Venous thromboembolism and amyotrophic lateral sclerosis: the Venous Thrombo-Embolism and Sclerosis Lateral Amyotrophic study.

Background: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease. Given the inflammatory nature of ALS and the high number of ALS-related clinical circumstances (eg, prolonged immobilization and infections), patients with ALS may have a high risk of venous thromboembolism (VTE). Objectives: To determine the annual incidence rate of VTE and the predictors of VTE in patients with ALS. Methods: We analyzed a prospective cohort of patients with ALS diagnosed between 2009 and 2019 followed in the Brest University Hospital ALS Centre. Results: Among 227 patients with ALS, VTE occurred in 19 patients during a median follow-up period of 717 days (IQR, 488-1308), yielding an annual incidence rate of 2.93% (95% CI, 1.88%-4.53%). Predictors for VTE were a family history of VTE (hazard ratio [HR], 15.24; 95% CI, 1.72-134.84; P = .01), the presence of noninvasive ventilation at ALS diagnosis (HR, 6.98; 95% CI, 1.09-44.59; P = .04) and a short time (ie, <213 days) between first symptoms and ALS diagnosis (HR, 5.48; 95% CI, 1.57-19.11; P = .01). Recurrent VTE occurred within 3 months after stopping anticoagulation in 5 patients (26.3%). Conclusion: The annual incidence of VTE in patients with ALS is high. Predictive factors of VTE were a VTE history, noninvasive ventilation, and a short time between first symptoms of ALS and ALS diagnosis.

Outpatient management of cancer-associated pulmonary embolism: A post-hoc analysis from the HOME-PE trial.

INTRODUCTION: Cancer-related pulmonary embolism (PE) is associated with poor prognosis. Some decision rules identifying patients eligible for home treatment categorize cancer patients at high risk of complications, precluding home treatment. We sought to assess the effectiveness and the safety of outpatient management of patients with low-risk cancer-associated PE. METHODS: In the HOME-PE trial, hemodynamically stable patients with symptomatic PE were randomized to either triaging with Hestia criteria or sPESI score. We analyzed 3 groups of low-risk PE patients: 47 with active cancer treated at home (group 1), 691 without active cancer treated at home (group 2), and 33 with active cancer as the only sPESI criterion qualifying them for hospitalization (group 3). The main outcome was the composite of recurrent venous thromboembolism, major bleeding, and all-cause death within 30 days after randomization. RESULTS: Patients treated at home had composite outcome rates of 4.3 % (2/47) for those with cancer vs. 1.0 % (7/691) for those without (odds ratio (OR) 4.98, 95%CI 1.15-21.49). Patients with cancer had rates of complications of 4.3 % when treated at home vs. 3.0 % (1/33) when hospitalized (OR 1.19, 95%CI 0.15-9.47). In multivariable analysis, active cancer was associated with an increased risk of complications for patients treated at home (OR 7.95; 95%CI 1.48-42.82). For patients with active cancer, home treatment was not associated with the primary outcome (OR 1.19, 95%CI 0.15-9.74). CONCLUSIONS: Among patients treated at home, active cancer was a risk factor for complications, but among patients with active cancer, home treatment was not associated with adverse outcomes.

Pulmonary embolism diagnostic strategies in patients with COPD exacerbation: Post-hoc analysis of the PEP trial.

