Major Bleeding Complications Among Patients Treated with Ibrutinib and Concomitant Antiplatelet, Anticoagulant, or Supplemental Therapy

Abstract Background: Ibrutinib, an orally bioavailable small molecular inhibitor of Bruton's tyrosine kinase (BTK), is an approved therapy for chronic lymphocytic leukemia (CLL), relapsed mantle cell lymphoma (MCL) and Waldenstrӧm's macroglobulinemia (WM). Beyond B lymphocytes, BTK signaling is important for collagen-mediated platelet activation, and BTK inhibition has been associated with primary hemostatic bleeding events (Levade et al Blood 2014). Although serious bleeding events have been uncommon (1-5%) in clinical trial populations, there is limited data describing the potential for increased serious bleeding incidence when ibrutinib is co-administered with other agents affecting the clotting cascade or platelet function. Methods: We conducted a retrospective cohort study to evaluate the incidence of major bleeding in patients receiving ibrutinib concomitantly with antiplatelet agents (non-steroidal anti-inflammatory agents, ADP inhibitors), anticoagulants (heparins, warfarin, novel oral anticoagulants), or supplements with potential anticoagulant activity (vitamin E and fish oil). Major bleeding events were identified using criteria developed by the International Society on Thrombosis and Haemostasis (Schulman et al J Thromb Haemost 2005). Patients 18-89 years of age and treated with ibrutinib for CLL, MCL, or WM between March 1, 2010 and March 1, 2015 were included. The primary endpoint of this study was the incidence of major bleeding events, but we also sought to identify risk factors associated with the development of major bleeding, focusing on potential drug interactions. Based on the historic prevalence of major bleeding in ibrutinib clinical studies, we calculated that at least 20 major bleeding events would need to be identified in order to perform blinded multinomial regression on the collected data of an estimated 400 patients. Results: 437 eligible patients were included in the analysis. Patients were overwhelmingly male (71.4%) and white (94.8%), with a mean age of 67.1 years (range: 29-89). 53.1% received ibrutinib as participants of a clinical trial, and the remainder received standard-of-care ibrutinib treatment. The table (upper panel) summarizes use of concomitant antihemostatic agents by presence or absence of major bleeding events. Characteristics of the major bleeding events are further detailed in the lower panel. The most commonly observed concomitant antihemostatic medication was aspirin, with 147 patients (33.6%) being exposed to aspirin within the study period. Fourteen instances of major bleeding were observed, corresponding to an overall incidence of 3.2%. These major bleeding events all occurred in CLL patients receiving ibrutinib at the standard dose of 420 mg daily. Two patients had platelet counts less than 50 k/µL at time of the bleeding event. One-half of the major bleeding events were observed in the absence of an antihemostatic medication, and 2 of the observed major bleeding events resulted in death (1 received concomitant warfarin). Fourteen patients (3.3%) in the group without major bleeding were on anticoagulation, 4 being warfarin. The most common sites of major bleeding were gastrointestinal (50%), intracranial (14.3%) and thoracic (14.3%). While most patients developing major bleeding permanently discontinued ibrutinib (57.1%), approximately one third of the patients who developed major bleeding subsequently resumed ibrutinib following resolution of the bleeding event. Subsequently, these patients did not experience a recurrent major bleeding event. The rate of major bleeding did not meet power to detect statistical differences in bleeding events when comparing concomitant therapy, Conclusions: Our observed incidence of major bleeding is consistent with previous controlled clinical trials, suggesting similar safety profile when ibrutinib is used outside of a controlled setting. Major bleeding events were uncommon despite the frequent co-administration of antiplatelet agents. However, because we modified practice early to avoid therapeutic anticoagulation during ibrutinib therapy whenever possible, the number of patients receiving such drugs in combination was small and precludes inferences regarding safety. Table Table. Disclosures Blum: Pharmacyclics: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Woyach:Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding. Christian:Pharmacyclics: Research Funding; Janssen: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Management and Outcomes of Atrial Fibrillation in Patients Receiving Ibrutinib for Hematologic Malignancies at a Single Center

Blood ◽

10.1182/blood.v128.22.2040.2040 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2040-2040 ◽

Cited By ~ 2

Author(s):

Tracy E Wiczer ◽

Lauren B Levine ◽

Jessica Brumbaugh ◽

Jessica Coggins ◽

Qiuhong Zhao ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Antiplatelet Therapy ◽

