Rate of Clonal Hematopoiesis in Patients with Venous Thromboembolism

Abstract Background Venous thromboembolism (VTE) is the third most common cardiovascular disease with an incidence over 1% in the elderly. About 50% of VTE is unprovoked, which is associated with higher rates of recurrent VTE and complications such as post-thrombotic syndrome. Clonal hematopoiesis (CH) refers to recurrent somatic mutations associated with hematologic malignancies that are present in otherwise healthy individuals. CH is more common with increased age, occurring in more than 10% of people over the age of 70 and has been associated with an increased risk of coronary artery disease. The rates of CH in patients with VTE or complications arising from this is not known. Methods Adult patients (age ≥ 18) with VTE were enrolled at the Ohio State University Thrombosis Clinic between 2017 and 2020. Clinical data was obtained at the time of routine clinic follow-up or ad hoc, and a research blood sample was collected with routine blood work. DNA extracted from peripheral blood mononuclear cells were analyzed for the presence of CH via error corrected next generation sequencing (NGS) using the Ion Gene Studio S5 System. A custom AmpliSeq panel IAH150087 was designed to detect CH, which included whole gene sequencing and hotspots in 25 common genes associated with myeloid malignancies, including DNMT3A, TET2, ASXL1, among others, with a sequencing depth of up to 50,000X. Data was collected and analyzed using Ion Torrent S5/GS-S5 Instrument with Torrent Suite 5.12.0 version. Final analysis of sequence data was performed using combination of software: Variant Caller v.5.12.10-1, IGV5.01 (0) and Ion Reporter v.5.12.3.0. The hg19 reference sequence was used to assess for deviation. CH was defined as a variable allele frequency ≥ 2%. Two sample t-test and chi-square test were used to compare patients with and without CH for continuous and categorical variables, respectively. Results A total of 167 patients are included the study. Median age is 60.3 years and 55% of patients are female. 80% of patients are white. The majority of patients have unprovoked VTE (81%); 23 patients (13.8%) have VTE associated with cancer. 84% of patients were treated with a direct oral anticoagulant. Over the median follow-up duration of 400 days, 7 patients had recurrent VTE and 19 patients had a total of 21 bleeding events (7 major bleeding and 14 clinically relevant non-major bleeding [CRNMB] by ISTH criteria). Overall, 22 patients (13.2%) have detectable CH. Patients with CH are significantly older than those without CH (mean age 70 vs 59, p <0.0001). There is a trend towards increased CH rate in male patients (17% of male patients vs 10% of female patients with CH). There are no other differences in baseline characteristics among patients with and without CH, including type or location of VTE or cancer status. Among the 144 VTE patients without cancer, the median age is 60 years old and the CH rate is also 13.2%. In this group, the mean age of patients with CH is 12 years older than those without CH (70.5 years vs 58.4 years, p <0.0001). No other significant baseline characteristics are noted. 30 distinct CH mutations are noted in these 22 patients. Most patients have a single gene mutation (77%). Gene mutations in DNMT3A are the most common (46%), followed by TET2 (13%), and PPM1D (10%) (see figure). Most mutations are missense (57%), followed by nonsense (30%) and insertion/deletion mutations (13%). One patient has a JAK2 V617F mutation without known history of myeloproliferative disease. 8 CH patients with serial samples collected over a median duration of 136 days (range 91 - 490 days) showed no significant change in CH clone size over time. Patients with CH have no differences in rates of recurrent VTE or arterial thrombosis compared to those without CH. Patients with CH have a trend towards increased rate of combined major bleeding and CRNMB events (23% vs 10%, p=0.14). Patients with CH also had a trend towards increased mean corpuscular volume (MCV) (mean 93.5 vs 90.7, p=0.13), although no other cytopenias or differences in complete blood count parameters were noted. Conclusion The CH rate in patients with VTE was not found to be much higher than what might be expected by age alone. We found no change in the CH rate after excluding cancer patients. A larger VTE population with age-matched controls will better determine the CH rate in patients with VTE. CH can be a consideration in designing future clinical VTE studies that assess bleeding risk. Figure 1 Figure 1. Disclosures Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria. Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding.

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Safety and Effectiveness of Apixaban, LMWH, and Warfarin Among Venous Thromboembolism Patients with Active Cancer: A Retrospective Analysis Using Four US Claims Databases

Blood ◽

10.1182/blood-2019-121769 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 326-326 ◽

Cited By ~ 1

Author(s):

Alexander T Cohen ◽

Allison Keshishian ◽

Theodore Lee ◽

Gail Wygant ◽

Lisa Rosenblatt ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Lower Risk ◽