BACKGROUND: The prevalence of pulmonary embolism (PE) is approximately 11-17 % in patients with an acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). The optimal diagnostic strategy for PE in these patients remains undetermined. AIMS: To evaluate the safety and efficacy of standard (revised Geneva and Wells PE scores combined with fixed D-dimer cut-off) and computed tomography pulmonary angiogram (CTPA)-sparing diagnostic strategies (ADJUST-PE, YEARS, PEGeD, 4PEPS) in patients with AE-COPD. METHOD: Post-hoc analyses of data from the multicenter prospective PEP study were performed. The primary outcome was the diagnostic failure rate of venous thromboembolism (VTE) during the entire study period. Secondary outcomes included diagnostic failure rate of PE and deep venous thrombosis (DVT), respectively, during the entire study period and the number of CTPA needed per diagnostic strategy. RESULTS: 740 patients were included. The revised Geneva and Wells PE scores combined with fixed D-dimer cut-off had a diagnostic failure rate of VTE of 0.7 % (95%CI 0.3 %-1.7 %), but >70.0 % of the patients needed imaging. All CTPA-sparing diagnostic algorithms reduced the need for CTPAs (-10.1 % to -32.4 %, depending on the algorithm), at the cost of an increased VTE diagnosis failure rate of up to 2.1 % (95%CI 1.2 %-3.4 %). CONCLUSION: Revised Geneva and Wells PE scores combined with fixed D-dimer cut-off were safe, but a high number of CTPA remained needed. CTPA-sparing algorithms would reduce imaging, at the cost of an increased VTE diagnosis failure rate that exceeds the safety threshold. Further studies are needed to improve diagnostic management in this population.

Family history of postpartum hemorrhage is a risk factor for postpartum hemorrhage after vaginal delivery: results from the French prospective multicenter Haemorrhages and Thromboembolic Venous Disease of the Postpartum cohort study.

BACKGROUND: Postpartum hemorrhage is a major component of perinatal morbidity and mortality that affects young women worldwide and is still often unpredictable. Reducing the incidence of postpartum hemorrhage is a major health issue and identifying women at risk for postpartum hemorrhage is a key element in preventing this complication. OBJECTIVE: This study aimed to estimate postpartum hemorrhage prevalence after vaginal delivery and to identify postpartum hemorrhage risk factors. STUDY DESIGN: Unselected pregnant women ≥16 years of age admitted to 1 of 6 maternity wards in Brittany (France) for vaginal birth after 15 weeks of gestation were recruited in this prospective, multicenter cohort study between June 1, 2015, and January 31, 2019. Postpartum hemorrhage was defined as blood loss ≥500 mL in the 24 hours following delivery. Independent risk factors for postpartum hemorrhage were determined using logistic regression. Missing data were imputed using the Multivariate Imputation by Chained Equations method. RESULTS: Among 16,382 included women, the postpartum hemorrhage prevalence was 5.37%. A first-degree family history of postpartum hemorrhage (adjusted odds ratio, 1.63; 95% confidence interval, 1.24-2.14) and a personal transfusion history (adjusted odds ratio, 1.90; 95% confidence interval, 1.23-2.92) were significantly associated with postpartum hemorrhage. The use of oxytocin during labor was also a risk factor for postpartum hemorrhage (adjusted odds ratio, 1.24; 95% confidence interval, 1.06-1.44). Inversely, smoking during pregnancy and intrauterine growth restriction were associated with a reduced risk for postpartum hemorrhage (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.91, and 0.34; 95% confidence interval, 0.13-0.87, respectively). CONCLUSION: In addition to classical risk factors, this study identified a family history of postpartum hemorrhage and personal transfusion history as new characteristics associated with postpartum hemorrhage after vaginal delivery. The association of postpartum hemorrhage with a family history of postpartum hemorrhage suggests a hereditary hemorrhagic phenotype and calls for genetic studies. Identifying women at risk for postpartum hemorrhage is a key element of being prepared for this complication.

In-depth characterization of pulmonary arterial hypertension in mixed connective tissue disease: a French national multicentre study.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients. METHODS: MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. RESULTS: Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. CONCLUSION: PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH.

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: a systematic review and meta-analysis of individual participant data.

