Relative Risk Of Venous Thromboembolism Research Articles

P126 Use of oral contraceptives in females with rheumatoid arthritis is not associated with an increased risk of venous thromboembolism: United Kingdom-population based study

Abstract Background/Aims While the use of oral contraceptives in females with immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) is acknowledged as a risk factor for venous thromboembolism (VTE), the interaction between oral contraceptive use and RA is poorly understood. In a large population-based study, we aimed to estimate RA-attributable VTE risk in females using oestrogen contraceptives and/or on hormone replacement therapy (HRT). Methods Females registered with a general practice from January 1999 to December 2018 were identified from the Royal College of General Practitioners Research (RCGP) and Surveillance Centre (RSC) database. Female RA patients and VTE outcome (composite of pulmonary embolism and deep vein thrombosis) were determined using previously-validated algorithms. Female unaffected controls (UCs) were matched 4:1 with RA patients by current age (per year), calendar time, and years since practice registration using nearest neighbour matching, with replacement. Absolute VTE rates over 20 years were compared in RA patients versus matched UCs, overall and in two different subgroups defined by the use of oestrogen contraceptives or HRT. Relative VTE risk over the same period was estimated using Cox proportional hazards models adjusted for sociodemographic and clinical features and established VTE risk factors (BMI [body-mass index], smoking status, alcohol use, evidence of reduced mobility, thrombophilia, fracture of the lower limb and family history of VTE). Results A total of 82,082 female adults were included in this study, of whom 16,634 were RA patients and 65,448 were UCs. Average study follow-up was 8.3 years (standard deviation [SD]=6.2 years). Female RA patients (mean age 58.3, SD 16.5; mean BMI 27.0, SD 5.9) were similar to matched UCs in their clinical characteristics. Compared to UCs, females with RA were less likely to receive oral contraceptives (RA n = 545 [3.3%], UCs n = 2,542 [3.9], p < 0.001) but more likely to receive HRT (RA n = 752 [4.5%], UCs n = 2,460 [3.8], p < 0.001). Unadjusted VTE events rates were consistently higher in females with RA compared to UCs (430.2 per 100,000 person-years [py], 95% confidence interval [CI]: 396.1, 466.3; UC: 260.5 per 100,000 py, 95%CI: 247.1, 274.4) and in those receiving and not receiving oral contraceptives and HRT. Overall, relative risk of VTE was 52% higher in females with RA compared UCs (adjusted hazard ratio [aHR]= 1.52, 95%CI: 1.36, 1.71, p < 0.001). Compared to UCs, relative risk increases were not statistically significant for females with RA receiving oral contraceptives (aHR 1.43; 95%CI 0.60, 3.63, p = 0.46) and HRT (aHR 2.32; 95%CI 0.92, 5.85, p = 0.08). Conclusion UK data suggest that all women with RA are at a similarly increased risk of VTE irrespective of the use of oestrogen contraceptives or HRT, although larger studies are needed to confirm this finding. It is therefore advisable to conduct routine VTE risk factor assessments for all females with RA. Disclosure J. Galloway: Honoraria; JG has received honoraria from Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi and UC. V. Basey: Corporate appointments; Pfizer employee. A. Barkaway: Corporate appointments; Pfizer employee. S. de Lusignan: Grants/research support; SdeL has received funding through his universities from Eli Lilly, GSK, Astra Zeneca, MSD, Sanofi, Seqirus, Takeda and Moderna. Other; Director of the RCGP RSC. M.H. Buch: Consultancies; M.H.B. has provided expert advice and received/paid to employer consultant fees from AbbVie, Eli Lilly, EMD serono, Gilead, Pfizer and Sanofi. Grants/research support; .H.B. has received research grants paid to her employer from Gilead Ltd, Pfizer Ltd, Roche and UCB.

