Bleeding in Patients with Atrial Fibrillation Treated with Different Doses of Direct Oral Anticoagulants and Vitamin K Antagonists: A Population-Based Study

Abstract INTRODUCTION Recent large randomized controlled trials have shown that direct oral anticoagulants (DOACs) are at least as effective as vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation (AF) and are associated with similar or lower rates of bleeding. The results for bleeding seen in Phase 3 trials might not be applicable to real world practice. Population-based studies suggest that the bleeding risk for DOACs and VKA is similar however neither the risk of bleeding associated with different doses of DOACs nor that associated with apixaban in routine clinical practice is well established. We performed a large population-based study to determine the incidence of bleeding in patients with AF beginning treatment with different doses of dabigatran, rivaroxaban, apixaban or a VKA. METHODS From the computerized database of the 4.5 million member Israeli Clalit Health Services health care provider, consecutive patients initiating a VKA or DOAC for AF between January 1, 2011 and December 31, 2014 were studied. Bleeding patients who required hospitalization were identified and key clinical and laboratory data were recorded. Incidence of bleeding was calculated during the first 20 months of treatment which was the minimum duration of treatment for all of the drugs. Adjusted hazard ratios for overall bleeding, intracranial hemorrhage (ICH) and gastrointestinal (GI) bleeding and all-cause mortality within 30 days were recorded and case fatality rates were calculated as the proportions of bleeding patients who died within 30 days. RESULTS 26184 patients initiated anticoagulants for AF: 14258 received VKA, 214 -received dabigatran 75 mg, 3563 received dabigatran 110 mg , 1410 received dabigatran 150 mg, 2570 received rivaroxaban 15 mg, 2140 received rivaroxaban 20 mg, 1227 received apixaban 2.5 mg and 802 received apixaban 5 mg. Key patient demographics and the overall and site-specific bleeding rates are shown in table 1. Hazard ratios for any bleeding, ICH and GI bleeding adjusted for age, renal failure, CHADS2 score, aspirin use and Charlson comorbidity score favored dabigatran 150 mg versus VKA (P<0.05). The case fatality rate for VKA bleeding was 11,4%, dabigatran 110mg-10.5%, dabigatran 150 mg- 6.25%. rivaroxaban 15mg- 15.5%, rivaroxaban 20 mg- 10%, apixaban 2.5 mg- 11.4% and for apixaban 5mg-7.14% CONCLUSIONS The results of our population-based non-randomized study of unselected AF patients demonstrate a decreased bleeding rate for dabigatran 150mg and an increased bleeding rate for apixaban 2.5 mg compared to VKA. There was a consistent tendency for increased bleeding in patients receiving lower versus higher doses of the NOACs which probably reflects physician tendency to select lower doses of DOACs for patients at greater risk for bleeding. Disclosures Ellis: Boehringer Ingelheim: Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau. Eikelboom:Pfizer: Honoraria, Research Funding; Eli Lilly: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Astra Zeneca: Honoraria, Research Funding; Bristol Myer Squibb: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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Bleeding in Patients with Atrial Fibrillation Treated with Non Vitamin K Antagonist Oral Anticoagulants: A Population-Based Study

Blood ◽

10.1182/blood.v124.21.343.343 ◽

2014 ◽

Vol 124 (21) ◽

pp. 343-343 ◽

Cited By ~ 1

Author(s):

Martin H. Ellis ◽

Tsipora Neumann ◽

Jeffrey S Ginsberg ◽

John W Eikelboom ◽

Haim Bitterman ◽

...

