Clinically Relevant Non-major Bleeding Research Articles

Hemorrhages in Polycythemia Vera and Essential Thrombocythemia: Epidemiology, Description, and Risk Factors-Learnings from a Large Cohort.

The management of myeloproliferative neoplasms (MPNs) is based on the reduction of thrombotic risk. The incidence, impact, and risk factors of bleedings have been less studied. All patients with polycythemia vera (n=339) or essential thrombocythemia (n=528) treated in our center are included in OBENE (Observatoire BrEstois des NEoplasies myéloprolifératives) cohort (NCT02897297). Major bleeding (MB) and clinically relevant nonmajor bleeding (CRNMB) occurring after diagnosis were included, except after leukemic transformation. With a median follow-up of 8.3 years, incidence of hemorrhages was 1.85% patient/year, with an incidence of MB of 0.95% patient/year. The 10-year bleeding-free survival was 89%. The most frequent locations were digestive tract, "mouth, nose and throat," and muscular hematoma. The case fatality rate of MB was 25%. The proportion of potentially avoidable postoperative bleeding was remarkable (17.6%). In multivariable analysis, eight risk factors of bleeding were identified: leukocytes >20 G/L at diagnosis (hazard ratio [HR]=5.13, 95% confidence interval [CI]: 1.77-14.86), secondary hemopathies (HR=2.99, 95% CI: 1.27-7.04), aspirin use at diagnosis (HR=2.11, 95% CI: 1.24-3.6), platelet count >1,000 G/L at diagnosis (HR=1.93, 95% CI: 1.11-3.36), history of hemorrhage (HR=1.82, 95% CI: 1.03-3.24), secondary cancers (HR=1.71, 95% CI: 1.01-2.89), atrial fibrillation (HR=1.66, 95% CI: 1.01-2.72), and male sex (HR=1.54, 95% CI: 1.02-2.33). The occurrence of a CRNMB increased the risk of a secondary MB (odds ratio=6.13, 95% CI: 2.86-12.6, p<0.00001). Most patients taking hydroxyurea displayed a nonmacrocytic median corpuscular value in the months preceding bleeding (51.4%). The morbidity and mortality of bleedings in MPN should not be underestimated, and patients with platelet count >1,000 G/L and/or leukocytes >20 G/L, and possibly patients who suffered from a CRNMB could benefit from cytoreduction to reducing bleeding risk. Postoperative bleedings represent a substantial proportion of bleeding and could be better prevented.

Efficacy and safety of direct oral anticoagulants for the treatment of cancer-associated venous thromboembolism: A systematic review and Bayesian network meta-analysis

IntroductionDirect oral anticoagulants (DOACs) could effectively prevent the occurrence of cancer-associated venous thromboembolism (CAVTE), which incidence rate was estimated to be 4–20%. But the efficacy and safety remain controversial between DOACs and low molecular weight heparin (LMWH). Materials and methodsPubMed, Cochrane Library, Embase, ClinicalTrials.gov databases for randomized controlled trials (RCTs) were systematically searched from inception to March 15, 2022. A random-effects model was used to report the odds ratio (OR) and 95% confidence interval (CI) for both direct and network meta-analyses. ResultsSeven studies were included totaling 3242 patients. A lower rate of recurrence VTE was noted in the DOACs compared with LMWH (OR 0.62, 95% CI 0.47–0.82, I2=0.0%). The aspect of major bleeding (MB) was similar (OR 1.30, 95% CI 0.77–2.18, I2=34.9%). When assessing clinically relevant nonmajor bleeding (CRNMB) (OR 1.61, 95% CI 1.17–2.22, I2=20.7%) and clinically relevant bleeding (CRB) (OR 1.39, 95% CI 1.11–1.74, I2=0.0%), a higher risk of events was observed in DOACs. In subgroup analyses, the MB of gastrointestinal and genitourinary malignancies had a higher rate in the DOACs. For ranking, apixaban ranked the first in prevention of VTE and reducing MB events. Edoxaban had the highest risk drug in MB. In terms of CRNMB and CRB, LMWH showed the lowest risk. ConclusionsCompared with LMWH, DOACs seemed to have a decreased risk of recurrence VTE while increasing CRNMB and CRB. DOACs and LMWH were equivalent to the aspect of MB, but DOACs had a higher MB risk in patients with gastrointestinal and genitourinary malignancies. Apixaban may be the lowest risk compared to the other DOACs in precaution of VTE and reducing bleeding events.