P052 Rheumatoid arthritis associated risk of venous thromboembolism is not dependent on disease duration: United Kingdom-based population study

Abstract Background/Aims Risk of venous thromboembolism (VTE) is higher in patients with rheumatoid arthritis (RA) compared to the general population; however, whether this risk changes with RA disease duration remains poorly understood. Acknowledging potential heterogeneity in risk by RA duration could support more tailored screening and effective preventive approaches. In a large population-based study, we aimed to characterise the RA-attributable VTE risk in patients with varying disease durations. Methods Adults registered with a general practice from January 1999 to December 2018 were identified from the Royal College of General Practitioners Research (RCGP) and Surveillance Centre (RSC) primary care database. RA patients (diagnosed prior to and during the study period), VTE outcome (as a composite of pulmonary embolism [PE] or deep vein thrombosis [DVT]) and individual PE and DVT outcomes were determined using previously validated algorithms. RA-unaffected controls (UCs) were matched 4:1 with RA patients by current age, sex, calendar time, and years since practice registration using nearest neighbour matching with replacement. Absolute VTE, PE and DVT rates over 20 years were compared in RA patients versus matched UC across four subgroups defined by disease duration (0-2, 2-5, 5-10 and ≥10 years since diagnosis). Across the same subgroups, relative risks over the same period were estimated using Cox proportional hazards models adjusted for sociodemographic and clinical features and established VTE risk factors (body-mass index [BMI], smoking status, alcohol use, evidence of reduced mobility, thrombophilia, fracture of the lower limb and family history of VTE). Results 117,050 individuals were included, of whom 93,640 were UCs and 23,410 were RA patients. Among those with RA, 63.9% were included at or within two years of diagnosis, 7.8% within two to five years of diagnosis, 9.8% within five to ten years of diagnosis, and 18.5% more than 10 years after diagnosis. Average study follow-up for the primary outcome (VTE) was 8.2 years (standard deviation [SD]=6.6 years). RA patients (mean age 59.0, SD 15.5; 28.9% male [n = 6776]; mean BMI 27.1, SD 5.6) were similar to matched UCs in clinical characteristics. Unadjusted VTE events rates were consistently higher in RA patients compared to UCs across all subgroups. Relative risk of VTE was similarly increased in RA patients compared to the general population regardless of the time elapsed since RA diagnosis (adjusted hazard ratios [aHR] range: 1.49-1.63, all p < 0.001). The results obtained when PE (aHR range 1.46-2.02, all p < 0.001) and DVT (aHR range 1.43-1.89, all p < 0.001) were analysed separately were similar to those observed in the composite outcome. Conclusion Healthcare professionals should recognize that individuals with RA face a consistently elevated VTE risk compared to the general population, irrespective of disease duration. This highlights the need for vigilant monitoring and assessment of VTE risk factors even in early-stage cases. Disclosure J. Galloway: Honoraria; JG has received honoraria from Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi and UC. V. Basey: Corporate appointments; Pfizer employee. S. Rana: Corporate appointments; Pfizer employee. S. de Lusignan: Grants/research support; SdeL has received funding through his universities from Eli Lilly, GSK, Astra Zeneca, MSD, Sanofi, Seqirus, Takeda and Moderna. Other; Director of the RCGP RSC. M.H. Buch: Consultancies; M.H.B. has provided expert advice and received/paid to employer consultant fees from AbbVie, Eli Lilly, EMD serono, Gilead, Pfizer and Sanofi. Grants/research support; M.H.B. has received research grants paid to her employer from Gilead Ltd, Pfizer Ltd, Roche and UCB.

Venous Thromboembolism (VTE) in Post-CAR-T Patients - a Meta-Analysis of Phase 2 & 3 Clinical Trials