Keyword(s):

Atrial Fibrillation ◽

Serum Creatinine ◽

Intracranial Hemorrhage ◽

Vitamin K ◽

Research Funding ◽

Oral Anticoagulants ◽

Case Fatality ◽

Population Based ◽

Vitamin K Antagonist ◽

Population Based Study

Abstract INTRODUCTION Recent large randomized controlled trials (RCTs) have shown non-vitamin K antagonist oral anticoagulants (NOACs) are at least as effective as vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation (AF) and are associated with similar or lower rates of bleeding. The results for bleeding seen in Phase 3 trials might not be applicable to real world practice. We performed a large population-based study to determine the incidence of bleeding in patients with AF beginning treatment with dabigatran, rivaroxaban or a VKA. METHODS From the computerized database of the 4.5 million member Israeli Clalit Health Services health care provider, consecutive patients initiating a VKA or NOAC for AF between January 1, 2011 and December 31, 2013 were studied. For prevention of embolism in AF, dabigatran had regulatory approval for 36 months and rivaroxaban for 24 months. Bleeding patients who required hospitalization were identified and key clinical and laboratory data were recorded. Because patients received different anticoagulants for different durations, time-to-event analyses were performed and bleeding incidences were calculated and reported as rates per 100 patient-years of treatment. Bleeding sites and all-cause mortality within 30 days were recorded and case fatality rates were calculated as the proportions of bleeding patients who died within 30 days. RESULTS (Table1) 18249 patients initiated anticoagulants for AF: 9564 received VKA, 4170 received dabigatran 110 mg bid , 1806 received dabigatran 150 mg bid and 2709 received rivaroxaban. The bleeding rates per 100 patient-years were 3.9 in VKA-treated patients, 2.8 in dabigatran 150 mg patients, 4.6 in dabigatran 110 mg patients and 4.3 in rivaroxaban patients. The intracranial hemorrhage (ICH) rates per 100 patient-years were 0.70 in VKA-treated patients, 0.37 in dabigatran 150 mg patients, 0.49 in dabigatran 110 mg patients and 0.27 in rivaroxaban patients. The gastrointestinal (GI) hemorrhage rates per 100 patient-years were 1.88 in VKA-treated patients, 1.85 in dabigatran 150 mg patients, 3.36 in dabigatran 110 mg patients and 2.39 in rivaroxaban patients. The case fatality rate for any bleed was 21%; for ICH 28.8%, and for GI bleeds it was 11.1%. Multivariate analysis revealed that increased age and increased serum creatinine were risk factors for bleeding in NOAC-treated patients. CONCLUSIONS The results of our population-based non-randomized study of AF patients are consistent with the RCTs in showing similar rates of overall bleeding, an increase in GI bleeding associated with dabigatran and a reduction in ICH seen with both dabigatran and rivaroxaban. Table 1: Clinical profile of patient cohort VKA Dabigatran 150 mg Dabigatran 110 mg Rivaroxaban Overall Number of patients 9564 1806 4170 2709 18249 Age in years) Median (Range) 79 (27-99) 78 (52-89) 82 (55-95) 82 (58-91) 80 (27-99) Women % 43.8 45.1 47 38.6 43.7 Serum creatinine mg/dL Median (Range) 1.2 (0.3-11.6) 1.0 (0.5-4.4) 1.2 (0.4-4.1) 1.3 (0.5-3.5) 1.2 (0.3-11.6) CHADS2 score Median (Range) 3 (0-6) 3 (1-6) 4 (1-6) 4 (2-6) 3 (0-6) Anti aggregant use (%) 52 50 35 55 48 Bleeds per 100 patient years (N) 3.9 (372) 2.8 (50) 4.6 (191) 4.3 (116) (729) Fatalities within 1 month of hemorrhage N 44 8 15 3 70 Intracranial hemorrhage N 67 4 16 3 90 Gastrointestinal hemorrhage N 178 20 108 26 332 Disclosures Ellis: Boehringer Ingelheim: Honoraria. Eikelboom:Bayer: Honoraria, Research Funding; Bristol Meyers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding.

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Use of Direct Oral Anticoagulants in Patients with Sickle Cell Disease and Venous Thromboembolism Is Associated with a Significant Decrease in Incidence of Bleeding Compared to Vitamin K Antagonists and Low-Molecular-Weight Heparins

Blood ◽

10.1182/blood.v130.suppl_1.978.978 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 978-978

Author(s):

Ameet Patel ◽

Hants Williams ◽

Maria R. Baer ◽

Ann Butler Zimrin ◽

Jennie Y Law

Keyword(s):