We aimed to assess the relationship between residual pulmonary vascular obstruction (RPVO) on planar lung scan after completion of at least 3 months of anticoagulant therapy for acute pulmonary embolism (PE) and the risk of recurrent venous thromboembolism (VTE) or death due to PE one year after treatment discontinuation. The systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42017081080). The primary outcome measure was to generate a pooled estimate of the rate of recurrent VTE at one year in patient with RPVO diagnosed on planar lung scan after discontinuation of at least 3 months of anticoagulant treatment for an acute PE. Individual data were obtained for 809 patients. RPVO (ie, obstruction >0%) was found in 407 patients (50.3%) after a median of 6.6 months of anticoagulant therapy for a first acute PE. Recurrent VTE or death due to PE occurred in 114 patients (14.1%), for an annual risk of 6.4% (95% confidence interval, 4.7%-8.6%). Out of the 114 recurrent events, 63 occurred within one year after discontinuation of anticoagulant therapy corresponding to a risk of 8.1% (6.4%-9.8%) at 1 year. The risk of recurrent VTE at one year was 5.8% (4.4-7.2) in participants with RPVO <5%, vs 11.7% (9.5-13.8) in participants with RPVO ≥5%. RPVO is a significant predictor of the risk of recurrent venous thromboembolism. However, the risk of recurrent events remains too high in patients without residual perfusion defect for it to be used as a stand-alone test to decide on anticoagulation discontinuation.

Venous Thromboembolism Associated with Assisted Reproductive Technology: A Systematic Review and Meta-analysis.

BACKGROUND: Hormonal exposure leads to an increased risk of venous thromboembolism (VTE) but the risk of VTE associated with assisted reproductive technology (ART) is not clearly determined. METHODS: We searched in PubMed, EMBASE, Web of Science, and the Cochrane Library databases and identified all relevant articles published up to February 1, 2021. The primary objective was to determine the frequency of VTE associated with ART. Secondary objectives were to determine (1) the risk of VTE associated with ART as compared to pregnancy without ART; (2) the risk of VTE associated with ovarian hyperstimulation syndrome (OHSS); and (3) to determine potential risk factors of VTE related to ART. RESULTS: Fourteen studies were included. The overall frequency of VTE associated with ART was 0.23% (95% confidence interval [CI]: 0.07-0.46). Women undergoing ART had a two- to threefold increased risk of VTE as compared to spontaneous pregnancy (relative risk [RR]: 2.66; 95% CI: 1.60-4.43). The overall frequency of VTE specifically related to OHSS was <0.001%. The risk of VTE after ART complicated by OHSS, as compared to ART without OHSS, was higher but not statistically significant (RR: 14.83; 95% CI: 0.86-255.62). Risk factors of VTE associated with ART were in vitro fertilization procedure (RR, odds ratio [OR], and hazard ratio varying from 1.77, 95% CI: 1.41-2.23 to 4.99, 95% CI: 1.24-20.05), hyperhomocysteinemia (OR: 15.2; 95% CI: 2.0-115.0), polycystic ovarian syndrome (PCOS) (RR: 4.8; 95% CI: 1.7-13.4), successful ART leading to pregnancy (OR: 13.94; 95% CI: 1.41-137.45). CONCLUSION: Further large prospective studies on risk factors of VTE in women undergoing ART are needed in order to optimize thromboprophylaxis in this context.

Noninvasive diagnostic work-up for suspected acute pulmonary embolism during pregnancy: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Few studies evaluated the performance of noninvasive diagnostic strategies for suspected acute pulmonary embolism (PE) in pregnant women. OBJECTIVES: The aim of this study was to establish the safety and efficiency of the Wells rule with fixed and adapted D-dimer threshold, and the YEARS algorithm, combined with compression ultrasonography (CUS), in pregnant women with suspected PE in an individual patient data meta-analysis. METHODS: We performed a systematic review to identify prospective diagnostic management studies in pregnant women with suspected PE. Primary outcomes were safety, defined as the failure rate, ie, the 3-month venous thromboembolism (VTE) incidence after excluding PE without chest imaging, and efficiency, defined as the proportion of patients in whom chest imaging could be avoided. RESULTS: We identified 2 relevant studies, of which individual patient-level data were analyzed in a fixed-effect meta-analysis, totaling 893 pregnant women. The Wells rule with fixed and adapted D-dimer threshold as well as the YEARS algorithm could safely rule out acute PE (failure rate, 0·37%-1·4%), but efficiency improved considerably when applying pretest probability-adapted D-dimer thresholds. The efficiency of bilateral CUS was limited (2·3% overall; number needed to test 43), especially in patients without symptoms of deep-vein thrombosis (efficiency 0·79%; number needed to test 127). CONCLUSION: This study supports the latest guideline recommendations (European Society of Cardiology 2019) to apply pretest probability assessment and D-dimer tests to rule out PE in pregnant women. From an efficiency perspective, the use of a strategy with pretest probability-adapted D-dimer threshold is preferred. The yield of CUS was very limited in patients without concomitant symptoms of deep-vein thrombosis.

