Bleeding Hazard Ratio Research Articles

Outcomes associated with sodium glucose co-transporter 2 inhibitors in anticoagulated atrial fibrillation patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Sodium glucose co-transporter 2 inhibitors (SGLT2i) have been associated with favourable outcomes in patients with heart failure. Studies also indicate a reduced risk of atrial fibrillation (AF). Purpose We performed an exploratory analysis to evaluate the impact of SGLT2 inhibitors in anticoagulated patients with AF. Method All anticoagulated patients with AF and type 2 diabetes between January 2014 and December 2018 were identified from a federated electronic medical record database (TriNetX), and followed up for 3 years. A 1:1 propensity score matched (PSM) analysis was performed to balance the SGLT-2i and non-SGLT-2i cohorts. The primary outcome was ischaemic stroke/ transient ischaemic attack (TIA), bleeding events, hospitalisation for AF and composite of cardioversion and ablations. Secondary outcomes included all-cause mortality, haemorrhagic stroke, ventricular arrhythmias, cardiac arrest, incident heart failure and composite of arterial and venous thrombotic events. Results A total of 236,493 and 20,841 were identified from the non-SGLT2 and SGLT2 inhibitor groups respectively. After PSM, each group had 17,968 patients. In anticoagulated AF patients, SGLT2 inhibitor use was associated with a significantly lower risk of ischaemic stroke/ TIA, hazard ratio (HR) 0.759 (95% CI 0.719-0.802), bleeding HR 0.657 (95% CI 0.619-0.697), hospitalisation for AF HR 0.875 (95% CI 0.855-0.897), and composite of cardioversion/ablations HR 0.705 (95% CI 0.655-0.759). A lower risk of all-cause mortality HR 0.481 (95% CI 0.453-0.510), haemorrhagic stroke HR 0.54 (95% CI 0.454-0.642), ventricular arrhythmias HR 0.766 (95% CI 0.719-0.816), cardiac arrests HR 0.539 (95% CI 0.476-0.611), incident heart failure HR 0.709 (95% CI 0.661-0.760) and composite of arterial and venous thrombotic events HR 0.737 (95% CI 0.712-0.763) were also observed with SGLT2 inhibitor use. Conclusion Our findings suggest that SGLT2i use is associated with a lower risk of AF-related complications such as ischaemic stroke/ TIA, bleeding, ventricular arrhythmias and reduced need for procedures such as cardioversion and ablations. Further studies are required to confirm this association.

Abstract 13168: Benefits of Apixaban Over Warfarin are Preserved Independent of Warfarin Time in Therapeutic Range: Insights From the AUGUSTUS Trial

Introduction: In the AUGUSTUS trial, patients randomized to apixaban had lower rates of major or clinically relevant non-major (CRNM) bleeding, lower rates of death or hospitalization, and similar rates of death or ischemic events compared with warfarin. Patients randomized to aspirin (ASA) had higher rates of bleeding with similar rates of death or hospitalization, and death or ischemic event. The impact of warfarin time-in-therapeutic-range (TTR) on these outcomes is not known; however, it is plausible that sites achieving better TTR might have better outcomes with warfarin use. Methods: Using average site TTR, we assessed the hazard of bleeding, ischemic events, and death/hospitalization across quartiles of site-based TTR. These analyses were performed for both randomized strategies: apixaban vs warfarin and ASA vs placebo. Results: This analysis included data from 4420 patients at 399 sites. Site TTR was separated into quartiles of TTR (Q1: 0-49%, Q2: 42-55%, Q3: 56-69%, Q4: 70-100%). Sites with higher TTR tended to have fewer female patients (32.4% Q1 vs 25.4% Q4), more White patients (88.5% Q1 vs 97.1% Q4), and more patients previously prescribed oral anticoagulants (44.5% Q1 vs 52.5% Q4). There was no significant interaction between site TTR quartile and the hazard ratio (HR) for bleeding, death or hospitalization, or death or ischemic event with apixaban vs warfarin, or on the HR for bleeding, or death or hospitalization with ASA vs placebo (Figure). There was a borderline significant interaction (p<0.047) between site TTR quartile and the HR for death or ischemic events with ASA vs placebo, such that patients at sites with higher TTR were more likely to derive a benefit from ASA compared with placebo. Conclusion: The benefits of apixaban over warfarin seen previously in AUGUSTUS are consistent across the spectrum of quartiles of site TTR. Patients at sites with higher average TTR may be more likely to derive a benefit from aspirin use to prevent death or ischemic events.

