. The best way to prevent PTS is to prevent DVT with pharmacologic or mechanical thromboprophylaxis used in high risk patients and settings. In patients whose DVT is treated with a vitamin K antagonist, subtherapeutic INRs should be avoided. We do not suggest routine use of elastic compression stockings (ECS) after DVT to prevent PTS, but in patients with acute DVT-related leg swelling that is bothersome, a trial of ECS is reasonable. We suggest that selecting patients for catheter-directed thrombolytic techniques be done on a case-by-case basis, with a focus on patients with extensive thrombosis, recent symptoms onset, and low bleeding risk, who are seen at experienced hospital centers. For patients with established PTS, we suggest prescribing 20-30 mm Hg knee-length ECS to be worn daily. If ineffective, a stronger pressure stocking can be tried. We suggest that intermittent compression devices or pneumatic compression sleeve units be tried in patients with moderate-to-severe PTS whose symptoms are inadequately controlled with ECS alone. We suggest that a supervised exercise training program for 6 months or more is reasonable for PTS patients who can tolerate it. We suggest that management of post-thrombotic ulcers should involve a multidisciplinary approach. We briefly discuss upper extremity PTS and PTS in children.

Background The assessment of patients with suspected deep vein thrombosis (DVT) remains challenging despite current diagnostic algorithms. 99m Tc-labelled DI-DD3B6/22-80B3 Fab´ fragments ( 99m Tc-DI-80B3, ThromboView®) is a novel diagnostic test that uses a radiolabelled humanized monoclonal antibody fragment specific for the D-dimer region of cross-linked fibrin to detect DVT. This test has an anatomic component to locate DVT and a functional component to differentiate acute (newly formed) thrombus from inactive (old) thrombus. Methods In a multi-centre prospective cohort trial we investigated the diagnostic accuracy and safety of 99m Tc-DI-80B3 in consecutive patients with suspected DVT who had the diagnosis confirmed or excluded by venography. Results We enrolled 94 patients with suspected DVT of whom 12 did not have 99m Tc-DI-80B3 imaging, leaving 82 patients for the safety analysis. Of these patients, there were 16 with non-evaluable imaging (11 venography, 7 99m Tc-DI-80B3, both in two patients) leaving 66 patients for the accuracy analysis. 99m Tc-DI-80B3 imaging was well-tolerated: 2 patients developed urticaria; none developed serious adverse events. For proximal DVT, the sensitivity (84.2%; 95% confidence interval [CI]: 62.4–94.5) and specificity (97.6%; CI: 83.3–99.4) were highest when the combined 0.25-hour and 3-hour 99m Tc-DI-80B3 images were used. The accuracy was lower for distal DVT, irrespective of the images used. There were insufficient patients to comment on the accuracy of 99m Tc-DI-80B3 imaging for suspected recurrent DVT. Conclusions 99m Tc-DI-80B3 (ThromboView®) is a novel diagnostic modality for patients with suspected DVT with a promising accuracy and safety profile that justifies additional clinical development in diagnostic accuracy and clinical management studies.