Major Bleeding ◽

Stroke Prevention ◽

Research Funding ◽

Bleeding Events ◽

Advisory Committees ◽

Major Bleeding Events ◽

Grade 3

Abstract Background Ibrutinib (IB) is Food and Drug Administration approved for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström's macroglobulinemia (WM). High overall response rates, extended progression free survival, and an acceptable adverse event profile make IB an impactful therapy for these malignancies. Atrial fibrillation (AF) has been identified as a less common but serious adverse effect of IB with reported incidence ranging from 2-16% in clinical trials and post-marketing experience. AF can be associated with significant morbidity and mortality, including congestive heart failure and embolic events such as stroke. Data regarding the management of AF in this patient population is thus far limited. Embolic stroke prevention poses a particular clinical challenge as IB carries an inherent bleeding risk that may be increased by antiplatelet therapy and therapeutic anticoagulation. We report the management and outcomes of a large cohort of patients who developed AF while on IB therapy. Methods Patients with hematological malignancies and incident or recurrent AF while on IB therapy at the Ohio State University were identified retrospectively. Incident AF was defined as new onset AF in patients without a history AF and recurrent AF as an AF event requiring new intervention in patients with a prior history of AF. Data pertaining to patient demographics, comorbid conditions, AF events, AF management, stroke prevention strategies, and complications of AF therapy were collected. AF events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 andcongestive heart failure, hypertension, age, diabetes mellitus, stroke (CHADs2) scores were calculated. Major bleeding was defined as a decrease in hemoglobin of 2g/dL or more, requiring a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site, or contributing to death. Clinically relevant non-major bleeding events were graded according to CTCAE criteria. Management strategies and outcomes are summarized. Results Seventy-two patients with incident or recurrent AF were identified. Fifty-nine patients developed incident AF while 13 patients developed recurrent AF while on IB. Baseline characteristics are presented in Table 1.Patients with recurrent AF were older, had worse baseline ECOG performance status, and longer baseline PR interval on electrocardiogram assessment.Patients were followed for a median of 4.3 years from the start of ibrutinib and 1.7 years from AF event.Ninety-three percent of the AF events were grade 1-2 and 7% were grade 3. First-line therapy forAF included rate-control for 54 (75%) patients, interventional procedural strategies for 8 (11.1%), and rhythm-control for 3 (4.2%). Seven (9.7%) patients required no intervention. Twenty-two patients (30.5%) required a second and 4 (5.5%) required third-line AF management intervention. Among those with a secondary AF management strategy, rhythm control was the most frequently utilized (n=10, 45.5%). During the AF events, 31 (43.1%) patients continued IB, 35 (48.6%) temporarily held IB, 5 (6.9%) discontinued IB, and one patient had the dose reduced. Stroke prevention strategies are described in Table 2. Patients with recurrent AF were less likely to be treated with anticoagulation when compared to patients with incident AF. Six (8.3%) patients had a major bleeding event and 2 of these patients went on to have a second major bleed. Of the 8 major bleeding events, 3 occurred with concomitant antiplatelet therapy and no patients were on anticoagulation therapy at the time of bleeding. Eighteen (25%) patients developed a total of 25 clinically relevant non-major bleeding events (9 grade 1 events, 13 grade 2 events, 2 grade 3 events, and 1 could not be graded). Only one potential embolic event occurred in a patient with a CHADs2 score of 1 on aspirin 325mg who developed symptoms consistent with stroke. Conclusions AF events in patients being treated with IB are generally manageable and in the majority of cases did not result in IB discontinuation. Clinically relevant bleeding events are common, and caution must be exercised when initiating routine antiplatelet therapy and/or anticoagulation in patients with IB. Risk of ischemic stroke was low in our patient population, though follow up was limited. The optimum strategy for stroke prophylaxis in patients with concurrent IB is unclear. Disclosures Christian: Pharmacyclics: Research Funding; Janssen: Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy.

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Pattern of Use of Anticoagulation and/or Antiplatelet Agents in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ibrutinib Therapy

Blood ◽

10.1182/blood.v124.21.1990.1990 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1990-1990 ◽

Cited By ~ 7

Author(s):

Jeffrey A. Jones ◽

Peter Hillmen ◽

Steven Coutre ◽

Constantine Tam ◽

Richard R. Furman ◽

...

Keyword(s):