Investigating the feasibility of recruitment to an observational, quality-of-life study of patients diagnosed with atrial fibrillation (AF) who have experienced a bleed while anticoagulated: EQUAL-AF feasibility study protocol

BackgroundOral anticoagulation therapies (OATs) are often prescribed in conjunction with medications to restore normal heart rate rhythm which can limit the risk of an atrial fibrillation (AF) related stroke and systemic thromboembolism. However, they are associated with the serious side effect of bleeding. Both clinically relevant nonmajor bleeding (CRNMB) and major bleeding while anticoagulated are believed to have a significant impact on patient quality of life (QoL). There is currently limited research into the effect bleeding has on QoL. The aim of this study is to evaluate the feasibility of identifying and recruiting patients diagnosed with AF, who are taking OATs and have recently experienced a bleed and collecting information on their QoL.MethodsWe will recruit a minimum of 50 patients to this cross-sectional, observational study. We will recruit from general practices, secondary care, and through an online AF forum. We will ask participants to complete three validated patient-reported outcome measures (PROMs), EQ5D, AFEQT, and PACT-Q, approximately 4 weeks following a bleed and again 3 months later. We will randomly select a subset of 10 participants (of those who agree to be interviewed) to undergo a structured interview with a member of the research team to explore the impact of bleeding on their QoL and to gain feedback on the three PROMs used. We will undertake a descriptive analysis of the PROMs and demographic data. We will analyse the qualitative interviews thematically to identify key themes.DiscussionWe aim to establish if it is possible to recruit patients and use PROMs to collect information regarding how patient QoL is affected when they experience either a clinically relevant non-major bleed (CRNMB) or major bleed while taking OATs for the management of AF. We will also explore the appropriateness, or otherwise, of the three identified PROMs for assessing quality of life following a bleed.PROMsThree PROMs were selected following a literature review of similar QoL studies and using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for comparison. A review of the current literature produced no suitable validated PROM to record QoL experiences in patients who have been diagnosed with AF and have experienced a bleed while anticoagulated. As such, the EQ5D, AFEQT, and PACT-Q (part 2) were deemed most appropriate for use in this feasibility study.Trial registrationThe trial has been adopted onto the NIHR Portfolio (ID no. 47771) and registered with www.ClinicalTrials.gov (no. NCT04921176) retrospectively registered in June 2021.

The Influence of ABCB1 (rs1045642 and rs4148738) Gene Polymorphisms on Rivaroxaban Pharmacokinetics in Patients Aged 80 Years and Older with Nonvalvular Atrial Fibrillation.

ABCB1 gene polymorphisms are associated with rivaroxaban distribution changes and adverse reactions but the data are controversial. Toevaluate the influence of ABCB1 (rs1045642 and rs4148738) gene polymorphisms on rivaroxaban pharmacokinetics in patients aged 80 years and older with nonvalvular atrial fibrillation (NAF). 128 patients aged 80 years and older (median [Me] age 87.5 [83.0-90.0] years) with NAF were included. We performed ABCB1 (rs1045642 and rs4148738) genotyping, measured the trough steady-state plasma concentration (Cmin,ss) of rivaroxaban and prothrombin time (PT) and analyzed prior medical records for clinically relevant non-major bleeding (CRNMB). CC genotype carriers had no differences in Cmin,ss (p>0.05) compared with the CT and TT rs1045642 and rs4148738 genotypes carriers. CC genotype carriers had no differences in PT (p>0.05) compared with the CT rs1045642 and rs4148738 and TT rs4148738 genotypes carriers. In the TT genotype PT levels were higher than in the CC rs1045642 genotype: Me 14.2 [13.0-16.1] sec vs 13.3 [12.4-14.5] sec (p=0.049). Incidence of CRNMB was higher in patients with the TT genotype compared with the CC rs1045642 (29.3% vs 4.5%, p=0.021) and rs4148738 (39.3% vs 8.1%, p=0.008) and the CT genotype rs4148738 (39.3% vs 14.3%, p=0.002). ABCB1 (rs1045642 and rs4148738) polymorphisms didn't influence rivaroxaban pharmacokinetics in patients aged 80 years and older with NAF. TT carriers developed CRNMB more frequently compared with the CC rs1045642 and the CC and CT rs4148738 genotypes. The haplotype TT-TT haplotype was associated with a higher frequency of CRNMB.

Early Versus Late Administration of P2Y 12 Inhibitors in Non-ST Segment Elevation Myocardial Infarction and Delayed Cardiac Catheterization.