Introduction: Chimeric Antigen Receptor T- cells (CAR-T) therapy is genetically engineered T cells that provide durable responses for patients with certain hematological malignancies. CAR-T therapy continues to expand as a treatment option for various malignant conditions. ICANS and CRS, a clinical syndrome of neurological symptoms, fever, hypotension, and hypoxia, are potentially serious complications of post-CAR-T. Both of these complications can, in turn, increase the risk of VTE. Only a few case reports and retrospective analyses have described the risk of VTE. The primary objective of this systematic review and meta-analysis is to review the data from phase 2 and 3 clinical trials to determine the incidence and risk of VTE post-CAR-T treatment. Material and methods: The National Institute of Health (NIH) library, Cochrane Library, and ClinicalTrials.gov database were scoured for all phase 2 and phase 3 clinical trials, completed by March 7, 2023, on CAR-T cell therapy. Two reviewers independently verified the results. Several data points were extracted. A biostatistician conducted the meta-analysis using the Meta package in the R version 4.1.2 (Balduzzi, Rücker, & Schwarzer, 2019; R Core Team, 2021). The endpoints of interest were the odds ratio and relative risk of developing VTE while in CRS using the Mantel-Haenszel method. Result: Nine phase 2 & 3 trials (Seven phase 2 and two phase 3 trials) were identified and were included in our study. The incidence of CRS, ICANS, and VTE was obtained from the toxicity list and supplemental data for analysis. Only KTE-X19 studying Brexucabtagene (Tecartus) for relapsed or refractory adult B-cell acute lymphoblastic leukemia and Relapsed or refractory Mantle-Cell Lymphoma mentioned the incidence of one and three cases of VTE, respectively, in patients getting CAR-T cell therapy. The total number of patients reviewed from these studies was 1784, of which 1017 received CAR-T cell therapy. The odds of VTE were 99.9995% lower than CRS, OR = 0.0005, 95% CI [0.0001, 0.0017] in patients receiving a CAR-T infusion, p < .0001. The Relative risk of VTE was 0.0050, 95% CI [0.0019, 0.0132]. The test of heterogeneity (p = .0430) suggests the presence of heterogeneous results. The heterogeneity statistic I2 is 49.86%, indicating moderate heterogeneity (percentage of variation across studies due to heterogeneity rather than chance). The odds of VTE were 99.9999% lower than no VTE, OR = 0.0001, 95% CI [0.0001, 0.0004], p <.0001 with a Relative risk of 0.0039, 95% CI [0.0015, 0.0105]. Discussion: CRS is a known risk factor for VTE. In patients with underlying malignancy undergoing CAR-T therapy, the risk can be much higher than those without malignancy who develop CRS for other reasons. In a retrospective single-center observational study, Hashmi et al. reported an 11% incidence of VTE in lymphoma patients treated with CAR-T directed against the CD-19 receptor. Our systematic review and metanalysis didn't find a statistically increased risk of VTE in the patients getting CAR-T cell therapy despite the risk of CRS/ ICANS and underlying malignancy. The findings suggest that the thrombotic risks are either low or were not reported in the interval specified in the studies. The need for thromboprophylaxis must be made on a case-by-case basis, factoring in other risk factors such as underlying disease, cytopenia, and other medical comorbidities. Conclusion: The Incidence of VTE is low following CAR-T therapy despite the risks, and the need for thromboprophylaxis should be based on individual patient characteristics. Patient selection, exclusion criteria, and short follow-up periods following phase 2 trials might impact our study results. In a long-term phase 3 trial, collecting data for VTE may be needed to appropriately stratify patients for their VTE risk so that an appropriate thromboprophylaxis can be recommended to prevent an additional serious complication post-CAR-T.

OC 35.3 Correlation between ETP-Based APC Resistance and the Relative Risk of Venous Thromboembolism in Women Using Combined Oral Contraceptives

OC 35.3 Correlation between ETP-Based APC Resistance and the Relative Risk of Venous Thromboembolism in Women Using Combined Oral Contraceptives

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer.

Testing for Factor V Leiden (FVL) and Prothrombin G20210A Genetic Variants.

Laboratory testing for Factor V Leiden and Prothrombin G20210A genetic variants permits defining the increased relative risk for venous thromboembolism in selected patients. Laboratory DNA testing for these variants may be undertaken by a variety of methods, including fluorescence-based quantitative real-time PCR (qPCR). This is a rapid, simple, robust, and reliable method to identify genotypes of interest. This chapter describes the method that employs PCR amplification of the patient DNA region of interest and genotyping by allele-specific discrimination technology on a quantitative real-time PCR (qPCR) instrument.

