Fatal events in cancer patients receiving anticoagulant therapy for venous thromboembolism

none144siIn cancer patients treated for venous thromboembolism (VTE), including deep-vein thrombosis (DVT) and pulmonary embolism (PE), analyzing mortality associated with recurrent VTE or major bleeding is needed to determine the optimal duration of anticoagulation. This was a cohort study using the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) Registry database to compare rates of fatal recurrent PE and fatal bleeding in cancer patients receiving anticoagulation for VTE. As of January 2013, 44,794 patients were enrolled in RIETE, of whom 7911(18%) had active cancer. During the course of anticoagulant therapy (mean, 181 ±210 days), 178 cancer patients (4.3%) developed recurrent PE (5.5 per 100 patient-years; 95% CI: 4.8-6.4), 194 (4.7%) had recurrent DVT (6.2 per 100 patient-years; 95% confidence interval [CI]: 5.3-7.1), and 367 (8.9%) bled (11.3 per 100 patient-years; 95% CI: 10.2-12.5). Of 4125 patients initially presenting with PE, 43 (1.0%) died of recurrent PE and 45 (1.1%) of bleeding; of 3786 patients with DVT, 19 (0.5%) died of PE, and 55 (1.3%) of bleeding. During the first 3 months of anticoagulation, there were 59 (1.4%) fatal PE recurrences and 77 (1.9%) fatal bleeds. Beyond the third month, there were 3 fatal PE recurrences and 23 fatal bleeds. In RIETE cancer patients, the rate of fatal recurrent PE or fatal bleeding was much higher within the first 3 months of anticoagulation therapy.openFarge D.; Trujillo-Santos J.; Debourdeau P.; Bura-Riviere A.; Rodriguez-Beltran E.M.; Nieto J.A.; Peris M.L.; Zeltser D.; Mazzolai L.; Hij A.; Monreal M.; Durante A.; Alcalde M.; Arcelus J.I.; Ballaz A.; Barba R.; Barron M.; Barron-Andres B.; Bascunana J.; Bedate P.; Blanco-Molina A.; Bueso T.; Casado I.; Conget F.; Del Molino F.; Del Toro J.; Falga C.; Fernandez-Capitan C.; Fuentes M.I.; Gallego P.; Garcia J.; Garcia-Bragado F.; Gavin O.; Gomez V.; Gonzalez J.; Gonzalez-Bachs E.; Grau E.; Guil M.; Guijarro R.; Gutierrez J.; Hernandez L.; Jara-Palomares L.; Jaras M.J.; Jimenez D.; Jimenez S.; Lobo J.L.; Lopez-Jimenez L.; Lopez-Saez J.B.; Lorente M.A.; Lorenzo A.; Luque J.M.; Madridano O.; Macia M.; Maestre A.; Marchena P.J.; Martin M.; Monreal M.; Mora J.M.; Munoz F.J.; Nauffal M.D.; Nieto J.A.; Nunez M.J.; Ogea J.L.; Otero R.; Pedrajas J.M.; Peris M.L.; Riera-Mestre A.; Rivas A.; Rodriguez-Davila M.A.; Roman P.; Rosa V.; Ruiz J.; Ruiz-Ribo M.D.; Ruiz-Gamietea A.; Ruiz-Gimenez N.; Sahuquillo J.C.; Samperiz A.; Sanchez Munoz-Torrero J.F.; Soler S.; Tiberio G.; Tilvan R.M.; Tolosa C.; Trujillo J.; Uresandi F.; Valdes M.; Valero B.; Valle R.; Vela J.; Vidal