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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 892-892 ◽  
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.

Pattern and Management of Vaginal Bleeding Complications, Especially Hypermenorrhea, with Direct Oral Anticoagulants - Results of the Prospective Dresden Noac Registry (NCT01588119)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1131-1131
Author(s):  
Sandra Marten ◽  
Luise Tittl ◽  
Katharina Daschkow ◽  
Jan Beyer-Westendorf
Keyword(s):  
Treatment Satisfaction ◽  
Research Funding ◽  
Vaginal Bleeding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Complications ◽  
Common Complication ◽  
Bleeding Events ◽  
Bayer Healthcare

Abstract Background : Bleeding is a common complication of oral anticoagulation (OAC). In anticoagulated women of child-bearing potential (WOCBP), increase of menstrual bleeding may be discomforting and severe cases of menorrhagia may require dedicated treatment or even discontinuation of OAC. Since hypermenorrhea seems to be more frequent in patients receiving direct oral anticoagulants (DOAC) compared to classic OAC with vitamin-K antagonists, patterns of menorrhagia need to be studied in daily care cohorts. Patients and methods: Using data from the prospective, non-interventional Dresden NOAC registry and phase-III DOAC trial patients at our site, we evaluated rates, severity and management of vaginal bleeding complications in WOCBP (defined as age ≤55 years and without sterilizing procedures or age >55 years with documented menstrual bleeding). All bleeding complications were centrally adjudicated and classified according to ISTH definition. Annualized rates of vaginal bleeding and hypermenorrhea were calculated as number of bleeding events divided by cumulative days of DOAC exposure divided by 365 days. OAC treatment satisfaction was assessed in all registry patients at every follow-up visit by a simple six-graded scale (ranging from 1=very satisfied to 6=very unsatisfied). To assess impact of vaginal bleeding on quality of live, the first available score after a vaginal bleeding was compared with the last available score of WOCBPs without vaginal bleeding. Results: Until March 31th 2015, 1343 women were enrolled, of which 154 were WOCBPs (mean age 39±12 years; range 14-56). In these patients, OAC consisted of dabigatran (1.3%), rivaroxaban (92.2%), apixaban (5.8%) or edoxaban (0.6%). During follow-up (mean FU duration 24.6 months), 85 female patients reported 107 vaginal bleeding complications, of which 68 occurred in 53 WOCBPs (53 cases of hypermenorrhea and 15 bleedings unrelated to cycle). Table 1 indicates severity of hypermenorrhea and vaginal bleedings unrelated to cycle. According to ISTH definition, 37/68 (54.4%) of the vaginal bleeding in WOCBPs were minor, 25/68 (36.8%) were non-major, clinically relevant (NMCR) and 6/68 (8.8%) major bleeding (classified as "major" due to drop of hemoglobin ≥2g/l in 5 cases and/or transfusion of ≥2 units of red blood cells in 5 cases). In relation to all exposed WOCBPs, the rate of vaginal bleeding events was found to be 0.41 events per exposure year and the rate of hypermenorrhea was found to be 0.32 events per exposure year (median exposure time 243d; 25th/75th percentile 105/674d and median time to first hypermenorrhea 26d; 25th/75th percentile 10/46d). Of the 53 WOCBPs that described vaginal bleeding complications (including hypermenorrhea and cycle-unrelated bleeding), 12/53 (22.6%) experienced a 2nd and 3/53 (5.7%) a 3rd event (figure 1). While bleeding intensity remained stable in most recurrent events, bleeding intensity increased in 6 cases with a 2nd bleeding episode while bleeding intensity remained stable or decreased in all 3 cases with a third episode. In only 16 of the 53 hypermenorrhea events, anatomical causes could be established and 3 of these cases progressed to major bleeding (necessity of at ≥2 units of red blood cells). In contrast, in the 34 hypermenorrhea events without anatomical causes, bleeding intensity was less severe (table 1). Surgical or interventional treatment was necessary in 6/68 (8.8%) vaginal bleeding events. The remaining 62 (91.2%) events were treated conservatively (start or change of hormone therapy, tranexamic acid, OAC dose reduction or temporary interruption). Overall, OAC treatment satisfaction in WOCBP was good (mean score 1.6; 25th/75th percentile 1/2 with data available for 98/154 WOCBPs) and not different in patients with and without vaginal bleeding complications (1.6; 25th/75th percentile 1/2 vs. 1.5; 1/2; p=0.548). Conclusion : Vaginal bleeding and especially hypermenorrhea is a common complication in WOCBPs receiving oral anticoagulation. Only a small proportion of affected patients have underlying anatomical causes for bleeding but these patients often develop more severe bleeding. The majority of cases can be conservatively managed and bleeding intensity rarely increases over time. Overall, the impact of vaginal bleeding complications on treatment satisfaction seems small. Disclosures Marten: Bayer HealthCare: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding.

