Feasibility of a screening algorithm for chronic thromboembolic pulmonary hypertension: The OSIRIS study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term sequel to pulmonary embolism (PE) whose incidence varies according to different published studies. We have carried out this study to determine its incidence within 2 years after index pulmonary embolism and to study limitations to an early diagnosis. MATERIAL AND METHODS: OSIRIS is a multicentre, longitudinal cohort study. Patients were followed for 3, 6, 12, and 24 months after pulmonary embolism using a structured three-step algorithm. A physician-centered questionnaire at least one positive response in a screening proceeded to the second step, transthoracic echocardiography. The third step consisted of ventilation/perfusion lung scintigraphy and right heart catheterisation. A transthoracic echocardiography was performed in patients without positive response in the screening questionnaire after 2 years. CTEPH diagnosis required haemodynamic confirmation by right heart catheterisation and mismatched perfusion defects on lung scintigraphy. RESULTS: A total of 1191 patients were enrolled in 18 Spanish hospitals. Cumulative CTEPH incidence after 2-years PE was: 2.49 % (95 % CI: 1.68-3.56) and the incidence rate of CTEPH was 1.1 cases per 1000 person-months (95 % CI: 0.725; 1.60). The CTEPH algorithm presented a lack of adherence of 29 %; patient and physician preferences posed barriers to the triage algorithm The screening questionnaire, in patients who completed the follow-up, shows a specificity of 91.3 % (89.0-93.2 %) and negative predictive value of 99.4 % (98.4-99.8 %).. CONCLUSIONS: OSIRIS provides practiced clinical based data on the chronic thromboembolic pulmonary hypertension incidence and identified barriers to the implementation of a 3-step triage algorithm for its detection. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03134898.

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism.

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.

Venous thromboembolism in solid-organ transplant recipients: Findings from the RIETE registry.

BACKGROUND: Venous thromboembolism (VTE) represents a relevant cause of morbidity in patients with solid-organ transplant (SOT), but there are scarce data on the management and outcomes in these patients. METHODS: RIETE is a worldwide, ongoing observational registry of patients with objectively confirmed, acute VTE. We used the RIETE database to compare the clinical characteristics, treatment and outcomes in SOT recipients vs. non-recipients. RESULTS: From January 2001 to December 2019, 83,210 patients were enrolled in RIETE. Of these, 329 (0.4%) were SOT recipients: in the kidney 221, liver 41, lung 28 and heart 25. Median duration of anticoagulation was similar in SOT recipients and non-recipients (174 vs. 182 days). During anticoagulation, 1180 patients developed deep vein thrombosis (DVT) recurrences, 1028 pulmonary embolism (PE) recurrences, 2392 had major bleeding, 3119 non-major bleeding and 8157 died. SOT recipients had a higher rate of major bleeding (hazard ratio [HR]: 2.55; 95% CI: 1.62-3.84) and clinically relevant non-major bleeding (HR: 1.94; 95% CI: 1.23-2.93) than non-recipients, with no differences in the rates of DVT recurrences (HR: 0.96; 95% CI: 0.30-2.32), PE recurrences (HR: 1.11; 95% CI: 0.35-2.67) or death (HR: 0.98; 95% CI: 0.67-1.40). On multivariable analysis, only liver transplant recipients were at an increased risk for major bleeding compared to non-recipients (adjusted HR: 3.17; 95% CI: 1.02-9.87). CONCLUSIONS: Treatment of VTE in SOT recipients is associated with an increased risk of bleeding compared to non-recipients. This is mainly due to the influence of liver transplant recipients. In non-liver SOT recipients, the risk for bleeding was similar to that in non-recipients.

Predicting the risk for major bleeding in elderly patients with venous thromboembolism using the Charlson index. Findings from the RIETE.