G.; Villalobos A.; Villalta J.; Gadelha T.; Maly R.; Hirmerova J.; Tomko T.; Bertoletti L.; Bura-Riviere A.; Farge-Bancel D.; Grange C.; Hij A.; Mahe I.; Merah A.; Quere I.; Schellong S.; Babalis D.; Papadakis M.; Tzinieris I.; Faul J.; Braester A.; Brenner B.; Tzoran I.; Zeltser D.; Barillari G.; Ciammaichella M.; Dalla Valle F.; Di Micco P.; Duce R.; Maida R.; Pasca S.; Piovella C.; Poggio R.; Prandoni P.; Quintavalla R.; Rocci A.; Rota L.; Schenone A.; Tiraferri E.; Tonello D.; Tufano A.; Visona A.; Zalunardo B.; Brinquinho M.; Gomes D.; Goncalves F.; Santos M.; Saraiva M.; Bosevski M.; Kovacevic D.; Alatri A.; Aujeski D.; Bounameaux H.; Calanca L.; Mazzolai L.; Caprini J.Farge, D.; Trujillo-Santos, J.; Debourdeau, P.; Bura-Riviere, A.; Rodriguez-Beltran, E. M.; Nieto, J. A.; Peris, M. L.; Zeltser, D.; Mazzolai, L.; Hij, A.; Monreal, M.; Durante, A.; Alcalde, M.; Arcelus, J. I.; Ballaz, A.; Barba, R.; Barron, M.; Barron-Andres, B.; Bascunana, J.; Bedate, P.; Blanco-Molina, A.; Bueso, T.; Casado, I.; Conget, F.; Del Molino, F.; Del Toro, J.; Falga, C.; Fernandez-Capitan, C.; Fuentes, M. I.; Gallego, P.; Garcia, J.; Garcia-Bragado, F.; Gavin, O.; Gomez, V.; Gonzalez, J.; Gonzalez-Bachs, E.; Grau, E.; Guil, M.; Guijarro, R.; Gutierrez, J.; Hernandez, L.; Jara-Palomares, L.; Jaras, M. J.; Jimenez, D.; Jimenez, S.; Lobo, J. L.; Lopez-Jimenez, L.; Lopez-Saez, J. B.; Lorente, M. A.; Lorenzo, A.; Luque, J. M.; Madridano, O.; Macia, M.; Maestre, A.; Marchena, P. J.; Martin, M.; Monreal, M.; Mora, J. M.; Munoz, F. J.; Nauffal, M. D.; Nieto, J. A.; Nunez, M. J.; Ogea, J. L.; Otero, R.; Pedrajas, J. M.; Peris, M. L.; Riera-Mestre, A.; Rivas, A.; Rodriguez-Davila, M. A.; Roman, P.; Rosa, V.; Ruiz, J.; Ruiz-Ribo, M. D.; Ruiz-Gamietea, A.; Ruiz-Gimenez, N.; Sahuquillo, J. C.; Samperiz, A.; Sanchez Munoz-Torrero, J. F.; Soler, S.; Tiberio, G.; Tilvan, R. M.; Tolosa, C.; Trujillo, J.; Uresandi, F.; Valdes, M.; Valero, B.; Valle, R.; Vela, J.; Vidal, G.; Villalobos, A.; Villalta, J.; Gadelha, T.; Maly, R.; Hirmerova, J.; Tomko, T.; Bertoletti, L.; Bura-Riviere, A.; Farge-Bancel, D.; Grange, C.; Hij, A.; Mahe, I.; Merah, A.; Quere, I.; Schellong, S.; Babalis, D.; Papadakis, M.; Tzinieris, I.; Faul, J.; Braester, A.; Brenner, B.; Tzoran, I.; Zeltser, D.; Barillari, G.; Ciammaichella, M.; Dalla Valle, F.; Di Micco, P.; Duce, R.; Maida, R.; Pasca, S.; Piovella, C.; Poggio, R.; Prandoni, P.; Quintavalla, R.; Rocci, A.; Rota, L.; Schenone, A.; Tiraferri, E.; Tonello, D.; Tufano, A.; Visona, A.; Zalunardo, B.; Brinquinho, M.; Gomes, D.; Goncalves, F.; Santos, M.; Saraiva, M.; Bosevski, M.; Kovacevic, D.; Alatri, A.; Aujeski, D.; Bounameaux, H.; Calanca, L.; Mazzolai, L.; Caprini, J