Regardless of early invasive or ischemia-guided approaches to non-ST segment elevation myocardial infarction (NSTEMI) management, P2Y 12 inhibitors remain the backbone in therapy. The ideal timing of administration remains unclear. The purpose of this study was to determine the safety and effectiveness of early versus late administration of P2Y 12 inhibitors in patients presenting with an NSTEMI who go to the catheterization laboratory beyond 24 hours from presentation. We performed a single center, retrospective cohort study. Patients were classified into groups depending on whether they received early versus late administration of a P2Y 12 inhibitor. The primary outcome was the rate of major and clinically relevant, nonmajor bleeding (CRNMB). Secondary outcomes included troponin peak and length of stay after cardiac catheterization. Of the 121 patients included, 53 patients were in the early and 68 patients were in the late group. The number of bleeding events were similar between both groups ( P = 1.00). There were 3 (5.7%) major bleeding events in the early group and 5 (7.4%) bleeding events in the late group. There were 5 (9.4%) CRNMB events in the early group and 6 (8.8%) CRNMB events in the late group. There was a significant difference in troponin peak, 4.56 ng/mL in the early group and 1.77 ng/mL in the late group ( P = 0.02). The rate of bleeding did not differ between patients who received early or late administration of P2Y 12 inhibitors for NSTEMI management who undergo delayed cardiac catheterization.

Direct oral anticoagulants versus low-molecular-weight heparins for the treatment of acute venous thromboembolism in patients with gastrointestinal cancer: a systematic review and meta-analysis

BackgroundThe association between gastrointestinal (GI) cancer and a high incidence of venous thromboembolism (VTE) is well known. Previous randomized controlled studies demonstrated that direct oral anticoagulants (DOACs) effectively treat cancer-associated thrombosis (CAT). However, some DOACs appeared to increase the risk of bleeding, particularly in patients with GI malignancies. Therefore, the current systematic review and meta-analysis were conducted to evaluate the safety and efficacy of DOACs in GI cancer-associated thrombosis.MethodsTwo investigators individually reviewed all studies that compared DOACs and low-molecular-weight heparins (LMWHs) in GI cancer-associated thrombosis and were published in MEDLINE and EMBASE before February 2022. The effect estimates and 95% confidence intervals (CIs) from each eligible study were combined using the Mantel–Haenszel method.ResultsA total of 2226 patients were included in the meta-analysis. The rates of major bleeding in the DOAC and LMWH groups were not significantly different (relative risk [RR]: 1.31; 95% CI: 0.84–2.04; P = 0.23; I2 = 41%). However, the rate of clinically relevant nonmajor bleeding (CRNMB) was significantly higher in the DOAC group (RR: 1.76; 95% CI: 1.24–2.52; P = 0.002; I2 = 8%). The risks of recurrent VTE in the groups did not significantly differ (RR: 0.72; 95% CI: 0.49–1.04; P = 0.08; I2 = 0%).ConclusionsThe current data suggest that treatment of GI cancer-associated thrombosis with DOACs significantly increases the risk of CRNMB. However, the risk of major bleeding was not significantly different. The efficacy of DOACs for preventing recurrent VTE in GI cancer was comparable to that of LMWHs.Trial registrationINPLASY202180113.

Rivaroxaban Plus Aspirin for Extended Thromboprophylaxis in Acutely Ill Medical Patients: Insights from the MARINER Trial.

Background The MARINER trial evaluated whether postdischarge thromboprophylaxis with rivaroxaban could reduce the primary outcome of symptomatic venous thromboembolism (VTE) or VTE-related death in acutely ill medical patients at risk for VTE. Although aspirin use was not randomized, approximately half of the enrolled patients were receiving aspirin at baseline. We hypothesized that thromboprophylaxis with once-daily rivaroxaban (10 mg or, if creatinine clearance was 30–49 mL/min, 7.5 mg) plus aspirin (R/A) would be superior to placebo without aspirin (no thromboprophylaxis [no TP]). Methods We compared the primary and major secondary outcomes in the intention-to-treat population in four subgroups defined at baseline: (1) R/A ( N = 3,159); (2) rivaroxaban alone ( N = 2,848); (3) aspirin alone ( N = 3,046); and (4) no TP ( N = 2,966). Major bleeding (MB) and nonmajor clinically relevant (NMCR) bleeding were assessed in the safety population on treatment plus 2 days. Results Patients on R/A had reduced symptomatic VTE and VTE-related death compared with no TP (0.76 vs 1.28%, p = 0.042), and experienced less symptomatic VTE and all-cause mortality ( p = 0.005) and all-cause mortality alone ( p = 0.01) compared with no TP. Event incidences for rivaroxaban alone (0.91%) or aspirin alone (0.92%) were similar. MB was low in all groups but lowest in the no TP group. NMCR bleeding was increased with R/A compared with no TP ( p = 0.009). Limitations Aspirin use was not randomized. Conclusion Extended postdischarge thromboprophylaxis with R/A was associated with less symptomatic VTE and VTE-related death compared with no TP in previously hospitalized medical patients at risk for VTE. NMCR bleeding was increased with R/A compared with no TP. These post hoc findings need confirmation in a prospective trial.