Predictors of Recurrent Venous Thromboembolism or Arterial Thrombotic Events during and after Anticoagulation for a First Venous Thromboembolism.

After first episodes of venous thromboembolism (VTE), patients are at increased risk of recurrent VTE and arterial thrombotic events (ATE) compared with the general population, two disorders that are influenced by anticoagulation. However, risk factors of these conditions occurring during and after anticoagulation are little described. Using cause-specific hazard regression models, we aimed to determine risk factors of the composite outcome recurrent VTE/ATE, and separately recurrent VTE or ATE, during and after anticoagulation in patients with first episodes of VTE from a prospective cohort. Hazard ratios (HRs) are given with 95% confidence intervals (CIs). A total of 2,011 patients treated for at least 3 months were included. A total of 647 patients had recurrent VTE/ATE (incidence: 4.69% per patient-years) during overall follow-up (median: 92 months). Of these events, 173 occurred during anticoagulation (incidence: 3.67% per patient-years). Among patients free of events at the end of anticoagulation, 801 had a post-anticoagulation follow-up ≥3 months; and 95 had recurrent VTE/ATE (incidence: 1.27% per patient-years). After adjustment for confounders, cancer-associated VTE (HR: 2.64, 95% CI: 1.70-4.11) and unprovoked VTE (HR: 1.95, 95% CI: 1.35-2.81) were the identified risk factors of recurrent VTE/ATE during anticoagulation (vs. transient risk factor-related VTE). Risk factors of recurrent VTE/ATE after anticoagulation included 50 to 65 years of age (vs. < 50, HR: 1.99, 95% CI: 1.04-3.81), older than 65 years (vs. < 50, HR: 5.28, 95% CI: 3.03-9.21), and unprovoked VTE (vs. transient risk factor-related VTE, HR: 2.06, 95% CI: 1.27-3.34). Cancer-associated VTE and unprovoked VTE are the main risk factors of recurrent VTE/ATE during anticoagulation, while older age and unprovoked VTE mainly predict the risk of these events after anticoagulation.

Incidence of venous thromboembolism and association with PD-L1 expression in advanced non-small cell lung cancer patients treated with first-line chemo-immunotherapy.

