Cumulative Incidence Of Major Bleeding Research Articles

Edoxaban for 12 Versus 3 Months in Cancer-associated Isolated Distal Deep Vein Thrombosis According to Different Doses: Insights from the ONCO DVT study.

The ONCO DVT study revealed the superiority of 12-month relative to 3-month edoxaban treatment for cancer-associated isolated distal deep vein thrombosis (DVT) regarding the thrombotic risk. In this pre-specified subgroup analysis of the ONCO DVT study, we stratified the patients into those with a standard edoxaban dose (60 mg/day; N=151) and those with a reduced edoxaban dose (30 mg/day; N=450) and evaluated the clinical outcomes for the 12-month and 3-month treatments. The cumulative 12-month incidence of symptomatic recurrent venous thromboembolism was lower in the 12-month than 3-month group for both the 60 mg (1.3% vs. 11.6%, P=0.02; odds ratio [OR], 0.12; 95% CI, 0.01-0.97) and 30 mg (1.1% vs. 7.6%, P=0.002; OR, 0.14; 95% CI, 0.03-0.60) edoxaban subgroups, which was consistent across the edoxaban doses without a significant interaction (P =0.90). The 12-month cumulative incidence of major bleeding was higher in the 12-month group than 3-month group for the 60 mg edoxaban subgroup (14.3% vs. 4.4%, P=0.046; OR, 3.61; 95% CI, 0.97-13.52), whereas it did not significantly differ between the two groups for the 30 mg edoxaban subgroup (8.7% vs. 8.6%, P=0.89; OR, 0.97; 95% CI, 0.49-1.91), signaling there was a potential interaction (P=0.07). A 12-month edoxaban regimen for cancer-associated isolated distal DVT was consistently superior to a 3-month regimen, across the edoxaban doses for the thrombotic risk. However, caution was suggested for the standard dose of edoxaban due to the potential for an increased risk of bleeding with prolonged anticoagulation therapy.

Anticoagulation in cancer patients with atrial fibrillation and grade 3–4 thrombocytopenia

IntroductionAtrial fibrillation or flutter (AF) is prevalent in cancer patients. Many of these patients have an indication for anticoagulation (AC) but are also at risk for developing chemotherapy-induced thrombocytopenia. There are scarce data regarding management of AC and risk of bleeding and thrombosis in cancer patients with AF and thrombocytopenia. AimTo assess anticoagulation management and incidence of bleeding and arterial thromboembolism (ATE) in cancer patients with AF and grade 3–4 thrombocytopenia (platelets <50 × 109/L). MethodsA retrospective cohort study included adults with active cancer, grade 3–4 thrombocytopenia and AF with CHA2DS2-VASc score ≥ 1. Patients were stratified according to AC discontinuation (No-AC) or continuation (Continue-AC) when platelets dropped below 50 × 109/L and followed for 30 days. The study outcomes were ATE (ischemic stroke, transient ischemic attack or systemic emboli) and major bleeding. Cox proportional hazards model was used to calculate hazard ratios (HR) with death as a competing risk (Fine and Gray model). ResultsThe cohort included 131 patients; 90 in the No-AC group and 41 in the Continue-AC group. Patient characteristics were balanced between the groups. The 30-day cumulative incidence of ATE was 2 % [95 % CI 0.4 %–7 %] in the No-AC group and 2 % [0.2 %–11 %] in the Continue-AC group (HR 0.92 [95 % CI 0.09–9.88]). The 30-day cumulative incidence of major bleeding was 7.8 % [95 % CI 3.40 %–14.52 %] and 2.44 % [95 % CI 0.18 %–11.22 %] in the No-AC and Continue-AC groups, respectively (HR 3.29 [95 % CI 0.42–26.04]). ConclusionsThe high rate of bleeding and low rate of ATE in thrombocytopenic cancer patients with AF suggests that holding AC during time-limited periods may be a reasonable approach.

Real-world Safety and Effectiveness of Edoxaban in Patients with Venous Thromboembolism with or without Preceding Parenteral Anticoagulants: A Single-center Retrospective Study.

Objective Edoxaban is an anticoagulant used for venous thromboembolism (VTE) treatment and requires pretreatment with parenteral anticoagulants. However, pretreatment is not always performed in the clinical setting. In this study, we investigated the safety and effectiveness of edoxaban treatment in patients with VTE with or without pretreatment. Methods We retrospectively enrolled 364 patients who received edoxaban for VTE treatment between September 2014 and March 2020 and investigated patient demographics, VTE recurrence, and major bleeding as clinical outcomes in patients with or without pretreatment. Furthermore, the factors contributing to pretreatment decisions were assessed. Results Patients without pretreatment (n=208) had more active cancer cases and fewer pulmonary embolism complications than those with pretreatment (n=156). Lower levels of hemoglobin and higher levels of white blood cell counts, C-reactive protein, and D-dimer at the diagnosis were found in patients who received pretreatment than in those without pretreatment. No symptomatic VTE recurrence was observed. After propensity score matching, the cumulative incidence of major bleeding was not significantly higher in patients with pretreatment than in those without it (log-rank test, p=0.136). The incidence of deteriorated VTE on imaging did not significantly differ between patients with and without pretreatment, even after propensity matching (log-rank test, p=0.414). Conclusion In a real-world clinical setting, where physicians determined the use of parenteral anticoagulant lead-in according to their experience, patient demographics, and VTE characteristics, no significant differences were found regarding safety and effectiveness in edoxaban-treated VTE patients with or without pretreatment with parenteral anticoagulants.