Select Committee ◽

Advisory Committees ◽

Recurrent Vte ◽

High Risk Cancer ◽

Similar Risk ◽

Active Cancer

BACKGROUND: Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. The treatment of cancer-associated VTE carries a significantly greater risk of major bleeding (MB) and recurrent VTE compared to that in non-cancer patients. CHEST Guidelines suggest the use of low molecular weight heparin (LMWH) over a vitamin K antagonist (VKA) in patients diagnosed with VTE and cancer. The last decade has seen an emergence of non-VKA anticoagulants (NOACs) for the treatment of VTE. Despite completed and ongoing clinical trials, there is a lack of real-world evidence comparing the effectiveness and safety of LWMH with VKAs and NOACs among VTE patients with active cancer. Therefore, this study evaluates the risk of MB, clinically relevant non-MB (CRNMB), and recurrent VTE (fatal or non-fatal) among VTE patients with active cancer prescribed apixaban, LMWH, or warfarin in routine clinical practice. METHODS: Four US commercial insurance claims databases were used to identify VTE patients with active cancer (defined as cancer diagnosis or cancer treatment [chemotherapy, radiation and cancer-related surgery] within 6 months before or 30 days after VTE diagnosis) who initiated apixaban, LMWH, or warfarin within 30-days following the first VTE event (01SEP2014-31MAR2018). Patients who used LMWH as bridging therapy for warfarin (≤14 days before or after warfarin initiation) were classified as warfarin users. Patients were followed to the earliest of: health plan disenrollment, death, index therapy discontinuation, switch to another anticoagulant, study end, or a maximum of 6 months. Additional analysis using all available follow-up was also conducted. Stabilized inverse probability treatment weighting (IPTW) was used to balance treatment cohorts. Cox proportional hazard models were used to evaluate the risk of MB, CRNMB, and recurrent VTE. RESULTS: After applying all eligibility criteria, 3,393 apixaban, 6,108 LMWH, and 4,585 warfarin patients were identified with mean ages of 65, 64, and 64 years, respectively. After IPTW, all patient characteristics were balanced. The mean follow-up was 105, 88, and 113 days for apixaban, LMWH, and warfarin, respectively. Among the weighted VTE cancer population, 51% of the patients had metastatic cancer and 77% of patients received cancer treatment. Further, 15% of patients had very high-risk cancer (brain, stomach, or pancreas), and 40% patients had high-risk cancer (lung, lymphoma, gynecologic, bladder, testicular, renal cell carcinoma). Apixaban patients had a lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH. Apixaban patients also had a lower risk of recurrent VTE and a similar risk of MB and CRNM bleeding compared to warfarin. Warfarin patients had a similar risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH (Figure). When the entire available follow-up period (mean follow-up was 137, 106, and 166 days for apixaban, LMWH, and warfarin, respectively) was used, the trends were similar to the 6-month analysis for apixaban vs. LMWH and warfarin vs. LMWH. However, apixaban patients were associated with a lower risk of both MB and recurrent VTE compared to warfarin patients. CONCLUSION: VTE patients with active cancer initiating apixaban had significantly lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH patients. Apixaban patients also had a lower risk of recurrent VTE compared to warfarin patients. These results may be helpful for clinicians in evaluating different anticoagulation treatments for VTE patients with active cancer. Further studies are needed to evaluate these outcomes between different anticoagulation treatment options. Figure Disclosures Cohen: Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Temasek Capital: Consultancy; ACI Clinical: Consultancy; Navigant: Consultancy; McKinsey: Consultancy; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy; Aspen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boston Scientific: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; GLG: Consultancy; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau. Keshishian:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company and Pfizer Inc.. Lee:Pfizer Inc.: Employment, Equity Ownership. Wygant:Bristol-Myers Squibb Company: Employment. Rosenblatt:Bristol-Myers Squibb: Other: Stock Owner ; Bristol-Myers Squibb Company: Employment. Hlavacek:Pfizer Inc.: Employment. Mardekian:Pfizer Inc.: Employment. Wiederkehr:Pfizer Inc.: Employment. Sah:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company and Pfizer Inc.. Luo:Pfizer Inc.: Employment.

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Validation of the Ottawa Score in Cancer Patients with Venous Thromboembolism. the Predicare Cohort Study

Blood ◽

10.1182/blood-2019-129087 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 167-167 ◽

Cited By ~ 1

Author(s):

Guy Meyer ◽

Celine Chapelle ◽

Philippe Girard ◽

Florian Scotté ◽

Anne Lamblin ◽

...

Keyword(s):

Cohort Study ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Cancer Patients ◽

