Recurrent venous thromboembolism and bleeding with extended anticoagulation: the VTE-PREDICT risk score.

AIMS: Deciding to stop or continue anticoagulation for venous thromboembolism (VTE) after initial treatment is challenging, as individual risks of recurrence and bleeding are heterogeneous. The present study aimed to develop and externally validate models for predicting 5-year risks of recurrence and bleeding in patients with VTE without cancer who completed at least 3 months of initial treatment, which can be used to estimate individual absolute benefits and harms of extended anticoagulation. METHODS AND RESULTS: Competing risk-adjusted models were derived to predict recurrent VTE and clinically relevant bleeding (non-major and major) using 14 readily available patient characteristics. The models were derived from combined individual patient data from the Bleeding Risk Study, Hokusai-VTE, PREFER-VTE, RE-MEDY, and RE-SONATE (n = 15,141, 220 recurrences, 189 bleeding events). External validity was assessed in the Danish VTE cohort, EINSTEIN-CHOICE, GARFIELD-VTE, MEGA, and Tromsø studies (n = 59 257, 2283 recurrences, 3335 bleeding events). Absolute treatment effects were estimated by combining the models with hazard ratios from trials and meta-analyses. External validation in different settings showed agreement between predicted and observed risks up to 5 years, with C-statistics ranging from 0.48-0.71 (recurrence) and 0.61-0.68 (bleeding). In the Danish VTE cohort, 5-year risks ranged from 4% to 19% for recurrent VTE and 1% -19% for bleeding. CONCLUSION: The VTE-PREDICT risk score can be applied to estimate the effect of extended anticoagulant treatment for individual patients with VTE and to support shared decision-making.

Ruling out pulmonary embolism across different healthcare settings: A systematic review and individual patient data meta-analysis.

BACKGROUND: The challenging clinical dilemma of detecting pulmonary embolism (PE) in suspected patients is encountered in a variety of healthcare settings. We hypothesized that the optimal diagnostic approach to detect these patients in terms of safety and efficiency depends on underlying PE prevalence, case mix, and physician experience, overall reflected by the type of setting where patients are initially assessed. The objective of this study was to assess the capability of ruling out PE by available diagnostic strategies across all possible settings. METHODS AND FINDINGS: We performed a literature search (MEDLINE) followed by an individual patient data (IPD) meta-analysis (MA; 23 studies), including patients from self-referral emergency care (n = 12,612), primary healthcare clinics (n = 3,174), referred secondary care (n = 17,052), and hospitalized or nursing home patients (n = 2,410). Multilevel logistic regression was performed to evaluate diagnostic performance of the Wells and revised Geneva rules, both using fixed and adapted D-dimer thresholds to age or pretest probability (PTP), for the YEARS algorithm and for the Pulmonary Embolism Rule-out Criteria (PERC). All strategies were tested separately in each healthcare setting. Following studies done in this field, the primary diagnostic metrices estimated from the models were the "failure rate" of each strategy-i.e., the proportion of missed PE among patients categorized as "PE excluded" and "efficiency"-defined as the proportion of patients categorized as "PE excluded" among all patients. In self-referral emergency care, the PERC algorithm excludes PE in 21% of suspected patients at a failure rate of 1.12% (95% confidence interval [CI] 0.74 to 1.70), whereas this increases to 6.01% (4.09 to 8.75) in referred patients to secondary care at an efficiency of 10%. In patients from primary healthcare and those referred to secondary care, strategies adjusting D-dimer to PTP are the most efficient (range: 43% to 62%) at a failure rate ranging between 0.25% and 3.06%, with higher failure rates observed in patients referred to secondary care. For this latter setting, strategies adjusting D-dimer to age are associated with a lower failure rate ranging between 0.65% and 0.81%, yet are also less efficient (range: 33% and 35%). For all strategies, failure rates are highest in hospitalized or nursing home patients, ranging between 1.68% and 5.13%, at an efficiency ranging between 15% and 30%. The main limitation of the primary analyses was that the diagnostic performance of each strategy was compared in different sets of studies since the availability of items used in each diagnostic strategy differed across included studies; however, sensitivity analyses suggested that the findings were robust. CONCLUSIONS: The capability of safely and efficiently ruling out PE of available diagnostic strategies differs for different healthcare settings. The findings of this IPD MA help in determining the optimum diagnostic strategies for ruling out PE per healthcare setting, balancing the trade-off between failure rate and efficiency of each strategy.