Diabetes mellitus is associated with a higher relative risk for venous thromboembolism in females than in males

AimsThe risk for developing venous thromboembolism (VTE) is about equal in both sexes. Research suggests diabetes mellitus (DM) is a risk factor for pulmonary embolism and deep vein thrombosis, both forms of VTE. We aimed at investigating the sex-specific impact of DM on VTE risk. Materials and methodsMedical claims data were analyzed in a retrospective, population-level cohort study in Austria between 1997 and 2014. 180,034 patients with DM were extracted and compared to 540,102 sex and age-matched controls without DM in terms of VTE risk and whether specific DM medications might modulate VTE risk. ResultsThe risk to develop VTE was 1.4 times higher amongst patients with DM than controls (95% CI 1.36–1.43, p < 0.001). The association of DM with newly diagnosed VTE was significantly greater in females (OR = 1.52, 95% CI 1.46–1.58, p < 0.001) resulting in a relative risk increase of 1.17 (95% CI 1.11–1.23) across all age groups with a peak of 1.65 (95% CI 1.43–1.89) between 50 and 59 years. Dipeptidyl peptidase 4 inhibitors were associated with a higher risk for VTE amongst female DM patients (OR = 2.3, 95% CI 1.3–4.3, p = 0.0096). ConclusionAmongst DM patients, females appear to be associated with a higher relative risk increase in VTE than males, especially during perimenopause.

Long-Term Outcomes of Perioperative Versus Nonoperative Myocardial Infarction: A Danish Population-Based Cohort Study (2000-2016).

Perioperative myocardial infarction is a serious cardiovascular complication of noncardiac surgery. The clinical course of perioperative myocardial infarction, other than all-cause mortality, is largely unknown. We examined long-term fatal and nonfatal outcomes of perioperative myocardial infarction compared with nonoperative myocardial infarction. We conducted a population-based cohort study of first-time myocardial infarction in Denmark from 2000 to 2016. We calculated cumulative incidence of all-cause mortality, cardiac mortality, recurrent myocardial infarction, heart failure, stroke, venous thromboembolism, acute kidney injury, and kidney failure with replacement therapy. We computed 5-year risk ratios adjusted for age, sex, year of diagnosis, educational level, and comorbidities. We identified 5068 patients with perioperative myocardial infarction and 137 862 patients with nonoperative myocardial infarction. The 5-year risk of all-cause mortality was 67.5% (95% CI, 66.1%-69.0%) for perioperative myocardial infarction patients and 38.0% (95% CI, 37.7%-38.3%) for nonoperative myocardial infarction patients. The adjusted risk ratio of all-cause mortality was 1.13 (95% CI, 1.11-1.16) at 5 years. After adjustment, we found no association between patients with perioperative myocardial infarction and 5-year cardiac mortality, recurrent myocardial infarction, heart failure, stroke, or kidney failure with replacement therapy when compared with nonoperative myocardial infarction patients. Perioperative myocardial infarction patients had a higher relative risk of venous thromboembolism (5-year risk ratio, 1.21 [95% CI, 1.01-1.46]) and acute kidney injury (5-year risk ratio, 1.37 [95% CI, 1.22-1.53]). Compared with nonoperative myocardial infarction patients, perioperative myocardial infarction patients had elevated risk of all-cause mortality, venous thromboembolism, and acute kidney failure. In addition to the myocardial infarction component of perioperative myocardial infarction, this poor prognosis seemed associated with the surgery or underlying comorbidities. These findings warrant further research on strategies to reduce the risk of perioperative myocardial infarction and on strategies to manage perioperative myocardial infarction.

Venous thrombosis risk during and after medical and surgical hospitalizations: The medical inpatient thrombosis and hemostasis (MITH) study

BackgroundThirty to seventy percent of all venous thromboembolism (VTE) events are associated with hospitalization. The absolute and relative risks during and after hospitalization are poorly characterized. ObjectivesQuantify the absolute rate and relative risk of VTE during and up to 3 months after medical and surgical hospitalizations. Patients/MethodsWe conducted an observational cohort study between 2010 and 2016 of patients cared for by the University of Vermont (UVM) Health Network's primary care population. Cox proportional hazard models with hospitalization modeled as a time‐varying covariate were used to estimate VTE risk. ResultsOver 4.3 years of follow‐up, 55 220 hospitalizations (156 per 1000 person‐years) and 713 first venous thromboembolism events (2.0 per 1000 person‐years) occurred. Among individuals not recently hospitalized, the rate of venous thromboembolism was 1.4 per 1000 person‐years and 71.8 per 1000 person‐years during hospitalization. During the first, second, and third months after discharge, the rates of venous thromboembolism were 35.1, 11.3, and 5.2 per 1000 person‐years, respectively. Relative to those not recently hospitalized, the age‐ and sex‐adjusted HRs of venous thromboembolism were 38.0 (95% CI 28.0, 51.5) during hospitalization, and 18.4 (95% CI 15.0, 22.6), 6.3 (95% CI 4.3, 9.0), and 3.0 (95% CI 1.7, 5.4) during the first, second, and third months after discharge, respectively. Stratified by medical versus surgical services the rates were similar. ConclusionHospitalization and up to 3 months after discharge were strongly associated with increased venous thromboembolism risk. These data quantify this risk for use in future studies.