Major Bleeding ◽

Research Funding ◽

Advisory Committees ◽

Patients With Cancer ◽

Recurrent Vte ◽

Support Research

Introduction Venous thromboembolism (VTE) is a difficult to treat condition in patients with cancer with a persisting risk of recurrent VTE during anticoagulant treatment with low-molecular weight heparin (LMWH). Recent data suggest that direct oral anticoagulants (DOACS) are associated with a lower risk of recurrence but a higher risk of bleeding in these patients. Predicting the risk of recurrent VTE with LMWH may help to select the best treatment option. We conducted a prospective multicenter observational cohort study in cancer patients with VTE treated with tinzaparin for 6 months in order to validate the Ottawa score (NCT03099031) and search for additional risk of recurrent VTE. The Ottawa score is composed of 5 variables, female sex (+1), lung cancer (+1), breast cancer (-1) cancer stage 1 (-2) and previous DVT (+1). A score ≤0 is associated with a low risk of recurrent VTE. Methods Adult cancer patients with recent diagnosis of documented symptomatic or incidental VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE) treated with tinzaparin for 6 months were included in the study. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment with tinzaparin. Other endpoints were symptomatic recurrent VTE, major bleeding, heparin induced thrombocytopenia (HIT), all-cause mortality within 3 and 6 months. All events were adjudicated by a Central Adjudication Committee. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. Cumulative incidences were presented with corresponding 95% confidence interval (95% CI). To validate the Ottawa score, the area under the curve (AUC) and its 95% CI were calculated on receiver operating characteristic (ROC) curve analysis; the most discriminant cut-off was then determined by calculating the Youden index. Univariate and multivariate analyses were performed to identify additional predictive factors of recurrent VTE to those included in the Ottawa score using the Fine and Gray method and adjusted on factors included in the Ottawa score. Hazard ratio and their 95% CI were calculated. Results A total of 409 patients were included and analyzed on an intention-to-treat basis; the median age was 68 years and 51% of patients were males. 60.4% of patients had a PE (with or without DVT) .64% received chemotherapy at inclusion or in the month before inclusion. Lung (31.3%) and digestive track (18.3%) cancers were the most common cancer types and 67.0% had stage IV cancers. According to Ottawa score, 58% of patients were classified at high clinical probability of recurrence (score ≥ 1). During the 6 months treatment period, 23 patients had a recurrent VTE, yielding a cumulative incidence of 6.1% (95% CI 4.0-9.3) with a median time for recurrent VTE of 33 days. The recurrence rate of VTE was estimated to 7.8% (95% CI 4.9-12.5) for patients classified at high risk of recurrence according to the Ottawa score (score ≥ 1) compared to 3.8% (95%CI 1.6-8.9) for other patients (Ottawa score < 1). AUC of the Ottawa score was 0.60 (95% CI 0.55-0.65). In multivariable analysis, none of the potential risk factors for recurrent VTE was significantly associated with recurrent VTE at 6 months. During the 6 months treatment period, 15 patients had a major bleeding and 2 patients experienced a HIT. At 3 and 6 months, 104 and 144 patients had died yielding a cumulative incidence of 26.1%, (95% CI 21.8-30.4) and 37.8% (95% CI 32.8-42.9), respectively. The main cause of death was underlying cancer. Conclusion In this prospective cohort of patients with cancer receiving LMWH for VTE, the Ottawa score did not accurately predict recurrent VTE. No other clinical predictor of recurrent VTE was identified in this study. Disclosures Meyer: Bayer: Other: travel support; LEO pharma: Other: travel support, Research Funding; SANOFI: Other: travel support, Research Funding; BMS-Pfizer: Other: travel support, Research Funding; Boehringer Ingelheim: Research Funding. Girard:Leo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Scotté:LEO Pharma A/S: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Tesaro: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; MSD: Honoraria, Research Funding, Speakers Bureau; Pierre Fabre Oncology: Honoraria, Research Funding, Speakers Bureau. Lamblin:Leo Pharma: Employment. Laporte:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boston scientific: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Leo-Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Low Dose Apixaban As Secondary Prophylaxis for Venous Thromboembolism in Cancer Patients, 30 Months Follow-up

Blood ◽

10.1182/blood-2021-148105 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3231-3231

Author(s):

Trine-Lise Hannevik ◽

Herish Garresori ◽

Jorunn Brekke ◽

Tone Ronnaug Enden ◽

Hege Froen ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Cancer Patients ◽

Incidence Rate ◽

Major Bleeding ◽

Low Dose ◽

Advisory Committees ◽

Full Dose ◽

Kaplan Meier ◽

Recurrent Vte

Abstract Background: Apixaban is a treatment option for venous thromboembolism (VTE) in cancer patients. There are no data on the effect of low dose apixaban after 6 months treatment. We wanted to assess the efficacy and safety of apixaban 2.5 mg twice daily as prophylaxis for recurrent VTE after 6 months initial treatment with full-dose apixaban. Patients and methods: We included 298 patients with cancer and any type of VTE. All patients were treated with full dose apixaban for the first 6 months. After 6 months, all patients with active cancer continued with apixaban 2.5 mg twice daily and were followed for the next 30 months. The primary endpoint of efficacy was recurrent VTE, the primary safety endpoint was major bleedings. Clinically relevant non-major bleedings was a secondary endpoint. The endpoints are reported as incidence rates or fractions with 95% confidence intervals, and as Kaplan-Meier plots. Results: During the first 6 months of full-dose anticoagulation 12 of 298 patients had recurrent VTE (4.0%, 95% confidence interval 2.1-6.9), 16 experienced major bleeding (5.4%, 95% CI 2.8-7.9%), and 26 patients experienced one or more episodes of CRNMB (8.9%, 95% CI 5.5-12) as previously reported. 1 Of the 298 patients included, 196 continued with apixaban 2.5 mg twice daily after 6 months. During treatment from 6 to 36 months with low-dose apixaban 15 of 196 (7.6%, 95% CI: 4.4-12) patients had recurrent VTE, 7 (3.6%, CI: 1.5-7.2) patients experienced major bleeding and 16 (8.2%, 95% CI: 4.7-13) patients experienced CRNMB. The highest incidence rate of both recurrent VTE and major bleedings were seen during the first month of full-dose apixaban (Table 1). After the dose reduction of apixaban, the incidence rate of recurrent VTE increased slightly during 6 to 12 months while the incidence rate of major bleeding decreased during the same time-period. After 12 months the incidence rate of both recurrent VTE and major bleeding was low and remained low during the entire 30 months follow-up (Table 1 and Figure 1). The Kaplan-Meier plot of the composite endpoint of recurrent VTE or major bleeding did not change after dose-reduction. After about 9 months treatment (i.e. 3 months on low dose apixaban) the Kaplan-Meier curve of the composite endpoint flattened out. Conclusion: Dose reduction of apixaban to 2.5 mg twice daily after 6 months of full dose anticoagulation resulted in a small increase in recurrent VTE, but a marked decrease in major bleedings during the 6-12 months period. After approximately 9 months the frequency of recurrent VTE and major bleedings remained low compared with the first 6 months of full-dose treatment. Reducing the dose of apixaban to 2.5 mg twice daily after 6 months of full-dose treatment appears safe and effective. References 1. Hannevik TL, Brekke J, Enden T, et al: Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism. Thromb Res, 2020 Figure 1 Figure 1. Disclosures Hannevik: Pfizer/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Garresori: Pfizer: Honoraria; Amgen: Honoraria; Bayer: Honoraria. Froen: Bristol-Myers Squibb: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees. Porojnicu: Bristol-Myers Squibb: Honoraria. Ghanima: Bayer, BMS/Pﬁzer: Research Funding; Amgen, Novartis, Pﬁzer, Bristol Myers Squibb, SOBI, Griffols, Sanoﬁ: Honoraria; Amgen, Novartis, Pﬁzer, Principia Biopharma Inc- a Sanoﬁ Company, Sanoﬁ, SOBI, Griffols, UCB, Argenx: Consultancy. Dahm: Pfizer: Honoraria; Novartis: Honoraria; Pfizer/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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Management of Secondary Prevention in Venous Thromboembolism: Use of Reduced Doses of Rivaroxaban and Apixaban in Extended Therapy