Efficacy and safety of increased doses of anticoagulants in COVID-19 patients

The aim of the study was to evaluate the efficacy and safety of increased doses of anticoagulants in comparison with standard doses in inpatients with COVID-19. A systematic review was carried out in October 2021 using the PubMed database. The analysis included only randomized clinical trials (RCTs) with ≥ 200 participants that reported the rate of death as the total number of cases or the percentage of patients. The primary outcome was all-cause mortality within the observational period. In addition, the risk of arterial and venous thrombotic events and major and clinically relevant nonmajor (CRNM) bleeding was assessed. Searching of Pubmed identified 8903 references. The final qualitative and quantitative analysis included the results of 6 RCTs that covered 5228 patients. Among all patients, 2660 received increased and 2568 standard doses of anticoagulants. The follow-up period varied from 21 to 30 days. The administration of increased doses did not affect the risk of death (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.73–1.25; I2 = 59.5%), was associated with a reduced risk of thrombotic events (OR, 0.56; 95% CI, 0.43–0.73; I2 = 20.6%), and increased risk of major bleeding (OR, 1.86; 95% CI, 1.23–2.80; I2 = 0%) or CRNM bleeding (OR, 3.65; 95% CI, 1.65–8.09; I2 = 0%). Within the sensitivity analysis, similar results were obtained in the subgroups of critically ill or stable patients and individuals with increased D-dimer. The maximal reduction in the risk of thrombotic events was found for the subgroup of patients with increased D-dimer (OR, 0.48; 95% CI, 0.32–0.70; I2 = 36.4%). The use of increased doses of anticoagulants in inpatients with COVID-19 does not reduce the risk of death. Still, it is associated with a decrease in the risk of thrombotic events and increased risk of major bleeding.

A Single Center Retrospective Cohort Study Comparing Different Anticoagulants for the Treatment of Catheter-Related Thrombosis of the Upper Extremities in Women With Gynecologic and Breast Cancer.

BackgroundCatheter-related thrombosis (CRT) of the upper extremities is a frequent complication among cancer patients that carry a central venous catheter (CVC) and may lead to pulmonary embolism (PE) and loss of CVC function. Despite its clinical impact, no anticoagulant treatment scheme has been rigorously evaluated in these patients. In addition, there is no proven evidence that direct oral anticoagulants (DOACs) are efficacious and safe in this setting because cancer patients with CRT of the upper extremities were not included in the clinical trials that led to the approval of DOACs for the treatment of cancer-associated venous thromboembolism (VTE).MethodsWe performed a single center retrospective cohort study on women with gynecologic or breast cancer treated with either low-molecular-weight heparin, fondaparinux, or DOACs for CRT of the upper extremities. Only patients who received anticoagulation at the proper therapeutic dose and for at least 3 months were included in the analysis. Effectiveness was evaluated in terms of preservation of line function, residual thrombosis, and recurrence of VTE (including PE). Safety was evaluated in terms of death, major bleeding (MB), and clinically relevant non-major bleeding (CRNMB).ResultsWe identified 74 women who fulfilled the criteria to be included in the analysis. Of these, 31 (41.9%) had been treated with fondaparinux, 21 (28.4%) with enoxaparin, and 22 (29.7%) with the DOAC edoxaban. We found no differences between patients treated with the three different therapeutic approaches, in terms of preservation of line function, incidence of residual thrombosis, and VTE recurrence (including PE). Safety was similar as well, with no MBs recorded in any treatment group.ConclusionThese results, although retrospective and based on a relatively small sample size, indicate that, in women with gynecologic or breast cancer, CRT of the upper extremities may be treated with similar effectiveness and safety with fondaparinux, enoxaparin, and edoxaban. Further studies are needed to substantiate these findings.

Anticoagulation strategies and clinical outcomes after bleeding events during anticoagulation therapy for venous thromboembolism in the practice-based Japanese registry.

There is a paucity of data on anticoagulation strategies and clinical outcomes after bleeding events for venous thromboembolism (VTE). In a multicenter Japanese registry enrolling 3027 patients with acute symptomatic VTE, after excluding 430 patients with thrombolysis and 207 patients without anticoagulation therapy, the current study population consisted of 2390 patients, who were divided into patients with major bleeding, clinically relevant non-major (CRNM) bleeding and no bleeding during anticoagulation therapy. All-cause death at 90days after the bleeding events was evaluated as the primary outcome. There were 189 patients with major bleeding, 147 patients with CRNM bleeding, and 2054 patients without bleeding. Among 189 patients with major bleeding, 142 patients (75%) discontinued anticoagulants, of whom patients with temporary discontinuation and those with permanent discontinuation accounted for 63 patients (44%) and 79 patients (56%), and 58 patients (30.7%) died within 90days after the bleeding events. The multivariable logistic regression model among patients with bleeding events revealed that active cancer and bleeding events within 90days after VTE diagnosis were independently associated with 90-day mortality after the bleeding events (active cancer: OR 5.05, 95%CI 2.82-9.05; bleeding events within 90days after VTE diagnosis: OR 2.23, 95%CI 1.25-3.96). In this practice-based large registry, anticoagulants were frequently discontinued in patients who experienced major bleeding events during anticoagulation therapy and nearly half of them restarted anticoagulants with mortality rate of approximately 30% within 90days after the bleeding events, and active cancer was the most prevalent cause of death.Clinical trial registration COMMAND VTE Registry: http://www.umin.ac.jp/ctr/index.htm . Unique identifier: UMIN000021132.