Molecular Weight ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Event ◽

Low Molecular Weight ◽

Inclusion Criteria ◽

Cell Disease ◽

Bleeding Events ◽

Bleeding Rate

Abstract Background: Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD). Several studies confirm that SCD itself is an independent risk factor for development of VTE. However, the optimal pharmacologic anticoagulant remains unknown. Methods: This retrospective single-institution cohort study was exempt by the Institutional Review Board. Data were collected via review of electronic medical records including ambulatory, emergency department, general floor, and intensive care unit encounters. Patients with SCD were identified spanning 1/2009-7/2017 using ICD 9/10 codes. Inclusion criteria were age ≥18 years at time of VTE diagnosis, imaging confirming VTE, and documented compliance based on INR values and/or provider/pharmacy documentation. VTE diagnosis included deep vein thrombosis (DVT) at any location and pulmonary embolism based on documented imaging and ICD 9/10 codes. Anticoagulants included direct oral anticoagulants (DOACs), vitamin K antagonists (VKA), and low-molecular-weight heparin (LMWH). The DOACs used in this study were rivaroxaban, apixaban and dabigatran. Exclusion criteria were known active malignancy, confirmed hypercoagulable risk factors beyond SCD, atrial fibrillation and/or history of major bleeding prior to anticoagulation. Due to low event rates, a log likelihood ratio test of independence was calculated for associations between drug type and two endpoints: bleeding rate and rate of VTE recurrence. Rate of VTE recurrence was defined as a newly diagnosed VTE within 6 months of initiation of anticoagulation. Bleeding rate was defined using International Society on Thrombosis and Hemostasis criteria: bleeding event into a critical site and/or a ≥2 point decrease in baseline hemoglobin. Results: A total of 109 patients with SCD met inclusion criteria. 66 patients (60%) were female. SCD genotypes represented included HbSS in 91 patients (83%), HbSC in 12 (11%) and HbS β+ thalassemia in 4 (4%). There were no patients with HbS-β0 thalassemia. VTEs consisted of 69 DVTs and 43 pulmonary emboli. 31 out of 109 VTEs were provoked, including 30 catheter-related incidents. After initial VTE event, 32 patients received a VKA, 34 received LMWH, and 43 received a DOAC. Within the class of DOACs, 31 patients received rivaroxaban, 5 received apixaban, and 7 received dabigatran. Sixteen of 109 patients (15%) experienced a clinically significant bleeding event, including 8 on VKA, 6 on LMWH, and 2 on a DOAC. Bleeding incidence was least with the DOAC class [0.22 CI (0.04-0.84) p < 0.05], greatest with warfarin [1.55 CI (0.57-4.33) p < 0.05] and slightly less with LMWH [0.64 CI (0.23-1.73) p < 0.05]. There was a significant decrease in incidence of bleeding events in patients receiving a DOAC for anticoagulation, compared to a VKA or LMWH (p = 0.033). At a median follow-up of 11.8 months (range, 3.4 - 60 months), 33 patients had a recurrent VTE, including 10 on VKA, 10 on LMWH and 13 taking a DOAC (p = 0.833). An association between VTE and SCD genotype could not be identified due to small numbers of patients with non-HbSS genotypes. Conclusion: In patients with SCD and VTE, there was a significant decrease in incidence of bleeding events in patients receiving a DOAC for anticoagulation, compared to a VKA or LMWH (p = 0.033). There was no difference between VTE recurrence rate and choice of initial anticoagulation. Figure Figure. Disclosures No relevant conflicts of interest to declare.

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Thrombotic and Bleeding Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants and Vitamin K Antagonists in Patients with Non-Valvular Atrial Fibrillation - a Comparative Analysis

Blood ◽

10.1182/blood-2018-99-111698 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1234-1234

Author(s):

Joseph R. Shaw ◽

Tinghua Zhang ◽

Gregoire Le Gal ◽

James Douketis ◽

Marc Carrier

Keyword(s):