Blood ◽

10.1182/blood-2020-141908 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

Desiree Campoy ◽

Katia Flores ◽

Gonzalo Artaza ◽

César A Velasquez ◽

Tania Canals ◽

...

Keyword(s):

Venous Thromboembolism ◽

Secondary Prevention ◽

Board Of Directors ◽

Dose Reduction ◽

Standard Dose ◽

Control Group ◽

Advisory Committees ◽

The Mean ◽

D Dimer

BACKGROUND After a standard anticoagulation period (3-6 months), the risk of venous thromboembolism recurrence (RVTER) needs to be considered. Such risk is higher in unprovoked events and patients with persistent risk factor. The increase of D-dimer (DD) levels during the therapy seems to be strongly associated to RVTER. The use of rivaroxaban 10 mg/day and apixaban 2.5mg/12h as an extended therapy (ET) after the standard anticoagulation period has been proven to be an effective strategy to prevent recurrence without increasing bleeding events. AIM To assess the effectiveness and safety of reduced doses of rivaroxaban and apixaban as ET in patients with RVTER and to compare their DD levels with those of a control group on anticoagulant therapy at a standard dose. METHODS From April 2016 to June 2020, we included patients with venous thromboembolism (VTE) who received ET with rivaroxaban and apixaban with/at reduced doses. Dose reduction was performed following the clinical algorithm of our unit (Fig. 1). The DD values were determined using HemosIl D-Dimer HS-500 and the cut-off value was established at 500 µg/L DD levels were compared with a control group of 235 patients with VTE who received ET with standard doses of anticoagulation. DD levels were measured at the time of diagnosis (D1), initiation of treatment (D2) and 3 months after treatment (D3). RESULTS From a total of 116 patients (65.5% women), 77.6% (n=90) received rivaroxaban 10 mg/24h and 22.4% received apixaban 2.5 mg/12h as an ET. The mean duration of the initial anticoagulant therapy was 12 +/- 8.8 months. The mean DD value prior to the ET was 388 µg/L. In this group, 63.8% (n=74) was an unprovoked VTE and 17.2% (20) had hereditary thrombophilia. The mean of follow-up time was 6.9 +/- 8.3 months. No recurrences of VTE were observed during the follow-up and only one major bleeding event was reported in a high-bleeding risk patient. We observed a progressive decrease of DD levels from the VTE diagnosis to the last visit, with D1, D2, and D3 values of 987 µg/L ± 324, 388 µg/L ± 134, and 288 µg/L ± 98, respectively. There were no differences in d-dimer concentrations between patients with reduce doses of rivaroxaban or apixaban and the control group with standard doses (D1: 85.6% vs 81%, p =0.22; D2: 10.2% vs 8.0%, p =0.14; and D3: 9.1% vs 9.5%, p =0.18). CONCLUSIONS Our data indicated that an ET strategy with reduced doses of rivaroxaban or apixaban is effective and safe. We did not observe significant differences in DD levels at follow-up compared to the control group receiving a standard dose of anticoagulation. Further studies are needed in order to select and standardize dose reduction criteria in secondary prevention. Figure 1 Disclosures Campoy: boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Olivera:Daiichi Sankyo: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BAYER: Consultancy.

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Long-Term Survival Benefit of Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria: Data from the International PNH Registry

Blood ◽

10.1182/blood-2021-153560 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2188-2188

Author(s):

Louis Terriou ◽

Christopher J. Patriquin ◽

Morag Griffin ◽

Jong Wook Lee ◽

Philippe Gustovic ◽

...

Keyword(s):