Old patients receiving anticoagulant therapy for venous thromboembolism (VTE) are at an increased risk for bleeding. We used data from the RIETE registry to assess the prognostic ability of the Comorbidity Charlson Index (CCI) to predict the risk for major bleeding in patients aged > 75 years receiving anticoagulation for VTE beyond the third month. We calculated the area under the receiver-operating characteristic curve (AUC), the category-based net reclassification index (NRI) and the net benefit (NB). We included 4303 patients with a median follow-up of 706 days (interquartile range [IQR] 462-1101). Of these, 147 (3%) developed major bleeding (27 died of bleeding). The AUC was 0.569 (95% CI 0.524-0.614). Patients with CCI ≤ 4 points were at a lower risk for adverse outcomes than those with CCI > 10 (major bleeding 0.81 (95% CI 0.53-1.19) vs. 2.21 (95% CI 1.18-3.79) per 100 patient-years; p < 0.05; all-cause death 1.9 (95% CI 1.45-2.44) vs. 15.67 (95% CI 12.63-19.22) per 100 patient-years; p < 0.05). A cut-off point of 4 points (CCI4) had a sensitivity of 82% (95% CI 75-89) and a specificity of 30% (95% CI 29-31) to predict major bleeding beyond the third month. CCI4 reclassification improved the NB of the RIETE bleeding score to predict bleeding beyond the third month (CCI4 NB 1.78% vs. RIETE NB 0.44%). Although the AUC of the CCI to predict major bleeding was modest, it could become an additional help to select patients aged > 75 years that obtain more benefit of extended anticoagulation, due to a lower risk for bleeding and better survival.

Edoxaban for the Long-Term Therapy of Venous Thromboembolism: Should the Criteria for Dose Reduction be Revised?

Edoxaban is used for venous thromboembolism (VTE) treatment. Real-life data are lacking about its use in long-term therapy. We aimed to assess the efficacy and the safety of edoxaban for long-term VTE treatment in a real-life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry, receiving edoxaban 60 or 30 mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long-term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60 mg daily, and 92 patients meeting criteria (63%) received 30 mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30 mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12-42.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63-262) than those receiving 60 mg. Among patients meeting criteria for dose reduction, those receiving 60 mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54-133) than those receiving 30 mg daily. In conclusion, edoxaban seems to be effective and safe for long-term VTE treatment in real life. Criteria for dose reduction should be reformulated.

Clinical characteristics and outcomes of venous thromboembolic events after hallux valgus surgery: insights from the RIETE registry.

Hallux valgus surgery (HVS) is one of the most common orthopedic procedures, often occurring in older adults. Guidelines provide inconsistent recommendations about venous thromboembolism (VTE) prophylaxis after HVS and data are scarce regarding VTE presentation and outcomes in this population. We reported the clinical characteristics and outcomes of VTE following HVS among patients enrolled in Registro Informatizado Enfermedad TromboEmbolica (RIETE), a prospective multicenter VTE registry. We compared the findings with those of other patients in RIETE. Consecutive patients with VTE post HVS were included in the study. Baseline characteristics, administration of VTE prophylaxis prior to diagnosis, presenting symptoms and signs, risk factors for VTE, and 90-day outcomes including recurrent VTE, major bleeding and death were determined. A total of 54 patients with VTE post HVS were identified in RIETE [median age: 64 (interquartile range 56-71) years; 85.2% female] and were compared with 74,111 VTE patients who had not undergone HVS. Among those with VTE post HVS, 63.0% had received VTE prophylaxis, in contrast to 35.6% in the rest of the RIETE cohort. Simplified Pulmonary Embolism Severity Index was zero in 66.7% of the patients with pulmonary embolism post HVS and 33.3% of other RIETE patients (P = 0.011). Compared with other VTE patients, use of estrogens was higher in HVS group (13.0% vs 5.4%, P = 0.01). All patients with VTE post HVS (100%) and most of other VTE patients (99.6%) were treated with anticoagulation, most commonly with low-molecular weight heparins. In contrast to the rest of the patients in RIETE, the absolute number of all fatal and non-fatal outcomes at 90 days was zero in the post HVS group (i.e. no deaths, no recurrence of VTE, and no major bleeding). In a large registry of patients with VTE, all patients with VTE post HVS underwent anticoagulation. These patients had much better outcomes than the rest of VTE patients, with no deaths, recurrences or major bleeding events at 90-day follow-up.

Thirty-day outcomes in patients with acute pulmonary embolism who discontinued anticoagulant therapy before 90 days.