Clinical outcome in patients with venous thromboembolism receiving concomitant anticoagulant and antiplatelet therapy

Introduction: Patients with arterial disease receiving antiplatelet agents may develop venous thromboembolism (VTE) and need anticoagulant therapy, although concomitant use of these drugsmay increase bleeding risk. We analyzed RIETE data and compared clinical outcomes depending on decision to discontinue or maintain antiplatelet therapy at VTE diagnosis. Methods: Consecutive patients with acute VTE were enrolled in RIETE. Only patients receiving antiplatelet therapy at baseline were included in this analysis. Primary outcomes were: rate of subsequent ischemic events, major bleeding or death during anticoagulation course. Results: 1178 patientswho received antiplatelet drugs at VTE diagnosis were included. Antiplatelet therapy was discontinued in 62% of patients. During anticoagulation course, patients also receiving antiplatelet therapy had higher rates of lower limb amputations (2.28 vs. 0.21 events per 100 patients-years; p < 0.01), any ischemic events (5.7 vs. 2.28 events per 100 patients-years; p < 0.05) or death (23.6 vs. 13.9 deaths per 100 patientsyears; p < 0.01). No differences in the rate of major bleeding or recurrent VTEwere revealed. In matched analysis, patients on antiplatelet therapy were found to have a significantly higher rate of limb amputations (odds ratio: 15.3; 95% CI: 1.02-229) and an increased number of composite outcomes including all-cause deaths, arterial and VTE events (odds ratio: 1.46; CI: 1.03-2.06), with no differences in major bleeding rate. Conclusion: Concomitant anticoagulant and antiplatelet therapy in patients with VTE and arterial disease is not associated with increased risk for bleeding, recurrent VTE or death. The worse outcome observed in patients who continued antiplatelet therapy requires further investigations

First three months of anticoagulation for venous thromboembolism in non-cancer patients: LMWH VS. VKAs. Findings from the RIETE registry

Background: The use of low-molecular-weight heparin (LMWH) for long-term therapy of venous thromboembolism (VTE) in patients without cancer has not been consistently evaluated. Methods: We used the data in the RIETE registry to compare the 3-month outcomes (VTE recurrences, major bleeding or death) in non-cancer patients with VTE, according to long-term therapy with LMWH or vitamin K antagonists (VKAs). Results: As of March 2018, 14,582 non-cancer patients with VTE had received initial therapy with LMWH and then switched to VKAs, while 9151 were prescribed LMWH for initial and long-term therapy. Overall, 11,494 had initially presented with pulmonary embolism (PE) and 12,239 with isolated deep vein thrombosis (DVT). Among 11,494 patients initially presenting with PE, 84 had VTE recurrences, 204 major bleeding and 406 died. Among 12,239 patients with isolated DVT, 133 developed VTE recurrences, 137 bled and 289 died. On propensity score analysis, PE patients on long-term LMWH therapy were at increased risk for PE recurrences (OR: 3.30; 95%CI: 1.67–6.48), major bleeding (OR: 1.68; 95%CI: 1.21–2.32) or death (OR: 3.16; 95%CI: 2.43–4.09) compared with those receiving VKAs. In patients with DVT, those on long-term LMWH also were at increased risk for PE recurrences (OR: 2.31; 95%CI: 1.13–4.73), major bleeding (OR 2.28; 95%CI: 1.51–3.44) or death (OR: 2.32; 95%CI: 1.54–3.51). Conclusions: In the RIETE non-cancer patients with VTE, long-term therapy with VKAs was associated with a lower risk for recurrences, major bleeding or death

Liver status and outcomes in patients without previous known liver disease receiving anticoagulant therapy for venous thromboembolism