Rare Disease ◽

Board Of Directors ◽

Survival Probability ◽

Advisory Committees ◽

Term Survival ◽

Treatment Status ◽

History Of ◽

Baseline Characteristics

Abstract Background Eculizumab, the first C5 inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH), transformed PNH treatment by improving survival to that of an age- and sex- matched general population. Previous analyses demonstrating the survival benefit of eculizumab in patients with PNH leveraged historical data and were limited by small patient numbers and short follow-up durations; few evaluated survival of patients receiving eculizumab compared with untreated patients. The objective of the current analysis was to describe the baseline characteristics and overall survival of a large international cohort of eculizumab-treated patients compared with a contemporaneous untreated cohort using data from the prospective, observational International PNH Registry (NCT01374360). Methods Data from patients enrolled in the Registry after March 16, 2007 with complete information for birth date, sex, enrollment date, and treatment status were included (database cut-off, April 12, 2021). Ever-treated patients were those who received eculizumab for a minimum treatment period of 35 days while enrolled in the Registry; never-treated patients did not receive eculizumab at any time before or during Registry participation. Univariate and multivariate analyses were performed using a Cox proportional hazards that incorporated the following parameters at baseline as covariates: treatment status, presence of high disease activity (HDA), age, sex, history of bone marrow failure (BMF), history of thrombotic events (TE), transfusion dependence, and estimated glomerular filtration rate ≤60 mL/min/1.73 m 2. HDA was defined as lactate dehydrogenase (LDH) ratio ≥1.5 × upper limit of normal (ULN) and ≥1 of the following: history of major adverse vascular events (including TE); anemia (hemoglobin <10 g/dL), or physician-documented abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, or erectile dysfunction at any time before and including baseline. Baseline was defined as the date of eculizumab treatment initiation (ever-treated patients) or date of Registry enrollment (never-treated patients). Survival time was analyzed using a left-truncation approach that mapped time in patients' survival based on disease start date, defined as the earliest date of first-reported PNH diagnosis, PNH symptom, or first consistent flow cytometry result. Results Baseline characteristics of the 4627 patients included in the analysis (mean [SD] age at disease start, 40.2 [18.71] years; 53% female; 75% white) were comparable between the ever-treated and never-treated groups (n=1892 and n=2735, respectively). Compared with never-treated patients, more ever-treated patients had LDH ≥1.5 × ULN (90% vs 35%), and fewer had <10% PNH granulocytes (3% vs 57%) or history of BMF (45% vs 76%). The univariate Cox proportional hazard ratio (HR) for mortality in ever-treated vs never-treated patients was 0.48 (95% CI, 0.39-0.60; P<0.0001), indicating a 52% increase in survival in the treated group (Table). Among ever-treated patients, those with HDA at baseline experienced the largest reduction in mortality risk (HR [95% CI], 0.46 [0.33-0.64]; n=174); however, decreased mortality was also evident in ever-treated patients without HDA (HR, 0.65 [0.39-1.10]; n=212) or with unknown HDA status (HR, 0.50 [0.32-0.76; n=120) at baseline. Overall survival probability by treatment status was consistently greater in ever-treated vs never-treated patients through 20 years of follow-up; survival probability at 20 years was 82% (ever-treated) vs 69% (never-treated). Although long-term survival probability was greatest throughout follow-up in ever-treated patients with HDA at baseline, increased survival among ever-treated patients was evident in all 3 HDA status groups (Figure). Conclusion In this analysis of Registry data, treatment with the C5 inhibitor eculizumab improved patient survival compared with a never-treated cohort at a comparable time point in their disease course. Covariates were assessed at baseline only and competing risks and time on treatment were not controlled for, which are potential limitations. Survival benefits conferred by eculizumab treatment were observed regardless of HDA status at baseline, were more pronounced in treated patients with HDA vs those without HDA, and were maintained through 2 decades of real-world follow-up. Figure 1 Figure 1. Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin: Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Biocryst: Honoraria; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease: Current Employment. Szer: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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The Safety and Efficacy of Full Versus Reduced Dose Betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) Trial

Blood ◽

10.1182/blood.v128.22.3824.3824 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3824-3824

Author(s):

Alexander T Cohen ◽

Rim Halaby ◽

Serge Korjian ◽

Yazan Daaboul ◽

Donald Szlosek ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Primary Analysis ◽

Advisory Committees ◽

Medically Ill ◽

Reduced Dose ◽

Efficacy Outcome ◽

Venous Thromboembolism Prevention ◽

Extended Duration

Abstract Background: The exposure of all the currently licenced DOACs is increased in renal impairment and by certain drug interactions. The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The full 80 mg dose of betrixaban was halved to 40 mg among subjects with severe renal insufficiency (calculated creatinine clearance <30ml/min), or receiving a concomitant strong P-glycoprotein (P-gp) inhibitor. Objectives and Methods: The goal of this analysis is to assess the efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Subjects were stratified into the two dose groups prior to randomization according to the pre-specified dosing criteria. The primary efficacy outcome was the composite of asymptomatic proximal and symptomatic venous thromboembolism (proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from venous thromboembolism). The principal safety outcome was major bleeding. Results: The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, p<0.0001). In the primary analysis Cohort 1 (the elevated D-dimer +ve patients), the primary efficacy outcome was significantly reduced among subjects treated with 80 mg of extended dose betrixaban vs enoxaparin [6.3% (95/1516) vs 8.4% (130/1549), RRR = 0.26 (0.04-0.42), p=0.023]. A similar reduction was observed in the entire modified Intention to Treat (mITT) population [4.87% (122/2506) vs 7.06% (181/2562), RRR = 0.30 (0.13 - 0.44), p=0.001]. In contrast, among subjects receiving 40 mg of betrixaban there was no significant difference in the primary outcomes compared with enoxaparin across Cohorts 1, 2, and 3. There was no excess of major bleeding associated with administration of either the full 80 mg dose or the reduced 40 mg dose of betrixaban as compared with enoxaparin. Conclusion: For extended duration prophylaxis against VTE in hospitalized medically ill patients, the full 80 mg dose of extended duration betrixaban achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding. Based upon the approximate halving of plasma concentrations in this analysis and the lack of improvement in clinical outcomes, the reduced 40 mg dose may have been excessively downwardly adjusted. Conversely, the 80 mg dose was efficacious in all cohorts, including cohort 1. The inclusion of the 40 mg dose in the primary analysis may explain at least in part the marginal statistical result in the original report. Disclosures Cohen: Takeda: Consultancy; Medscape: Speakers Bureau; XO1: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; NHS: Membership on an entity's Board of Directors or advisory committees; Lifeblood: Membership on an entity's Board of Directors or advisory committees; Department of Health: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Janssen: Consultancy; Aspen: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; Leo Pharma: Consultancy; UK Government Health Select Committee: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria. Goldhaber:Portola: Consultancy. Hull:Portola: Consultancy. Hernandez:Portola: Consultancy. Gold:Portola Pharmaceuticals: Employment. Wiens:Portola: Employment, Equity Ownership. Harrington:Portola: Consultancy. Gibson:Portola: Consultancy.