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.

BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

A cross-sectional study of the interrelationship between burnout, empathy and resilience in academic physicians.

Burnout is a growing concern, with significant negative consequences for physicians and patient care. Burnout is negatively associated with physician empathy, while resilience may be a protective factor against the development of burnout but few studies have examined all three constructs in the same cohort. Understanding the associations between these constructs could aid in the development of interventions for physicians experiencing burnout and improve the delivery of compassionate care. We conducted a cross-sectional survey to determine levels of burnout, empathy and resilience in a sample of academic physicians and investigate the relationships between these variables. Validated scales were administered online to measure burnout (Maslach Burnout Inventory - Human Services Survey, MBI-HSS), empathy (Jefferson Scale of Empathy - Physicians/Health Professions Version, JSE) and resilience (Connor-Davidson Resilience Scale, CD-RISC). Descriptive statistics, correlation coefficients, and group comparisons were examined. Eighty-three physicians completed the JSE and CD-RISC, while a subset of 49 physicians also completed the MBI-HSS. Response rates were 31.9% and 18.8%, respectively. High burnout was reported by 49% of the sample. Physicians with high burnout reported lower levels of resilience than those who were not burnt-out. No differences in levels of empathy were observed between these two groups. Older physicians (>45 years) reported higher resilience scores than younger physicians. Resilience and empathy were significantly positively correlated. The reported rate of physician burnout in this sample of academic physicians is concerning, with burnout associated with lower levels of resilience. Further research is required to explore the relationship between physician age and resilience, the impact of resilience-building interventions on burnout and empathy in physicians, and how modifying these variables influences the delivery of compassionate care for patients.

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty.

BACKGROUND: Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) after total hip or total knee arthroplasty, but comparisons with direct oral anticoagulants are lacking for prophylaxis beyond hospital discharge. METHODS: We performed a multicenter, double-blind, randomized, controlled trial involving patients who were undergoing total hip or knee arthroplasty. All the patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and then were randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism (the primary effectiveness outcome) and bleeding complications, including major or clinically relevant nonmajor bleeding (the primary safety outcome). RESULTS: A total of 3424 patients (1804 undergoing total hip arthroplasty and 1620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1707 patients (0.64%) in the aspirin group and in 12 of 1717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], -0.55 to 0.66; P<0.001 for noninferiority and P=0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, -0.65 to 0.29; P=0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, -1.07 to 0.47; P=0.43). CONCLUSIONS: Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT01720108 .).

Direct oral anticoagulant use in special populations.

PURPOSE OF REVIEW: The pivotal phase III trials demonstrating efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF) excluded patients with important and common comorbidities, including obesity, advanced chronic kidney disease, cirrhosis, cancer and antiphospholipid antibody syndrome. Despite the lack of large prospective randomized control trials in these patient populations, the use of DOACs has led to a wealth of efficacy and safety data within these groups. RECENT FINDINGS: Retrospective studies, meta-analyses, national databases and pharmacokinetic data have shed light on the efficacy and safety of DOACs in these patient populations. Although DOACs should be avoided in those with high-risk triple positive antiphospholipid antibody syndrome, advanced cirrhosis, advanced kidney disease and intact gastrointestinal cancers, and used with caution in genitourinary cancers, their use extends beyond the inclusion criteria of the initial randomized control trials. SUMMARY: DOACs have revolutionized anticoagulant management and have become the cornerstone for VTE treatment and stroke prevention in NVAF. The decision to use DOACs must be individualized. Patient preference, underlying comorbidities and informed consent must always be considered when selecting the most appropriate anticoagulant.