No Increased Incidence of Bleeding in Essential Thrombocythemia Patients with Extreme Thrombocytosis

CONCLUSIONS About 25% of essential thrombocythemia (ET) patients present with extreme thrombocytosis (ExT), defined as having a platelet count ≥1000 x 10^9/L. ExT patients may have an increased bleeding risk, at least in part associated with acquired von Willebrand disease. There are no specific guidelines for managing ExT patients, and many are started on cytoreduction, even if they are younger and otherwise at low thrombotic risk by the revised International Prognostic Score of Thrombosis for ET (R-IPSET). We analyzed the risk of bleeding and thrombosis in ExT vs. non-ExT ET patients to inform treatment decisions. METHODS : We retrospectively analyzed patients who received targeted gene sequencing at Massachusetts General Brigham / Dana-Farber Cancer Institute from 2014-2021 and met WHO 2016 criteria for ET. We performed medical record review and recorded information on treatment, diagnosis, blood counts, and von Willebrand antigen and activity levels. We abstracted the first major bleed, clinically relevant non-major bleed (CRNMB), and thrombotic event in a patient's disease course. Bleeding was categorized using the International Society on Thrombosis &amp; Haemostasis definitions.We determined the cumulative incidence rates of bleeding and thrombosis in ExT and non-ExT patients with death as a competing event and compared these rates using a Gray test. Risk factors for bleeding and thrombosis were evaluated using univariate and multivariate Fine Gray models. We identified 408 patients diagnosed with ET, of which 344 had a platelet count reported at diagnosis. There were 96 ExT patients and 248 non-ExT patients. Median follow-up was 11 and 6 years, and median platelet count at ET diagnosis was 1194 and 651, respectively. ExT patients, compared with non-ExT patients, were more likely to be younger (51 vs. 58 years old, p&amp;lt;.001), have the CALR mutation (49% vs. 23%, p&amp;lt;.001), have lower IPSET-thrombosis risk (65% vs. 49% very low or low risk, p&amp;lt;.001), and have lower von Willebrand activity levels at diagnosis or in disease course (60% vs. 94%, p&amp;lt;.001, Table 1). There were 7 (7%) major bleeds and 7 (7%) CRNMBs in the 96 ExT patients, and 11 (4%) major bleeds and 22 (9%) CRNMBs in the 248 non-ExT patients (p=.29 for major bleeding, p=.83 for CRNMB). 10 year cumulative incidence of major bleed and CRNMB was not different in ExT vs. non-ExT patients (4% vs. 5%, p=.68 for major bleed; 3% vs. 10%, p=.27 for CRNMB, Figure 1). Despite 65% of ExT patients in our sample categorized as very low or low risk for thrombosis, these patients were more likely to be treated with cytoreduction compared to non-ExT patients (63% vs. 50%, p=.21 for very low risk; 81% vs. 51%, p=.022 for low risk). However, there was no difference in the 10 year cumulative incidence of major bleeding and CRNMB in ExT patients who were treated vs. not treated with cytoreduction (6% vs. 0%, p=.13 for major bleed; 2% vs. 8%, p=.13 for CRNMB). There was also no difference in the cumulative incidence of bleeding in ExT and non-ExT patients who were not treated with cytoreduction (untreated or aspirin alone, 0% vs. 4%, p=.34 for major bleed; 8% vs. 9%, p=.75 for CRNMB). In univariate analysis, diabetes mellitus and thrombosis during disease course were significantly associated with increased combined major bleeding and CRNMB. In a multivariable analysis adjusting for these factors in addition to platelet count ≥1000 x 10^9/L and age at ET diagnosis, first von Willebrand factor activity, aspirin and cytoreduction during disease course, and JAK2 mutation status, diabetes mellitus (HR 3.45, 95% CI 1.31-8.72) and thrombosis during disease course (HR 2.92, 95% CI 1.41-6.03) remained as significant risk factors for bleeding. Cytoreduction was not significantly associated with a lower rate of bleeding in multivariable analysis (HR .42, 95% CI .09-3.06). 10 year cumulative incidence of thrombosis was not different in ExT vs. non-ExT patients (22% vs. 26%, p=.94). We found no difference in the cumulative incidence of bleeding and thrombosis in ET patients with ExT and importantly, no clear role for initiation of cytoreductive therapy in these patients who are otherwise low risk by R-IPSET. This confirms the current recommendations to initiate cytoreduction based on thrombotic risk and suggests that ExT alone should not be an indicator for cytoreduction.

Clinical features and long-term outcomes of venous thromboembolism in the warfarin era versus in the direct oral anticoagulant era