Board Of Directors ◽

Vitamin K ◽

Major Bleeding ◽

Research Funding ◽

Single Agent ◽

Antiplatelet Agent ◽

Antiplatelet Agents ◽

Bleeding Complications ◽

Advisory Committees ◽

Grade 3

Abstract Background: Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase (BTK) that has shown single-agent efficacy and an acceptable safety profile in patients (pts) with CLL. While BTK is expressed in platelets, bleeding diathesis has not been reported in pts with hereditary BTK deficiency (e.g., X-linked agammaglobulinemia). Pts with CLL often have comorbidities requiring anticoagulants and/or antiplatelet agents, which can increase bleeding risk. We sought to characterize the pattern of use of these agents and describe bleeding adverse events (AEs) observed in 2 trials of single-agent ibrutinib in pts with CLL. Methods: Event-based analysis of data from the ibrutinib phase 2 PCYC-1102 trial and interim analysis of the phase 3 RESONATETM(PCYC-1112 trial) of ibrutinib vs. ofatumumab were analyzed to determine the use of concomitant anticoagulants and/or antiplatelet therapy. Precautionary language on the use of anticoagulant or antiplatelet agents, particularly regarding restrictions on the use of vitamin K antagonists (e.g., warfarin), and recommendations for perioperative holding of ibrutinib, were added late during the 1102 trial. Major bleeding was defined as any grade ≥ 3 bleeding event, or hemorrhage of any grade resulting in one of the following: intraocular bleeding causing loss of vision, need for ≥ 2 units of RBC transfusion, hospitalization, prolonged hospitalization, or any intracranial hemorrhage. Results: In the 2 trials, 327 pts with CLL/SLL were treated; 132 in 1102 trial and 195 in the ibrutinib arm of 1112. Median age was 68 and 67 years, respectively, and median number of prior therapies was 3 in both trials. Overall, 65 pts (20%) received concomitant anticoagulation across the 2 trials, 70 (21%) received ASA, and 7 (2%) received clopidogrel (Table). The most common bleeding AEs were grade 1 petechiae and contusion. In the 1102 trial, grade 1 bleeding AEs occurred in 52%, grade 2 in 5%, and grade 3 in 3%. In the ibrutinib arm of 1112, grade 1 bleeding AEs occurred in 41%, grade 2 in 4%, and grade 3 in 1%. Overall, major bleeding occurred in 8 of 327 pts (2.4%): 5% in 1102 (6 of 132) and 1% in the ibrutinib arm of 1112 (2 of 195). For comparison, in the ofatumumab arm of 1112, major bleeding occurred in 1.6% of pts (3 of 191). Among the 8 ibrutinib-treated pts with major bleeding, 5 were reported to have concomitant use of either an anticoagulant alone (LMWH, n=1), an antiplatelet agent alone (ASA, n=1; NSAID, n=1), or both an anticoagulant and an antiplatelet agent (ASA and warfarin, n=1; NSAID, heparin and LMWH, n=1). The case of major bleeding on warfarin occurred on the 1102 trial before a protocol amendment restricted its use. Bleeding AEs led to discontinuation of ibrutinib in 4 pts (1.2%) from the 2 studies (3 on 1102 and 1 on 1112), all due to major bleeding. Conclusions: In summary, the concomitant use of anticoagulant or antiplatelet agent was common in 2 clinical trials of single-agent ibrutinib in 327 pts with CLL/SLL. Bleeding AEs in these trials were primarily grade 1 and associated with low rates of treatment discontinuation. Major bleeding events were uncommon and most cases occurred in pts taking one or more concomitant anticoagulant and/or antiplatelet agents. Importantly, there was no difference in the incidence of major bleeding between the 2 arms of the randomized 1112 trial while many of these pts were receiving concomitant anticoagulants or antiplatelet agents. Adherence to appropriate drug-withholding guidelines perioperatively and precautions surrounding the use of antiplatelet agents and anticoagulants, as applied in the 1112 trial, resulted in few major bleeding complications. Table. Concomitant anticoagulants or antiplatelet agents used in single-agent trials n (%) 1102 (n=132) 1112 ibrutinib arm(n=195) Total (N=327) Any anticoagulant 23 (17) 42 (22) 65 (20) Vitamin K antagonist* Heparin LMWH Dabigatran Rivaroxaban Apixaban Alteplase 6 (5) 3 (2) 14 (11) 0 0 0 1 (1) 4 (2) 5 (3) 34 (17) 3 (2) 1 (1) 1 (1) 0 10 (3) 8 (2) 48 (15) 3 (1) 1 (<1) 1 (<1) 1 (<1) Any antiplatelet 67 (51) 73 (37) 140 (43) ASA Clopidogrel NSAIDs Dipyridamole/ASA 33 (25) 0 46 (35) 1 (1) 37 (19) 7 (4) 45 (23) 1 (1) 70 (21) 7 (2) 91 (28) 2 (1) *Included warfarin (n=8), acenocoumarol (n=1) and fluindione (n=1). Disclosures Jones: Pharmacyclics: Consultancy, Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Barr:Pharmacyclics: Research Funding. Kipps:Pharmacyclics: Research Funding. Flinn:Pharmacyclics: Research Funding. Jaeger:Janssen Cilag: Honoraria. Burger:Pharmacyclics: Consultancy, Honoraria, Research Funding. Cheng:Pharmacyclics: Employment. Lee:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Byrd:Pharmacyclics: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

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Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenia (ITP) Treated with Romiplostim in Two Phase 3 Placebo-Controlled Clinical Trials.

Blood ◽

10.1182/blood.v114.22.891.891 ◽

2009 ◽

Vol 114 (22) ◽

pp. 891-891 ◽

Cited By ~ 1

Author(s):

Ilene Ceil Weitz ◽

Miguel A Sanz ◽

David H. Henry ◽

Martin Schipperus ◽

Bertrand Godeau ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Rescue Medication ◽

Bleeding Event ◽

Bleeding Events ◽

Phase 3 ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp

Abstract Abstract 891 Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts and increased risk of bleeding. Rescue medications used to treat or prevent bleeding produce transient increases in platelet counts but may be associated with additional toxicities and costs. Romiplostim, approved for the treatment of adult chronic ITP, is a TPO mimetic peptibody protein that increases platelet production. Previously published data from phase 3 romiplostim trials showed that despite the increased use of rescue medication in the placebo arm, patient (pt) incidence of bleeding was reduced in the romiplostim arm vs placebo arm: 15% vs 34% (p = 0.02) for bleeding of grade ≥2 severity and 7% vs 12% (p=0.36) for grade ≥3 severity. Objective: To evaluate the effects of romiplostim treatment on bleeding outcomes in the phase 3 placebo controlled studies in chronic ITP pts with and without previous splenectomy. Bleeding events were captured as adverse events making it difficult to identify a single event reported multiple times versus persistent or recurrent bleeding. Further, we have developed a composite endpoint, termed bleeding-related episodes (BREs), which combines bleeding events and rescue medication administration to account for use of rescue medications to prevent bleeding. Methods: Adults with chronic ITP and a mean baseline platelet count <30 × 109/L were eligible. The previously published studies were conducted separately in splenectomized and nonsplenectomized populations. Pts were randomized (2:1) to receive romiplostim or placebo by subcutaneous injection once weekly for 24 weeks, with dose adjustments to maintain platelet counts between 50-200 × 109/L. Rescue medications were permitted to treat or prevent bleeding and included immunoglobulins, platelet transfusions, corticosteroids, or an increase in dose or frequency of a concurrent ITP medication. A BRE was defined as an actual bleeding event and/or the use of rescue medication. To collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single BRE. Bleeding events beginning 7 or more days after the start of the initial bleeding event were considered a new BRE. To account for differences in time spent on-study, rates of BRE per 100 pt-weeks were calculated. Results: A total of 125 pts (41 placebo, 84 romiplostim) were enrolled in the two studies. Baseline characteristics were well-balanced between the placebo and romiplostim-treated groups. During the treatment period, the rate of BREs was lower in the romiplostim group than in the placebo group, and results were consistent between splenectomized and nonsplenectomized pts (Table). Across both studies, the rate of BREs was reduced by 55% in pts receiving romiplostim compared to those receiving placebo (95% CI, 41% to 65%). BREs were more frequent at platelet counts <50 × 109/L (Table). BREs associated with hospitalizations were less common among romiplostim- than placebo-treated pts, and occurred at platelet counts <50 × 109/L in 10 of 11 cases. Corticosteroids (58 romiplostim, 38 placebo) and immunoglobulins (30 romiplostim, 73 placebo), were the most commonly used rescue medications and the rate of BREs including immunoglobulins was reduced by 88% in pts receiving romiplostim compared to placebo. Conclusions: In adults with chronic ITP, romiplostim was associated with a significant reduction in BREs compared to placebo. There was a marked reduction in BREs requiring immunoglobulins in the romiplostim arm compared to the placebo arm. Results were comparable in splenectomized and nonsplenectomized populations. The platelet count for a BRE starting ≥1 day after a platelet count measurement was calculated from the 2 proximal weekly measurements. Disclosures: Weitz: Amgen Inc.: Speakers Bureau. Sanz:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Henry:Amgen Inc.: Research Funding, Speakers Bureau; Orthobiotech: Research Funding, Speakers Bureau; Watson Pharma: Research Funding, Speakers Bureau. Schipperus:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Godeau:Amgen Inc.: Consultancy, Research Funding; Laboratoire Français de Fractionnement et de Biotechnologies (LFB): Consultancy; Roche: Research Funding. Gleeson:Amgen Inc.: Consultancy, Research Funding. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

