Sleep Apnea and Incident Unprovoked Venous Thromboembolism: Data from the Pays de la Loire Sleep Cohort.

BACKGROUND: Previous studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and incident venous thromboembolism (VTE). More specifically, the association between OSA and unprovoked VTE was barely evaluated. We aimed to evaluate whether apnea hypopnea index (AHI) and nocturnal hypoxemia markers were associated with unprovoked VTE incidence in patients investigated for OSA. MATERIAL AND METHODS: Data from the Pays de la Loire Sleep Cohort were linked to the French health administrative data to identify incident unprovoked VTE in patients suspected for OSA and no previous VTE disease. Cox proportional hazards models were used to evaluate the association of unprovoked VTE incidence with AHI and nocturnal hypoxemia markers including the time spent under 90% of saturation (T90), oxygen desaturation index, and hypoxic burden (HB), a more specific marker of respiratory events related to hypoxia. The impact of continuous positive airway pressure (CPAP) was evaluated in the subgroup of patients who were proposed the treatment. RESULTS: After a median [interquartile range] follow-up of 6.3 [4.3-9.0] years, 104 of 7,355 patients developed unprovoked VTE, for an incidence rate of 10.8 per 1,000 patient-years. In a univariate analysis, T90 and HB predicted incident VTE. In the fully adjusted model, T90 was the only independent predictor (hazard ratio: 1.06; 95% confidence interval: [1.01-1.02]; p = 0.02). The CPAP treatment has no significant impact on VTE incidence. CONCLUSION: Patients with more severe nocturnal hypoxia are more likely to have incident unprovoked VTE.

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.

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.

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.

Adjusting D-dimer to Lung Disease Extent to Exclude Pulmonary Embolism in COVID-19 Patients (Co-LEAD).

OBJECTIVE: D-dimer measurement is a safe tool to exclude pulmonary embolism (PE), but its specificity decreases in coronavirus disease 2019 (COVID-19) patients. Our aim was to derive a new algorithm with a specific D-dimer threshold for COVID-19 patients. METHODS: We conducted a French multicenter, retrospective cohort study among 774 COVID-19 patients with suspected PE. D-dimer threshold adjusted to extent of lung damage found on computed tomography (CT) was derived in a patient set (n = 337), and its safety assessed in an independent validation set (n = 337). RESULTS: According to receiver operating characteristic curves, in the derivation set, D-dimer safely excluded PE, with one false negative, when using a 900 ng/mL threshold when lung damage extent was <50% and 1,700 ng/mL when lung damage extent was ≥50%. In the derivation set, the algorithm sensitivity was 98.2% (95% confidence interval [CI]: 94.7-100.0) and its specificity 28.4% (95% CI: 24.1-32.3). The negative likelihood ratio (NLR) was 0.06 (95% CI: 0.01-0.44) and the area under the curve (AUC) was 0.63 (95% CI: 0.60-0.67). In the validation set, sensitivity and specificity were 96.7% (95% CI: 88.7-99.6) and 39.2% (95% CI: 32.2-46.1), respectively. The NLR was 0.08 (95% CI; 0.02-0.33), and the AUC did not differ from that of the derivation set (0.68, 95% CI: 0.64-0.72, p = 0.097). Using the Co-LEAD algorithm, 76 among 250 (30.4%) COVID-19 patients with suspected PE could have been managed without CT pulmonary angiography (CTPA) and 88 patients would have required two CTs. CONCLUSION: The Co-LEAD algorithm could safely exclude PE, and could reduce the use of CTPA in COVID-19 patients. Further prospective studies need to validate this strategy.

Incidence of Cancer after a Second Unprovoked Venous Thromboembolic Event.

Patients with two unprovoked venous thromboembolism (VTE) events could be at high risk for cancer diagnosis and may therefore benefit from extended cancer screening strategies. However, accurate data on the incidence of cancer in this population is lacking. In a prospective cohort study, we followed-up with all patients who experienced two unprovoked symptomatic VTE events that occurred in less than 2 years apart. We estimated the 1-year incidence rate of cancer following the second unprovoked VTE event using the Kaplan-Meier method. Potential predictors for cancer diagnosis were assessed using a Cox proportional hazard regression model. Between May 2000 and December 2013, we included 197 patients with two episodes of symptomatic unprovoked VTE that occurred in less than 2 years apart. Their mean age was 66.2 ± 16.3 years, and 122 (51.8%) were male. Seventeen patients were diagnosed with cancer during the year following the second episode of unprovoked VTE, corresponding to a cumulative incidence rate of 9.19% (95% confidence interval [CI]: 5.81-14.37). The 1-year cumulative incidence rate of cancer was 35.88% (95% CI: 19.75-59.25) in patients with VTE recurrence on anticoagulation, 5.51% (95% CI: 2.9-10.32) among patients with a second episode of unprovoked VTE occurring after stopping anticoagulation and 1.15% (95% CI: 0.16-7.88) when time elapsed between the first and recurrent VTE was > 1 year. Our study suggests that the incidence of cancer in patients with a second episode of unprovoked VTE that occurs off anticoagulation, or > 1 year after the first event, is similar to that of patients with a first unprovoked VTE event.