Abstract Background/Introduction After the introduction of direct oral anticoagulant (DOAC) for venous thromboembolism (VTE), DOAC for VTE have prevailed all over the world, which could change the daily clinical practice and clinical outcomes. However, there have been still limited data on the issue in the real world. Purpose We aimed to investigate demographics, practice patterns and long-term clinical outcomes in patients with VTE comparing a large observational study in the warfarin era and that in the DOAC era. Methods The COMMAND VTE Registry-1 (enrolled 3,027 VTE patients among 29 center between January 2010 and August 2014 in the warfarin era) and Registry-2 (enrolled 5,197 VTE patients among 31 centers between January 2015 and August 2020 in the DOAC era) are the series of a multicenter observational study in Japan enrolling consecutive patients with acute symptomatic VTE. Results Patients characteristics were comparable in most of aspects between the groups, whereas prevalence of active cancer was higher in the Registry-2 (Registry-1: 23% vs. Registry-2: 29%, P&amp;lt;0.001). As for oral anticoagulation therapy, 88% (2,676/3,027) of patients were treated with warfarin in the Registry-1 and 79% (4,128/5,197) of patients were treated with DOAC in the Registry-2. The proportion of patients admitted to the hospital was lower in the Registry-2 (80% vs. 69%, P&amp;lt;0.001). The discontinuation rate of anticoagulation therapy was significantly higher in the Registry-2 (42.8% vs. 52.5% at 3-year, Log rank P&amp;lt;0.001). The cumulative 5-year incidence of recurrent VTE was lower in the Registry-2 (10.5% vs. 9.5%, Log rank P=0.02), which remained significant even after adjusting the confounders (adjusted hazard ratio [HR]: 0.78 (0.65-0.93), P=0.006). There was no significant difference in the cumulative incidence of major bleeding between the groups (12.1% vs. 13.7%, Log-rank P=0.26), which remained insignificant even after adjusting the confounders (adjusted HR: 1.03 (0.89-1.20), P=0.67). After stratifying a total cohort into sub-groups according to the risk classification of recurrent VTE in the current guidelines (major transient risk factors, minor transient risk factors, unprovoked, non-malignant persistent risk factors, and active cancer), the risks of recurrent VTE and major bleeding were significantly lower in the Registry-2 among active cancer group (recurrent VTE: 17.7% vs 10.1% at 5-year, Log rank P&amp;lt;0.001, major bleeding: 26.6% vs 20.4% at 5-year, Log rank P=0.04), while those were not significantly different between the groups among other sub-groups. Conclusion In the current series of large real-world VTE registries, there seemed to be a significant risk reduction of recurrent VTE in the DOAC era compared with in the warfarin era, while there was no sign of increased risk of major bleeding in the DOAC era.

Clinical characteristics and outcomes of super-low-dose edoxaban of 15 mg in patients with acute venous thromboembolism: insight from the COMMAND VTE Registry-2

Abstract Background/Introduction The current guidelines recommend specific durations of anticoagulation therapy depending on the risks of recurrent venous thromboembolism (VTE), and prolonged anticoagulation therapy is recommended for patients at not-low risk of recurrence. However, clinicians are sometimes reluctant to continue anticoagulation therapy for patients with high-bleeding risk. A recent study reported that super-low-dose edoxaban of 15 mg was useful in preventing thromboembolic events for elderly patients with atrial fibrillation who were considered as high-bleeding risk patients. However, super-low-dose edoxaban of 15 mg is currently off-label for VTE all over the world, which could be a potential option for patient with VTE at high-bleeding risk. Purpose The current study aimed to investigate clinical characteristics and outcomes of VTE patients with super-low-dose edoxaban of 15 mg, using a large-scale multicenter observational database of patients with VTE. Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. After excluding 3193 patients without edoxaban as oral anticoagulation therapy, the current study population was consisted of 2004 patients with edoxaban, who were divided into 3 groups according to initial dosage of edoxaban; 60 mg/day (N=664, 33%) 30 mg/day (N=1309, 65%) and 15 mg/day (N=31, 1.5%). Results Patients with edoxaban of 15 mg/day were oldest (60 mg/day: 62.3 years, 30 mg/day: 72.9 years and 15 mg/day: 79.2 years, P&amp;lt;0.001), were most often women (44%, 73% and 84%, P&amp;lt;0.001), showed a lowest mean body weight (68.4, 51.9 and 48.7 kg, P&amp;lt;0.001). Pulmonary embolism as initial presentation was least frequent in patients with edoxaban of 15 mg/day (58%, 44% and 13%, P&amp;lt;0.001). Patients with edoxaban of 15 mg/day most frequently had chronic kidney disease (10%, 22% and 26%, P&amp;lt;0.001) and anemia (45%, 66% and 74%, P&amp;lt;0.001). The discontinuation rates of anticoagulation therapy were not significantly different among the 3 groups (54.4%, 56.5% and 64.8% at 3-year, Log rank P=0.38). The cumulative incidences of recurrent VTE were not significantly different among the 3 groups (6.0%, 6.6% and 0.0% at 3-year, Log rank P=0.31). Similarly, the cumulative incidences of major bleeding were not significantly different among the 3 groups (9.2%, 11.6% and 15.3% at 3-year, Log rank P=0.11). Conclusions In the current real-world large VTE registry, a very minority of VTE patients received edoxaban of 15 mg/day, including patients at high-bleeding risk such as old age, low body weight and chronic kidney disease, who did not show significant worse outcomes in terms of recurrent VTE.

Influence of thrombocytopenia on bleeding and vascular events in atrial fibrillation

AbstractWhether thrombocytopenia substantively increases the risk of hemorrhage associated with anticoagulation in patients with atrial fibrillation (AF) is not established. The purpose of this study was to compare rates of bleeding in patients with AF and thrombocytopenia (platelet count < 100 000/μL) to patients with AF and normal platelet counts (>150 000/μL). We performed a propensity score–matched, retrospective cohort study of adults (n = 1070) with a new diagnosis of AF who received a prescription for an oral anticoagulant between 2015 and 2020. The thrombocytopenia cohort was defined as having at least 2 platelet counts <100 000/μL on separate days in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks after the initiation of anticoagulation. The primary end point was the 1-year cumulative incidence of major bleeding; secondary end points included clinically relevant bleeding, arterial and venous thrombotic events, and all-cause mortality. Patients with AF and thrombocytopenia experienced a higher 1-year cumulative incidence of major bleeding (13.3% vs 5.7%; P < .0001) and clinically relevant bleeding (24.5% vs 16.7%; P = .005) than the controls. Thrombocytopenia was identified as an independent risk factor for major bleeding (hazard ratio, 2.20; confidence interval, 1.36-3.58; P = .001), with increasing risk based on the severity of thrombocytopenia. The cumulative incidence of arterial thrombosis at 1 year was 3.6% in the group with thrombocytopenia and 1.5% in controls (Gray test, P = .08). These findings suggest that baseline platelet counts are an important biomarker for hemorrhagic outcomes in AF and that the degree of thrombocytopenia is an important factor in determining the level of risk.