Summary. Background: Few studies have evaluated the long-term economic consequences of deep vein thrombosis (DVT).None of them have incorporated prospectively collectedclinical data to ensure accurate identification of incident casesof DVT and DVT-related health outcomes of interest, such aspost-thrombotic syndrome (PTS). Objectives: To prospectivelyquantify medical and non-medical resource use and costsrelated to DVT during 2 years following diagnosis, and toidentify clinical determinants of costs. Methods: Three hun-dred and fifty-five consecutive patients with acute DVT wererecruited at seven Canadian hospital centers. Resource use andcost information were retrieved from three sources: weeklypatient-completed cost diaries, nurse-completed case reportforms, and the Quebec provincial administrative healthcaredatabase (RAMQ). Results: The rate of DVT-related hospi-talization was 3.5 per 100 patient-years (95% confidenceinterval [CI] 2.2–4.9). Patients reported a mean (standarddeviation) of 15.0 (14.5) physician visits and 0.7 (1.2) otherhealthcare 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 predictorsof costs: concomitant pulmonary embolism (relative increasein cost [RIC] 3.16; 95% CI 2.18–4.58), unprovoked DVT(RIC 1.65; 95% CI 1.28–2.13), development of PTS duringfollow-up (RIC 1.35; 95% CI 1.05–1.74), and management ofDVT in the inpatient setting (RIC 1.79; 95% CI 1.33–2.40).Conclusions: The economic burden of DVT is substantial. Theuse of measures to prevent the occurrence of PTS andfavoring outpatient care of DVT has the potential to diminishcosts.Keywords: cohort study, cost determinants, deep vein throm-bosis, economic burden, post-thrombotic syndrome.IntroductionDeepveinthrombosis(DVT)isacommonandseriousvascularcondition[1].TheclinicalburdenofDVToftenextendsbeyondthe initial event, with increased risks of recurrent venousthromboembolism (VTE), bleeding while on anticoagulanttherapy, and development of the chronic post-thromboticsyndrome (PTS).Few studies have evaluated the long-term economic conse-quences of DVT. Studies to date have relied on retrospectiveadministrative claims database analysis [2–5] or Markovmodeling [6], and assessed medical costs only. Non-medicalcosts, including productivity losses that impact on patients,their families, and society, have not been adequately consid-ered. None has incorporated prospectively collected clinicaldata to ensure accurate identification of incident cases of DVTand DVT-related health outcomes of interest, such as PTS.We conducted a study to prospectively quantify medicaland non-medical costs associated with DVT during the

Summary. Background: The role of D-dimer in excluding deep vein thrombosis (DVT) in pregnancy is currently uncertain. We hypothesized that the specificity of sensitive D-dimer assays could be improved without compromising sensitivity by using higher D-dimer cut-off values. Objective: To determine the test characteristics of two rapid enzyme-linked immunosorbent assays and three latex agglutination assays in pregnancy. Method: We recruited consecutive pregnant women who presented to participating centers with suspected DVT for the study. Symptomatic women were investigated with compression ultrasonography, and received 3 months of clinical follow-up to assess for the presence of venous thrombosis. Plasma samples for D-dimer were collected and frozen at the time of presentation. The median and mean D-dimer values for respective trimesters of pregnancy in patients with and without DVT were calculated. Receiver operating curves (ROCs) were plotted for respective assays to establish the best cut-points. The test characteristics corresponding to standard cut-points and these ‘pregnancy’ cut-points are presented. Results: The prevalence of DVT in our cohort was 6.6% (95% confidence interval 4.0–10.6%). The mean and median D-dimer values were significantly increased throughout pregnancy. Overall, women with confirmed DVT had higher D-dimer levels than women without DVT (P

In a collaborative care model (CCM) for managing oral anticoagulant therapy, patients are followed at a pharmacist-managed anticoagulation service and, once stabilized, are transferred to their primary care physician. The objective of this study was to describe physicians' clinical practices and the practice characteristics associated with better international normalized ratio (INR) control in a CCM.A telephone questionnaire about their practices was administered to 121 physicians exposed to a CCM. The physicians followed 121 patients for a mean of 14.5 weeks. The percentage of time within the exact INR target range was computed and dichotomized (or = ormedian time within target range). Determinants of better INR control were identified using logistic regression models.The survey revealed that, after discharge from the pharmacist-managed anticoagulation service, patients are followed mainly by physicians and their secretaries. Physicians do not often consult other health professionals. Few report using technological resources to obtain INR results (39.7%), document medical follow-up (6.6%), or detect drug (32.2%) and food (9.9%) interactions. The median percentage of time within the exact INR target range was 84%. Determinants of better INR control include using computerized support to monitor patients (odds ratio [OR] 9.16, 95% CI 1.77-47.4) and detect drug interactions (OR 3.49, 95% CI 1.71-7.10) and consulting specialists (OR 5.92, 95% CI 1.49-32.48).Primary care physicians are poorly supported by technological and human resources to monitor patients on oral anticoagulant. Even in a CCM, interprofessional collaboration and better technological support may be associated with optimal INR control.