Background: Venous thromboembolism (VTE) is a serious complication in non-small cell lung cancer (NSCLC) patients. The use of thromboprophylactic therapy is subject to an accurate assessment of the VTE risk depending on patients, tumor characteristics and type of systemic antineoplastic treatments. However, little is known concerning the risk of VTE in patients suffering from an advanced NSCLC treated with first-line chemo-immunotherapy and the impact of tumor biomarkers such as PD-L1 expression. Methods: We performed a retrospective, observational, single-centre study in a cohort of advanced NSCLC patients treated with first-line chemo-immunotherapy. The primary endpoint was the incidence of VTE. Secondary endpoints were the cumulative incidence of VTE, the impact of PD-L1 on VTE occurrence, overall survival, the rate of VTE recurrence under anticoagulant treatment and the rate of bleeding complications. Results: 109 patients were included, of whom 21 (19.3%) presented a VTE event during a median follow-up of 13 months. VTE incidence at 3, 6 and 12 months was 12.1%, 15.1% and 17.5% respectively. 61% were pulmonary embolisms, 9.5% were isolated deep vein thrombosis and 14.3% were central venous catheter-related thrombosis. Our study did not show a significant impact of PD-L1 on VTE occurrence. Overall survival at 6, 12 and 24 months was 81.9%, 74.4% and 70.3% respectively. Four patients developed a recurrent VTE under anticoagulation therapy 3 to 5 months after the first VTE event. One patient suffered from a major bleeding complication while under anticoagulation therapy, leading to death. Conclusion: VTE is a common complication in advanced NSCLC patients treated with concomitant chemo-immunotherapy. In our study, 19.3% of patients developed a VTE during a median follow-up of 13 months. PD-L1 did not appear to be associated with VTE occurrence. We recorded high VTE recurrence rates despite anticoagulant treatment. Further investigations are needed to determine if high PD-L1 expression is associated with VTE.

Quantification of the pulmonary vascular obstruction index on ventilation/perfusion lung scintigraphy: Comparison of a segmental visual scoring to the Meyer score.

Introduction: Quantifying the pulmonary vascular obstruction index (PVOI) is essential for the management of patients with pulmonary embolism or chronic thromboembolic pulmonary hypertension (CTEPH). The reference method for quantifying the PVOI with planar lung ventilation/perfusion (V/Q) scintigraphy is the Meyer score, which was validated using pulmonary angiography as a reference standard. However, it is complex to use in daily practice. In contrast, a rapid and fast quantification method consists in estimating the PVOI based on the number of segmental perfusion defects. However, the accuracy of this method has never been evaluated. In this study, we aimed to compare PVOI quantification on planar V/Q scintigraphy assessed by a segmental visual scoring (SVS) to the Meyer score. Materials and methods: The eligible study population consisted of consecutive patients who underwent planar V/Q scan for CTEPH screening. A central review was performed by three nuclear medicine physicians. PVOI was assessed by summing the number of segmental perfusion defects or equivalent (2 sub-segments = 1 segment = 5%) and by Meyer's method. The two interpretations were performed 6 months apart. A Spearman rank correlation coefficient was calculated to evaluate correlation between the two measurement methods. An intra-class correlation (ICC) was calculated to assess agreement. A Bland et Altman plot analysis was used to evaluate agreement between the two measurements. Results: A total of 226 V/Q scans were interpreted. Spearman rank correlation coefficient between SVS and Meyer was 0.963 (95%CI 0.952-0.971) for mismatched perfusion defects and 0.963 (95%CI 0.953-0.972) for perfusion defects regardless of ventilation. Intra-class correlation (ICC) for agreement was 0.978 (95%CI 0.972-0.983) for mismatched perfusion defects and 0.968 (95%CI 0.959-0.976) for perfusion defects regardless of ventilation. In Bland & Altmann analysis, the mean difference between the SVS method and the Meyer score was 0.42 and 0.61 for the mismatched or matched evaluation, respectively. Conclusion: Our study shows a high correlation, and low differences in PVOI quantification when using a segmental visual scoring (SVS) as compared to the Meyer score. The SVS has the great advantage to be easy and rapid to apply in daily practice.

Development of an international standard set of outcome measures for patients with venous thromboembolism: an International Consortium for Health Outcomes Measurement consensus recommendation.

The International Consortium for Health Outcomes Measurement assembled an international working group of venous thromboembolism experts and patient representatives to develop a standardised minimum set of outcomes and outcome measurements for integration into clinical practice and potentially research to support clinical decision making and benchmarking of quality of care. 15 core outcomes important to patients and health-care professionals were selected and categorised into four domains: patient-reported outcomes, long term consequences of the disease, disease-specific complications, and treatment-related complications. The outcomes and outcome measures were designed to apply to all patients with venous thromboembolism aged 16 years or older. A measurement tool package was selected for inclusion in the core standard set, with a minimum number of items to be measured at predefined timepoints, which capture all core outcomes. Additional measures can be introduced to the user by a cascade opt-in system that allows for further assessment if required. This set of outcomes and measurement tools will facilitate the implementation of the use of patient-centred outcomes in daily practice.