P4779High facility preference for rivaroxaban in atrial fibrillation increases risk of major bleeding compared to facility preference for apixaban

Abstract Background No randomized trial has compared efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF). Previous real-world comparisons could be biased by patient characteristics of importance for treatment selection, but instrumental variables could potentially account for measured and unmeasured confounders. Purpose To compare efficacy and safety of rivaroxaban and apixaban using facility preference for type of NOAC as instrumental variable. Methods AF patients started on apixaban or rivaroxaban were identified using nationwide registries. We categorized patients according to facility preference for type of NOAC, measured as percentage of the prior 20 AF patients started on rivaroxaban in the same facility. Occurrence of stroke/thromboembolism (TE), major bleeding, myocardial infarction and all-cause mortality during two years of follow-up were investigated using adjusted Cox regressions. To further examine general frailty according to facility preferences we also investigated occurrence of cancer, urogenital tract infection, dehydration and fracture. Results We analyzed 6264 AF patients initiated on rivaroxaban or apixaban. Compared with patients treated in facilities that used rivaroxaban in 0–20% of cases, the adjusted hazard ratio for bleeding was 1.05 when treated in a facility with 25–40% use; 1.40 with 45–60% use; 1.50 with 65–80% use; and 1.81 for 85–100% use (Ptrend=0.002). Higher facility level use of rivaroxaban was not associated with increased risk of stroke/TE (Ptrend=0.06), myocardial infarction (Ptrend=0.87) or all-cause mortality (Ptrend=0.91), and there was no association between facility preference for rivaroxaban and risk of cancer (Ptrend=0.83), urogenital tract infection (Ptrend=0.49), dehydration (Ptrend=0.91) or fracture (Ptrend=0.47). Characteristics by facility preference Percent of previous AF patients from facility started on rivaroxaban P for trend 0–20% 25–40% 45–60% 65–80% 85–100% No. of patients 1406 1421 1551 930 956 Received rivaroxaban, (%) 279, (19.8) 499, (35.1) 711, (45.8) 632, (68.0) 774, (81.0) <0.001 Standard dose, (%) 1216, (86.5) 1232, (86.7%) 1366, (88.1%) 793, (85.3%) 824, (86.2%) 0.62 Median age, (interquartile range) 70, (63.3–74) 69, (63–74) 70, (64–74) 70, (64–75) 70, (63–75) 0.11 Below median income, (%) 740, (52.6) 699, (49.2) 764, (49.3) 458, (49.3) 471, (49.3) 0.31 Prior stroke, (%) 99, (7.0) 115, (8.1) 134, (8.6) 69, (7.4) 74, (7.7) 0.56 Prior bleeding, (%) 136, (9.7) 141, (9.9) 163, (10.5) 91, (9.8) 97, (10.1) 0.51 Antiplatelet therapy, (%) 445, (31.7) 465, (32.7) 491, (31.7) 303, (32.6) 317, (33.2) 0.49 Rate of events according to instrument Conclusion High facility preference for rivaroxaban increases risk of major bleeding compared to facility preference for apixaban. Acknowledgement/Funding This study was funded by an unrestricted grant from the Capital Region of Denmark, Foundation for Health Research.

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

INTRODUCTIONRecent 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.METHODSFrom 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.RESULTS26184 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%CONCLUSIONSThe 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. [Display omitted] DisclosuresEllis: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.

Incremental Value of the CRUSADE, ACUITY, and HAS-BLED Risk Scores for the Prediction of Hemorrhagic Events After Coronary Stent Implantation in Patients Undergoing Long or Short Duration of Dual Antiplatelet Therapy.