SummaryUnanticipated elevation of the INR is common in patients receiving warfarin. We performed a prospective cohort study of 107 warfarintreated patients with INR values of more than 10 who received a single 2.5 mg dose of oral vitamin K. During the first week, one patient experienced major bleeding, and one died. In the first 90 days after enrolment four patients had major bleeding (3.7%, 1.0% to 9.3%), eight patients (7.5%, 3.3% to 14.2%) died and two had objectively confirmed thromboembolism. Based on our low rate of observed major bleeding we conclude that 2.5 mg of oral vitamin K is a reasonable treatment for patients with INR values of more than 10 who are not actively bleeding.

Objective.To compare live birth rates in women with recurrent pregnancy loss (RPL) and either autoantibodies or a coagulation abnormality, treated with low molecular weight heparin plus aspirin (LMWH/ASA) or ASA alone, and to place our results in context with other randomized clinical trials (RCT) with similar cohorts.Methods.The HepASA Trial was an RCT including patients with a history of RPL and at least 1 of the following: antiphospholipid antibody (aPL), an inherited thrombophilia, or antinuclear antibody. Treatment groups were stratified by aPL status and history of early versus late pregnancy losses. Patients received either LMWH/ASA or ASA alone. The primary outcome was live birth; secondary outcomes included adverse events and bone loss at the spine and femoral neck. Literature over the past 20 years was reviewed to identify comparable RCT.Results.Over 4 years, 859 women with RPL were screened: 88 (10.2%) fulfilled inclusion criteria, became pregnant and were randomized to receive either LMWH/ASA or ASA alone. aPL were present in 42 (47.7%) patients in each group. The trial was stopped after 4 years when an interim analysis showed no difference in live birth rates in the 2 groups, and a lower rate of pregnancy loss in the ASA only group than expected. In the LMWH/ASA group, 35/45 (77.8%) had a live birth versus 34/43 (79.1%) in the ASA only group (p = 0.71). Neither number of prior losses nor aPL status was correlated with pregnancy outcome. There were no cases of pregnancy related thrombosis in either group. Mean change in BMD did not differ by treatment group at either the lumbar spine (p = 0.57) or femoral neck (p = 0.15). RCT since 2000 for aPL positive women with RPL and similar inclusion criteria report a mean live birth rate of 75% with either LMWH or ASA.Conclusion.LMWH/ASA did not confer incremental benefit compared to ASA alone for this population. Regardless of treatment regimen, number of prior losses, or aPL positivity, almost 80% of women in our RPL cohort had a successful pregnancy outcome. These findings contribute to a growing body of literature that contests the emerging standard of care comprising LMWH/ASA for this population.

Summary. Background: As assessment of clinical pretest probability is the first step in the diagnostic evaluation of deep vein thrombosis (DVT), it is important to know if the clinical features of DVT are the same in men and women. Objectives: To compare the prevalence and clinical characteristics of DVT, and the accuracy of clinical pretest probability assessment, between men and women with suspected DVT. Methods: A retrospective analysis of individual patient data from three prospective studies by our group that evaluated diagnostic tests for a suspected first episode of DVT. Clinical characteristics, clinical pretest probability for DVT, and prevalence and extent of DVT was assessed in a total of 1838 outpatients. Results: The overall prevalence of DVT was higher in men than in women (14.4% vs. 9.4%) (P = 0.001). The prevalence of DVT was higher in men than in women who were categorized as having a clinical pretest probability that was low (6.9% vs. 3.5%; P = 0.025) or moderate (16.9% vs. 8.7%; P = 0.04), but similar in patients in the high category (40.2% vs. 44.0%; P = 0.6). In patients diagnosed with DVT, swelling of the entire leg occurred more often (41.5% vs. 15.7%; P