Major Bleeding ◽

Research Funding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Risk ◽

Advisory Board ◽

Bleeding Events ◽

Chads2 Score ◽

High Bleeding Risk

Abstract Background: Atrial fibrillation (AF) is a common disorder that will affect up to 5.6 million patients in the U.S. by 2050. Both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs), typically warfarin, are used for stroke prevention in AF and such patients frequently undergo invasive procedures requiring anticoagulant interruption. Temporary interruption of anticoagulants can be associated with significant morbidity and mortality in the form of thromboembolic and bleeding complications. DOACs have a short half-life and fast onset of action, thereby facilitating their perioperative management as compared to VKAs. Despite important differences in perioperative management and pharmacokinetics between DOACs and VKAs, there is a paucity of data comparing perioperative outcomes in DOAC and VKA-treated patients. Methods: We undertook a single-center, retrospective chart review that compared consecutive DOAC- or warfarin-treated patients with AF who underwent perioperative anticoagulant interruption for invasive procedures between January 2017 and March 2018. Perioperative warfarin interruption was done as per CHEST guidelines (Douketis et al. Chest 141,2 Suppl). Perioperative bridging with low-molecular-weight heparin was only used for patients with CHADS2 scores of 5-6 or in patients with stroke within the past 6 months. Perioperative interruption of DOACs was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Primary outcomes included the 30-day post-operative thromboembolic and major bleeding rates. Secondary outcomes included the 30-day clinically relevant non-major bleeding (CRNMB) andl mortality rates. Major bleeding and CRNMB were defined according to ISTH definitions. Procedural bleeding risk was defined as per Schulman et al (Circulation 2015; 132(3)). Outcome events were independently adjudicated by two investigators. Outcomes from patients on DOACs and VKAs were compared. Demographic data was analyzed on a per-patient basis, p-values were calculated using independent T-Test, Chi-Square/Fisher's Exact Test where appropriate. Outcome data was analyzed on a per-interruption basis. P-values for unadjusted and adjusted comparisons were calculated using generalized estimating equations (GEE) to account for correlation between multiple procedures on the same patients. Results: 325 DOAC patients and 199 warfarin patients underwent 351 and 221 periprocedural interruptions, respectively. Warfarin patients had a significantly higher mean age, CHADS2 score, and proportion with renal dysfunction (Table 1). There was no statistically significant difference in 30-day post-operative rates of thromboembolism, CRNMB, and overall mortality, but warfarin patients had a significantly higher rate of major bleeding (Table 2). This latter result remained statistically significant following multivariate logistic regression correction for age, CHADS2 score and level of renal dysfunction. All bleeding events occurred post-procedure, with major bleeding events occurring from post-operative day 1 to post-operative day 25. None of the warfarin patients with major bleeding received perioperative bridging; the mean international normalized ratio (INR) at the time of major bleeding was 3.3. Most major bleeding events (7/8) in the VKA arm were surgical, with a single non-surgical major-bleed (spontaneous ICH on post-operative day 15 following urological surgery). Conclusions: The perioperative interruption of warfarin was associated with a higher 30-day rate of major bleeding as compared with DOAC interruption. Re-initiation of warfarin should be done judiciously following high bleeding risk procedures, and close INR monitoring may be warranted. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:Janssen: Consultancy; Pfizer: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; Portola: Other: Advisory Board; The Medicines Company: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Biotie: Other: Advisory Board; Bayer: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; BMS: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board. Carrier:Bayer: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

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Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study

Gastroenterology ◽

10.1053/j.gastro.2016.12.018 ◽

2017 ◽

Vol 152 (5) ◽

pp. 1014-1022.e1 ◽

Cited By ~ 81

Author(s):

Neena S. Abraham ◽

Peter A. Noseworthy ◽

Xiaoxi Yao ◽

Lindsey R. Sangaralingham ◽

Nilay D. Shah

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Large Population ◽

Population Based ◽

Population Based Study ◽

Gastrointestinal Safety

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

Blood ◽

10.1182/blood-2018-99-111207 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 426-426 ◽

Cited By ~ 1

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.

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Shifting the Paradigm: A Population Health Approach to the Management of Direct Oral Anticoagulants

Journal of the American Heart Association ◽

10.1161/jaha.121.022758 ◽

2021 ◽

Author(s):

Arthur L. Allen ◽

Jessica Lucas ◽

David Parra ◽

Patrick Spoutz ◽

Jeffery L. Kibert ◽

...