BackgroundMultiple scores have been proposed to stratify bleeding risk, but their value to guide dual antiplatelet therapy duration has never been appraised. We compared the performance of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HAS‐BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) scores in 1946 patients recruited in the Prolonging Dual Antiplatelet Treatment After Grading Stent‐Induced Intimal Hyperplasia Study (PRODIGY) and assessed hemorrhagic and ischemic events in the 24‐ and 6‐month dual antiplatelet therapy groups.Methods and ResultsBleeding score performance was assessed with a Cox regression model and C statistics. Discriminative and reclassification power was assessed with net reclassification improvement and integrated discrimination improvement. The C statistic was similar between the CRUSADE score (area under the curve 0.71) and ACUITY (area under the curve 0.68), and higher than HAS−BLED (area under the curve 0.63). CRUSADE, but not ACUITY, improved reclassification (net reclassification index 0.39, P=0.005) and discrimination (integrated discrimination improvement index 0.0083, P=0.021) of major bleeding compared with HAS‐BLED. Major bleeding and transfusions were higher in the 24‐ versus 6‐month dual antiplatelet therapy groups in patients with a CRUSADE score >40 (hazard ratio for bleeding 2.69, P=0.035; hazard ratio for transfusions 4.65, P=0.009) but not in those with CRUSADE score ≤40 (hazard ratio for bleeding 1.50, P=0.25; hazard ratio for transfusions 1.37, P=0.44), with positive interaction (P int=0.05 and P int=0.01, respectively). The number of patients with high CRUSADE scores needed to treat for harm for major bleeding and transfusion were 17 and 15, respectively, with 24‐month rather than 6‐month dual antiplatelet therapy; corresponding figures in the overall population were 67 and 71, respectively.ConclusionsOur analysis suggests that the CRUSADE score predicts major bleeding similarly to ACUITY and better than HAS BLED in an all‐comer population with percutaneous coronary intervention and potentially identifies patients at higher risk of hemorrhagic complications when treated with a long‐term dual antiplatelet therapy regimen.Clinical Trial Registration URL: http://clinicaltrials.gov. Unique identifier: NCT00611286.

Abstract 17718: New Oral Anticoagulants: Bleeding Rates Among Medicare Beneficiaries With Atrial Fibrillation

Introduction: In randomized trials of patients with non-valvular atrial fibrillation (AF), new oral anticoagulants (NOACs) have been shown to confer a lower risk of major bleeding than warfarin. Outside of these select study settings, bleeding outcomes for these medications have not been examined sufficiently. We studied a national sample of patients with AF to explore bleeding risks associated with NOACs in routine clinical settings. Methods: Using a 40% Medicare random sample denominator file and associated inpatient, outpatient and prescription administrative data from 2009-2012, we identified patients age 65 and older with new onset, non-valvular AF. Cox regression models estimated risk of upper gastrointestinal (UGI) and nontraumatic intracranial (IC) bleeding associated with NOAC (dabigatran and rivaroxaban) compared to warfarin use, adjusting for individual characteristics, morbidities, and time-varying medication use. The analysis excluded person-months with concurrent prescriptions filled for an antiplatelet medication (e.g. clopidogrel). Results: We identified 157,390 incident AF patients, mean age 77.8 (standard deviation (SD) 7.8); mean follow up was 10.8 months (SD 6.9); In the first year post-index diagnosis, 41.5% of patients received some oral anticoagulant; of these, 28.2% used NOACs (75% dabigatran, 25% rivaroxaban). Overall 24,661 bleeding events were observed (11,015 UGI and 1,868 IC). Out of 1,487,675 person-months, 212,670 (14.3%) were excluded due to concurrent prescription antiplatelet exposure. Compared to warfarin, the hazard ratio for bleeding associated with NOAC was 1.33 (95% CI 1.21 to 1.47) for UGI, 0.59 (95% CI 0.42 to 0.82) for IC, and 1.09 (95% CI 1.02, 1.17) for all significant bleeding combined. Conclusions: Compared with warfarin, NOACs were associated with a lower risk of IC bleeding, a higher risk of UGI bleeding and a modestly higher risk of significant bleeding overall. These results should inform clinical decision-making and selection of individualized thromboembolism prophylaxis strategies among AF patients. Further studies are needed to illuminate the divergent UGI and IC bleeding risks observed and to identify patient-level factors predictive of these outcomes.