Cost-utility analysis of apixaban compared with usual care for primary thromboprophylaxis in ambulatory patients with cancer.

BACKGROUND: Apixaban (2.5 mg) taken twice daily has been shown to substantially reduce the risk of venous thromboembolism (VTE) compared with placebo for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE. We aimed to compare the health system costs and health benefits associated with primary thromboprophylaxis using apixaban with those associated with the current standard of care (where no primary thromboprophylaxis is given), from the perspective of Canada's publicly funded health care system in this subpopulation of patients with cancer over a lifetime horizon. METHODS: We performed a cost-utility analysis to estimate the incremental cost per quality-adjusted life-year (QALY) gained with primary thromboprophylaxis using apixaban. We obtained baseline event rates and the efficacy of apixaban from the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial on apixaban prophylaxis. We estimated relative risk for bleeding, risk of complications associated with VTE treatment, mortality rates, costs and utilities from other published sources. RESULTS: Over a lifetime horizon, apixaban resulted in lower costs to the health system (Can$7902.98 v. Can$14 875.82) and an improvement in QALYs (9.089 v. 9.006). The key driver of cost-effectiveness results was the relative risk of VTE as a result of apixaban. Results from the probabilistic analysis showed that at a willingness to pay of Can$50 000 per QALY, the strategy with the highest probability of being most cost-effective was apixaban, with a probability of 99.87%. INTERPRETATION: We found that apixaban is a cost-saving option for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE.

Thromboprophylaxis for patients with newly diagnosed vs. recurrent cancers: a post-hoc analysis of the avert trial.

Venous thromboembolic disease (VTE) is a common complication among patients with cancer. Data reporting risk of VTE among patients receiving chemotherapy for recurrent cancer compared to those with newly diagnosed tumors is scarce. Furthermore, it is unclear if thromboprophylaxis is beneficial and safe in these specific patient populations. Post-hoc analysis of the AVERT trial which was a randomized, placebo-controlled, double-blind trial comparing apixaban therapy to placebo for VTE prophylaxis among cancer patients who were intermediate-to-high risk for VTE and who were initiating chemotherapy. The HRs for recurrent VTE and major bleeding episodes in patients with newly diagnosed and recurrent cancers were calculated using a Cox regression model controlling for age, gender, and center. Of the 563 included patients 469 and 93 patients had newly diagnosed and recurrent cancers, respectively. Patients with recurrent cancer have a higher risk of VTE (Hazard ratio (HR): 1.53 (95% CI 1.0 to 2.33; p = 0.047) and major bleeding episodes (HR 2.89 (95% CI 1.52 to 5.49; p = 0.001) compared to those with newly diagnosed cancer. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR 0.45; 95% CI 0.27-0.76; p = 0.002) and a higher rate of major bleeding (HR 2.10; 95% CI 1.09-4.08; p = 0.028). In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR 0.26; 95% CI 0.13-0.53; p < 0.001) without an associated significantly increased risk of major bleeding (HR 1.82; 95% CI 0.36-9.15; p = 0.466). Patients with recurrent cancer seem to be at higher risk of recurrent VTE and major bleeding complications compared to those with newly diagnosed tumors. Apixaban appears to be safe and effective in these patient populations.

D-Dimer Enhances Risk-Targeted Thromboprophylaxis in Ambulatory Patients with Cancer.