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Inappropriate Prescribing ◽

Population Based ◽

Management Tool ◽

Management Approach ◽

Veterans Health ◽

Health Administration ◽

The Impact

Abstract Over the past decade, direct oral anticoagulants (DOACs) have contributed to a major paradigm shift in thrombosis management, replacing vitamin K antagonists as the most commonly prescribed anticoagulants in many countries. While DOACs provide distinct advantages over warfarin (eg, convenience, simplicity, and safety), they are frequently associated with inappropriate prescribing and adverse events. These events have prompted regulatory agencies to mandate oversight, which individual institutions may find difficult to comply with given limited resources. Veterans Health Administration (VHA) has leveraged technology to develop the DOAC Population Management Tool (PMT) to address these challenges. This tool has empowered VHA to update a 60‐year standard of care from one‐to‐one provider‐to‐patient anticoagulation monitoring to a population‐based management approach. The DOAC PMT allows for the oversight of all patients prescribed DOACs and leads to intervention only when clinically indicated. Using the DOAC PMT, facilities across VHA have maximized DOAC oversight while minimizing resource usage. Herein, we discuss how the DOAC PMT was conceived, developed, and implemented, along with the challenges encountered throughout the process. Additionally, we share the impact of the DOAC PMT across VHA, and the potential of this approach beyond anticoagulation and VHA.

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Adherence and persistence to direct oral anticoagulants in atrial fibrillation: a population-based study

Heart ◽

10.1136/heartjnl-2019-315307 ◽

2019 ◽

Vol 106 (2) ◽

pp. 119-126 ◽

Cited By ~ 11

Author(s):

Amitava Banerjee ◽

Valerio Benedetto ◽

Philip Gichuru ◽

Jane Burnell ◽

Sotiris Antoniou ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Median Number ◽

Population Based ◽

Cardiovascular Comorbidities ◽

One Year ◽

Over Time

BackgroundDespite simpler regimens than vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF), adherence (taking drugs as prescribed) and persistence (continuation of drugs) to direct oral anticoagulants are suboptimal, yet understudied in electronic health records (EHRs).ObjectiveWe investigated (1) time trends at individual and system levels, and (2) the risk factors for and associations between adherence and persistence.MethodsIn UK primary care EHR (The Health Information Network 2011–2016), we investigated adherence and persistence at 1 year for oral anticoagulants (OACs) in adults with incident AF. Baseline characteristics were analysed by OAC and adherence/persistence status. Risk factors for non-adherence and non-persistence were assessed using Cox and logistic regression. Patterns of adherence and persistence were analysed.ResultsAmong 36 652 individuals with incident AF, cardiovascular comorbidities (median CHA2DS2VASc[Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category] 3) and polypharmacy (median number of drugs 6) were common. Adherence was 55.2% (95% CI 54.6 to 55.7), 51.2% (95% CI 50.6 to 51.8), 66.5% (95% CI 63.7 to 69.2), 63.1% (95% CI 61.8 to 64.4) and 64.7% (95% CI 63.2 to 66.1) for all OACs, VKA, dabigatran, rivaroxaban and apixaban. One-year persistence was 65.9% (95% CI 65.4 to 66.5), 63.4% (95% CI 62.8 to 64.0), 61.4% (95% CI 58.3 to 64.2), 72.3% (95% CI 70.9 to 73.7) and 78.7% (95% CI 77.1 to 80.1) for all OACs, VKA, dabigatran, rivaroxaban and apixaban. Risk of non-adherence and non-persistence increased over time at individual and system levels. Increasing comorbidity was associated with reduced risk of non-adherence and non-persistence across all OACs. Overall rates of ‘primary non-adherence’ (stopping after first prescription), ‘non-adherent non-persistence’ and ‘persistent adherence’ were 3.5%, 26.5% and 40.2%, differing across OACs.ConclusionsAdherence and persistence to OACs are low at 1 year with heterogeneity across drugs and over time at individual and system levels. Better understanding of contributory factors will inform interventions to improve adherence and persistence across OACs in individuals and populations.