Impact of COVID-19 on risk of venous thromboembolism (VTE) in cancer patients: A single institution analysis.

e18732 Background: Cancer is known to increase the risk of VTE when compared to the non-cancer population. Additionally, SARS-CoV-2 infection has been associated with hypercoagulability and VTE. A study by Patell et al noted similar cumulative incidence of thrombotic events (arterial and venous) in patients hospitalized with COVID-19 with active cancer than those without cancer (14.2% vs 18.2%). Data from the COVID-19 and Cancer Consortium (CCC19) Registry reported incidence of VTE of 7.6% in cancer patients within 90 days of hospitalization for COVID-19. However, it is unknown whether patients with cancer are at significantly higher risk for VTE in the setting of COVID-19 compared to cancer patients without COVID-19. Our study objectives were to: 1) determine the overall incidence of VTE in patients with cancer with and without COVID-19, regardless of hospitalization status; 2) assess the relative risk of VTE due to COVID-19 in cancer patients; 3) examine risk for VTE in cancer patients with COVID-19 based on certain demographic characteristics and comorbidities. Methods: An institutional retrospective cohort analysis was performed from March 1, 2020 through July 31, 2021. 228 patients with COVID-19 and cancer were identified and compared to matched controls without COVID-19 (n = 448) during the same study period based on age, gender, and BMI. Results: Incidence of VTE in cancer patients with COVID-19 was significantly higher than in cancer patients without COVID-19 (11% vs 3.1%) [RR 3.45, 95% CI 1.85-6.67]. There was no significantly increased risk of VTE in cancer patients with COVID-19 based on the following characteristics: non-White race, male gender, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and end-stage renal disease receiving dialysis. However, patients with any history of smoking (including current smokers) had increased risk of VTE compared to never-smokers (RR 2.2756, 95% CI 1.0498-4.9326). Conclusions: COVID-19 further increases the risk of VTE in cancer patients, a population with an independent risk factor for VTE at baseline. Whether the increased risk is additive or synergistic is currently unknown. Demographic factors and comorbidities that have been associated with increased severity of COVID-19 in other studies do not appear to significantly increase risk of VTE in cancer patients with COVID-19, with the exception of smoking status (either current or past). Given the impact on morbidity and mortality, further analyses, including with larger datasets, are warranted.

The Risk of Thrombosis Around Pregnancy: Where Do We Stand?

Pregnancy and puerperium increase the relative risk of venous thromboembolism (VTE) and the absolute risk remains low, around 1 per 1,000, with induced mortality of around 1 per 100,000. Analysis of large databases has helped specify the modes of presentation and risk factors (RF) whose impact is greater after than before childbirth, since VTE during pregnancy and post-partum obey different RFs. The evolution of the population concerned (mostly women over 35, obese, of multi-ethnicity undergoing medically assisted reproduction) affects the frequency of these RFs. Pulmonary embolism (PE) is over-represented after childbirth, but 30% of PE in pregnancy occurs without any RFs. Recommendations for prevention, mainly from expert groups, are heterogeneous and often discordant. Low molecular weight heparins (LMWH) are the mainstay of pharmacological thromboprophylaxis, in a field where randomized controlled studies are definitely lacking. VTE risk assessment in pregnancy must be systematic and repetitive. Risk assessment methods and scores are beginning to emerge to guide thromboprophylaxis and should be used more systematically. In the future, analyzing observational data from huge, nationwide registries and prospective cluster clinical trials may bring to light clinically relevant outcomes likely to feed comprehensive guidelines.