BACKGROUND: Thromboprophylaxis for ambulatory patients with cancer is effective, although uncertainties remain on who should be targeted. Using D-dimer values from individuals enrolled to the AVERT trial, we sought to identify and validate a more efficient venous thromboembolism (VTE) risk threshold for thromboprophylaxis. MATERIALS AND METHODS: The AVERT trial compared thromboprophylaxis with apixaban with placebo among patients with cancer with a Khorana Risk Score ≥2. The D-dimer measured at randomization was used to calculate an individualized 6-month VTE risk using the validated CATScore. A modified intention-to-treat analysis was used to assess efficacy (VTE) and safety (major and overall bleeding) in the (a) complete cohort and (b) ≥8% and < 8% 6-month VTE risk thresholds. RESULTS: Five hundred seventy-four patients were randomized in the AVERT trial; 466 (81%) with baseline D-dimer were included in the study. Two hundred thirty-seven subjects received apixaban; 229 received placebo. In the complete cohort, there were 13 (5.5%) VTE events in the apixaban arm compared with 26 (11.4%) events in the placebo arm (adjusted hazard ratio [aHR] 0.49 [0.25-0.95], p < .05). Number needed to treat (NNT) to prevent one VTE = 17. Eighty-two (35%) and 72 (31%) patients in the apixaban and placebo arms, respectively, had a 6-month VTE risk ≥8%. In this subgroup, 7 (8.4%) VTE events occurred with apixaban and 19 (26.3%) events with placebo (aHR 0.33 [0.14-0.81], p < .05), NNT = 6. Individuals with a VTE risk <8% derived no benefit from apixaban thromboprophylaxis (aHR 0.89 [0.30-2.65), p = .84). Increased rates of overall bleeding were observed with apixaban in both the complete (aHR 2.11 [1.09-4.09], p < .05) and ≥ 8% predicted risk cohorts (aHR 2.87 [0.91-9.13], p = .07). CONCLUSION: A 6-month VTE risk threshold of ≥8% increases the efficiency of risk-targeted thromboprophylaxis in ambulatory patients with cancer. IMPLICATIONS FOR PRACTICE: Ambulatory patients with cancer receiving chemotherapy have an increased risk of venous thromboembolism (VTE). A Khorana Risk Score (KRS) ≥2 is currently the suggested threshold for thromboprophylaxis. Using baseline D-dimer values from individuals enrolled to the AVERT trial, this retrospective validation study identifies a 6-month VTE risk of ≥8% as a more efficient threshold for thromboprophylaxis. At this threshold, the number needed to treat to prevent one VTE is 6, compared with 17 when using a KRS ≥2. Conversely, individuals with a predicted risk of <8% derive no clinical benefit from thromboprophylaxis. Future prospective studies should validate this threshold for outpatient thromboprophylaxis.

Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism.

BACKGROUND: Although many patients with venous thromboembolism require extended treatment, it is uncertain whether it is better to use full- or lower-intensity anticoagulation therapy or aspirin. METHODS: In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. All the study patients had completed 6 to 12 months of anticoagulation therapy and were in equipoise regarding the need for continued anticoagulation. Study drugs were administered for up to 12 months. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. RESULTS: A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. The incidence of adverse events was similar in all three groups. CONCLUSIONS: Among patients with venous thromboembolism in equipoise for continued anticoagulation, the risk of a recurrent event was significantly lower with rivaroxaban at either a treatment dose (20 mg) or a prophylactic dose (10 mg) than with aspirin, without a significant increase in bleeding rates. (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439 .).

Impact of Anticoagulation on Mortality and Resource Utilization Among Critically Ill Patients With Major Bleeding.