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Major Bleeding with Ibrutinib: More Than Expected

Blood ◽

10.1182/blood.v128.22.3229.3229 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3229-3229 ◽

Cited By ~ 11

Author(s):

Paul R Kunk ◽

Joesph Mock ◽

Michael E. Devitt ◽

Surabhi Palkimas ◽

Jeremy Sen ◽

...

Keyword(s):

Adverse Events ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Event ◽

Lymphocytic Leukemia ◽

Significant Activity ◽

University Of Virginia ◽

Bleeding Events ◽

Major Bleeding Events

Abstract Introduction: Ibrutinib is a Bruton's tyrosine kinase inhibitor that has significant activity in treating lymphoma. While approved for patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), its activity in other lymphomas and solid tumors is under investigation and its use is increasing dramatically. Overall it is well tolerated compared to chemotherapy, but bleeding has emerged as a common adverse event with rates as high as 50% and major bleeding around 3% (Jones, abstract #1990, 2014 ASH Annual Meeting). As the use of ibrutinib increases outside of a clinical trial setting, the rate of major bleeding is likely to rise. Methods: To better understand the risk of bleeding in ibrutinib treated patients, we reviewed all patients at the University of Virginia and satellite clinics who were treated with ibrutinib between January 2012 and May 2016. Patients were required to be treated for at least 1 month with documented follow up for assessment of adverse events. Medical charts were reviewed for age, gender, ibrutinib indication and dose, length of treatment, concurrent medications, blood tests and bleeding events. All forms of anti-platelets and anticoagulants drugs, as well as medications interacting with cytochrome P450 3A4 (3A4), which metabolizes ibrutinib, were recorded. All bleeding events were recorded and graded according the Common Toxicity Criteria for Adverse Events, v4.0. Major bleeding events were reviewed by all investigators. Results: Eighty-nine patients were identified. Eighteen patients were excluded for insufficient follow up leaving 71 patients for analysis. Median age was 73 years old (44-92) with 74% male. The most common indications for treatment were CLL (65%) and MCL (27%). Most patients were treated with either 420mg (64%) or 560mg (21%). Median length of time on ibrutinib was 412 days, most with ongoing use at time of data collection. Seventy percent of patients were also treated with an anti-platelet medication, mostly aspirin for CAD with several patients on multiple anti-platelet medications. Seventeen percent were treated with an anti-coagulant, mostly apixaban for atrial fibrillation. Thirteen percent of patients (9/71) were treated with combined anti-platelet and anti-coagulant medications. Ten percent of patients were treated with a medication that has a moderate or strong interaction with 3A4. Bleeding of any grade occurred in 56% of patients, mostly bruising and epistaxis. Major bleeding, defined as grade 3 or higher, occurred in 18% of patients. Three patients developed major bleeding after an invasive procedure without ibrutinib being held. One patient died as a result of peri-procedural bleeding. Of the 9 patients treated with combined anti-platelet and anti-coagulant therapy, 78% suffered a major bleeding event. Of the ten patients on ibrutinib alone, without concurrent use of an anti-platelet, anti-coagulant or 3A4 drug interaction, no major bleeding events occurred. Conclusion: In this study examining real world use of ibrutinib, the rates of major bleeding are higher than previously reported. Most patients who suffered major bleeding were also treated with an anti-coagulant and/or anti-platelet medication. As the use of ibrutinib increases outside of clinical trials, a careful review of medications should be performed in addition to adherence to perioperative drug withholding guidelines. Patients requiring anti-coagulant and/or anti-platelet medications while on ibrutinib need careful consideration of the risks and benefits given the higher incidence of bleeding in this population. Table 1 Table 1. Disclosures Portell: AbbVie: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; Acerta: Research Funding. Williams:Janssen and Pharmacyclics: Research Funding; University of Virginia: Employment.

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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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Ristocetin-Induced Platelet Aggregation for Monitoring of Bleeding Tendency in Ibrutinib-Treated Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v126.23.718.718 ◽

2015 ◽

Vol 126 (23) ◽

pp. 718-718 ◽

Cited By ~ 3

Author(s):

Lukas Kazianka ◽

Christa Drucker ◽

Cathrin Skrabs ◽

Philipp Bernhard Staber ◽

Edit Anna Porpaczy ◽

...