BACKGROUND: The contemporary natural history of patients with acute pulmonary embolism (PE) not receiving (or early discontinuing) anticoagulant therapy has not been consistently evaluated. OBJECTIVE: To assess the rate of the composite outcome of PE-related death, sudden death, or recurrent thromboembolism (VTE) within 30 days in all PE patients in whom anticoagulation was not administered or discontinued prematurely (<90 days of anticoagulation). METHODS: We used the RIETE database to assess the incidence rates (per 100 person-days) of the composite outcome within the subsequent 30 days. The risk of these events was compared to PE patients who were anticoagulated for ≥90 days. RESULTS: Of 34,447 PE recruited from 2001 to 2017, 47 (0.14%) did not receive anticoagulants and 1348 (3.91%) discontinued it before 90 days. Fatal PE developed in 25 (53%) of those without any anticoagulation and in 45 (3.33%) with premature discontinuations. Sudden death or non-fatal recurrent VTE occurred in 6 (0.45%) and 24 (1.48%) patients, respectively. The incidence of the primary outcome declined logarithmically from 6.36 per 100 patient-days in untreated patients to 0.32-0.13 in those treated for 8-90 days. During the first week of follow-up, the incidence rate was 13.9 and 0.60-0.31 per 100 patient-days, respectively. The adjusted odds of the primary outcome was 27 fold higher in untreated than in treated patients, and progressively decreased to 2.5-7 fold higher in patients treated for at least 7 days. CONCLUSION: The incidence of the composite outcome was highest during the first week, and inversely and logarithmically correlated with the duration of anticoagulant therapy.

Predictors of Early Mortality in Cancer-Associated Thrombosis: Analysis of the RIETE Database.

Cancer-associated thrombosis (CT) carries a high, heterogeneous, and poorly predicted likelihood of mortality. Thus, we aimed to define predictors of 30-day mortality in 10,025 patients with CT. In a randomly selected derivation cohort, we used recursive partitioning analysis to detect variables that select for a risk of mortality within 30 days. In a validation cohort, we evaluated our results using Cochran-Armitage test. The most common types of cancer were lung (16%), breast (14%), and colorectal (14%); median age was 69 years (range, 14-101); most had metastatic disease (63%); 13% of patients died within 30 days. In the derivation cohort ( n = 6,660), a white blood cell (WBC) count in the highest quartile predicted early mortality (odds ratio, 7.8; 95% confidence interval [CI], 4.6-13.1); and the presence of metastatic disease, pulmonary embolism (PE), and immobility defined the risk of those with normal WBC count. We defined death risk according four sequential questions: (1) Does the patient have an elevated WBC count? (Yes, group D). (2) If no, does the patient have metastasis? (No, group A). (3) If yes, is the patient immobile? (Yes, group D). (4) If no, does the patient have a PE? (Yes, group C; no, group B). In the validation cohort ( n = 3,365), the 30-day risk of death was 2.9% in group A (95% CI, 1.9-4.3), compared with 25% in group D (95% CI, 22.5-27.5), and there was a rate escalation between groups ( p for trend < 0.01). In conclusion, with four sequential questions, the risk of death in CT can be easily stratified. An elevated WBC count at baseline predicted 30-day mortality better than metastases, PE, or immobility.

Sex Differences in Patients With Occult Cancer After Venous Thromboembolism.

In patients with venous thromboembolism (VTE), male sex has been associated with an increased risk of occult cancer. The influence of sex on clinical characteristics, treatment, cancer sites, and outcome has not been thoroughly investigated yet. We used the Registro Informatizado Enfermedad TromboEmbólica registry to compare the clinical characteristics, treatment strategies, cancer sites, and clinical outcomes in patients with VTE having occult cancer, according to sex. As of June 2014, 5864 patients were recruited, of whom 444 (7.6%; 95% confidence interval: 6.8-8.2) had occult cancer. Of these, 246 (55%) were men. Median time elapsed from VTE to occult cancer was 4 months (interquartile range: 2-8.4), with no sex differences. Women were older, weighed less, and were less likely to have chronic lung disease than men. The most common cancer sites were the lung (n = 63), prostate (n = 42), and colorectal (n = 29) in men and colorectal (n = 38), breast (n = 23), uterine (n = 18), hematologic (n = 17), or pancreas (n = 15) in women. Men were more likely to have lung cancer than women (2.18% vs 0.30%; P < .01) and less likely to have pancreatic cancer (0.17% vs 0.5%; P = .03). Interestingly, breast cancer was more likely found in women aged ≥50 years than in those aged <50 years (0.97% vs 0.14%; P = .03). This study highlights the existence of sex differences in patients with VTE having occult cancer. One in every 2 men had lung, prostate, or colorectal cancer. In women, there is a heterogeneity of cancer sites, increasing risk of breast cancer in those aged >50 years.