OBJECTIVES: Patients with major bleeding are commonly admitted to the ICU. A growing number are on either oral or parenteral anticoagulation, but the impact of anticoagulation on patient outcomes is unknown. We sought to examine this association between anticoagulation therapy and mortality, as well as the independent effects of warfarin compared to direct oral anticoagulants. DESIGN: Analysis of a prospectively collected registry (2011-2017) of consecutive ICU patients admitted with major bleeding (as defined by International Society on Thrombosis and Haemostasis clinical criteria). SETTING: Two hospitals within a single tertiary care level hospital system. PATIENTS: We analyzed 1,598 patients identified with major bleeding, of which 245 (15.3%) had been using anticoagulation at the time of ICU admission. Of patients on anticoagulation, 149 were using warfarin, and 60 were using a direct oral anticoagulant. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome, in-hospital mortality, was analyzed using a multivariable logistic regression model. Patients with anticoagulation-associated major bleeding had higher in-hospital mortality (adjusted odds ratio, 1.49; 95% CI, 1.16-1.92). Among survivors, anticoagulation use was associated with longer median hospital length of stay, and higher mean costs. No differences in hospital mortality were seen between warfarin- and direct oral anticoagulant-associated major bleeding. Patients with warfarin-associated major bleeding had longer median length of stay (11 vs 6 d; p = 0.02), and higher total costs than patients with direct oral anticoagulant-associated major bleeding. CONCLUSIONS: Among ICU patients admitted with major bleeding, pre-admission anticoagulation use was associated with increased hospital mortality, prolonged length of stay, and higher costs among survivors. As compared to direct oral anticoagulants, patients with warfarin-associated major bleeding had increased length of stay and costs. These findings have important implications in the care of ICU patients with major bleeding.

DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis.

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

Accuracy of the Ottawa score in risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism: a systematic review and meta-analysis.

In patients with cancer-associated venous thromboembolism, knowledge of the estimated rate of recurrent events is important for clinical decision-making regarding anticoagulant therapy. The Ottawa score is a clinical prediction rule designed for this purpose, stratifying patients according to their risk of recurrent venous thromboembolism during the first six months of anticoagulation. We conducted a systematic review and meta-analysis of studies validating either the Ottawa score in its original or modified versions. Two investigators independently reviewed the relevant articles published from 1st June 2012 to 15th December 2018 and indexed in MEDLINE and EMBASE. Nine eligible studies were identified; these included a total of 14,963 patients. The original score classified 49.3% of the patients as high-risk, with a sensitivity of 0.7 [95% confidence interval (CI): 0.6-0.8], a 6-month pooled rate of recurrent venous thromboembolism of 18.6% (95%CI: 13.9-23.9). In the low-risk group, the recurrence rate was 7.4% (95%CI: 3.4-12.5). The modified score classified 19.8% of the patients as low-risk, with a sensitivity of 0.9 (95%CI: 0.4-1.0) and a 6-month pooled rate of recurrent venous thromboembolism of 2.2% (95%CI: 1.6-2.9). In the high-risk group, recurrence rate was 10.2% (95%CI: 6.4-14.6). Limitations of our analysis included type and dosing of anticoagulant therapy. We conclude that new therapeutic strategies are needed in patients at high risk for recurrent cancer-associated venous thromboembolism. Low-risk patients, as per the modified score, could be good candidates for oral anticoagulation. (This systematic review was registered with the International Prospective Registry of Systematic Reviews as: PROSPERO CRD42018099506).

Diagnosis of Venous Thromboembolism: 20 Years of Progress.

Many guidelines suggest incorporating clinical assessment, imaging, and D-dimer testing into diagnostic algorithms in patients with suspected deep venous thrombosis (DVT) and pulmonary embolism (PE). This special article reviews the evidence supporting the use of algorithms and their individual components for diagnosis of upper- and lower-extremity DVT and PE in adults, including pregnant women. The authors identified evidence through several electronic database searches to April 2017, evaluated the robustness of selected evidence, assessed whether diagnostic approaches that do not use algorithms are acceptable, and identified knowledge gaps that require further research.

Screening for Occult Cancer in Unprovoked Venous Thromboembolism.

BACKGROUND: Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism. METHODS: We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period. RESULTS: Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75). CONCLUSIONS: The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.).

Impact of Thrombus Sidedness on Presentation and Outcomes of Patients with Proximal Lower Extremity Deep Vein Thrombosis.