Balloon pulmonary angioplasty versus riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (RACE): a multicentre, phase 3, open-label, randomised controlled trial and ancillary follow-up study.

BACKGROUND: Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, randomised controlled trials comparing these treatments are lacking. We aimed to evaluate the efficacy and safety of BPA versus riociguat in patients with inoperable CTEPH. METHODS: In this phase 3, multicentre, open-label, parallel-group, randomised controlled trial done in 23 French centres of expertise for pulmonary hypertension, we enrolled treatment-naive patients aged 18-80 years with newly diagnosed, inoperable CTEPH and pulmonary vascular resistance of more than 320 dyn·s/cm5. Patients were randomly assigned (1:1) to BPA or riociguat via a web-based randomisation system, with block randomisation (block sizes of two or four patients) without stratification. The primary endpoint was change in pulmonary vascular resistance at week 26, expressed as percentage of baseline pulmonary vascular resistance in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of riociguat or had at least one BPA session. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with pulmonary vascular resistance of more than 320 dyn·s/cm5 benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed. FINDINGS: Between Jan 19, 2016, and Jan 18, 2019, 105 patients were randomly assigned to riociguat (n=53) or BPA (n=52). At week 26, the geometric mean pulmonary vascular resistance decreased to 39·9% (95% CI 36·2-44·0) of baseline pulmonary vascular resistance in the BPA group and 66·7% (60·5-73·5) of baseline pulmonary vascular resistance in the riociguat group (ratio of geometric means 0·60, 95% CI 0·52-0·69; p<0·0001). Treatment-related serious adverse events occurred in 22 (42%) of 52 patients in the BPA group and five (9%) of 53 patients in the riociguat group. The most frequent treatment-related serious adverse events were lung injury (18 [35%] of 52 patients) in the BPA group and severe hypotension with syncope (two [4%] of 53 patients) in the riociguat group. There were no treatment-related deaths. At week 52, a similar reduction in pulmonary vascular resistance was observed in patients treated with first-line riociguat or first-line BPA (ratio of geometric means 0·91, 95% CI 0·79-1·04). The incidence of BPA-related serious adverse events was lower in patients who were pretreated with riociguat (five [14%] of 36 patients vs 22 [42%] of 52 patients). INTERPRETATION: At week 26, pulmonary vascular resistance reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. The finding of fewer BPA-related serious adverse events among patients who were pretreated with riociguat in the follow-up study compared with those who received BPA as first-line treatment points to the potential benefits of a multimodality approach to treatment in patients with inoperable CTEPH. Further studies are needed to explore the effects of sequential treatment combining one or two medications and BPA in patients with inoperable CTEPH. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health and Bayer HealthCare. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Frequency and predictors for chronic thromboembolic pulmonary hypertension after a first unprovoked pulmonary embolism: Results from PADIS studies.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined. OBJECTIVE: To determine the frequency and predictors for CTEPH after a first unprovoked PE. PATIENTS/METHODS: In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated. RESULTS: During a median follow-up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95-4.64), and of 1.31% (95% CI 0.01-2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64-667.00, p = .02) and 12.50 (95% CI 2.10-74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11-1310.00, p < .01]and HR 17.2 [95% CI 2.75-108, p < .01]). CONCLUSION: After a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8-year follow-up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis.

Risk Factors for Major Adverse Cardiovascular Events and Major Adverse Limb Events after Venous Thromboembolism: A Large Prospective Cohort Study.