scholarly journals Evaluation of Definitions for Oral Anticoagulant–Associated Major Bleeding: A Population-Based Cohort Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 426-426 ◽  
Author(s):  
Yan Xu ◽  
Tara Gomes ◽  
Philip S. Wells ◽  
Ana Johnson ◽  
Michelle Sholzberg
Keyword(s):  
Major Bleeding ◽  
Oral Anticoagulant ◽  
Research Funding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Tertiary Care ◽  
Population Based ◽  
Bleeding Events ◽  
Risk Of Death ◽  
Major Bleeding Events

Abstract Background: Major bleeding is the most serious complication of oral anticoagulation. Consensus criteria to define major bleeding have been established by the International Society for Thrombosis and Haemostasis (ISTH), Bleeding Academic Research Consortium (BARC) and Thrombolysis in Myocardial Infarction (TIMI). Significant variability exists across these definitions, and their agreement for identifying oral anticoagulant (OAC) related major bleeding is unknown. Furthermore, the association between each definition and mortality in cases of OAC bleeding has not been evaluated. We therefore, sought to evaluate the agreement of cases identified as major bleeding by the ISTH, BARC and TIMI definitions, and to assess associated in-hospital (emergency department or inpatient) and 30-day mortality of cases identified by these criteria. Methods: We used an existing dataset of individuals ≥66 years in Ontario, Canada, who presented to one of five tertiary care institutions with OAC related bleeding across three cities from 2010-2015. Detailed clinical data on consecutive episodes of OAC-associated bleeding were linked to population-based databases held at the Institute for Clinical Evaluative Sciences. We calculated Cohen's κ for agreement between the three major bleeding definitions, and used Pearson's χ2 to determine any differences in in-hospital and 30-day mortality for cases defined as major bleeding by ISTH, BARC and TIMI criteria. Results: We included 2,002 cases of OAC related bleeding in the analysis (460 on direct oral anticoagulants, 1,542 on warfarin). ISTH, BARC and TIMI major bleeding definitions were met in 75%, 77% and 29% of cases, respectively. 18% of cases did not meet criteria for major bleeding by any definition. Age, sex, CHA2DS2-VASc and HAS-BLED score, as well as proportion of chronic kidney disease were similar across ISTH-, BARC- and TIMI-defined cases. Over 9 in 10 cases of TIMI-defined major bleeding events involved an intracranial hemorrhage (94.4%), compared to 37% and 36% of cases identified by ISTH or BARC definitions respectively (p<0.001 across three groups). Agreement in case identification between ISTH and BARC was substantial (agreement 89%; Cohen's κ=0.69). On the other hand, agreement between TIMI and both ISTH (agreement 54%; Cohen's κ =0.24) and BARC (agreement 52%; Cohen's κ=0.21) were poor. The association between in-hospital mortality and TIMI-defined major bleeding was higher (29%) than that for ISTH and BARC (17% for both; p<0.001 for TIMI vs. ISTH and TIMI vs. BARC). The association with 30-day mortality showed a similar trend (30%, 18% and 18% for TIMI-, ISTH- and BARC- defined major bleeding events respectively; p<0.001 for TIMI vs. ISTH and TIMI vs. BARC). 6% of cases that were not categorized as major bleeding by ISTH or BARC definitions died within 30 days of hospital presentation, and this was 10% for cases not meeting criteria for TIMI major bleeding (10%, p=0.036 by Pearson's χ2). Conclusions: Among patients with OAC-associated bleeding, major bleeding events identified by ISTH and BARC criteria showed good agreement and similar prognostic utility. Meanwhile, TIMI criteria identified patients with higher clinical risk and subsequent mortality. Patients presenting with OAC-associated bleeding who did not fulfill ISTH or BARC major bleeding criteria had considerable risk of 30-day mortality and was even higher among those not meeting the TIMI criteria. Our findings suggest the need to refine current major bleeding definitions to identify additional patients at risk of death. Disclosures Wells: Bayer: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Janssen: Honoraria. Sholzberg:Amgen: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Shire: Research Funding.