The association between elevated liver enzymes or FIB-4 (fibrosis index 4) and outcome in patients with venous thromboembolism (VTE) has not been evaluated. Data from patients in RIETE (Registro Informatizado Enfermedad TromboEmbólica) were used to assess the association between elevated liver enzymes or FIB-4 levels and the rates of major bleeding or death in apparent liver disease-free patients with acute VTE under anticoagulation therapy. A total of 6206 patients with acute VTE and without liver disease were included. Of them, 92 patients had major bleeding and 168 died under anticoagulation therapy. On multivariable analysis, patients with elevated liver enzymes were at increased mortality risk (HR: 1.58; 95% CI: 1.10–2.28), while those with FIB-4 levels > 2.67 points were at increased risk for major bleeding (HR: 1.69; 95% CI: 1.04–2.74). Evaluation of liver enzymes and FIB-4 index at baseline in liver disease-free patients with VTE may provide additional information on the risk for major bleeding or death during anticoagulation

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 TromboEmb\uf3lica (RIETE) registry, receiving edoxaban 60 or 30&nbsp;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&nbsp;mg daily, and 92 patients meeting criteria (63%) received 30&nbsp;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&nbsp;mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12\u201342.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63\u2013262) than those receiving 60&nbsp;mg. Among patients meeting criteria for dose reduction, those receiving 60&nbsp;mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54\u2013133) than those receiving 30&nbsp;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

Timing and characteristics of venous thromboembolism after noncancer surgery

Background: Venous thromboembolism (VTE) is a major cause of morbidity and mortality postoperatively. The use of pharmacologic prophylaxis is effective in reducing the incidence of VTE. However, the prophylaxis is often discontinued at hospital discharge, especially for those with benign disease. The implications of this practice are not known. We assessed the data from a large, ongoing registry regarding the time course of VTE and outcomes after noncancer surgery. Methods: We analyzed the RIETE (Computerized Registry on Venous Thromboembolism) registry, which includes data from consecutive patients with symptomatic confirmed VTE. In the present study, we focused on general surgical patients who had developed symptomatic postoperative VTE in the first 8 weeks after noncancer surgery. The main objective was to assess the interval between surgery and the occurrence of VTE. Additional variables included the clinical presentation associated with the event, the use of thrombosis prophylaxis, and unfavorable outcomes. Results: The data from 3296 patients were analyzed. The median time from surgery to the detection of VTE was 16 days (interquartile range, 8-30 days). Of the VTE events, 77% were detected after the first postoperative week and 27% after 4 weeks. Overall, 43.9% of the patients with VTE had received pharmacologic prophylaxis after surgery for a median of 8 days (interquartile range, 5-14 days), and three quarters of the VTE events were detected after pharmacologic prophylaxis had been discontinued. Overall, 54% of the patients with VTE had presented with pulmonary embolism. For 15% of the patients, the clinical outcome was unfavorable, including 4% who had died within 90 days. Conclusions: The risk of VTE after noncancer general surgery remains high for ≤2 months. More than one half of the patients had presented with symptomatic PE as the VTE event, and 15% had had unfavorable outcomes. Only 44% of these patients had received pharmacologic prophylaxis for around 1 week

Long-term anticoagulant therapy of patients with venous thromboembolism. What are the practices?

Current guidelines of antithrombotic therapy suggest early initiation of vitamin K antagonists (VKA) in non-cancer patients with venous thromboembolism (VTE), and long-term therapy with low-molecular weight heparin (LMWH) for those with cancer. We used data from RIETE (international registry of patients with VTE) to report the use of long-term anticoagulant therapy over time and to identify predictors of anticoagulant choice (regarding international guidelines) in patients with- and without cancer. Among 35,280 patients without cancer, 82% received long-term VKA (but 17% started after the first week). Among 4,378 patients with cancer, 66% received long term LMWH as monotherapy. In patients without cancer, recent bleeding (odds ratio [OR] 2.70, 95% CI 2.26-3.23), age >70 years (OR 1.15, 95% CI 1.06-1.24), immobility (OR 2.06, 95% CI 1.93-2.19), renal insufficiency (OR 2.42, 95% CI 2.15-2.71) and anemia (OR 1.75, 95% CI 1.65-1.87) predicted poor adherence to guidelines. In those with cancer, anemia (OR 1.83, 95% CI 1.64-2.06), immobility (OR 1.51, 95% CI 1.30-1.76) and metastases (OR 3.22, 95% CI 2.87-3.61) predicted long-term LMWH therapy. In conclusion, we report practices of VTE therapy in real life and found that a significant proportion of patients did not receive the recommended treatment. The perceived increased risk for bleeding has an impact on anticoagulant treatment decision