Background Some pharmacist-managed anticoagulation services (PMAS) provide initial follow-up to patients on oral anticoagulant, who are transferred to their physician once they are stabilized. This may be as effective as and less expensive than long-term PMAS follow-up. Methods Once PMAS patients were stabilized and ready for discharge, they were randomized to be transferred to their physician or stay with the PMAS. Quality of international normalized ratio (INR) control, incidence of complications, health-related quality of life, use of health care services, and direct incremental cost of PMAS follow-up were evaluated. Results One hundred thirty-eight physicians and 250 patients participated. Patients were initially followed at the PMAS for a mean of 11.3 weeks and afterwards were followed by their physician (n = 122) or by the PMAS pharmacists (n = 128) for a mean of 14.9 and 14.5 weeks, respectively. Pharmacist-managed anticoagulation services' and physician's patients were within the exact target range 77.3% and 76.7% of the time (95% CI of the difference −4.9% to 6.0%) and within the extended range 93.0% and 91.6% of the time (95% CI −2.1% to 4.7%), respectively. Pharmacist-managed anticoagulation services patients have seen their family physician less often (95% CI −3.1 to −0.1 visit per year). Number of INR tests, incidence of complications, and health-related quality of life were similar in both groups. The incremental cost of PMAS follow-up was estimated at CAN$123.80 per patient year. Conclusion Once PMAS patients are well stabilized, maintaining a PMAS follow-up or transferring them to their physician is associated with excellent INR control. However, long-term PMAS follow-up may be more expensive.

Summary. Background/objectives: We prospectively measured change in quality of life (QOL) during the 2 years after a diagnosis of deep vein thrombosis (DVT) and evaluated determinants of QOL, including development of the post-thrombotic syndrome (PTS). Patients/methods: Consecutive patients with acute DVT were recruited from 2001 to 2004 at eight hospitals in Canada. At study visits at baseline, and 1, 4, 8, 12 and 24 months, clinical data were collected, standardized PTS assessments were performed, and QOL questionnaires were self-completed. Generic QOL was measured using the Short-Form Health Survey-36 (SF-36) questionnaire. Venous disease-specific QOL was measured using the Venous Insufficiency Epidemiological and Economic Study (VEINES)-QOL/Sym questionnaire. The change in QOL scores over a 2-year follow-up was assessed. The influence of PTS and other characteristics on QOL at 2 years was evaluated using multivariable regression analyses. Results: Among the 387 patients recruited, the average age was 56 years, two-thirds were outpatients, and 60% had proximal DVT. The cumulative incidence of PTS was 47%. On average, QOL scores improved during follow-up. However, patients who developed PTS had lower scores at all visits and significantly less improvement in QOL over time (P-values for PTS*time interaction were 0.001, 0.012, 0.014 and 0.006 for PCS, MCS, VEINES-QOL and VEINES-Sym). Multivariable regression analyses showed that PTS (P

SummaryIt is not known whether women who develop venous throm-boembolism (VTE) during pregnancy have a higher or lower incidence of recurrent VTE than women with unprovokedVTE. The aim of the study was to compare the risk of recurrent VTE among women with pregnancy-associated VTE to women with unprovoked VTE. Hospital discharge data identified women age 18–46 years old with pregnancy-associated or unprovoked index VTE between 1994 and 2005. Risk of recurrent VTE was compared between six and 60 months after the index event using both age-matched comparison of disease-free survival and proportional hazard modelling, adjusting for age and other risk factors. The Kaplan-Meier incidence of recurrent VTE in 1085 women with pregnancy-associatedVTE was 5.8% versus 10.4% in 7625 women with unprovoked VTE (p=0.02). Twelve of 34 (35%) recurrent events in the pregnancy-associated group occurred during a subsequent pregnancy compared with 29 of 331 (8.7%) events in the unprovoked group (p