Incidence of bleeding and recurrence in isolated distal deep vein thrombosis: findings from the Venous Thrombosis Registry in Østfold Hospital

BackgroundIsolated distal deep vein thrombosis (IDDVT) is a common presentation of deep vein thrombosis. There are limited data on the long-term risk of recurrence after IDDVT. ObjectivesWe aimed to determine the short- and long-term incidence of venous thrombosis (VTE) recurrence after cessation of anticoagulation and the 3-month incidence of bleeding during anticoagulant treatment in patients with IDDVT. MethodsBetween January 2005 and May 2020, 475 patients with IDDVT and without active cancer were identified from the Venous Thrombosis Registry in Østfold Hospital, which is an ongoing registry of consecutive patients with VTE at Østfold Hospital, Norway. Major and clinically relevant, nonmajor bleeding as well as recurrent VTE were registered, and the cumulative incidences of these events were assessed. ResultsThe median age of the patients was 59 years (IQR, 48-72 years), 243 (51%) patients were women, and 175 events (36.8%) were classified as unprovoked. The 1-, 5-, and 10-year cumulative incidences of recurrent VTE were 5.6% (95% CI, 3.7-8.4), 14.7% (95% CI, 11.1-19.4), and 27.2% (95% CI, 21.1-34.5), respectively. The recurrence rates were higher for unprovoked IDDVT than for provoked IDDVT. Among the recurrent events, 18 (29%) were pulmonary embolisms and 21 (33%) were proximal deep vein thromboses. The 3-month cumulative incidence of major bleeding was 1.5% (95% CI, 0.7-3.1) overall and 0.8% (95% CI, 0.2-3.1) when restricted to patients treated with direct oral anticoagulants. ConclusionDespite initial treatment, the long-term risk of VTE recurrence after first-time IDDVT is high. The bleeding rates during anticoagulation, particularly with direct oral anticoagulants, were acceptably low.

Bleeding Risk in Atrial Fibrillation and Thrombocytopenia: A Propensity Matched Cohort Study

Background: Anticoagulation is the major therapeutic strategy in the management of patients with atrial fibrillation (AF). Thrombocytopenia is a frequent coexisting condition that may predispose to bleeding in these patients. However, the risk of bleeding in patients with AF and thrombocytopenia has not been well studied. Moderate thrombocytopenia (<100,000/μL) was an exclusion criteria in the clinical trials used to approve non-vitamin K oral anticoagulants for stroke prophylaxis. Similarly, studies examining warfarin's safety and efficacy in AF have not included significant numbers of thrombocytopenic patients. This paucity of data describing the safety of oral anticoagulants in patients with AF and thrombocytopenia represents a major challenge in clinical practice. Present treatment guidelines do not include specific guidance for anticoagulation in patients with these coexisting conditions. Thus, the purpose of this study was to compare rates of bleeding among patients with and without thrombocytopenia who begin oral anticoagulation for AF. Methods: A propensity matched cohort study was designed to compare rates of bleeding among patients with thrombocytopenia who began oral anticoagulation for AF between 2015-2020 at a quaternary care hospital in Boston, MA against patients with AF starting anticoagulation in the absence of thrombocytopenia. The thrombocytopenic cohort was defined as having at least two platelet counts on separate days <100,000/μL in the period spanning the 12 weeks preceding the initiation of anticoagulation to 6 weeks following the initiation of anticoagulation. Patients with only one platelet count <100,000/μL were excluded. Individuals from the thrombocytopenic cohort were matched with patients (1:3 ratio) from the non-thrombocytopenic cohort using propensity matching on the basis of age, sex, CHA2DS2-VASc score, and anticoagulant agent used. Bleeding outcomes were determined by blinded manual chart review and verified by a second reviewer; all bleeding events were classified as per the International Society on Thrombosis and Haemostasis. The primary endpoint of the study was the cumulative incidence of clinically relevant bleeding, a composite of major bleeding and clinically relevant non-major bleeding (CRNMB), within one year of the initiation of anticoagulation. Results: The study population included 1,075 patients who started oral anticoagulation for AF (274 with thrombocytopenia, 801 controls). Overall, 38% of the cohort was female, with a median age of 72 years; 14.6% of the total cohort had cancer and 2.8% had liver disease at the time they began anticoagulation. The median CHA2DS2-VASc score was 3 (IQR 2-4). Warfarin (48.2%) and apixaban (39.6%) were the anticoagulants used in the majority of patients. Notably, the thrombocytopenic cohort included more patients with significant comorbidities, such as cancer (23.0% vs 11.7%), liver disease (4.7% vs. 2.1%), and kidney disease (12.8% vs. 7.5%). There were a total 219 bleeding events recorded, including 90 (41.1%) major bleeding events and 122 (55.7%) CRNMB events. (Table 1) The cumulative incidence of clinically relevant bleeding at 1 year was significantly higher (18.3%; 95% CI, 13.6-22.9) in those with thrombocytopenia at the time of starting anticoagulation compared with the control cohort (13.2%; 95% CI, 10.9-15.6) (P < 0.001, Gray test). Similarly, the cumulative incidence of major bleeding at 1 year was 10.1% (95% CI, 6.5-13.7) in those with thrombocytopenia compared with 5.2% (95% CI, 3.7-6.8) among controls (P < 0.001, Gray test). (Figure 1) Conclusions: Oral anticoagulation for AF in patients with thrombocytopenia at the time of starting anticoagulation significantly increased the risk of clinically relevant and major bleeding relative to patients with normal platelet counts. These findings support the need for further characterization of the risk-benefit profile of anticoagulation in this population to guide clinicians faced with this common clinical scenario. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Thrombocytopenia on Bleeding and Recurrent Thrombosis in Cancer Associated Thrombosis: A Post Hoc Analysis of Hokusai VTE Cancer Study