Pattern and Management Of Bleeding Complications With Novel Oral Anticoagulants – Results Of The Prospective Dresden Noac Registry (NCT01588119)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 214-214
Author(s):  
Kati Förster ◽  
Franziska Ebertz ◽  
Vera Gelbricht ◽  
Denise Röllig ◽  
Luise Tittl ◽  
...  
Keyword(s):  
Gastrointestinal Bleeding ◽  
Major Bleeding ◽  
Research Funding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Safety Data ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Daily Care

Abstract Background The most common side effect of oral anticoagulants are bleeding complications. In large trials, novel direct oral anticoagulants (NOAC) have been shown to reduce the risk of major bleeding compared to warfarin. However, little is known about the distribution pattern, management and outcome of NOAC-related bleeding complications in daily care. Patients and methods Using data from a large regional registry of patients treated with novel direct oral anticoagulants (NOAC) in the district of Saxony, Germany, we evaluated pattern and management of NOAC-related bleeding complications in daily care. In this ongoing registry, a network of 239 physicians enrols up to 2500 daily care NOAC patients who receive central prospective follow up (FU) by the registry office at day 30 day and quarterly thereafter to collect efficacy and safety data. All outcome events are centrally adjudicated using standard scientific definitions. Results Until July 31th 2013, 2249 patients were enrolled into the registry. Of these, 1738 (77.3%) patients received rivaroxaban, 356 (15.8%) received dabigatran and 155 (6.9%) received apixaban. During follow-up (2674.0 patient years), a total of 825 patients reported 1137 bleeding complications (59.1% minor, 33.9% non-major, clinically relevant (NMCR) and 6.9% major bleeding according to ISTH definition). For non-major bleedings, mucosal and skin bleeding were the most common bleeding sites (67.9% of all bleedings), followed by genitourinary (10.9%) and gastrointestinal bleeding (10.9%). For major bleeding, gastrointestinal bleeding was the most common manifestation (2.8%), followed by genito-urinary (0.6%) bleeding. In 93% of all bleeding events, treatment was not necessary or consisted of conservative treatment with compression, tamponade or red blood transfusion. Surgical or interventional treatment was reqired in 7.0% of all bleedings (0.0% of minor, 13.0% of NMCR and 38.0% of major bleedings). Prothrombin complex concentrate was used in 1.3% (24% of all major bleedings). No patient received recombinant factor VII. Bleeding-associated mortality was 0.5% for all and 7.5% for major bleeding. Of the six fatal bleedings observed, three were intracranial bleedings. Conclusion Bleeding complications are common in daily care NOAC patients and are usually managed conservatively. Only 7% of all observed bleedings fulfil the ISTH criteria of major bleeding (mainly for RBC transfusion criterion) and are managed using interventions, FFP or PCC. Overall, only few NOAC-associated bleeding complications in daily care are fatal, indicating that available management strategies are sufficient. For presentation at ASH, updated results including risk assessments will be reported. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

scholarly journals The Risk of Bleeding in Patients Receiving Ibrutinib Combined with Novel Direct Oral Anticoagulants

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4314-4314
Author(s):  
Michal Ariela Raz ◽  
Jon E. Arnason ◽  
Osnat Bairey ◽  
Lev Shvidel ◽  
Ariel Aviv ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Lymphoproliferative Disorders ◽  
Bleeding Events ◽  
Concurrent Administration ◽  
Risk Of Bleeding ◽  
Grade 3