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Two Years Versus Six Months of Oral Anticoagulation after a First Episode of Unprovoked Pulmonary Embolism: The Padis PE Multicenter, Double-Blind, Randomized Trial

Blood ◽

10.1182/blood.v124.21.lba-3.lba-3 ◽

2014 ◽

Vol 124 (21) ◽

pp. LBA-3-LBA-3

Author(s):

Francis Couturaud ◽

Olivier Sanchez ◽

Gilles Pernod ◽

Patrick Mismetti ◽

Patrick Jego ◽

...

Keyword(s):

Pulmonary Embolism ◽

Placebo Group ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Composite Outcome ◽

Advisory Committees ◽

Entire Study ◽

Warfarin Group ◽

Recurrent Vte

Abstract Background: Patients with a first episode of unprovoked pulmonary embolism have a high risk of recurrent venous thromboembolism (VTE) after anticoagulation is discontinued. Prolongation of anticoagulant therapy beyond the initial period of 3 to 6 months is associated with a significant reduction of recurrent VTE, but an excess of bleeding events. In addition, most studies assessing prolonged treatment did not follow the patients after treatment had been stopped. Thus, the optimal duration of anticoagulation in patients with a first unprovoked pulmonary embolism remains uncertain. Method: In a multicenter, randomized, double-blind, controlled trial, we compared an additional 18 months of warfarin (target International Normalized Ratio, 2 to 3) with placebo in patients with a first episode of unprovoked pulmonary embolism that had been initially treated with a vitamin K antagonist for 6 uninterrupted months. In both groups, all patients were followed up for an additional median period of 2 years after treatment had been stopped. Primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Secondary outcomes included the composite outcome during the entire study period (i.e. 18 months plus a median follow-up of 2 years), deaths not caused by pulmonary embolism or major bleeding and the components of the composite outcome during the treatment period and during the entire study period. All outcomes were centrally adjudicated. Results: A total of 371 patients were included in the study and analyzed on an intention-to-treat basis. During the treatment period, the composite outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 patients (13.5%) in the placebo group (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.09-0.55; p=0.0004). Recurrent VTE occurred in 3 (1.7%) patients in the warfarin group and in 25 (13.5%) in the placebo group (HR, 0.11; 95%CI, 0.03-0.37); major bleeding occurred in 4 (2.2%) patients in the warfarin group and in 1 (0.5%) in the placebo group (HR, 4.07; 95%CI, 0.45-36.38). Two deaths not related to the study outcome occurred in each group. During the entire median study period of 41 months, the composite outcome occurred in 33 (20.8%) patients in the warfarin group and in 41 (23.5%) in the placebo group (HR, 0.76; 95%CI, 0.48-1.20; p=0.24) (Figure 1). Recurrent VTE occurred in 28 (17.9%) patients in the warfarin group and in 39 (22.1%) in the placebo group (HR, 0.67; 95%CI, 0.41-1.08); major bleeding occurred in 6 (3.5%) patients in the warfarin group and in 4 (2.5%) in the placebo group (HR, 1.57; 95%CI, 0.44-5.55). Thirteen (11.9%) patients died in the warfarin group, four deaths being related to recurrent VTE and one to major bleeding; six (3.6%) patients died in the placebo group from a cause unrelated to recurrent VTE or bleeding (p=0.08). Of the 67 episodes of recurrent VTE, 52 (77.6%) were pulmonary embolism and 58 (86.6%) were unprovoked. Conclusion: After 6 months of anticoagulation for a first episode of unprovoked pulmonary embolism, extending anticoagulation for an additional 18 months was associated with a major reduction in the risk of recurrent VTE or major bleeding during the treatment period. However, this benefit was not maintained after discontinuation of anticoagulation. (ClinicalTrials.gov number NCT00740883). Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Disclosures Couturaud: Astra Zeneka: Co-investigator in clinical trial, Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees; Bayer: Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees. Sanchez:Bayer: Membership on an entity's Board of Directors or advisory committees. Mismetti:Bayer: Membership on an entity's Board of Directors or advisory committees; pfizer: Membership on an entity's Board of Directors or advisory committees; boerhinger ingelheim: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Jego:Bayer: Membership on an entity's Board of Directors or advisory committees; actelion: Research Funding; GlaxoSmithKline: Research Funding. Parent:Bayer: Membership on an entity's Board of Directors or advisory committees. Lorillon:Astra Zeneka: Membership on an entity's Board of Directors or advisory committees, symposium invitation Other; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Girard:Leo Pharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Lacut:Bayer-Healthcare: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Boehringer Ingelheim: Research Funding. Leroyer:Novartis: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Investigator in COPD clinical trials, Investigator in COPD clinical trials Other, Membership on an entity's Board of Directors or advisory committees; Astra Zeneka: Investigator in asthma clinical trials Other, Membership on an entity's Board of Directors or advisory committees. Decousus:Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Meyer:Sanofi-Aventis: Research Funding; LEO Pharma: Research Funding; Bayer: Research Funding; Boehringer Ingelheim: Research Funding. Mottier:Pfizer: Membership on an entity's Board of Directors or advisory committees; bayer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding.