Background: Thrombosis and thrombocytopenia are both frequent complications in patients with active cancer. Thrombocytopenia can complicate decisions around anticoagulation in cancer associated thrombosis (CAT) but data to guide clinicians is limited. Much of the data on the safety and efficacy of anticoagulation in patients with CAT and thrombocytopenia have been retrospective, single-center, cohort studies. The benefit and risk of direct oral anticoagulants in cancer patients with acute venous thromboembolism (VTE) and thrombocytopenia is incompletely understood. The HOKUSAI VTE Cancer study was a randomized open-label, non-inferiority, phase III trial in CAT that compared dalteparin with edoxaban for at least 6 months. We conducted a post hoc analysis of this trial to investigate the impact of platelet count on bleeding and recurrent thrombosis. Methods: Patients with platelet counts less than 100,000/µL at specified time points (enrollment, day 31 or day 90) were compared with patients with platelet count > 100,000/µL on all three time points. The primary outcomes for these analyses was major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB), recurrent thrombosis and survival. Cumulative incidences of bleeding and thrombosis outcomes were calculated with death as a competing risk. Results: A total of 1045 patients were included in the analyses. , The median age was 65 years and 52% were male. Most common malignancies included colorectal (16%), lung (15%), genitourinary (13%), breast (12%), and hematologic malignancies (11%). Of patients with solid cancers, 53% had metastatic disease and 30% recurrent disease at enrollment. Qualifying thrombotic events included pulmonary embolism for 63% and isolated deep vein thrombosis in 37%. Thrombocytopenia (<100,000/µL) was present in 101 patients (9.6%) of the total cohort. Only 14 patients had a platelet count <50,000/µL at any of the three time points. For the overall trial period the rates of major bleeding were significantly higher in patients with platelet count <100,000/µL (11.9% vs. 4.8%, HR 2.5 P=0.004). (Table 1) Rates of CRNMB were similarly higher in patients with platelet count <100,000/ µL (21.8% vs. 11.9%, HR 1.93, P=0.005), however there was no significant difference in rates of recurrent VTE (11.9% vs. 9.2%, HR 1.28 P=0.42) or overall mortality (37.6% vs. 38%, HR 0.98, P=0.90). Cumulative incidence of major bleeding at 180 days was higher 8.9% (95% CI 3.4-14.5%) in patients with platelet count <100,000/ µL compared to 3.9% (95% CI 2.7-5.2%) in those higher than 100,000/µL. (Figure 1) Conclusion: In this post hoc analysis of a randomized controlled study in CAT, thrombocytopenia (<100,000/µL) was associated with an increased risk of major bleeding by two-fold. No difference in the risk of recurrent thrombosis was detected. These data highlight the importance of recognizing even mild thrombocytopenia as an important risk factor for bleeding in patients being anticoagulated for CAT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of Effectiveness and Safety Among 3 Direct Oral Anticoagulants in Patients With Venous Thromboembolism - A Single-Center Retrospective Study.

Background: Direct oral anticoagulants (DOACs), including edoxaban, rivaroxaban, and apixaban, are administered for the treatment of venous thromboembolism (VTE) in Japan. However, only a few reports have compared the effectiveness and safety of these DOACs. Methods and Results: We retrospectively enrolled 702 patients who received DOACs for VTE treatment between September 2014 and March 2020. We investigated patient demographics, VTE recurrence, major bleeding, and mortality until March 2021, and compared them among the 3 DOACs. Most patients (~70%; n=496) were prescribed edoxaban, followed by apixaban (n=107) and rivaroxaban (n=99). Age, body mass index, renal function, and the proportion of cancer patients did not differ significantly among the DOACs. Edoxaban was administered relatively more in women with low body weight and anemia. The rate of pulmonary embolism was significantly lower among patients receiving edoxaban than apixaban or rivaroxaban (24.4% vs. 41.1% and 53.5%, respectively). VTE reoccurred in 2 patients administered apixaban and 1 patient administered edoxaban. The cumulative incidence of major bleeding at 1 year was 11.7%, 18.5%, and 9.0% in the edoxaban, apixaban, and rivaroxaban groups, respectively. There were no significant differences in the cumulative incidence of major bleeding and all-cause death, estimated by Kaplan-Meier analysis, among the DOACs (log-rank P=0.316 and 0.722, respectively). Conclusions: The safety of the 3 DOACs did not differ significantly in clinical settings, despite differences in patient demographics.