Introduction: Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, is an established therapeutic agent in a variety of B-cell lymphoproliferative disorders. Ibrutinib induces platelet dysfunction and concurrent treatment with ibrutinib and warfarin was shown to significantly increase the risk of bleeding. The current study was designed to investigate the safety of direct oral anticoagulants (DOACs) in patients receiving ibrutinib, considering their expanding employment together with the lack of data regarding their safety in patients receiving ibrutinib. Methods: We conducted a retrospective cohort study to evaluate risks of major bleeding in patients with B-cell lymphoproliferative disorders (CLL, MCL, DLBCL, MZL or WM) that were treated with ibrutinib and DOACs but without concurrent antiplatelet therapy, between January 2010 and October 2018 in 5 participating centers. Patient medical charts were reviewed for demographic parameters, comorbidities, ibrutinib dosage, DOACs dosage (including the adjustment for renal function), blood count and chemistry tests, bleeding site and grade. Results: The study included 30 patients, median age at starting concurrent administration of ibrutinib and DOACs was 71.58 years (range 50.9-88.2). Most patients were treated for CLL (n=18, 60%) and MCL (n=8, 26%). The most common daily doses of ibrutinib were 420 mg and 560 mg in 63.3% and 30% of patients respectively. None of the patients received an additional antiplatelet agent. Twenty-three patients were treated with apixaban (76.7%), 4 with rivaroxaban (13.3%) and 3 (10%) with dabigatran. The main indications for DOACs were atrial fibrillation and VTE (venous thromboembolism). The median follow-up after initiation of the ibrutinib-DOAC combination was 13.4 months (range 1.8-47.9 months). Bleeding was reported in 22 patients (73.3%), mostly mucocutaneous (n=12, 40%) and gastrointestinal tract (n=7, 23.3%), followed by CNS bleeding (n=4, 13.3%). Mucocutaneous bleedings were all grade 1-2 and gastrointestinal tract and CNS bleeding events were grade 1-4. Major bleeding events, defined as grade 3 or 4, occurred in 5 patients (16.6%) and did not result in death of any of the patients. The median time for bleeding following ibrutinib-DOAC initiation was 5.6 months. Over a follow-up period of 21 months of combined treatment, the incidence of bleeding events (of all grades) increased to 75% (Figure 1). Incidence of bleeding events (including all grades) was quite similar between all DOAC subtypes (73.9% with apixaban, 75% with rivaroxaban and 66.7% with dabigatran). No statistically significant predictors for increased risk of bleeding in patients receiving ibrutinib combined with DOACs were detected. Ibrutinib was stopped in 8 patients (26.7%) due to grade 1 to 4 bleeding events and was re-initiated in 6 patients, resulting in recurrent grade 3 and 4 bleeding events in 2 patients. Conclusions: Concurrent administration of DOACs and ibrutinib appears to be feasible. However, risk of bleeding is not neglectable, and treatment resumption in patients that experienced a significant bleeding event should be considered with caution. Disclosures Arnason: Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Herishanu:Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria.

Abstract 17152: Frequency and Management of Major Bleeding in Atrial Fibrillation Patients Treated With Warfarin and Non-vitamin K Oral Anticoagulants in Community Practice: Results From the ORBIT-AF II Registry

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Benjamin A Steinberg ◽  
DaJuanicia N Simon ◽  
Laine Thomas ◽  
Jack Ansell ◽  
Gregg C Fonarow ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Practice ◽  
Vitamin K ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Recurrent Bleeding ◽  
Bleeding Events ◽  
Reversal Agents ◽  
Major Bleeding Events