Outcome of Patients with Venous Thromboembolism and Factor V Leiden or Prothrombin 20210 Carrier Mutations During the Course of Anticoagulation.

BACKGROUND: Individuals with factor V Leiden or prothrombin G20210A mutations are at a higher risk to develop venous thromboembolism. However, the influence of these polymorphisms on patient outcome during anticoagulant therapy has not been consistently explored. METHODS: We used the Registro Informatizado de Enfermedad TromboEmbólica database to compare rates of venous thromboembolism recurrence and bleeding events occurring during the anticoagulation course in factor V Leiden carriers, prothrombin mutation carriers, and noncarriers. RESULTS: Between March 2001 and December 2015, 10,139 patients underwent thrombophilia testing. Of these, 1384 were factor V Leiden carriers, 1115 were prothrombin mutation carriers, and 7640 were noncarriers. During the anticoagulation course, 160 patients developed recurrent deep vein thrombosis and 94 patients developed pulmonary embolism (16 died); 154 patients had major bleeding (10 died), and 291 patients had nonmajor bleeding. On multivariable analysis, factor V Leiden carriers had a similar rate of venous thromboembolism recurrence (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.82-1.64), half the rate of major bleeding (adjusted HR, 0.50; 95% CI, 0.25-0.99) and a nonsignificantly lower rate of nonmajor bleeding (adjusted HR, 0.66; 95% CI, 0.43-1.01) than noncarriers. Prothrombin mutation carriers and noncarriers had a comparable rate of venous thromboembolism recurrence (adjusted HR, 1.00; 95% CI, 0.68-1.48), major bleeding (adjusted HR, 0.75; 95% CI, 0.42-1.34), and nonmajor bleeding events (adjusted HR, 1.10; 95% CI, 0.77-1.57). CONCLUSIONS: During the anticoagulation course, factor V Leiden carriers had a similar risk for venous thromboembolism recurrence and half the risk for major bleeding compared with noncarriers. This finding may contribute to decision-making regarding anticoagulation duration in selected factor V Leiden carriers with venous thromboembolism.

Infection as cause of immobility and occurrence of venous thromboembolism: analysis of 1635 medical cases from the RIETE registry.

Several risk assessment models include infection and immobility among the items to be considered for venous thromboembolism (VTE) prevention. However, information on patients with infection leading to immobility and developing VTE are limited, as well as on the role of specific types of infection. Data were collected from the worldwide RIETE registry, including patients with symptomatic objectively confirmed VTE, and followed-up for at least 3 months. The overall population of RIETE at June 2013 (n = 47,390) was considered. Acute infection leading to immobility was reported in 3.9 % of non-surgical patients. Compared with patients immobilized due to dementia, patients with infection had a shorter duration of immobilization prior to VTE (less than 4 weeks in 94.2 vs. 25.9 % of cases; p < 0.001). During the 3-month follow-up, VTE patients with infection versus those with dementia had a lower rate of fatal bleeding (0.5 vs. 1.1 %; p < 0.05) or fatal PE (1.7 vs. 3.5 %; p < 0.01). Patients with respiratory tract infections had more likely PE as initial VTE presentation than other types of infection (62.3 vs. 37.7 %; p < 0.001). Significantly more patients with pneumonia than those with other respiratory infections had received VTE prophylaxis (50.2 vs. 30.6 %; p < 0.001). Following VTE, patients with sepsis showed a significantly higher risk of fatal bleeding. Based on our real-world data, infection seems to contribute to the pathogenesis of VTE by accelerating the effects of immobility. Its role as VTE risk factor probably deserves further attention and specific assessment in order to optimize VTE prophylaxis and treatment.