High bleeding risk in all-comers with ST-segment elevation myocardial infarction and use of P2Y12-inhibitiors

Abstract Background Bleeding has an important prognostic impact in patients with ST-segment elevation myocardial infarction (STEMI), yet stratification of bleeding risk to guide dual antiplatelet therapy (DAPT) is not routinely performed in clinical practice. Purpose To describe high bleeding risk (HBR) patients according to the PRECISE-DAPT (predicting bleeding complications in patients undergoing stent implantation and subsequent DAPT) score and use of P2Y12-inhibitors. Methods This single-centre observational study included consecutive patients with STEMI who were treated with percutaneous coronary intervention (PCI) from 2009–2016. Individual linkage to Danish nationwide registries was conducted to obtain information on diagnoses, claimed drugs, and vital status. Age, prior bleeding diagnosis, and blood samples before PCI (maximum 30 days before hospitalisation) were used to calculate the PRECISE-DAPT score. A score ≥25 was considered as HBR. Due to 26.7% missing on blood parameters (mainly leucocytes), the maximum and minimum values of the missing parameters and respective imputed PRECISE-DAPT scores were calculated. If both the maximum and minimum score were ≥25 or &amp;lt;25, patients were categorised accordingly, and a maximum score of ≥25 and minimum score of &amp;lt;25 as missing. Differences between continuous (median [interquartile range, IQR]) and categorical variables (frequency [percentage]) were assessed using Wilcoxon rank-sum and χ2-test for patients with vs. without HBR. Cumulative incidence of major bleeding (composite of bleedings leading to hospitalisation) and major adverse cardiovascular events (MACE) (composite of all-cause mortality, recurrent MI, and ischemic stroke) 1 year after PCI were plotted for patients with and without HBR. Number of HBR patients alive and collecting a P2Y12-inhibitor prescription within 30 days from discharge was reported. Results We identified 6179 PCI-treated patients with STEMI, of whom 5530 (89.5%) had imputed PRECISE-DAPT scores (Figure 1). A total of 1821 (32.9%) were at HBR, and these were more often female (38.3 vs. 18.2%, p-value&amp;lt;0.001), elderly (median age 75 [IQR 67, 81] vs. 57 years [IQR 51, 64], p-value&amp;lt;0.001), and had more comorbidities (diabetes [16.7 vs. 12.1%], heart failure [16.2 vs. 7.6%], cardiac arrhythmia [24.9 vs. 12.3%], cancer [17.5 vs. 5.7%], and ischemic stroke [8.1 vs. 2.6%], all p-values&amp;lt;0.001) compared with patients not at HBR. One-year cumulative incidence of major bleeding and MACE for patients with and without HBR were plotted (Figure 2). Of the 1431 (78.6%) HBR patients who were alive and claimed a P2Y12-inhibitior prescription 30 days from discharge, 459 (32.1%) were treated with clopidogrel, 672 (46.9%) with ticagrelor, and 300 (21.0%) with prasugrel (Figure 1). Conclusion Every third PCI-treated all-comer with STEMI was at HBR according to the PRECISE-DAPT score. HBR patients were more often treated with potent P2Y12-inhibitors (prasugrel or ticagrelor) instead of clopidogrel. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship.

Aortic valve replacement in patients aged 50 to 69 years: Analysis using Korean National Big Data.

The aim of this study was to compare the clinical outcomes and long-term survival in patients who underwent isolated aortic valve replacement (AVR) with mechanical versus bioprosthetic valves. Patients aged 50-69 years who had undergone AVR from 2002 to 2018 were identified and their characteristics were collected from Korean National Health Information Database formed by the National Health Insurance Service, Republic of Korea. Of the 5792 patients, 1060 patients were excluded due to missing values on characteristics. Of the 4732 study patients, 1945 patients (41.1%) had received bioprosthetic valves (Group B) and 2787 patients (58.9%) had received mechanical valves (Group M). A propensity score-matched analysis was performed to match 1429 patients in each group. Data on mortality, cardiac mortality, reoperations, cerebrovascular accidents, and bleeding complications were obtained. The overall survival rates at 5 and 10 years postoperatively were 87.8% and 75.2% in the matched Group B and 91.2% and 76.7% in the matched Group M, respectively (p = .140). Freedom from cardiac death rates at postoperative 5 and 10 years were 95.6% and 92.4% in the matched Group B and 96.0% and 92.1% in the matched Group M, respectively (p = .540). The cumulative incidence of reoperation was higher in the matched Group B than in the matched Group M (p = .007), and the cumulative incidence of major bleeding was higher in the matched Group M than in the matched Group B (p = .039). In patients aged 50-69 years who underwent isolated AVR, the patients who received bioprosthetic valves showed similar cardiac mortality-free survival and long-term survival rates to the patients who received mechanical valves.

Correlation Between the Japanese Version of the High Bleeding Risk (J-HBR) Criteria and the PRECISE-DAPT Score, and Optimal J-HBR Cut-Off Score to Predict Major Bleeding.

Background: The correlation between the Japanese version of high bleeding risk (J-HBR) criteria and the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score is unknown, as is the relationship of both risk scores with ischemic events.Methods and Results: This study enrolled 842 patients who underwent percutaneous coronary intervention (PCI) between January 2016 and December 2020. The 2 bleeding risk scores at the time of PCI and the subsequent risk of bleeding and ischemic events over a 1-year follow-up were examined. The J-HBR score was significantly correlated with the PRECISE-DAPT score (r=0.731, P<0.001). However, 1 year after PCI, the J-HBR was not significantly associated with the incidence of major bleeding and ischemic events (log-rank, P=0.058 and P=0.351, respectively), whereas the PRECISE-DAPT score predicted both the incidence of major bleeding and ischemic events (log-rank, P=0.006 and P=0.019, respectively). According to receiver operating characteristic curve analysis, a J-HBR score ≥1.5 was significantly associated with a higher cumulative incidence of major bleeding, but not ischemic events (log-rank, P=0.004 and P=0.513, respectively).Conclusions: The J-HBR score is highly correlated with the PRECISE-DAPT score. A J-HBR score ≥1.5 can identify high bleeding risk patients without an increased risk of ischemic events.