Background: Non-vitamin K oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the frequency of major bleeds on NOACs and how these events are managed in clinical practice. Methods: We assessed the rates, management, and outcomes of ISTH major bleeding events among AF patients in the ORBIT-AF II registry (mean follow-up 213 days). Results: Overall, 103 patients experienced 110 major bleeding events during follow-up n=90/4986 (1.8%) on NOAC, and n=20/1320 (1.5%) on warfarin. Patients with bleeding events on NOAC were slightly younger than those on warfarin (median age 76 vs. 80; p=0.2). Among mutually-exclusive bleeding types, intracranial bleeding was more common in warfarin treated patients than NOAC-treated (15% vs 6.7%), whereas GI bleeding was more common on NOACs (56% vs. 40%, overall p=0.1 for bleeding type). Management of bleeding differed by anticoagulation type: blood products and reversal agents were more commonly used in patients on warfarin (Table). No patient received prothrombin complexes, recombinant factor VIIa, aminocaproic acid, tranexamic acid, aprotinin, or desmopressin. Out of 90 major bleeding events in NOAC patients, only 1 was fatal (1%). Within 30 days following bleeding, there were no strokes and 1 TIA (NOAC). Following a major bleed, the recurrent bleeding rate in NOAC patients in the next 30-days was 4% and the death rate was 4%. Conclusions: Rates of major bleeding with NOACs in clinical practice are comparable to those reported in clinical trials. Compared with warfarin, bleeding among NOAC users was less likely intracranial and more likely to be GI. Management of bleeding in the setting of NOAC rarely includes reversal agents.

Major Bleeding with Ibrutinib: More Than Expected

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3229-3229 ◽  
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.

The Effectiveness and Safety of Direct Oral Anticoagulants (DOACs) Vs. Traditional Anticoagulants in Patients with Cirrhosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5015-5015
Author(s):  
Justin Hum ◽  
Janice Jou ◽  
Thomas G. Deloughery ◽  
Joseph Shatzel
Keyword(s):  
Major Bleeding ◽  
Conflicts Of Interest ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Complications ◽  
Efficacy And Safety ◽  
Recurrent Thrombosis ◽  
Bleeding Events ◽  
Cirrhotic Patients

Abstract Introduction: The coagulopathy associated with cirrhosis is complex and places patients at risk for both bleeding and thrombosis. Direct oral anticoagulants (DOACs) have been shown to have superior efficacy and safety compared to vitamin K antagonists; however their efficacy and safety in cirrhotic patients is not clear. The aim of this study is to retrospectively compare the effectiveness and bleeding complications of DOACs as compared to traditional anticoagulants in cirrhotic patients. Methods: This study was a retrospective review of patients treated at a single academic center between 2012-2015 who were prescribed a DOAC (apixaban or rivaroxaban), or a traditional anticoagulant (warfarin or low molecular weight heparin), with an ICD-9 code for the diagnosis of cirrhosis. The primary outcomes of interest are recurrent thrombosis or stroke (efficacy failure), or bleeding events (safety failure). Major bleeds were characterized as fatal bleeding, symptomatic bleeding in critical organ area, or bleeding causing a fall in hemoglobin level >2 or leading to transfusion of 2+ units of packed red blood cells. Results: During the study period, 27 cirrhotic patients were prescribed a DOAC and 18 were prescribed a traditional anticoagulant (either LMWH or warfarin). Both groups had similar total bleeding events (8 DOAC vs. 10 traditional anticoagulation, p = 0.12). There were significantly less major bleeding episodes in the DOAC group, (1 (4%) vs. 5 (28%), p = 0.03) and less intracranial bleeding (3 (17% ) vs. 0 (0%) p=0.06). Recurrent thrombosis or stroke occurred in 1 (4%) patient in the DOAC group and 1 (6%) patient in the traditional group (p = 1.0). Conclusions: Anticoagulation with DOACs in cirrhotic patients may be as safe as traditional anticoagulants with respect to bleeding events. Patients with cirrhosis at our center prescribed DOACs had less major bleeding events, while maintaining efficacy at preventing stroke or recurrent thrombosis. Table Table. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4387-4387 ◽  
Author(s):  
Aaron Pavlik ◽  
Hallie Barr ◽  
Emily Dotson ◽  
John C. Byrd ◽  
Kristie A. Blum ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Event ◽  
Antiplatelet Agents ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Major Bleeding Events

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.