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Impact of Reduced-Dose Nonvitamin K Antagonist Oral Anticoagulants on Outcomes Compared to Warfarin in Korean Patients with Atrial Fibrillation: A Nationwide Population-Based Study

Journal of Clinical Medicine ◽

10.3390/jcm10173918 ◽

2021 ◽

Vol 10 (17) ◽

pp. 3918

Author(s):

Sola Han ◽

Young-Hoon Kim ◽

Myung-Yong Lee ◽

Oh Young Bang ◽

Sung-Won Jang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Lower Risk ◽

Oral Anticoagulants ◽

Population Based ◽

Systemic Embolism ◽

Nonvalvular Atrial Fibrillation ◽

Population Based Study ◽

Reduced Dose ◽

Asian Patients ◽

Hazard Ratios

Reduced-dose nonvitamin K antagonist oral anticoagulants (NOACs) are commonly prescribed to Asian patients with nonvalvular atrial fibrillation (NVAF). We aimed to compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between patients treated with reduced-dose NOACs and those treated with warfarin, using the claims database in Korea. Patients with NVAF newly initiated on oral anticoagulants (OACs; apixaban, dabigatran, rivaroxaban, and warfarin) between 1 July 2015 and 30 November 2016 were included. Among all patients with NVAF treated with OACs, 5249, 6033, 7602, and 8648 patients were treated with reduced-dose apixaban, dabigatran, rivaroxaban, and warfarin, respectively. Patients treated with reduced-dose NOACs were older and had higher CHA2DS2-VASc and HAS-BLED scores than those treated with warfarin. Compared to warfarin, all reduced-dose NOACs showed significantly lower risk of S/SE (hazard ratios (95% confidence interval), 0.63 (0.52–0.75) for apixaban; 0.51 (0.42–0.61) for dabigatran; and 0.67 (0.57–0.79) for rivaroxaban) and MB (0.54 (0.45–0.65) for apixaban; 0.58 (0.49–0.69) for dabigatran; 0.73 (0.63–0.85) for rivaroxaban). In the real-world practice among Asians with NVAF, all reduced-dose NOACs were associated with a significantly lower risk of S/SE and MB compared to those of warfarin.

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Bleeding Outcomes of Gastrointestinal Cancer Patients Treated with Direct Oral Anticoagulants Vs. Low Molecular Weight Heparin

Blood ◽

10.1182/blood-2020-136757 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-27

Author(s):

Dana E Angelini ◽

Doaa Attia ◽

Wei Wei ◽

Mailey L Wilks ◽

Barbara Tripp ◽

...

Keyword(s):

Molecular Weight ◽

Cancer Patients ◽

Research Funding ◽

Low Molecular Weight Heparin ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Low Molecular Weight ◽