Keyword(s):

Platelet Aggregation ◽

Board Of Directors ◽

Platelet Function ◽

Research Funding ◽

Bleeding Event ◽

Normal Subjects ◽

Lymphocytic Leukemia ◽

Bleeding Tendency ◽

Bleeding Events ◽

Advisory Committees

Abstract Background. Inhibition of Bruton´s tyrosine kinase (BTK) with the small molecule ibrutinib has significantly improved the survival of patients with chronic lymphocytic leukemia (CLL). BTK is also expressed in platelets. Collagen- and von Willebrand Factor (vWF)-dependent (ristocetin-induced) impairment of platelet function has recently been described (Levade M et al., Blood 2014, 124:3991-5;Kamel S et al., Leukemia 2015, 29:783-787) . Bleeding events were observed in 61% of patients in a recently published 3 year follow-up (Byrd JC et al., Blood 2015, 125:2497-2506). Bleeding under ibrutinib is generally mild (CTC grade 1-2 corresponding to spontaneous bruising or petechiae), but grade 3 or 4 bleeding can be observed, particularly after trauma. We hypothesized that quantitative assessment of platelet aggregation in ibrutinib CLL patients could help (1) to predict bleeding tendency, and (2) to guide patients through invasive procedures. Patientsand Methods. Twenty-four adult patients with previously treated CLL (16 male/8 female, median age 67 years, range 55-84) received ibrutinib orally at a planned dose of 420mg/day and were regularly monitored and thoroughly investigated for bleeding tendency. The median time on ibrutinib was 7.5 months, (range 1-27). Bleeding events (any CTC grade) occurred in 13 (54%) and dose-reductions to 280 (N=12) or 140mg (N=3) (for bleeding, infections, or neutropenia) were made in 15 (63%) of patients during a median observation period of 5 months (range 1-12). Bleeding was observed in 4 of 6 patients with concomitant anticoagulation. Of note, only 1 of the 24 patients had a CTC grade 3 bleeding event, and no grade 4 or 5 events were observed. Ristocetin-induced platelet aggregation (RIPA, herein referred to as RCoF) was quantitatively measured in fresh hirudin-blood by whole blood aggregometry with a Multiplate® Analyzer (Roche Diagnostics). Platelet aggregation was expressed in AUC units (U) (normal range 98-180U). Controls included normal subjects (N=53). Consecutive samples before and during treatment were available in all patients. Statistical methods comprised t-Test and ANOVA using SAS. Results. Ristocetin-induced platelet aggregation was already diminished before ibrutinib treatment (median 51 RCoF U) when compared to normal controls (Table 1). This is likely due to lower platelet counts in CLL patients influencing overall platelet aggregability (Hanke AA et al., Eur J Med Res 2010, 15:214-219). During ibrutinib treatment, platelet aggregation was substantially impaired (median of 22U). A direct comparison of available paired samples in 5 patients showed a significant decrease after ibrutinib initiation (51 to 14.5U; p=0.0028). Of note, significantly lower values were measured at visits when bleeding events were documented (N=34) compared to patient visits without bleeding tendency (N=70) (median 13 vs. 42U; p<0.001). The median RCoF value was lower in patients with CTC grade > 2 (N=10) vs. <2 bleeding (11 vs. 14U). Similar results were obtained for collagen-dependent platelet function (bleeding vs. no bleeding: 17 vs. 19.5U; p=0.002). RCoF values were correlated with platelet count (r2 =0.34; p<0.0001) at median values of 103 vs. 138 G/L in patients with or without bleeding, respectively. There was also a significant difference between the lowest RCoF values in individual patients with or without bleeding (7.5 vs. 16.5U; p=0.027) (Figure 1). No bleeding event was observed in patients whose lowest RCoF value was greater than 25U. Long-term kinetics of vWF-dependent platelet function was assessed in 7 patients and corresponded with ibrutinib dose. When ibrutinib was stopped, recovery of RCoF to greater than 70U was observed in as little as 48hours, suggesting a short time to normalization of platelet function. Conclusion. These data indicate that quantitative assessment of vWF-dependent platelet function in ibrutinib treated patients may serve to monitor therapy particularly in the setting of bleeding tendency, anticoagulation, or planned invasive procedures. Further evaluation of platelet function as a pharmacodynamic marker seems warranted. Figure 1. VWF-dependent platelet function (RCoF) in normal subjects or CLL patients before and during ibrutinib treatment with or without bleeding. Figure 1. VWF-dependent platelet function (RCoF) in normal subjects or CLL patients before and during ibrutinib treatment with or without bleeding. Figure 2. Lowest RCoF values in individual patients with or without bleeding. Figure 2. Lowest RCoF values in individual patients with or without bleeding. Disclosures Staber: Genactis: Research Funding; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Takeda-Millenium: Research Funding; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Pabinger:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Jilma:True North Therapeutics, Inc.: Consultancy, Research Funding. Jaeger:Hoffmann La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; True North Therapeutics, Inc.: Research Funding.

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Update from an Open-Label Extension Study Evaluating the Long-Term Safety and Efficacy of Romiplostim In Thrombocytopenic Patients (Pts) with Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v116.21.1885.1885 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1885-1885 ◽

Cited By ~ 2

Author(s):

Pierre Fenaux ◽

Hagop Kantarjian ◽

Roger M Lyons ◽

Richard A Larson ◽

Mikkael A Sekeres ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Bleeding Event ◽