Small studies have suggested differences in demographics and outcomes between left- and right-sided deep vein thrombosis (DVT), and also unilateral versus bilateral DVT. We investigated the clinical presentation and outcomes of patients with DVT based on thrombus sidedness. The authors used the data from the Registro Informatizado Enfermedad TromboEmbólica (RIETE) database (2001-2016) to identify patients with symptomatic proximal lower-extremity DVT. Main outcomes included cumulative 90-day symptomatic pulmonary embolism (PE) and 1-year mortality. Overall, 30,445 patients were included. The majority of DVTs occurred in the left leg (16,421 left-sided, 12,643 right-sided, and 1,390 bilateral; p < 0.001 for chi-squared test comparing all three groups). Comorbidities were relatively similar in those with left-sided and right-sided DVT. Compared with those with left-sided DVT, patients with right-sided DVT had higher relative frequency of PE (26% versus 23%, p < 0.001) and 1-year mortality (odds ratio [OR]: 1.08; 95% confidence interval [CI]: 1.00-1.18). This difference in mortality did not persist after multivariable adjustment (OR: 1.01; 95% CI: 0.93-1.1). Patients with bilateral DVT had a greater burden of comorbidities such as heart failure, and recent surgery compared with those with unilateral DVT (p < 0.001), and higher relative frequency of PE (48%), and 1-year mortality (24.1%). Worse outcomes in patients with bilateral DVT were attenuated but persisted after multivariable adjustment for demographics and risk factors (OR: 1.64; 95% CI: 1.43-1.87). Patients with bilateral DVT had worse outcomes during and after discontinuation of anticoagulation. There is a left-sided preponderance for proximal lower-extremity DVT. Compared with those with left-sided DVT, patients with right-sided DVT have slightly higher rates of PE. Bilateral DVT is associated with markedly worse short-term and 1-year outcomes.

Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use.

Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence densities in percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs off) as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence densities on and off hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR, 0.56; 95% confidence interval [CI], 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding (on vs off hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR, 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration.

Venous Thromboembolism: Advances in Diagnosis and Treatment.

IMPORTANCE: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common and potentially fatal disease. OBJECTIVE: To summarize the advances in diagnosis and treatment of VTE of the past 5 years. EVIDENCE REVIEW: A systematic search was conducted in EMBASE Classic, EMBASE, Ovid MEDLINE, and other nonindexed citations using broad terms for diagnosis and treatment of VTE to find systematic reviews and meta-analyses, randomized trials, and prospective cohort studies published between January 1, 2013, and July 31, 2018. The 10th edition of the American College of Chest Physicians Antithrombotic Therapy Guidelines was screened to identify additional studies. Screening of titles, abstracts, and, subsequently, full-text articles was performed in duplicate, as well as data extraction and risk-of-bias assessment of the included articles. FINDINGS: Thirty-two articles were included in this review. The application of an age-adjusted D-dimer threshold in patients with suspected PE has increased the number of patients in whom imaging can be withheld. The Pulmonary Embolism Rule-Out Criteria safely exclude PE when the pretest probability is low. The introduction of direct oral anticoagulants has allowed for a simplified treatment of VTE with a lower risk of bleeding regardless of etiology or extent of the VTE (except for massive PE) and has made extended secondary prevention more acceptable. Thrombolysis is best reserved for patients with massive PE or those with DVT and threatened limb loss. Insertion of inferior vena cava filters should be avoided unless anticoagulation is absolutely contraindicated in patients with recent acute VTE. Graduated compression stockings are no longer recommended to treat DVT but may be used when acute or chronic symptoms are present. Anticoagulation may no longer be indicated for patients with isolated distal DVT at low risk of recurrence. CONCLUSIONS AND RELEVANCE: Over the past 5 years, substantial progress has been made in VTE management, allowing for diagnostic and therapeutic strategies tailored to individual patient characteristics, preferences, and values.