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Response to Treatment Among SF3B1 Mutated Myelodysplastic Syndromes (MDS): A Case-Control Study from the MDS Clinical Research Consortium (MDS CRC)

Blood ◽

10.1182/blood.v126.23.1697.1697 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1697-1697 ◽

Cited By ~ 2

Author(s):

Rami S. Komrokji ◽

Amy E. DeZern ◽

Katrina Zell ◽

Najla H. Al Ali ◽

Eric Padron ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Somatic Mutations ◽

Response To Treatment ◽

Wild Type ◽

Advisory Committees ◽

Baseline Characteristics ◽

Matching Criteria

Abstract Introduction Somatic mutations in SF3B1 ,a gene encoding a core component of RNA splicing machinery, have been identified in patients (pts) with myelodysplastic syndrome (MDS). The SF3B1 mutation (MT) is more commonly detected in pts with ring sideroblasts (RS) morphology and is associated with favorable outcome. The pattern of response among SF3B1 mutated MDS pts to available treatment options, including erythropoiesis stimulating agents (ESA), hypomethylating agents (HMA) and lenalidomide is not known. The distinct underlying disease biology among such pts may alter response to treatment. Methods Pts treated at MDS CRC institutions with MT vs wild-type SF3B1 (WT) controls were matched 1:2. Matching criteria were age at diagnosis, year of diagnosis and International Prognostic Scoring System (IPSS) category at diagnosis. IPSS category was split into two groups (Low or Int-1 vs. Int-2 or High). Matching was performed using the R package by calculating a propensity score, which was then used to determine the two most similar WT SF3B1 patients for each SF3B1-mutated pt, without replacement. Additionally, to be included in the population, pts also had to have been treated with one of the following: ESAs, HMA, or lenalidomide. Response to treatment was evaluated by international Working Group criteria (IWG 2006) and classified as response if hematological improvement or better was achieved (HI+). Survival was calculated from date of treatment until date of death or last known follow-up, unless otherwise noted. Results: We identified 48 Pts with MT and 96 matched controls. Table 1 summarizes baseline characteristics comparing MT vs WT SF3B1 cohorts. SF3B1 MT was detected more often in association with RS, as expected. The majority of pts had lower-risk disease by IPSS and revised IPSS (IPSS-R). Pts with MT had higher platelets than controls. The most common concomitant somatic mutations observed were TET2 (30%), DNMT3A (21%), and ASXL1 (7%). Median follow-up time from diagnosis was 35 months (mo). Median overall survival (OS) from diagnosis was significantly longer for patients with SF3B1 MT (108.5 mo (68.8, NA)) than wild-type controls (28.3 mo (22.3, 36.4); p < 0.001). Patients with an SF3B1 MT had a decreased hazard of death (hazard ratio [HR]: 0.49 (95% confidence limits [95% CL]: 0.29, 0.84); p = 0.009) ESA was the first line therapy for 43 pts (88%) with MT and 55 WT Pts (56%). For ESA treated pts, 14 out 40 MT Pts responded (35%) compared to 9/56 among WT Pts (16%), p 0.032. Among those treated with HMA therapy, 5 out 21 (24%) MT pts responded compared to 11/46 (24%) WT Pts (p 0.99). Finally, for Pts treated with lenalidomide 4/16 (25%) and 4/21 (19%) responded among SF3B1 MT and WT Pts respectively, p 0.7. Conclusions SF3B1 somatic mutation in MDS is commonly associated with RS, lower risk disease, and better OS. Pts with SF3B1 mutation had higher response to ESA compared WT SF3B1. No difference in response to HMA or lenalidomide was observed compared to WT patients. Response rates to lenalidomide and HMA were low in both MT patients and controls. Biologically rational therapies are needed that target this molecular disease subset. Table 1. Baseline characteristics SF3B1 MT (n=48) SF3B1 WT (n=96) P value Age median 65 67 0.6 Gender male 29 (60%) 64(67%) 0.5 Race White 44/45 (98%) 83/90 (92%) 0.34 WHO classification RA RARS RCMD RARS-T Del5 q RAEB-I RAEB-II MDS-U MDS/MPN CMML 3 24 8 4 1 3 3 2 0 0 6 9 17 2 6 10 9 3 11 9 IPSS Low Int-1 Int-2 High 29 (60%) 16 (33%) 3 (6%) 0 21 (22%) 69 (72%) 4 (4%) 2 (2%) < 0.001 IPSS-R Very low Low Intermediate High Very High 15 (31%) 26 (54%) 5 (10%) 2 (4%) 0 11 (11%) 37 (39%) 26 (27%) 18 (19%) 4 (4%) <0.001 Lab values (mean) Hgb Platelets ANC myeloblasts 9.7 274 2.63 1 9.6 108 1.92 2 0.46 <0.001 0.04 0.05 Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Incyte: Consultancy; Pharmacylics: Speakers Bureau. Padron:Novartis: Speakers Bureau; Incyte: Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

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Clinical Impact and Course of Anticoagulant-Related Major Bleeding in Cancer Patients

Blood ◽

10.1182/blood.v128.22.2611.2611 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2611-2611 ◽