Prophylactic anticoagulation with low molecular weight heparin in COVID-19: cohort studies in Denmark and Sweden

ObjectivesTo evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19. MethodsUsing healthcare records from the Capital Region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis. ResultsWe included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N = 432) and the pooled risk ratio was 0.91 (CI 0.60-1.38) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (0.76-1.66), while we observed no increased risk of bleeding 0.63 (0.13-2.94). The relative risk of venous thromboembolism was 0.80 (0.43-1.47). ConclusionWe found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH.

Postoperative Thromboembolism According to the Type of Surgery: A Nationwide Study in the Republic of Korea.

Postoperative thromboembolism (TE) is a serious, but preventable, complication in surgical patients. Orthopedic surgery, neurosurgery, and vascular surgery are considered high risk for TE, and current guidelines recommend TE prophylaxis. However, insufficient data exist regarding TE risk in other general surgeries. This study identified the actual incidence and relative risk of postoperative TE in the real world, according to surgery type. Twenty-six surgeries between 1 December 2017 and 31 August 2019 were selected from the Health Insurance Review and Assessment Service database and analyzed for postoperative TE events. Among all patients, 2.17% had a TE event within 6 months of surgery and 0.75% had a TE event owing to anticoagulant treatment. The incidence of total TE events was the highest in total knee replacement (12.77%), hip replacement (11.46%), and spine surgery (5.98%). The incidence of TE with anticoagulant treatment was the highest in total knee replacement (7.40%), hip replacement (7.20%), and coronary artery bypass graft (CABG) surgery (3.81%). Hip replacement, total knee replacement, CABG surgery, spine surgery, and cardiac surgery except CABG surgery, showed relatively higher risks for total claimed venous TE. The relative risk of venous TE with anticoagulant treatment was the highest for hysterectomy, partial hepatectomy, hip replacement, cardiac surgery except CABG surgery, and total knee replacement. The relative risk of arterial TE was the highest for cardiac surgery, total knee replacement, and hip replacement. In the real world, the incidence of postoperative TE events from total knee replacement and those from hip replacement remain high, and some surgeries could have a relatively higher risk of TE than other surgeries. For patients undergoing these surgeries, studies to reduce the incidence of postoperative TE in clinical practice should be conducted.

Association between glycemic control and risk of venous thromboembolism in diabetic patients: a nested case\u2013control study

BackgroundPrevious studies suggested an elevated risk of venous thromboembolism (VTE) among patients with type 2 diabetes mellitus (T2DM), with a possible sex difference. The impact of glycemic control on the risk of VTE is unclear. Our objective was to analyze the association between glycemic control and the risk of unprovoked (idiopathic) VTE in men and women with T2DM.MethodsWe conducted a nested case–control analysis (1:4 matching) within a cohort of patients with incident T2DM between 1995 and 2019 using data from the CPRD GOLD. We excluded patients with known risk factors for VTE prior to onset of DM. Cases were T2DM patients with an unprovoked treated VTE. The exposure of interest was glycemic control measured as HbA1c levels. We conducted conditional logistic regression analyses adjusted for several confounders.ResultsWe identified 2′653 VTE cases and 10′612 controls (53.1% females). We found no association between the HbA1c level and the risk of VTE in our analyses. However, when the most recent HbA1c value was recorded within 90 days before the index date, women with HbA1c levels > 7.0% had a 36–55% increased relative risk of VTE when compared to women with HbA1c > 6.5–7.0%.ConclusionsOur study raises the possibility that female T2DM patients with HbA1c levels > 7% may have a slightly higher risk for unprovoked VTE compared to women with HbA1c levels > 6.5–7.0%. This increase may not be causal and may reflect differences in life style or other characteristics. We observed no effect of glycemic control on the risk of VTE in men.

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.

Contraceptive Preference, Continuation Rates, and Unintended Pregnancies in Patients with Comorbidities: A Prospective Cohort Study.