P97 VALIDATION OF THE ACADEMIC RESEARCH CONSORTIUM HIGH BLEEDING RISK CRITERIA IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: A SYSTEMATIC REVIEW AND METANALYSIS OF 10 STUDIES AND 67,862 PATIENTS

Abstract Background The Academic Research Consortium for High Bleeding Risk (ARC–HBR) has recently proposed, by consensus, twenty clinical criteria for the assessment of the bleeding risk after percutaneous coronary intervention (PCI). A major criterion was defined as any individual clinical condition conferring in isolation a risk for major bleeding ≥4% up to 1 year after PCI; instead, a minor criterion was considered to confer a bleeding risk of &amp;lt; 4%. The aim of this meta–analysis was to assess the performance of the ARC–HBR criteria in stratifying the risk of bleeding and ischemic events after PCI. Methods MEDLINE, COCHRANE, Web of Sciences, and SCOPUS were searched for studies aimed at validating the ARC–HBR criteria in patients treated with PCI. The primary outcome measure of this meta–analysis was major bleeding. Results The analysis included 10 studies encompassing 67,862 patients undergoing PCI; the HBR definition was fulfilled in 44.7% of the cases. The risk of major bleeding was significantly higher in HBR vs. Non–HBR group (RR, 2.56, 95% CI 2.28–2.89). The average C–statistic was 0.64 (95% CI 0.60–0.68), indicating modest discrimination. The risk of intracranial hemorrhage, gastrointestinal bleeding, fatal bleeding, ischaemic stroke, cardiac death and all–cause death was higher in HBR vs. Non–HBR group. Despite a higher incidence of myocardial infarction and stent thrombosis in patients deemed at HBR, the rate of target lesion revascularization was comparable between groups (RR, 1.01, 95% CI 0.88–1.16). When assessed in isolation, the mean cumulative incidence of major bleeding at 1 year exceeded the cut–off value of 4% for all the major criteria and for two out of six minor criteria, including age ≥75 years and moderate chronic kidney disease (CKD) (Figure). Conclusion The ARC–HBR definition identifies patients at higher risk of major bleeding and other adverse cardiovascular events after PCI. Almost all major criteria, but also two of the minor criteria, were individually associated with rates of major bleeding above 4% thus fulfilling the definition of major HBR criteria. These findings corroborate the ability of ARC–HBR major criteria in identifying PCI patients who are more likely to develop adverse events, but also suggest caution in the decision making of patients with isolated minor criteria, including age≥75 years and moderate CKD.

Long-term use of tinzaparin for the treatment of cancer-associated thrombosis in clinical practice: Insights from the prospective TROPIQUE study.

Real word data on the efficacy and safety of long-term use of tinzaparin for the treatment of cancer-associated thrombosis (CAT) are scarce. We performed a post-hoc analysis of all cancer patients included in the prospective multicenter observational TROPIQUE study who received long-term treatment with tinzaparin for a first venous thromboembolism (VTE) event. We evaluated the patterns of anticoagulant prescription, the adherence to clinical practice guidelines (CPGs) for the treatment of CAT, and the clinical outcomes within a 6-month follow-up. In total, 301 patients were included in this post-hoc analysis. At study entry, their mean age was 64.6±11.9years and 143 (47.5%) patients were men. The most frequent cancer type was gastrointestinal (23.9%), followed by breast (17.9%) and lung (15.3%) cancer. At time of VTE diagnosis, 164 (57.8%) patients had metastatic disease and 245 (81.42%) were receiving chemotherapy. Based on the aggregation of all study pre-defined criteria, tinzaparin prescription was fully compliant with CPGs in 219 (72.8%) patients. The mean effective treatment duration with tinzaparin was 6.07±0.17months. At 6-month follow-up, the cumulative incidence of recurrent VTE was 5.4% (95% CI: 3.2-9.2%) and the cumulative incidence of major bleeding was 5.8% (95% CI: 3.6-9.6%). Clinical outcomes tended to differ across different types of cancer. Death from any cause occurred in 102 (33.9%) patients, mainly related to cancer progression. This post-hoc analysis of TROPIQUE confirms the favorable benefit-risk ratio of tinzaparin for the long-term treatment of CAT.

Long-Term Risk of Major Bleeding after Discontinuing Anticoagulation for Unprovoked Venous Thromboembolism: A Systematic Review and Meta-analysis.

The long-term risk of major bleeding after discontinuing anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. To determine the incidence of major bleeding up to 5 years after discontinuing anticoagulation for a first unprovoked VTE. We searched MEDLINE, EMBASE, and Cochrane CENTRAL (from inception to January 2021) to identify relevant randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding after discontinuing anticoagulation in patients with a first unprovoked or weakly provoked VTE who had completed (IMAGE_)3 months of initial treatment. Unpublished data on major bleeding events and person-years were obtained from authors of included studies to calculate study-level incidence rates. Random-effects meta-analysis was used to pool results across studies. Of 1,123 records identified by the search, 20 studies (17 RCTs) and 8,740 patients were included in the analysis. During 13,011 person-years of follow-up after discontinuing anticoagulation, the pooled incidence of major bleeding (n = 41) and fatal bleeding (n = 7) per 100 person-years was 0.35 (95% confidence interval [CI]: 0.20-0.54) and 0.09 (95% CI: 0.05-0.15). The 5-year cumulative incidence of major bleeding was of 1.0% (95% CI: 0.4-2.4%). The case-fatality rate of major bleeding after discontinuing anticoagulation was 19.9% (95% CI: 10.6-31.1%). The risk of major bleeding once anticoagulants are discontinued in patients with a first unprovoked VTE is not zero. Estimates from this study can help clinicians counsel patients about the incremental risk of major bleeding with extended anticoagulation to guide decision making about treatment duration for unprovoked VTE.