Heart Rate and Mortality in Patients With Acute Symptomatic Pulmonary Embolism

Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE

Derivation and validation of a clinical prediction rule for thrombolysis-associated major bleeding in patients with acute pulmonary embolism: The BACS score

Background: Improved prediction of the risk of major bleeding in patients with acute pulmonary embolism (PE) receiving systemic thrombolysis is crucial to guide the choice of therapy. Methods: The study included consecutive patients with acute PE who received systemic thrombolysis in the RIETE registry. We used multivariable logistic regression analysis to create a risk score to predict 30-day major bleeding episodes. We externally validated the risk score in patients from the COMMAND VTE registry. In addition, we compared the newly created risk score against the Kuijer and RIETE scores. Results: Multivariable logistic regression identified four predictors for major bleeding: recent major bleeding (3 points), age &gt;75 years (1 point), active cancer (1 point) and syncope (1 point) (BACS). Among 1172 patients receiving thrombolytic therapy in RIETE, 446 (38%) were classified as having low risk (none of the variables present, 0 points) of major bleeding according to the BACS score, and the overall 30-day major bleeding rate of this group was 2.9% (95% CI 1.6–4.9%), compared with 44% (95% CI 14–79%) in the high-risk group (&gt;3 points). In the validation cohort, 51% (149 out of 290) of patients were classified as having low risk, and the overall 30-day major bleeding rate of this group was 1.3%. In RIETE, the 30-day major bleeding event rates in the Kuijer and RIETE low-risk strata were 5.3% and 4.4%, respectively. Conclusions: The BACS score is an easily applicable aid for prediction of the risk of major bleeding in the population of PE patients who receive systemic thrombolysis

Comparative clinical prognosis of massive and non-massive pulmonary embolism: A registry-based cohort study

Aims: Little is known about the prognosis of patients with massive pulmonary embolism (PE) and its risk of recurrent venous thromboembolism (VTE) compared with non-massive PE, which may inform clinical decisions. Our aim was to compare the risk of recurrent VTE, bleeding, and mortality after massive and non-massive PE during anticoagulation and after its discontinuation. Methods and results: We included all participants in the RIETE registry who suffered a symptomatic, objectively confirmed segmental or more central PE. Massive PE was defined by a systolic hypotension at clinical presentation (&lt;90&nbsp;mm&nbsp;Hg). We compared the risks of recurrent VTE, major bleeding, and mortality using time-to-event multivariable competing risk modeling. There were 3.5% of massive PE among 38&nbsp;996 patients with PE. During the anticoagulation period, massive PE was associated with a greater risk of major bleeding (subhazard ratio [sHR] 1.72, 95% confidence interval [CI] 1.28\u20132.32), but not of recurrent VTE (sHR 1.15, 95% CI 0.75\u20131.74) than non-massive PE. An increased risk of mortality was only observed in the first month after PE. After discontinuation of anticoagulation, among 11&nbsp;579 patients, massive PE and non-massive PE had similar risks of mortality, bleeding, and recurrent VTE (sHR 0.85, 95% CI 0.51\u20131.40), but with different case fatality of recurrent PE (11.1% versus 2.4%, P&nbsp;=.03) and possibly different risk of recurrent fatal PE (sHR 3.65, 95% CI 0.82\u201316.24). Conclusion: In this large prospective registry, the baseline hemodynamic status of the incident PE did not influence the risk of recurrent VTE, during and after the anticoagulation periods, but was possibly associated with recurrent PE of greater severity