Background: Patients with comorbidities are more susceptible to adverse pregnancy outcomes, morbidity, and mortality than healthy patients. The goal of this study was to evaluate how comorbidities influence contraceptive choice, continuation rates, and the unintended pregnancy rate in reproductive-age participants. Methods: We analyzed data from the Contraceptive CHOICE Project. Baseline data included demographic, reproductive, and medical history, including self-reported hypertension (HTN), venous thromboembolism (VTE), migraines, cerebrovascular accidents (CVA), transient ischemic attack (TIA), or stroke. Participants were provided contraceptive counseling and their method of choice at no cost. Results: Among 9253 participants included in our analysis, 659 participants reported a history of HTN (7%), 20 participants reported a history of CVA/TIA/stroke (<1%), 1803 participants reported a history of migraine (19%), and 85 reported a history of VTE (<1%). Compared to baseline, use of long-acting reversible contraceptive methods (long-acting reversible contraception [LARC]: intrauterine devices and implants) increased for participants with all comorbidities: HTN 2.3%-84.2%; CVA/TIA/stroke 0%-85%; migraines 1.7%-77%, and VTE 1.2%-88.2%. Participants with HTN, VTE, and migraines were more likely to choose LARC than those without those conditions: HTN: relative risk (RR) = 1.14, 95% confidence interval (CI) 1.10-1.18; migraines RR = 1.04, 95% CI 1.01-1.07; and VTE RR = 1.18, 95% CI 1.09-1.28. Twelve-month continuation and unintended pregnancy rates did not differ significantly based on comorbidity status. Conclusions: Participants with serious comorbidities were more likely to choose LARC than healthy participants. Contraceptive counseling should always be individualized to the patient. Clinical Trials.gov Identifier: NCT01986439.

The risk of venous thromboembolic events in patients with inflammatory bowel disease: a systematic review and meta-analysis.

BackgroundInflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract that has been associated with increased risk of extraintestinal manifestations, amongst which is venous thromboembolism (VTE). We assessed the risk for VTE in patients with IBD through systematic review and meta-analysis.MethodsA systematic search for English language studies was conducted in Medline, Scopus, and the Cochrane Library of publications from database inception till August 10, 2020, to identify relevant studies reporting the risk of VTE in patients with IBD. The random-effects and fixed-effect models were used to estimate relative risks (RRs) with their respective 95% confidence intervals (CIs). The quality of the included studies was assessed using the Newcastle-Ottawa scale.ResultsEleven observational studies were included in this meta-analysis, involving 3,175,012 patients with IBD and 920,144,253 controls without IBD. The overall RR for VTE in patients with IBD compared to non-IBD individuals was 2.03 (95%CI 1.72-2.39). An analysis of studies with larger population size demonstrated a lower risk for VTE (RR 1.77, 95%CI 1.48-2.13) among patients with IBD, whereas studies with a smaller population size yielded a greater risk for VTE (RR 2.67, 95%CI 1.97-2.93). After adjustment for smoking and body mass index, the RR for VTE was moderately increased (RR 2.65, 95%CI 1.51-4.65).ConclusionsThe present meta-analysis shows that IBD is linked to a 2-fold increased risk for VTE. Thus, primary prevention against VTE is of the utmost importance.

PAR4 activation involves extracellular loop 3 and transmembrane residue Thr153

AbstractProtease-activated receptor 4 (PAR4) mediates sustained thrombin signaling in platelets and is required for a stable thrombus. PAR4 is activated by proteolysis of the N terminus to expose a tethered ligand. The structural basis for PAR4 activation and the location of its ligand binding site (LBS) are unknown. Using hydrogen/deuterium exchange (H/D exchange), computational modeling, and signaling studies, we determined the molecular mechanism for tethered ligand–mediated PAR4 activation. H/D exchange identified that the LBS is composed of transmembrane 3 (TM3) domain and TM7. Unbiased computational modeling further predicted an interaction between Gly48 from the tethered ligand and Thr153 from the LBS. Mutating Thr153 significantly decreased PAR4 signaling. H/D exchange and modeling also showed that extracellular loop 3 (ECL3) serves as a gatekeeper for the interaction between the tethered ligand and LBS. A naturally occurring sequence variant (P310L, rs2227376) and 2 experimental mutations (S311A and P312L) determined that the rigidity conferred by prolines in ECL3 are essential for PAR4 activation. Finally, we examined the role of the polymorphism at position 310 in venous thromboembolism (VTE) using the International Network Against Venous Thrombosis (INVENT) consortium multi-ancestry genome-wide association study (GWAS) meta-analysis. Individuals with the PAR4 Leu310 allele had a 15% reduction in relative risk for VTE (odds ratio, 0.85; 95% confidence interval, 0.77-0.94) compared with the Pro310 allele. These data are consistent with our H/D exchange, molecular modeling, and signaling studies. In conclusion, we have uncovered the structural basis for PAR4 activation and identified a previously unrecognized role for PAR4 in VTE.