Benefice and pitfall of direct oral anticoagulants in very high-risk myeloproliferative neoplasms

IntroductionDirect oral anticoagulants (DOACs) have recently proven their efficacy and safety, as primary and secondary prevention agents for thrombosis in cancer patients. We aimed to determine if DOACs might be a suitable choice to reduce the thrombotic risk in myeloproliferative neoplasm (MPN) patients. Materials and methodsWe analysed a large multicentric cohort of MPN patients treated with rivaroxaban or apixaban after atrial fibrillation (AF) or thrombotic events. ResultsWe included 135 MPN patients with a median follow-up of 23.8 months since DOAC initiation. Twenty patients (14.8 %) developed 30 thrombotic events (28 arterial thromboses in 19 patients) for a global incidence of 6.5 % patient-years. No difference was highlighted between apixaban and rivaroxaban in terms of thrombosis risk, but the incidence of arterial thrombosis was significantly higher on low-dose DOACs (11.9 vs. 4.5 % patient-years, p = 0.04). Bleeding events were more frequent in the full-dose group (41.2 vs. 15.2 %, p = 0.006). However, major and clinically relevant non major (CRNM) bleeding events occurred in 18 patients (13.3 %), with no difference between the groups. Age was the only identified thrombotic risk factor, whereas risk factors for major or CRNM bleeding were a full-dose treatment regimen and a combination of DOAC/low-dose aspirin. ConclusionsDOACs seem effective in preventing venous thrombosis in MPN patients with AF or VTE. For these high-risk patients, low-dose DOACs exposed patients to more arterial thrombosis but fewer bleeding events. Prospective studies are needed to evaluate and compare DOACs to the currently recommended antithrombotic drugs for high-risk MPN patients.

Treatment of cancer associated thrombosis: A living interactive systematic review and bayesian network meta-analysis.

e24070 Background: We have maintained a living interactive systematic review (LISR) on the treatment of CAT ( CAT LISR ). Recent publications of CASTA-DIVA and CANVAS trials prompted this report of updated analysis. Methods: The approach to creating LISRs has been previously published and is available on our website. ( LIvE synthesis framework ). Patient important outcomes included venous thromboembolism (VTE) recurrence, major bleeding (MB), clinically relevant non-major bleeding (CRNMB), net clinical benefit (NCB) and all-cause mortality. Mantel-Haenszel method was used to pool treatment effect estimates. A Paul-Mendel random-effects meta-analysis was conducted to compare DOACs with LMWH. Mixed-treatment comparisons were computed using fixed-effect model within a Bayesian framework owing to a sparse and open network. Effect estimates were expressed as odds ratio (OR) with 95% confidence intervals (CI). Surface under the cumulative ranking curve (SUCRA) was used to assess relative treatment rankings. Results: This systematic review currently includes six RCTs with a total of 3690 patients and four unique treatment choices. Apixaban was assessed in two trials (ADAM-VTE, CARAVAGGIO), rivaroxaban in two (SELECT-D, CASTA-DIVA) and edoxaban in one (HOKUSAI-VTE). CANVAS trial reported efficacy of DOACs as a class and hence, was only included in direct comparisons with LMWH. Direct comparisons showed that DOACs as a class significantly decreased the odds of VTE recurrence (OR 0.63, 95% CI: 0.49-0.82) without significantly increasing major bleeding (OR 1.23, 95% CI: 0.84-1.79) when compared to LMWH. However, higher odds of CRNMB (OR 1.65, 95% CI: 1.18-2.31) was observed with DOACs when compared to LMWH. Mortality rates were not different between the two groups (OR: 1.03, 95% CI: 0.87-1.21). Mixed treatment comparisons showed decreased VTE recurrences with rivaroxaban (rank 1; OR 0.49, 95% CI: 0.23-0.99) and apixaban (rank 2; OR 0.58, 95% CI: 0.36-0.90) relative to LMWH (rank 4). No significant differences were observed between edoxaban (rank 3) and LMWH in terms of VTE risk reduction. Edoxaban (rank 4) increased the risk of major bleeding (OR 1.77, 95% CI: 1.05-3.15) compared to LMWH (rank 2); there were no significant differences among rivaroxaban (rank 3) apixaban (rank 1), and LMWH. Rivaroxaban (rank 4; OR 3.16; 95% CI: 1.61-6.68) and apixaban (rank 3; OR 1.51, 95% CI: 1.01-2.28) increased the risk of CRNMB compared to LMWH (rank 1). Significant net clinical benefit was observed with apixaban (rank 1; OR 0.66; 95% CI: 0.46-0.94) when compared to LMWH (rank 4). No significant differences were observed among other mixed treatment comparisons. Conclusions: Patients treated with DOACs have 31 fewer VTE events per 1000 CAT patients compared to LMWH. Amongst DOACs, apixaban offers the greatest net clinical benefit with 39 fewer VTE and MB events per 1000 patients compared to LMWH.