BACKGROUND: There is an increased risk of arterial events including major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after venous thromboembolism (VTE). However, their risk factors remain little explored. METHODS: We aimed to determine the risk factors for MACE (acute coronary syndrome/stroke/cardiovascular death) and MALE (limb ischemia/critical limb ischemia/non-traumatic amputation/any limb revascularization) after VTE. Competing risk models (Fine-Gray) were used in a multicenter prospective cohort of 4,940 patients (mean age: 64.6 years and median follow-up: 64 months). RESULTS: MACE occurred in 17.3% of participants (2.35% per patient-years) and MALE in 1.7% (0.27% per patient-years). In multivariable analysis, the identified risk factors for MACE were the age of 50 to 65 years (vs. <50 years, hazard ratio [HR]: 2.00, 95% confidence interval [CI]: 1.38-2.91), age >65 years (vs. <50 years, HR 4.85, 95% CI: 3.35-7.02), pulmonary embolism + deep vein thrombosis (DVT) (vs. isolated-DVT, HR: 1.25, 95% CI: 1.02-1.55), unprovoked-VTE (vs. transient risk factor associated-VTE, HR: 1.29, 95% CI: 1.04-1.59), current tobacco use (vs. never, HR: 1.45, 95% CI: 1.07-1.98), hypertension (HR: 1.61, 95% CI: 1.30-1.98), past history of symptomatic atherosclerosis (HR: 1.52, 95% CI: 1.17-1.98), heart failure (HR: 1.71, 95% CI: 1.21-2.42), atrial fibrillation (HR: 1.55, 95% CI: 1.15-2.08), and vena cava filter insertion (HR: 1.46, 95% CI: 1.03-2.08). The identified risk factors for MALE were the age of 50-65 years (vs. <50 years, HR: 3.49, 95% CI: 1.26-9.65) and atrial fibrillation (HR: 2.37, 95% CI: 1.15-4.89). CONCLUSIONS: Risk factors for MACE and MALE after VTE included some traditional cardiovascular risk factors, patient's comorbidities, and some characteristics of VTE.

Risk Factors of Cardiovascular Death after Venous Thromboembolism: Results from a Prospective Cohort Study.

BACKGROUND: Cardiovascular deaths (CVDTs) are more frequent in patients with venous thromboembolism (VTE) than in the general population; however, risk factors associated with this increased risk of CVDT in patients with VTE are not described. METHODS: To determine the risk factors of CVDT in patients with VTE from a multicenter prospective cohort study, Fine and Gray subdistribution hazard models were conducted. RESULTS: Of the 3,988 included patients, 426 (10.7%) died of CVDT during a median follow-up of 5 years. The risk factors of CVDT after multivariate analyses were: age of 50 to 65 years (vs. <50 years, hazard ratio [HR]: 3.22, 95% confidence interval [CI]: 1.67-6.62), age >65 years (vs. <50 years, HR: 7.60, 95% CI: 3.73-15.52), cancer-associated VTE (vs. transient risk factor-related VTE, HR: 1.73, 95% CI: 1.15-2.61), unprovoked VTE (vs. transient risk factor-related VTE, HR: 1.42, 95% CI: 1.02-2.00), past tobacco use (vs. never, HR: 1.43, 95% CI: 1.06-1.94), current tobacco use (vs. never, HR: 1.87, 95% CI: 1.15-3.01), hypertension (HR: 2.11, 95% CI: 1.51-2.96), chronic heart failure (HR: 2.28, 95% CI: 1.37-3.79), chronic respiratory failure (HR: 1.72, 95% CI: 1.02-2.89), and atrial fibrillation (HR: 1.67, 95% CI: 1.06-2.60). The risk of CVDT was significantly reduced with direct oral anticoagulants (vs. vitamin-K antagonists) and with longer duration of treatment (>3 months). CONCLUSION: Risk factors of CVDT after VTE include some traditional cardiovascular risk factors and other risk factors that are related to characteristics of VTE, and patients' comorbidities.

Anticoagulation for VTE: Impact on the Risk of Major Adverse Cardiovascular Events.