Clinical Effectiveness and Safety of Aspirin for Venous Thromboembolism Prophylaxis After Total Hip and Knee Replacement

Patients undergoing total hip replacement (THR) and total knee replacement (TKR) receive venous thromboembolism (VTE) pharmacoprophylaxis. It is unclear which anticoagulant is preferable. Observational data suggest aspirin provides effective VTE prophylaxis. To assess the effectiveness and safety of aspirin for VTE prophylaxis after THR and TKR. A systematic review and meta-analysis was performed of randomized clinical trials (RCTs), with no language restrictions, from inception to September 19, 2019, using MEDLINE, Embase, Web of Science, Cochrane Library, and bibliographic searches. The computer-based searches combined terms and combinations of keywords related to the population (eg, hip replacement, knee replacement, hip arthroplasty, and knee arthroplasty), drug intervention (eg, aspirin, heparin, clexane, dabigatran, rivaroxaban, and warfarin), and outcome (eg, venous thromboembolism, deep vein thrombosis, pulmonary embolism, and bleeding) in humans. This study included RCTs assessing the effectiveness and safety of aspirin for VTE prophylaxis compared with other anticoagulants in adults undergoing THR and TKR. The RCTs with a placebo control group were excluded. The searches and study selection were independently performed. This study followed PRISMA recommendations and used the Cochrane Collaboration's risk of bias tool. Data were screened and extracted independently by both reviewers. Study-specific relative risks (RRs) were aggregated using random-effects models. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The primary outcome was any postoperative VTE (asymptomatic or symptomatic). Secondary outcomes were adverse events associated with therapy, including bleeding. Of 437 identified articles, 13 RCTs were included (6060 participants; 3466 [57.2%] women; mean age, 63.0 years). The RR of VTE after THR and TKR was 1.12 (95% CI, 0.78-1.62) for aspirin compared with other anticoagulants. Comparable findings were observed for deep vein thrombosis (DVT) (RR, 1.04; 95% CI, 0.72-1.51) and pulmonary embolism (PE) (RR, 1.01; 95% CI, 0.68-1.48). The risk of adverse events, including major bleeding, wound hematoma, and wound infection, was not statistically significantly different in patients receiving aspirin vs other anticoagulants. When analyzing THRs and TKRs separately, there was no statistically significant difference in the risk of VTE, DVT, and PE between aspirin and other anticoagulants. Aspirin had a VTE risk not statistically significantly different from low-molecular-weight heparin (RR, 0.76; 95% CI, 0.37-1.56) or rivaroxaban (RR, 1.52; 95% CI, 0.56-4.12). The quality of the evidence ranged from low to high. In terms of clinical effectiveness and safety profile, aspirin did not differ statistically significantly from other anticoagulants used for VTE prophylaxis after THR and TKR. Future trials should focus on noninferiority analysis of aspirin compared with alternative anticoagulants and cost-effectiveness.

Influence of Tobacco Smoking on Perioperative Risk of Venous Thromboembolism.

Venous thromboembolism (VTE) is generally considered a process very different from arterial atherosclerosis. The role of tobacco is well known in arterial thrombosis. However, its role in VTE is less obvious and remains controversial. In this mini review, we analysed the literature to identify the role of active or passive smoking in perioperative VTE and the relationship between arterial atherosclerosis and VTE. We carried an Internet search in French and English including the following keywords: deep vein thrombosis, tobacco, cigarette smoking, pulmonary embolism, postoperative, postoperative, atherosclerosis. Regarding the relationship between tobacco and VTE, a total of 9 studies were identified. Studies were ranked by the risk of VTE in relation to active or passive smoking. In conclusion, the management of smoking during the perioperative period for a short-term arrest (minimum 4–8 weeks before the intervention), or long term, allows among others a reduction of arterial or venous thrombotic events. However, it is clear that the training of anaesthesiologists in the management of smoking will contribute to the reduction of this public health problem.