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke

Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI). Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE). In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded. Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo. Major or clinically relevant nonmajor (CRNM) bleeding. Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant). The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status. ClinicalTrials.gov Identifier: NCT02415400.

Effectiveness and Safety of Lower Dose of Rivaroxaban for Cancer-Related Venous Thromboembolism: A Retrospective Cohort Study.

Primary and recurrent venous thromboembolism (VTE) commonly occur in patients with cancer. However, because of the National Health Insurance regulations, available dosage forms, and clinical conditions, the prescribed dose of rivaroxaban may not be consistent with its recommended dose. To evaluate the 6-month recurrence rate of VTE and safety of rivaroxaban for patients with cancer. Patients with new cancer diagnosis or recurrence from 2014 to 2018 who initiated rivaroxaban for VTE from January 2015 to January 2019 were included. We set the rivaroxaban initiation date as the index date and followed up the patients for 180 days. We collected information regarding the starting and maintenance dose/frequency and the treatment duration. The efficacy outcome was the recurrence of VTE within 180 days. The safety outcome included the major bleeding rate and clinically relevant nonmajor bleeding (CRNMB) rate. Approximately, 46.2% of the 65 included patients received a standard starting dose, and 45% of patients received a maintenance dose above 15 mg (median: 23.9 and 13.1 mg per day, respectively). Two-thirds of the patients stopped treatment within 180 days. Recurrent VTE occurred in 2 (3.1%) patients within 6 months. The major bleeding rate was 7.7%, and the CRNMB rate was 3.1%. The 6-month recurrence rate of VTE and safety profile were similar between the lower and standard dose of rivaroxaban. This result may be applied to the institutions with dosage availability limited by formulary regulation and patients who cannot use full dose because of clinical considerations.

Incidence and clinical impact of bleeding events in older patients with acute venous thromboembolism

AbstractOlder patients anticoagulated for venous thromboembolism (VTE) have an increased risk of bleeding compared with younger patients. Little is known about the clinical impact of anticoagulation-related bleeding in this growing patient group. To prospectively assess the incidence, clinical impact, and predictors of bleeding in older patients anticoagulated for VTE, we analyzed 981 patients aged ≥65 years with acute VTE in a prospective multicenter cohort. Eight-eight percent were anticoagulated with vitamin K antagonists. Outcomes were the occurrence of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) event during the initial anticoagulation period up to 36 months. We described the incidence and clinical impact of bleeding and examined the association between risk factors and time to a first bleeding using competing risk regression; 100 MB and 125 CRNMB events occurred during follow-up. The incidence of MB and CRNMB was 8.5 (95% confidence interval [CI], 7.0-10.4) and 13.4 events (95% CI, 11.4-15.7) per 100 patient-years, respectively. In patients with MB, 79% required hospitalization, 18% required surgical intervention, and 19% required permanent discontinuation of anticoagulation; 15% of MB were intracranial and 6% were fatal. After adjustment, active cancer (subhazard ratio [SHR], 1.81; 95% CI, 1.12-2.93) and low physical activity (SHR, 1.88; 95% CI, 1.19-2.98) were associated with MB and high risk of falls with CRNMB (SHR, 2.04; 95% CI, 1.39-3.00). Older patients anticoagulated for VTE had a high incidence of MB and CRNMB, and these bleeding episodes caused a great burden of disease. Physicians should carefully weigh the risks/benefits of extended anticoagulation in the older population with VTE.

Revised HAS-BLED score for bleeding prediction in atrial fibrillation patients with oral anticoagulants.