P2529Efficacy and safety of oral anticoagulation in nonagenarian patients with atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Dominguez Rodriguez ◽  
S Raposeiras Roubin ◽  
D Alonso Rodriguez ◽  
S J Camacho Freire ◽  
E Abuassi ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Major Bleeding ◽  
Oral Anticoagulation ◽  
Lower Risk ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Events ◽  
The Impact ◽  
Similar Risk

Abstract Introduction Embolic prevention with oral anticoagulation is the cornerstone for the management of patients with atrial fibrillation (AF). However, data about the efficacy and safety of oral anticoagulation in nonagenarian patients are limited. We aimed to analyze the impact of oral anticoagulation in mortality, embolic and hemorrhagic events, in patients ≥90 years with non-valvular AF. Methods We used data from a multicentric registry of 1,750 consecutive nonagenarian patients diagnosed of AF between 2013 and 2018. A propensity-matched analysis was performed to match the baseline characteristics of patients treated or not with oral anticoagulants, and for those treated with vitamin K antagonists (VKAs) vs direct oral anticoagulants (DOACs). The impact of oral anticoagulation in the embolic and hemorrhagic risk was assessed by a competitive risk analysis, using a Fine and Gray regression model, with death being the competitive event. For embolic risk, we have considered a stroke, pulmonary or peripheral embolism. For bleeding risk, we have considered any bleeding requiring hospital admission. Results The mean of CHA2DS2-VASC and HASBLED scores was 4.5±1.3 and 2.8±1.0 points, respectively. Most of patients were anticoagulated (70.1%; n=1,256). DOACs were used in 709 patients, and VKAs in 517 patients. During a median follow-up of 25.2 months (IQR 12.2–44.3 months), 988 patients died (56.5%), 180 presented embolic events (10.3%), 186 had bleeding events (10.6%), and 29 had intracranial hemorrhage (ICH, 1.7%). After propensity-score matching, anticoagulation (versus non anticoagulation) was associated with lower mortality rate (HR 0.73, 95% CI 0.60–0.89; p=0.002), less mortality and embolic events (HR 0.77, 95% CI 0.64–0.92; p=0.005), but more bleeding events (HR 2.05, 95% CI 1.25–3.35; p=0.004). In comparison with VKAs, DOACs showed similar risk of mortality and embolic events (HR 1.14, 95% CI 0.88–1.47; p=0.337), and similar risk of bleeding events (HR 0.75, 95% CI 0.43–1.28; p=0.287), although a trend to lower risk of ICH was found (HR 0.17, 95% CI 0.02–1.39; p=0.097). Conclusions Among nonagenarian patients with AF, oral anticoagulation was associated with lower all-cause mortality. Although survival free of embolic events was significantly higher in patients with anticoagulation, the risk of major bleeding was twice than in non-anticoagulated patients. There was not differences between VKAs and DOACs in terms of embolic events and total major bleeding. However, compared with VKAs, DOACs were showed a trend to lower risk of ICH.

scholarly journals Major Bleeding Events and Associated Factors in a Cohort of Adult Patients Taking Warfarin in an Armed Forces Hospital

2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Manvikram Singh Gill
Keyword(s):  
Sample Size ◽  
Major Bleeding ◽  
Oral Anticoagulants ◽  
Demographic Data ◽  
Direct Oral Anticoagulants ◽  
Bleeding Event ◽  
Armed Forces ◽  
Bleeding Events ◽  
Medication Therapy ◽  
Major Bleeding Events

Introduction: Warfarin is widely utilized in patients with Atrial Fibrillation (AF) in Malaysia. However, risk of haemorrhage which necessitates monitoring of International Normalised Ratio (INR) and extensive interaction which varies across ethnicity supports the use of Direct Oral Anticoagulants (DOACS). This study is to assess whether demographic data, medical history, and medication history are associated with the risk of major bleeding events. Methodology: Data was collected retrospectively in a case-controlled environment from the Electronic Medical Record (EMR) database. These patients were attending Medical Out-patient Department (MOPD) clinic, Tuanku Mizan Armed Forces Hospital (TMAFH) from 2nd to 31st January 2018. Results: Among 60 AF patients reviewed, 83% had labile INR range and 35% reported to have 1 or more bleeding event. It is found there is significant association (p<0.05) for variables of sex, history of stroke, and NSAID usage with the outcome. Discussion: Majority of patients with major bleeding events are Chinese males. The sample size of the current study is too small to be able to arrive at any conclusive results. Conclusion: Further studies with bigger sample size are needed among Malaysian Chinese male population. MOPD should establish a warfarin Medication Therapy Adherence Clinic (MTAC) to optimise pharmaceutical care.

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