Extension Study ◽

Platelet Response ◽

Bleeding Events ◽

Open Label ◽

Advisory Committees ◽

Previously Treated

Abstract Abstract 1885 Background: Thrombocytopenia is a significant clinical problem in MDS, found in approximately 35% to 65% of pts, and is an independent risk factor for survival. Romiplostim increases platelet production by binding to and activating the thrombopoietin receptor. MDS pts who completed a romiplostim clinical study could continue romiplostim treatment in an open-label extension study. Interim results from this ongoing study are reported to provide updated safety and efficacy information on the effects of continued, long-term romiplostim treatment in pts with MDS. Methods: MDS pts who had completed a prior romiplostim study and had platelets ≤50 × 109/L with no evidence of disease progression were eligible. Pts enrolled into the extension study from 3 prior studies with the following study designs: (1) romiplostim only for up to 52 weeks [Kantarjian JCO 2009], (2) romiplostim or placebo plus decitabine for ≥4 cycles [Greenberg ASH 2009], and (3) romiplostim or placebo plus lenalidomide for ≥4 cycles [Lyons ASH 2009]. The primary endpoint was adverse event (AE) incidence; secondary endpoints were incidence of bleeding events, platelet transfusions, and platelet response durations. On the basis of previous dosing, pts received romiplostim at 250, 500, 750, 1000, or 1500 mcg weekly, with subsequent adjustments based on platelet count. If no response was observed after 4 weeks at 1000 mcg/week, treatment was discontinued. Results: As of July 2, 2010, 40 pts had enrolled: 28 from 72 previously treated with romiplostim only, 7 from 29 previously treated with decitabine plus romiplostim or placebo, and 5 from 39 previously treated with lenalidomide plus romiplostim. In the extension study, 3 pts continued receiving decitabine and 3 pts continued receiving lenalidomide. Twenty-eight pts (70%) were male, the median age was 72 (Q1-Q3: 64–77) years, median baseline platelets were 31 × 109/L (Q1-Q3: 19–45 × 109/L), 11 pts (28%) had platelets < 20 × 109/L. At the end of their prior study, IPSS status was low (19 pts), int-1 (15), int-2 (1), or missing (5), and MDS subtypes at diagnosis were RA (11 pts), RCMD (10), MDS-U (6), RAEB-1 (8), MDS del 5q (2), RAEB-2 (1), RCMD-RS (1), and RARS (1). Twenty-one pts (53%) had bleeding events during the year before entering this study. Median duration of treatment in the extension study was 50 weeks (range: 6–134 weeks), with a median average weekly dose of 729 mcg (Q1-Q3: 593–893 mcg). The incidence of all AEs during 12-week study periods ranged from 60% to 92% and did not increase with time on study. Most AEs were mild-to-moderate; the most common being epistaxis (40%), fatigue (33%), and cough (30%). No neutralizing antibodies to romiplostim or endogenous TPO were detected. No pts died during the study; one pt died 3 months after withdrawing from the study (causality was uncertain). Peripheral blasts were increased in 2 pts (MDS-U and RA at baseline) and resolved in both cases after discontinuation of romiplostim. Three cases of progression to AML were reported, corresponding to an annual on-study event rate of 5.9% (95% CI: 1.9% to 18.3%). These pts were IPSS-risk low or int-1 at baseline and had a WHO classification of RAEB-1 or RCMD. During this study, they received 750 mcg romiplostim for 6, 49, and 36 weeks. Bone marrow blasts were 39%, 65%, and 40% at AML diagnosis. Thirty pts (75%) reported ≥1 bleeding event(s), with 17 pts (43%) reporting ≥1 clinically significant bleeding event(s) [CTCAE grade ≥3, serious AE, or any bleeding AE requiring intervention]. The proportion of pts experiencing a significant bleeding event decreased from 23% (9/40) during weeks 1–12 to 0% (0/21) during weeks 48–60. Similarly, the proportion of pts receiving a platelet transfusion decreased from 28% (11/40) during weeks 1–12 to 0% (0/21) during weeks 48–60. From week 3 onwards, the median platelet count was ≥ 50 × 109/L (Figure). Thirty-four pts (85%) had a platelet response (per IWG 2006). The median duration of platelet response was 41 weeks (Q1-Q3: 15–87 weeks). Conclusion: In this study, long-term treatment of MDS pts with romiplostim demonstrated a toxicity profile consistent with published data and disease progression was consistent with expected rates. Most pts achieved a sustained platelet response while receiving romiplostim. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Romiplostim is approved for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). Kantarjian:Amgen Inc.: Research Funding. Lyons:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Larson:Amgen Inc.: Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy. Becker:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jia:Amgen Inc.: Employment, Equity Ownership. Yang:Amgen Inc: Employment, Equity Ownership.

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Unfractionated Heparin Use in Children: Clinical Outcomes in a Pediatric Cohort Managed Using an Anti-Factor Xa Based Nomogram

Blood ◽

10.1182/blood.v130.suppl_1.701.701 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 701-701

Author(s):

Surbhi Saini ◽

Katherine L Harsh ◽

Joseph R Stanek ◽

Sarah O'Brien ◽

Amy L. Dunn ◽

...

Keyword(s):