BackgroundThere were several limitations to the original HAS‐BLED (oHAS‐BLED) score in patients with atrial fibrillation (AF). This trial studied the revised HAS‐BLED (rHAS‐BLED) score for predicting bleeding events in anticoagulated AF patients.MethodsThis study retrospectively recruited anticoagulated AF patients in the Central Chest Institute of Thailand between 2014 and 2021. The rHAS‐BLED score was oHAS‐BLED using the estimated glomerular filtration rate of <60 ml/min/1.73 m2 for abnormal renal function, SAMe‐TT2R2 score of ≥3 for labile INR, and adding clinically relevant nonmajor bleeding (CRNMB) into bleeding history. The outcome was major bleeding (MB) and/or CRNMB at 1‐year follow‐up visit. The outcome between both groups was compared by using the chi‐square test or Fisher's exact test. Receiver‐operating characteristics curve was used to analyze the discrimination performances of both scores and the results were illustrated by using c‐statistics.ResultsA total of 256 anticoagulated AF patients were enrolled. The average age was 73.6 ± 10.1 years. The average oHAS‐BLED and rHAS‐BLED scores were 1.7 ± 0.9 and 2.6 ± 1.2, respectively. Twenty patients in rHAS‐BLED ≥3 (15.9%) and 9 patients in rHAS‐BLED <3 (6.9%) experienced MB and/or CRNMB. The rHAS‐BLED score of ≥3 increased the bleeding risk with statistical significance (OR 2.54, 95% CI 1.11–5.81, p = .04). The discriminative performance of the rHAS‐BLED score was illustrated with c‐statistics of 0.61 (95% CI 0.50–0.71).ConclusionsThe rHAS‐BLED score could predict bleeding events in anticoagulated AF patients. However, a larger study is needed to confirm these results in the future.

Oral anticoagulation versus antiplatelet therapy for secondary stroke prevention in patients with embolic stroke of undetermined source: A systematic review and meta-analysis.

PurposeWe performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of direct oral anticoagulation (DOAC) compared with antiplatelet therapy for secondary stroke prevention in adult patients with embolic stroke of undetermined source (ESUS).MethodWe searched major databases (Embase, MEDLINE, CINAHL, CENTRAL, and Web of Science) for RCTs published until March 2021. The primary outcome was recurrent stroke, and the main safety outcomes were major bleeding and clinically relevant non-major bleeding (CRNB). We assessed risk of bias using the Cochrane Risk of Bias tool. We used a random-effects model to determine pooled risk ratios and 95% confidence intervals in the datasets and key subgroups.FindingsOur search identified two RCTs, involving a total of 12,603 patients with ESUS. Anticoagulation with dabigatran or rivaroxaban compared with aspirin did not reduce the risk of recurrent stroke (RR, 0.96 [0.76–1.20]) or increase major bleeding (RR, 1.77 [0.80–3.89]) but significantly increased the composite of major or clinically relevant non-major bleeding (RR, 1.57 [1.26–1.97]). Prespecified subgroup analysis demonstrated consistent results according to age and sex. Additional post-hoc subgroup analyses demonstrated consistent results according to prior stroke and presence of a patent foramen ovale but suggested that DOACs reduced recurrent stroke in patients with an estimated glomerular filtration rate (eGFR) <50 and 50-80 ml/min but not in those with eGFR >80 ml/min (interaction P = 0.0234).Discussion/conclusionDirect oral anticoagulations are not more effective than aspirin in preventing stroke recurrence in patients with ESUS and increase bleeding.RegistrationPROSPERO ID: CRD42019138593

Efficacy and safety of fondaparinux versus unfractionated heparin in patients hospitalised with severe COVID-19 pneumonia and coagulopathy: a randomised, open-label clinical trial