Cited By ~ 1

Author(s):

Noémie Kraaijpoel ◽

Nick van Es ◽

Suzanne M Bleker ◽

Marjolein P Brekelmans ◽

Elise S Eerenberg ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Cancer Patients ◽

Major Bleeding ◽

Clinical Presentation ◽

Clinical Course ◽

Vitamin K Antagonists ◽

Phase Iii ◽

Anticoagulant Treatment ◽

Advisory Committees

Abstract Background Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a frequent complication in cancer patients. During anticoagulant treatment for VTE, the risk of major bleeding events (MBE) is 2- to 6-fold higher in cancer patients than in those without cancer. It is unknown whether the clinical presentation and course of anticoagulant-related MBE in cancer patients differ from patients without cancer. Methods Individual patient data from 4 randomized controlled phase III trials in which factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) were compared with vitamin K antagonists for the treatment of VTE were used for the present analysis. The severity of the clinical presentation and clinical course of anticoagulant-related MBE were compared between patients with and without cancer. Using predefined criteria, the severity of the clinical presentation and course of MBE were classified into four categories by independent adjudicators, who were blinded to treatment allocation. Category 1 indicates a mild clinical presentation or course, while category 4 indicates a severe presentation or course (Table 1). A one-stage meta-analysis was used to estimate crude odds ratios (ORs) and ORs adjusted for age, sex, and type of anticoagulant treatment with 95% confidence intervals (CIs) for the effect of cancer on the severity of the clinical presentation and course. For this analysis categories 3 and 4 were combined. We also explored the cause and site of bleeding in these patients. Results The study group comprised 290 patients with MBE, of whom 50 (17%) had active cancer or were diagnosed with cancer during follow-up. The clinical presentation was judged to be severe (category 3 or 4) in 38% of patients with cancer and 44% of patients without cancer (adjusted OR 0.90, 95% CI 0.47-1.72). Clinical course was judged to be severe in 20% and 25% of patients with and without cancer, respectively (adjusted OR 0.75, 95% CI 0.35-1.61) (Table 2). The bleeding pattern varied significantly between the two groups (p=0.002); cancer patients more often had gastrointestinal (52% vs. 35%) and vaginal (14% vs. 6%) MBE, whereas intracranial (19% vs. 6% and retroperitoneal (5% vs. 0%) MBE occurred more often in patients without cancer (Table 3). MBE was related to the tumor site in 40% of cancer patients. Conclusion The findings of the present study indicate that the clinical presentation and course of anticoagulant-related MBE are not more severe in cancer patients than in patients without cancer, which is reassuring for physicians who treat cancer-associated VTE. Disclosures Eerenberg: Sanquin: Consultancy; CSL Behring: Consultancy; Baxter: Consultancy. Middeldorp:Aspen: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Bayer: Consultancy; Sanquin: Consultancy; GSK: Consultancy, Honoraria; BMS/Pfizer: Consultancy, Honoraria. Cohen:Takeda: Consultancy; Leo Pharma: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Department of Health: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Medscape: Speakers Bureau; UK Government Health Select Committee: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Speakers Bureau; Colation to Prevent Venous Thromboembolism: Other: Founder; NHS: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Aspen: Consultancy, Speakers Bureau; ONO: Consultancy, Honoraria; XO1: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Lifeblood: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria.

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Efficacy and Safety of Primary Thromboprophylaxis for the Prevention of Venous Thromboembolism in Patients with Cancer and Central Venous Catheter: A Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2021-146904 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2139-2139

Author(s):

Allen Li ◽

Willem Brandt ◽

Cameron Brown ◽

Tzu-Fei Wang ◽

Rick Ikesaka ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Venous Catheter ◽

Bleeding Complications ◽

Efficacy And Safety ◽

Central Venous ◽

Advisory Committees ◽

Patients With Cancer

Abstract Background Venous thromboembolism (VTE) is a leading cause of mortality in patients with cancer and is associated with significant morbidity and healthcare expenditure. The risk of VTE is also increased following the insertion of a central venous catheter (CVC) for chemotherapy deliverance and supportive care. The risks and benefits of primary thromboprophylaxis in patients with cancer and newly inserted CVC are unclear. Objective We sought to assess the rates of VTE and major bleeding complications to determine the safety and efficacy of primary thromboprophylaxis in adult patients with cancer and a CVC. Methods A systematic search of MEDLINE, EMBASE, and all EBM was conducted. Randomized controlled trials (RCTs) of adult patients with cancer and a CVC receiving primary thromboprophylaxis or observation/placebo were included. The primary efficacy and safety outcomes were total VTE and major bleeding episodes, respectively. Results A total of 9 RCTs (3155 patients) were included in the analysis. The total rates of VTE were significantly lower in patients receiving primary thromboprophylaxis compared to those not receiving primary prevention (7.6% vs. 13%; Odds Ratio (OR) 0.51, 95% CI 0.32 to 0.82, p < 0.01, I² = 52%) (Figure 1). The rate of major bleeding complication was not increased in patients receiving thromboprophylaxis (0.9% vs. 0.7%; OR 1.12, 95% CI 0.29 to 4.40, p = 0.87, I² = 32%) (Figure 2). Conclusions Primary thromboprophylaxis significantly reduced the risk of VTE without increasing the risk of major bleeding complications in patients with cancer and CVC. Future studies are needed to confirm these findings. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Ikesaka: LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wells: Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; BMS/Pfizer: Research Funding; Servier: Honoraria. Carrier: Servier: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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