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Risk ◽

Advisory Board ◽

Minor Bleeding ◽

Direct Oral Anticoagulant ◽

Bleeding Events ◽

Advisory Committees ◽

Educational Grant

Abstract Background: Given its short half-life and immediate, complete reversibility with protamine sulfate, unfractionated heparin (UFH) remains the anticoagulant of choice for critically-ill children. The American College of Chest Physicians recommends that a therapeutic activated partial thromboplastin time (APTT) range in children on treatment doses of UFH should reflect an anti-FXa level of 0.35-0.7 IU/mL. A previous study from our institution showed moderate correlation between APTT and anti-FXa, prompting an institution-wide change to an anti-FXa based nomogram. Per the new nomogram, APTT and anti-FXa levels were simultaneously collected at pre-specified time points, though dose titrations were made on anti-FXa levels alone. In this study, we present our 20-month experience using this nomogram. Objectives: To assess the utility of anti-FXa based UFH dosing guidelines in children over a 20-month period (September 2015-May 2017). Methods: Permission for this study was obtained from the Institutional Review Board. Data was abstracted for all pediatric patients (age<21 yrs.) receiving therapeutic dosing of UFH (≥18 u/kg/hr) at Nationwide Children's Hospital (NCH) over the study period. Patients receiving UFH for <24 hrs, patients with mechanical circuits (ECMO and ventricular assist devices), and patients receiving concomitant anti-platelet therapy were excluded. Data were analyzed using descriptive statistics and comparisons were made using non-parametric methods. Correlations were assessed using the Bland-Altman method for repeated measures. Results: Over a 20-month period, 176 patients received UFH therapy at NCH. Of these, 95 patients met our pre-specified inclusion criteria. These 95 patients had 1102 simultaneous APTT and anti-FXa measurements performed. Baseline demographic information is described in Table 1. Mean duration of UFH therapy was 5.2 days (range: 1-45 days). Median UFH dose required to reach therapeutic anti-FXa goal was 22 units/kg/hr (range: 18-55 units/kg/hr), and was significantly higher in infants (<1yr of age) compared to older children (33.9 u/kg and 20 u/kg respectively; p<0.0001). Median time to achieve therapeutic anti-Xa was 10 hours (range: 2-96 hours), and was significantly shorter in patients who received a bolus (n=44) compared to those who did not (5 hrs and 12 hrs respectively; p=0.03). Five patients never achieved therapeutic anti-FXa levels. In patients with thrombo-embolism (n=75), 65 had end-of-therapy imaging (complete response: 36; partial or no response: 29). Time to achieve therapeutic anti-FXa was not predictive of radiological response (p=0.27). Moderate linear correlation between the APTT and anti-FXa (r = 0.74; 95% CI = 0.71-0.77) (Figure 1) was noted for the entire cohort. Eleven (10.6%) major and non-major bleeding events and 10 (10.5%) minor bleeding events were noted. When comparing coagulation parameters of patients with major and non-major bleeding to those with no-bleeding and minor bleeding age, indication for anticoagulation, peak anti-FXa, peak APTT, lowest platelet count and fibrinogen were not predictive of bleeding. Critically high APTT (>250 sec) was noted on 43 occasions in 21 unique patients and not associated with an increased risk of major and non-major bleeds (p=0.07). Conclusions: UFH monitoring is challenging in children. Time to achieve therapeutic anticoagulation and bleeding risk in our cohort is consistent with previous publications. Contrary to previous publications, extreme elevation of APTT was not associated with increased bleeding risk. Disclosures O'Brien: Pfizer: Consultancy, Other: study of direct oral anticoagulant in treatment of pediatric VTE; Glaxo Smith Kline: Other: DSMB for Arixtra Study in Pediatric VTE; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - von Willebrand Disease diagnosis & management; Bristol Myers Squibb: Other: study of direct oral anticoagulant in prevention of pediatric VTE, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - VWD diagnosis and management. Dunn: Alnylam: Other: Unrestricted educational grant; Bayer: Consultancy, Other: Unrestricted educational grant; Kedrion: Other: Unrestricted educational grant; NovoNordisk: Other: Unrestricted educational grant; Octapharma: Other: Unrestricted educational grant; Shire: Consultancy, Other: Unrestricted educational grant, Research Funding; Biogen: Other: Unrestricted educational grant, Research Funding; CSL Behring: Consultancy, Other: Unrestricted educational grant; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees. Kumar: Bayer: Consultancy; CSL Behring: Consultancy.

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Association of Bleeding Severity with Mortality with in-Hospital and Extended Thromboprophylaxis in the Medically Ill in the Magellan Trial

Blood ◽

10.1182/blood-2019-122930 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2441-2441

Author(s):

Alex C. Spyropoulos ◽

Gary E. Raskob ◽

Alexander T Cohen ◽

Walter Ageno ◽

Jeffrey I. Weitz ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Events ◽

Employment Equity ◽

Advisory Committees ◽

Increased Risk ◽

Bayer Healthcare ◽

Equity Ownership

Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MAGELLAN study (NCT00571649) evaluated whether rivaroxaban (10 mg QD for 35±4 days) compared with enoxaparin (40 mg QD for 10±4 days) followed by placebo could prevent asymptomatic deep vein thrombosis, symptomatic VTE, and VTE-related death. Through Day 35, rivaroxaban was superior to enoxaparin/placebo in the modified intent-to-treat population (4.4% vs 5.7%, RR 0.77, 95%CI, 0.62 to 0.96, p=0.02), but there was an increase in clinically relevant bleeding, the composite of major and non-major clinically relevant (NMCR) bleeding (4.1% vs 1,7%, RR 2.5, 95%CI 1.85-3.25, p<0.001). Although major bleeding has been associated with increased mortality, the relationship between NMCR bleeding and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MAGELLAN trial with major bleeding but not those with NMCR bleeding, would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 90 visit in 3 mutually exclusive groups: (1) subjects with no major or NMCR bleeding; (2) subjects whose first event was NMCR bleeding; and (3) subjects whose first event was major bleeding. Subjects only developing minimal or trivial bleeding were grouped with those who had no clinically relevant bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates significantly associated with ACM at p<0.05 (age, BMI, history of cancer, history of anemia, inflammatory disease, acute ischemic stroke, and acute respiratory insufficiency), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM for subjects who had NMCR bleeding was numerically higher but not significantly increased compared with subjects with no bleeding (20/176, 11.4% vs 468/7763, 6.0%, HR 1.41 95%CI 0.88, 2.25, p=0.151), while subjects with major bleeding were at a significantly increased risk of death (28/59, 47.5% vs 468/7763, 6.0%, HR 7.74 95%CI 5.16, 11.59, p<0.0001). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and may have been underpowered to detect differences in ACM associated with NMCR bleeding. Conclusion: Major bleeding was associated with a significantly increased risk of ACM but NMCR bleeding was not. This suggests that a modest increase in NMCR bleeding associated with extended thromboprophylaxis with rivaroxaban may be acceptable to prevent VTE. Strategies to better select patients at lower risk of bleeding may improve the benefit risk profile of extended thromboprophylaxis with rivaroxaban. Disclosures Spyropoulos: Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Portola: Consultancy; Bayer Healthcare: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Janssen R&D, LLC: Consultancy. Raskob:Janssen R&D, LLC: Consultancy, Honoraria; Novartis: Consultancy; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Eli Lilly: Consultancy. Cohen:Boston Scientific: Consultancy; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Speakers Bureau; GLG: Consultancy; AbbVie: Consultancy; ACI Clinical: Consultancy; Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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; McKinsey: Consultancy; Navigant: Consultancy; 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; Temasek Capital: 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; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Ageno:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Weitz:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.

