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

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.

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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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Real Life Efficacy and Safety of Dabigatran for Stroke Prevention in Atrial Fibrillation – First Results of the Prospective Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v120.21.502.502 ◽

2012 ◽

Vol 120 (21) ◽

pp. 502-502

Author(s):

Vera Gelbricht ◽

Sebastian Werth ◽

Christina Koehler ◽

Ulrike Haensel ◽

Luise Tittl ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Cardiovascular Events ◽

Safety Data ◽

Real Life ◽

Bleeding Complications ◽

Efficacy And Safety ◽

Daily Care ◽

Short Period

Abstract Abstract 502 Background: In the RE-LY trial, dabigatran (DB) has been found to be at least as effective and safe as warfarin to prevent stroke in atrial fibrillation (AF), which lead to approval in many countries. However, patients in RCT‘s present a selected population treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of new oral anticoagulants (NOAC) need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of dabigatran anticoagulation in AF in daily care. Patients and methods: In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data. Results: Until July31th 2012, 938 patients were registered. Of these, 201 received DB for AF (table 1). The population in our registry is older than in RELY (74.2 vs. 71.5 years) and has a higher CHADS2-Score (2.7 vs. 2.1). Interestingly, 110 mg BID was the preferred dosage in DB patients (55.7%) despite the fact that these patients had higher CHADS2-scores than patients receiving 150 mg BID (2.3 vs. 2.9). Two third of patients were newly anticoagulated and one third was switched from Vitamin-K antagonists, mainly due to poor INR control or bleeding complications. Results of 30-day-, 3-month and 6-month FU are shown in table 2. Currently, FU data cumulate to 86.8 patient years. During FU, Three patients (1.5%) experienced major cardiovascular events (xyz) and another two patients (1.0%) minor cardiovascular events (syncope). Until now, no deaths occurred. Bleeding complications were frequent (14.9%) but major bleeding was rare (n=3; 1.5%) none of which was fatal. At 3 month, 93% of patients were still taking DB but switch to other anticoagulants increased between 3 and 6 month, mainly due to side effects or incompliance. Conclusion: In unselected patients in daily care, DB is effective and safe with low rates of cardiovascular or major bleeding events. However, within 6 month, about 20% of patients are switched to other anticoagulants. Long-term data will be reported. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

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

Blood ◽

10.1182/blood.v126.23.1131.1131 ◽

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.

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Real Life Efficacy and Safety of Rivaroxaban for Stroke Prevention in Atrial Fibrillation – First Results of the Prospective Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v120.21.1156.1156 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1156-1156

Author(s):

Sebastian Werth ◽

Christina Koehler ◽

Vera Gelbricht ◽

Ulrike Haensel ◽

Luise Tittl ◽

...

Keyword(s):

Atrial Fibrillation ◽

Major Bleeding ◽

Cardiovascular Events ◽

Safety Data ◽

Real Life ◽

Bleeding Complications ◽

Efficacy And Safety ◽

Daily Care ◽

Short Period

Abstract Abstract 1156 Background: In the ROCKET-AF trial, rivaroxaban (RX) has been found to be at least as effective and safe as warfarin to prevent stroke in atrial fibrillation (AF) and is approved in many countries. However, patients in RCT‘s present a selected population which is treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of new oral anticoagulants (NOAC) need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of rivaroxaban anticoagulation in AF in daily care. Patients and methods: In the district of Saxony, Germany, a network of 200 physicians from private practice and hospitals enrol patients in the prospective NOAC registry. Inclusion criteria are: 1) indication for NOAC anticoagulation >3 month; 2) age > 18 years; 3) written informed consent; 4) availability for follow-up. No Exclusion criteria apply. In the registry, up to 2000 patients will receive prospective follow up (FU) by phone visits at day 30 day and quarterly thereafter to collect efficacy and safety data. Results: Until July 31th 2012, 938 patients were registered. Of these, 504 patients received RX for atrial fibrillation (demographic data in table 1). Despite similar age (mean 75 years), our real world cohort has lower CHADS2-Scores compared to ROCKET-AF (2.4 vs. 3.5). The preferred dosage in most RX patients (68.8%) was 20mg, but these patients had lower CHADS2-scores than patients receiving 15 mg (2.2 vs. 2.8). Two third of patients were newly anticoagulated and one third was switched from Vitamin-K antagonists, mainly due to poor INR control or bleeding complications. Results of 30-day-, 3-month and 6-month FU are shown in table 2. Currently, FU data cumulate to 112.2 patient years. Five patients (1.0%) experienced major cardiovascular events (3 ACS, 1 ischemic stroke, 1 TIA). Another five patients experienced minor cardiovascular events (syncope). Three patients (0.6%) died within the first month of treatment (one due to sudden cardiac death, possibly related to ventricular fibrillation, two of underlying disease). Bleeding complications were frequent (15.2%) but major bleeding was rare (n=1; 0.2%). At 3 month, 95% of patients were still taking RX. Conclusion: In unselected patients in daily care, RX is effective and safe with low rates of cardiovascular or major bleeding events and low rates of treatment discontinuation in the first 180 days of treatment. Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Bayer Healthcare: Bayer provided a grant to support the NOAC registry in part Other, Honoraria; Boehringer Ingelheim: Boehringer provided a grant to support the NOAC registry in part, Boehringer provided a grant to support the NOAC registry in part Other, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