BACKGROUND In clinical practice, physicians are given the choice of selecting one of two dabigatran doses based on patient characteristics, with the lower dose typically used in patients at a higher risk of bleeding. OBJECTIVES The objectives of the study were to (i) estimate the inter- and intra-patient variability in dabigatran levels with 110 mg (DE110) and 150 mg (DE150) doses, (ii) examine the effect of physicians' dose selection on levels in DE110 and DE150 subgroups, and (iii) explore whether a single trough measurement identifies patients with extreme levels on subsequent visits. METHODS In this prospective observational study of 100 patients with atrial fibrillation (AF), peak and trough levels of dabigatran were measured with the Hemoclot(®) assay at baseline and every 2 months thereafter (maximum four visits). RESULTS Inter-patient variability in dabigatran levels (geometric coefficient of variation [gCV], 51-64%) was greater than intra-patient variability (gCV, 32-40%). Similar medians and distributions of levels were observed in DE110 and DE150 subgroups. Patients receiving DE110 were older, had lower renal function and weighed less than those receiving DE150. Up to 40% of patients whose trough levels were in the upper extremes, and up to 80% of patients whose trough levels were in the lower extremes at baseline, showed subsequent levels that fell in the middle quartiles. CONCLUSIONS Our data support the practice of selecting the dabigatran dose based upon clinical characteristics because it results in similar levels of drug exposure in patients given DE110 or DE150. They do not support the concept that a single Hemoclot(®) measurement reliably identifies patients with consistently high or low values.

Summary. Background: Upper extremity deep vein thrombosis (UEDVT) is uncommon and is associated with well-defined risk factors in the general population. Increasingly, UEDVTs are being reported during pregnancy, particularly those achieved with the use of assisted reproductive techniques (ART), and in conjunction with ovarian hyperstimulation syndrome (OHSS). Aim: We performed this review was to estimate the incidence of UEDVT associated with ART, to examine the risk factors and presentation of UEDVT in pregnancy, and to determine if differences exist between this cohort and the general population. Results: There were 35 published case reports of UEDVT in pregnant women. The incidence of this condition is estimated to be 0.08–0.11% of treatment cycles in women undergoing ART. The development of UEDVT is not always be preceded by OHSS. In addition, commonly associated risk factors for UEDVT were not often reported for UEDVT that developed during pregnancy. Instead the association of UEDVT and ART was common. UEDVT in pregnancy also appears to involve the internal jugular vein more often than the subclavian vein. The reported risk of thrombus extension in this cohort, despite anticoagulation therapy, is also disconcerting. Conclusion: Because UEDVT may not be a rare entity during pregnancy in association with the use of ART, clinicians should be better informed of its presentation and clinical course in these women. Once UEDVT develops, appropriate therapeutic anticoagulation should be instituted and patient carefully monitored. The long-term implications and recurrence rate of this condition in pregnancy warrants further prospective studies.

Summary Background Individual risk of recurrent venous thromboembolism affects patient management and might differ between men and women. We did a meta-analysis to assess from available evidence whether men and women have the same risk of recurrent venous thromboembolism after stopping anticoagulant treatment. Methods Eligible articles were identified by searches of MEDLINE (source PubMed, 1966 to February 2005), EMBase (1980 to February 2005), and the Cochrane database 2005, issue 1. Prospective cohort studies and randomised trials were eligible if they included patients with objectively diagnosed venous thromboembolism treated for a minimum of 1 month and followed up for recurrence after anticoagulant treatment was stopped. Data were extracted for study design, study quality, and the number, sex, and age of enrolled patients, risk factors for venous thromboembolism, treatment given, duration of follow-up, and the number of episodes of recurrent venous thrombosis. Findings 15 studies (nine randomised controlled trials and six prospective observational studies) enrolling a total of 5416 individuals (2729 men), of whom 816 (523 men) had recurrent venous thromboembolism after stopping treatment, were eligible for inclusion. The pooled estimate of the relative risk (RR) of recurrent venous thromboembolism for men compared with for women was 1·6 (95% CI 1·2–2·0). Significant heterogeneity was shown among individual study findings; however, the higher risk of recurrent venous thromboembolism in men than in women was consistent across predefined subgroups. The relative risk for recurrence in men from randomised trials (RR 1·3; 95% CI 1·0–1·8) was lower than that from observational studies (2·1; 1·5–2·9). The lower risk of recurrent venous thromboembolism in women did not seem to be accounted for by a reduced rate of recurrence after venous thromboembolism associated with oestrogen treatment or pregnancy. Interpretation Men seem to have a 50% higher risk than women of recurrent venous thromboembolism after stopping anticoagulant treatment. If confirmed by further prospective studies, this difference in risk of recurrence should be considered when duration of anticoagulant treatment is determined in individual patients.