600 Validation of the academic research consortium high bleeding risk criteria in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis of 10 studies and 67 862 patients

Abstract Aims The Academic Research Consortium for High Bleeding Risk (ARC-HBR) has recently proposed, by consensus, 20 clinical criteria for the assessment of the bleeding risk after percutaneous coronary intervention (PCI). A major criterion was defined as any individual clinical condition conferring in isolation a risk for major bleeding ≥4% up to 1 year after PCI; instead, a minor criterion was considered to confer a bleeding risk of &amp;lt; 4%. The aim of this meta-analysis was to assess the performance of the ARC-HBR criteria in stratifying the risk of bleeding and ischaemic events after PCI. Methods and results MEDLINE, COCHRANE, Web of Sciences, and SCOPUS were searched for studies aimed at validating the ARC-HBR criteria in patients treated with PCI. The primary outcome measure of this meta-analysis was major bleeding. The analysis included 10 studies encompassing 67 862 patients undergoing PCI; the HBR definition was fulfilled in 44.7% of the cases. The risk of major bleeding was significantly higher in HBR vs. Non-HBR group (RR: 2.56, 95% CI: 2.28–2.89). The average C-statistic was 0.64 (95% CI: 0.60–0.68), indicating modest discrimination. The risk of intracranial haemorrhage, gastrointestinal bleeding, fatal bleeding, ischaemic stroke, cardiac death and all-cause death was higher in HBR vs. Non-HBR group. Despite a higher incidence of myocardial infarction and stent thrombosis in patients deemed at HBR, the rate of target lesion revascularization was comparable between groups (RR, 1.01, 95% CI: 0.88–1.16). When assessed in isolation, the mean cumulative incidence of major bleeding at 1 year exceeded the cut-off value of 4% for all the major criteria and for two out of six minor criteria, including age ≥75 years and moderate chronic kidney disease (CKD) (Figure). Conclusions The ARC-HBR definition identifies patients at higher risk of major bleeding and other adverse cardiovascular events after PCI. Almost all major criteria, but also two of the minor criteria, were individually associated with rates of major bleeding above 4% thus fulfilling the definition of major HBR criteria. These findings corroborate the ability of ARC-HBR major criteria in identifying PCI patients who are more likely to develop adverse events, but also suggest caution in the decision making of patients with isolated minor criteria, including age ≥ 75 years and moderate CKD.

Less bleeding associated with apixaban versus other direct acting oral anticoagulation in solid organ transplant recipients.

The purpose of this study was to evaluate outcomes of bleeding and thrombosis resulting from the use of direct oral anticoagulants (DOACs) in a large cohort of solid organ transplant (SOT) recipients. This was a single center, retrospective cohort study of adult kidney, heart, lung, and liver transplant recipients transplanted between August 2009 and May 2018. Patients were stratified into two groups: those who received apixaban (apixaban group) or those patients receiving either rivaroxaban or dabigatran (non-apixaban group). The primary endpoint was the cumulative incidence of bleeding while receiving DOAC therapy. The secondary endpoints were incidence of major bleeding and thrombosis at any time while receiving DOAC therapy. A total of 106 patients were included; 70 patients received apixaban and 36patients received non-apixaban anticoagulation. Cumulative incidence of any bleeding was lower in the apixaban group compared to the non-apixaban group at both 90days (4.9% vs. 16.1%) and 180 days (11.4% vs. 24.9%, P=.034). Cumulative incidence of major bleeding (P=.686) and thrombosis (P=.515) were similar between groups. DOAC dosing congruent with the package insert(s) was associated with a lower risk of thrombosis. Apixaban-based anticoagulation was associated with a lower cumulative incidence of any bleeding compared to non-apixaban DOACs.

Validation of the academic research consortium high bleeding risk criteria in patients undergoing percutaneous coronary intervention: A systematic review and meta-analysis of 10 studies and 67,862 patients

BackgroundTo assess the performance of the Academic Research Consortium High Bleeding Risk (ARC-HBR) criteria in stratifying the risk of bleeding and ischaemic events after percutaneous coronary intervention (PCI). MethodsMEDLINE, COCHRANE, Web of Sciences, and SCOPUS were searched for studies aimed at validating the ARC-HBR criteria in patients treated with PCI. The primary outcome measure of this meta-analysis was major bleeding. ResultsThe analysis included 10 studies encompassing 67,862 patients undergoing PCI; the HBR definition was fulfilled in 44.7% of the cases. The risk of major bleeding was significantly higher in HBR vs. Non-HBR group (RR, 2.56, 95% CI 2.28–2.89). The average C-statistic was 0.64 (95% CI 0.60–0.68), indicating modest discrimination.The risk of intracranial hemorrhage, gastrointestinal bleeding, fatal bleeding, ischaemic stroke, cardiac death and all-cause death was higher in HBR vs. Non-HBR group. Despite a higher incidence of myocardial infarction and stent thrombosis in patients deemed at HBR, the rate of target lesion revascularization was comparable between groups (RR, 1.01, 95% CI 0.88–1.16).The mean effect size for the cumulative incidence of major bleeding exceeded the HBR cut-off value of 4% for all major criteria except one, and for two out of six minor criteria, namely age ≥ 75 years and moderate CKD. ConclusionThe ARC-HBR definition identifies patients at higher risk of major bleeding and other adverse cardiovascular events after PCI. Almost all major criteria, but also two of the minor criteria, were individually associated with rates of major bleeding above 4% thus fulfilling the definition of major HBR criteria.