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Acute Treatment Of Pulmonary Embolism With Rivaroxaban - Real Life Data From The Prospective Dresden Noac Registry (NCT01588119)

Blood ◽

10.1182/blood.v122.21.2380.2380 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2380-2380

Author(s):

Christina Köhler ◽

Sebastian Werth ◽

Luise Tittl ◽

Jan Beyer-Westendorf

Keyword(s):

Pulmonary Embolism ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Complications ◽

Daily Care ◽

Study Results ◽

Bayer Healthcare ◽

Recurrent Vte ◽

Acute Pe

Abstract Background and Objectives In the EINSTEIN PE study rivaroxaban (RX) was found to be as effective as warfarin in the treatment of acute pulmonary embolism (PE) with superior safety. However, study results need to be confirmed in unselected PE patients in daily care. Patients and Methods Using prospectively collected data from a large regional registry of patients treated with novel direct oral anticoagulants (NOAC) in the district of Saxony, Germany, we evaluated the rate of recurrent VTE, other cardiovascular complications and bleeding events in patients receiving rivaroxaban for acute PE. 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. Of these, 72 patients received RX for acute PE treatment (demographic data in table 1). Registry patients were older than the EINSTEIN PE population (67.3 vs. 55.8 years), 55.6% were female and 23.6% were treated for a recurrent VTE. During follow-up, unplanned rivaroxaban discontinuation rates were low (around 5%; table 1). So far, only one recurrent VTE event occurred (1.7 events per 100 patient years). One patient experienced non-fatal ischaemic stroke within 4 weeks after PE diagnosis (1.7 events per 100 patient years). Bleeding complications were frequent but only 2 major bleeding (non-fatal vaginal bleeds) occurred (3.3 events per 100 patient years). During follow-up three patients died of underlying diseases but none of these deaths were related to VTE or bleeding complications. Conclusion Acute PE treatment with rivaroxaban in daily care is effective, safe and well tolerated with low rates of unplanned treatment discontinuation. Thromboembolic and major bleeding complications are rare and seem to occur predominantly in the early phase of PE treatment. At ASH, updated results from our registry will be presented Disclosures: Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Pfizer: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Bayer Healthcare: Research Funding, Speakers Bureau.

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A Review on the Use of Reversal Agents of Direct Oral Anticogulant Drugs in Case of Gastrointestinal Bleeding

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200624193938 ◽

2020 ◽

Vol 15 ◽

Author(s):

Veronica Ojetti ◽

Angela Saviano ◽

Mattia Brigida ◽

Luisa Saviano ◽

Alessio Migneco ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Medical Emergency ◽

Management Approach ◽

Emergency Setting ◽

Reversal Agents ◽

Life Threatening ◽

Andexanet Alfa

Background : Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant’s intake. Anticoagulants are commonly used for the prevention and the treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, betrixaban) showed a better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. Methods: We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. AIM: This review summarizes the current evidences about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with an active major bleeding or who need urgent surgery to offer physicians indications for a better management approach in order to increase patient’s safety. Conclusion: Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

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The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial Fibrillation

TH Open ◽

10.1055/s-0040-1721499 ◽

2020 ◽

Vol 04 (04) ◽

pp. e417-e426

Author(s):

Carline J. van den Dries ◽

Sander van Doorn ◽

Patrick Souverein ◽

Romin Pajouheshnia ◽

Karel G.M. Moons ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Routine Care ◽

P Value ◽

Risk Of Mortality ◽

Mortality Effect

Abstract Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0–5, 6–8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87–1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68–0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88–0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use (p-value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed (p-value for interaction <0.01). Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.

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

Blood ◽

10.1182/blood-2019-125356 ◽

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.

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Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and cancer a meta-analysis

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-020-02304-3 ◽

2020 ◽

Cited By ~ 2

Author(s):

Marco Valerio Mariani ◽

Michele Magnocavallo ◽

Martina Straito ◽

Agostino Piro ◽

Paolo Severino ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Major Bleeding ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Significant Risk ◽

Bleeding Complications ◽

Efficacy And Safety

Abstract Background Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established. Objective We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF. Methods An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users. Results The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52–0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74–0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52–0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50–0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47–0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78–1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78–1.06; p 0.24). Conclusions In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results.

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