BACKGROUND: It was recently established that patients who developed VTE are at increased risk of major adverse cardiovascular events (MACE) compared with the general population. However, whether the anticoagulation used for VTE influences the risk of MACE remains undescribed. RESEARCH QUESTION: Does the anticoagulant treatment for VTE affect the risk of subsequent MACE? STUDY DESIGN AND METHODS: This study included patients from a large prospective cohort who received only one family of anticoagulant treatment after the acute phase of VTE, including vitamin K antagonist (VKAs) and direct oral anticoagulants (DOACs). MACE included nonfatal acute coronary syndrome, nonfatal stroke, and all-cause death. The secondary outcome, MACE-2, included cardiovascular death instead of all-cause death. Cox proportional and Fine-Gray models served to study the relationship between anticoagulation characteristics and the risk of outcomes. RESULTS: A total of 3,790 patients (47.2% male; mean age, 60.48 years) were included. A total of 1,228 patients (32.4%) were treated for 0 to 3 months (median in overall population, 6 months). Compared with these patients, those treated for 3 to 12 months (hazard ratio [HR], 0.64; 95% CI, 0.54-0.76) or > 12 months (HR, 0.47, 95% CI, 0.39-0.56) had a significant reduced risk of MACE following adjustment for confounders. Findings were similar for MACE-2 (sub-HR for 3-12 months, 0.61 [95% CI, 0.47-0.79]; sub-HR > 12 months, 0.52 [95% CI, 0.39-0.68]). After adjustment for confounders, there was a reduced risk of MACE (HR, 0.53; 95% CI, 0.39-0.71) and MACE-2 (sub-HR, 0.48; 95% CI, 0.29-0.77) in patients treated with DOACs (vs VKAs). INTERPRETATION: Treatment of VTE for > 3 months is associated with a reduced risk of MACE, as is treatment with DOACs vs VKAs. These findings, which may influence the choice of anticoagulation strategies for VTE, need confirmation by randomized clinical trials.

Risk factors of arterial thrombotic events after unprovoked venous thromboembolism, and after cancer associated venous thromboembolism: A prospective cohort study.

INTRODUCTION: The increased risk of arterial thrombotic (ATE) after VTE, particularly when they are unprovoked or cancer-associated has been established. However, the risk factors of ATE after these VTE remain unclear. MATERIAL AND METHODS: Using cause-specific hazard regression models, we determined risk factors of ATE (myocardial infarction, ischemic stroke, acute limb ischemia, digestive tract ischemia, or renal ischemia) in 2242 patients with unprovoked VTE and in 914 patients with cancer-associated VTE from a multi-center prospective cohort. RESULTS: Of patients with unprovoked-VTE, 174 developed ATE (7.8%, incidence: 1.26 per 100 patient-years) during follow-up (median: 68 months). Among patients with cancer-associated VTE, 57 developed ATE (6.2%, incidence: 1.98 per 100 patient-years) during follow-up (median: 30 months). After multivariable analysis, the identified risk factors of ATE in patients with unprovoked-VTE were age > 65 years (vs. <50 years, HR 2.59, 95% CI: 1.56-4.29), past history of symptomatic atherosclerosis (HR 2.11, 95% CI: 1.40-3.19), and treatment with low molecule weight heparin (vs. vitamin K antagonists, HR: 2.26, 95% CI: 1.13-4.52). In patients with cancer-associated VTE, the identified risk factors of ATE were: past history of symptomatic atherosclerosis (HR: 3.13, 95% CI: 1.72-5.67), and ongoing anticoagulation at the diagnosis of VTE (HR: 2.77, 95% CI: 1.07-7.22). CONCLUSIONS: The risk of ATE after unprovoked VTE and after cancer-associated VTE, is determined by some classic cardiovascular risk factors and appears to be influenced by anticoagulant treatment introduced for VTE, as well as the presence or absence of ongoing anticoagulation at the diagnosis of VTE.