Funding AcknowledgementsType of funding sources: Public hospital(s). Main funding source(s): Syarifah Ambami Rato Ebu General Hospital, Bangkalan, East Java, IndonesiaBackgroundThe use of unfractionated heparin (UFH) has been renowned to reduce mortality in COVID-19. There are no data about the efficacy and safety of fondaparinux (FPX) in COVID-19.PurposeTo evaluate the efficacy and safety of FPX as compared to UFH in patients hospitalised with severe COVID-19 and coagulopathy.MethodsThis was a single-center, open-label, equally randomised, parallel-group study conducted between April 1st and July 15th, 2021. Eligible and consenting patients were randomly assigned (1:1 ratio) to receive either FPX or UFH, in prophylactic and therapeutic dose. The primary efficacy endpoint was 28-day all-cause mortality; and secondary efficacy endpoints were episode of acute myocardial infarction (MI), objectively confirmed venous (VTE) or arterial thromboembolism (ATE), progression to non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), progression to ARDS, sepsis, acute kidney injury (AKI) and acute lung oedema (ALO). The primary safety endpoint was major bleeding (MB); and secondary safety endpoint was clinically relevant non-major bleeding (CRNMB). All composite endpoints were analysed on a 28-day intention-to-treat basis. All patients received guideline-driven therapy throughout the study.ResultsDuring allocated period, 250 (71%) of 352 patients were eligible and were assigned to either FPX or UFH group. The baseline characteristics were well-matched between the two groups (all p > 0.05). FPX compared with UFH revealed no significant difference in 28-day all-cause mortality (35.2% vs. 39.2%, hazard ratio [HR] 0.88, p = 0.59). FPX exhibited no significant difference in the trend of thromboembolic events i.e. acute MI (16.8% vs. 16.8%, HR 0.78, p = 0.53); VTE (2.4% vs. 3.2%, HR 0.49, p = 0.42); and ATE (1.6% vs. 1.6%, HR 0.94, p = 0.95) compared to UFH. Among those not on NIV or IMV at randomisation, FPX showed no significant difference in the proportion of patients meeting the composite endpoint of progression to NIV/IMV (33.6% vs. 35.2%, HR 0.91, p = 0.74) or ARDS (25.6% vs. 24.8%, HR 0.91, p = 0.77). FPX group demonstrated no significant difference in the progression to septic shock (24% vs. 24.8%, HR 0.97, p = 0.92), AKI (19.2% vs. 16%, HR 1.01, p = 0.98), and ALO (10.4% vs. 12%, HR 1.19, p = 0.79) than UFH. Allocation to FPX had no significant effect on the proportion of patients discharged from hospital within 28 days (64% vs. 59.2%, HR 0.72, p = 0.43). Regarding safety, there was no significant difference between FPX and UFH group in terms of major bleeding (1.6% vs. 1.6%, HR 0.88, p = 0.88) or CRNMB (8% vs. 8.8%, HR 0.74, p = 0.53) at 28 days. Our prespecified sub-analysis comparing patients who received the respective therapeutic or prophylactic dose revealed that the efficacy and safety outcomes at 28 days did not differ between the FPX and UFH group (all p > 0.05).ConclusionIn patients hospitalised with severe COVID-19 and coagulopathy, FPX was associated with similar efficacy and safety as compared to UFH. Figure. Baseline characteristics of study groups Figure. Allocation of FPX on composite endpoints

Apixaban in Japanese patients with cancer-associated venous thromboembolism: a multi-center phase II trial

Recent pivotal phase III trials involving direct oral anticoagulant (DOAC) versus low molecular weight heparin have demonstrated the utility of DOACs in Western patients with cancer-associated venous thromboembolism (VTE). However, these trials did not include Japanese patients. This phase II trial evaluated the safety and efficacy of apixaban in Japanese patients with cancer-associated VTE (UMIN000028447). Apixaban was initiated at 10mg twice daily for 7days, followed by 5mg twice daily for 23weeks. The primary endpoint was the incidence of major or clinically relevant non-major (CRNM) bleeding events during the treatment period. The study was terminated due to safety concerns after enrolling 27 patients. Median age was 71years; median body weight was 51.3kg; and major primary tumor sites were the gastrointestinal tract (26%) and lung (19%). During the median follow-up period of 5.4months, major or CRNM bleeding occurred in in 26% of patients (major, n = 5; CRNM, n = 2; 95% confidence interval, 11-46%). No recurrent VTE or VTE-related death occurred. Estimated overall survival at 6months was 68%. This study demonstrated the excessive bleeding risk of apixaban at the standard dose in Japanese patients with cancer-associated VTE.

Comparison of co-administration of amiodarone and rivaroxaban to co-administration of dronedarone and rivaroxaban for hemorrhage risks after atrial fibrillation ablation

PurposeTo investigate whether co-administration of antiarrhythmic dronedarone and anticoagulant rivaroxaban would increase the risks of hemorrhage after atrial fibrillation (AF) ablation.MethodsA total of 100 patients with AF who underwent radiofrequency catheter ablation (CA) in the Department of Cardiology, the Affiliated Hospital of Qingdao University from 2019–12 to 2020–11 were included. Patients were divided into an oral dronedarone and rivaroxaban group (D-R group, N = 50) and an oral amiodarone and rivaroxaban group (A-R group, N = 50) according to the postoperative antiarrhythmic and anticoagulation strategies. Patients in 2 groups were given propensity score matching (PSM) to obtain a sample with balanced inter-group covariates. A retrospective observational study was conducted. After 3 months of follow-up, the incidence of clinically relevant non-major bleeding (CRNMB), major hemorrhages, and early AF recurrence was observed.ResultsAfter PSM, 41 patients were included in each group. With similarly distributed baseline characteristics and ablation characteristics after PSM, the CRNMB rate after AF ablation was significantly higher in the D-R group than in the A-R group (26.8% versus 7.3%, P = 0.02), and no major hemorrhages were detected in both groups. No significant difference was observed in the sinus rhythm maintenance rate between the D-R group and the A-R group (26.8% vs. 22.0%, P = 0.43).ConclusionsCompared to co-administration of amiodarone and rivaroxaban, co-administration of dronedarone and rivaroxaban increases the risk of CRNMB but it does not increase the risk of major hemorrhages in blanking period after AF ablation.