Bleeding Rate ◽

Gi Cancer ◽

Gi Cancers

Introduction: In recent years, direct oral anticoagulants (DOACs) have been adopted as a treatment option for cancer associated thrombosis (CAT). Randomized trials comparing anti-Xa drugs to low molecular weight heparin (LMWH) showed treatment with DOACs conferred less risk of recurrent venous thromboembolism (VTE), but found higher rates of clinically important bleeding, especially in patients with gastrointestinal (GI) malignancies. Given these findings, there is a need for additional data regarding the safety of DOAC use in GI malignancies. Here, we report bleeding events of GI cancer patients treated with anticoagulation in a large centralized CAT clinic. Methods: We evaluated a prospective cohort of patients referred to our CAT clinic from 8/2014-10/2019. Patients with primary gastrointestinal malignancies treated with therapeutic anticoagulation with LMWH or a DOAC for acute VTE were included. Bleeding was defined using the ISTH criteria for major and clinically relevant non-major bleeding (CRNMB). Bleeding rates were compared between luminal [anus/anal, colon, esophagus, rectal, stomach] and extraluminal GI cancers [gallbladder, liver/bile duct, and pancreas]. Patient characteristics associated with bleeding were evaluated with Fisher's exact test and the association of age with bleeding was analyzed by Wilcoxan rank sum test. Results: Of 463 patients with acute VTE, 73 patients (15.8%) with primary GI tumors were included in the analysis. Males comprised 57.5% of the population, median age was 62 (range 36-86), and 61.6% had stage 4 disease. Figure 1 shows a breakdown of tumor types. Enoxaparin was the most commonly used anticoagulant (n=48, 65.8%), followed by DOAC (n=25, 34.2%). Overall, 16 (21.9%) patients had a bleeding event within 6 months of treatment (7 major bleeds and 9 CRNMB). There was no difference in 6-month bleeding rate between patients treated with LMWH (n= 9, 18.8%) vs. DOAC (n=7, 28.0%), p=0.39. None of the clinical factors analyzed were significantly associated with bleeding (Table 1). There was no difference in bleeding rate in patients with luminal GI cancers vs. extraluminal GI cancers and no difference was found in a three-way association between site, treatment, and bleeding, p=0.40 (Table 2). Conclusions: In our centralized cancer thrombosis clinic, patients with GI malignancies had similar rates of major and CRNMB when treated with LMWH or DOAC. In both cohorts, bleeding rates were high within 6 months of starting anticoagulation. There were no statistically significant differences in bleeding rates based on several clinical characteristics evaluated in this study. Although limited by a small patient population, this study adds to the knowledge of treating GI malignancies with DOACs. There is a need for further prospective evaluations regarding the safety of DOAC use in GI cancer patients and there remains an unmet need for antithrombotic treatments that do not increase bleeding potential. Disclosures McCrae: Novartis: Honoraria; Momenta Pharmaceuticals: Consultancy; Rigel: Consultancy; Dova: Consultancy. Khorana:Bayer: Honoraria; Pharmacyte: Honoraria; Pharmacyclics: Honoraria; Array: Other: Research funding (to institution); Merck: Research Funding; Leap: Research Funding; BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Medscape: Honoraria; Leo Pharma: Honoraria; Janssen: Honoraria.

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Safety and efficacy of direct acting oral anticoagulants and vitamin K antagonists in nonvalvular atrial fibrillation – a network meta-analysis of real-world data

VASA ◽

10.1024/0301-1526/a000746 ◽

2019 ◽

Vol 48 (2) ◽

pp. 134-147 ◽

Cited By ~ 8

Author(s):

Mirko Hirschl ◽

Michael Kundi

Keyword(s):

Real World ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Efficacy And Safety ◽

Nonvalvular Atrial Fibrillation ◽

Real World Data ◽

Hazard Ratios ◽

Direct Acting ◽

Event Rates

Abstract. Background: In randomized controlled trials (RCTs) direct acting oral anticoagulants (DOACs) showed a superior risk-benefit profile in comparison to vitamin K antagonists (VKAs) for patients with nonvalvular atrial fibrillation. Patients enrolled in such studies do not necessarily reflect the whole target population treated in real-world practice. Materials and methods: By a systematic literature search, 88 studies including 3,351,628 patients providing over 2.9 million patient-years of follow-up were identified. Hazard ratios and event-rates for the main efficacy and safety outcomes were extracted and the results for DOACs and VKAs combined by network meta-analysis. In addition, meta-regression was performed to identify factors responsible for heterogeneity across studies. Results: For stroke and systemic embolism as well as for major bleeding and intracranial bleeding real-world studies gave virtually the same result as RCTs with higher efficacy and lower major bleeding risk (for dabigatran and apixaban) and lower risk of intracranial bleeding (all DOACs) compared to VKAs. Results for gastrointestinal bleeding were consistently better for DOACs and hazard ratios of myocardial infarction were significantly lower in real-world for dabigatran and apixaban compared to RCTs. By a ranking analysis we found that apixaban is the safest anticoagulant drug, while rivaroxaban closely followed by dabigatran are the most efficacious. Risk of bias and heterogeneity was assessed and had little impact on the overall results. Analysis of effect modification could guide the clinical decision as no single DOAC was superior/inferior to the others under all conditions. Conclusions: DOACs were at least as efficacious as VKAs. In terms of safety endpoints, DOACs performed better under real-world conditions than in RCTs. The current real-world data showed that differences in efficacy and safety, despite generally low event rates, exist between DOACs. Knowledge about these differences in performance can contribute to a more personalized medicine.

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