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Pattern and Management of ISTH Major Bleeding Complications with Direct Oral Anticoagulants - Results of the Prospective Dresden Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v126.23.892.892 ◽

2015 ◽

Vol 126 (23) ◽

pp. 892-892 ◽

Cited By ~ 2

Author(s):

Sandra Marten ◽

Luise Tittl ◽

Katharina Daschkow ◽

Jan Beyer-Westendorf

Keyword(s):

Major Bleeding ◽

Research Funding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Red Blood Cell Transfusion ◽

Bleeding Complications ◽

Bleeding Events ◽

Major Bleeding Events ◽

The Impact

Abstract Background: The most common side effects of oral anticoagulants are bleeding complications. In large trials, direct oral anticoagulants (DOAC) have been shown to reduce the risk of major bleeding compared to warfarin. However, little is known about the management and outcome of survivors of major DOAC bleeding. Patients and methods: Using data from the prospective, non-interventional Dresden NOAC registry, we evaluated the management and outcome of survivors of major DOAC bleeding. All DOAC bleeding complications were centrally adjudicated and classified according to ISTH definition. For this analysis, every ISTH major bleeding was identified in the database and for each case, the first major bleeding was evaluated. Restart of oral anticoagulation (OAC) 30 days after major DOAC bleeding was assessed and the impact of restart on the composite endpoint of (recurrent major bleeding, stroke, TIA, systemic embolism, venous thromboembolism) or survival was evaluated using Kaplan-Meier time-to-first event estimation. Results: Until January 31th 2015, 2771 patients were enrolled into the registry (1898 treated with rivaroxaban, 525 apixaban and 348 dabigatran). During follow-up (mean follow-up duration 23.6 months) 127 patients developed 170 ISTH major bleeding events during DOAC exposure (drop of hemoglobin ≥2g/l in 106 (62.4%) cases, transfusion of ≥2 units of red blood cells in 105 (61.8%) cases, critical site bleeding in 43 (25.3%) cases and/or fatal outcome in 9 cases (5.3%)). Of the 127 patients with major bleeding (mean age 77±11 years; range 37-94), 53.5% were male the median HAS-BLED score was 2 (25th/75th percentile 1/2, range 0-5). The majority major bleeding events occurred spontaneously (64.6%). In contrast, 14.2% major bleeding events occurred after trauma and 21.3% occurred after surgical or interventional procedures that were performed during treatment or within 3 days after last DOAC intake. Most common sites of bleeding were gastrointestinal tract (37%), diffuse bleeding during or after surgery (15.7%), intracranial (11%), skin/mucosal (9.4%), intraocular (8.7%), genitourinary (7.9%), intraarticular bleeding (6.3%) and bleeding in other sites (4%). 85 cases lead on to a hospitalization (mean duration 9±7d) and 11 cases were managed as outpatient. The remaining 31 bleeding events occurred during a hospital stay. The majority of cases were managed with surgical or interventional treatment (55.9%; mainly endoscopic treatment for gastrointestinal bleeding. In 75 (57.1%) cases red blood cell transfusion was given and 11 (8.7%) of cases received fresh frozen plasma. Furthermore, 15 (11.8%) of cases received PCC and 4 (3.1%) fibrinogen. The restart of OAC (DOAC or vitamin K antagonists; VKA) was assessed at day 30 after major bleeding. While OAC was restarted in 80 patients (63%) it was not restarted 30 days after bleeding in the remaining 47 (37%). Patients who restarted OAC had a similar mean age (76 vs. 78y, p=0.309) and a similar mean HAS-BLED score (1.8 vs. 2.1, p=0.115) compared to patients who did not restart OAC. During follow up after bleeding (mean follow-up duration 15.2 months), the rate of combined endpoint of recurrent major bleed and thromboembolism was significantly lower in patients that restarted OAC compared to those who did not restart (14.7/100 patient years; 95%-CI 8.0-24.7 vs. 38.6/100 patient years; 21.1-64.7; p=0.0342). All-cause mortality was found to be 23.9/100 patient years (95% CI 16.9-32.8). Mortality was significantly lower in patients that restarted OAC compared to those who did not restart (16.4/100 patient years [9.7-25.9] vs. 40.6/100 patient years [24.8-62.7]; p=0.0099). Most common cause of death was fatal cardiovascular event (12/38, 31.6%) and fatal bleeding (9/38, 23.7%) followed by terminal malignant disease (6/38, 15.8%), infection/sepsis (6/38, 15.8%) and age related death (5/38, 13.2%). Conclusion: Even in cases with major DOAC bleeding, acute mortality is low with a case-fatality rate of 5.3%. Furthermore, OAC is restarted within 30 days after major bleeding in only 63%. Patients who restarted OAC had significantly lower rates of the combined endpoint of thromboembolism or recurrent major bleeding and had a significantly better survival. Therefore, benefits of OAC continuation may outweigh the risks even in patients with major DOAC-related bleeding. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Marten: Bayer HealthCare: Honoraria. Beyer-Westendorf:Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bristol- Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

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