Prior Bleeding Research Articles

AF in TAVR patients: double trouble means double care

Abstract Introduction Atrial fibrillation (AF) and aortic stenosis share multiple common risk factors and aortic valve stenosis itself is associated with higher rate of AF. Patients submitted to transcatheter aortic valve replacement (TAVR) are particularly frail and AF is associated with increased mortality, ischemic and hemorrhagic events. Thus, a thorough approach, especially in such frail population, is warranted to reduce morbi-mortality. Bearing this in mind, a risk assessment tool derived from ENVISAGE-AF trial was recently developed to stratify the mortality risk of AF patients after completion of successful TVR. Purpose To characterize a population of patients with AF who implanted TAVR and test a newly proposed mortality score to estimate prognosis in this population. Methods Single-center observational retrospective study including consecutive pts with AF who implanted TAVI from 2017 to 2021. Clinical data was collected at baseline and during follow-up. The AF mortality score groups pts in three crescent strata of severity (0-10; 11-16; >16) by summing seven variables: age, creatinine clearance, duration of AF, NYHA class, alcohol consumption, peripheral artery disease and prior major bleeding. Kaplan Meyer survival analysis was performed using SPSS statistics. Results For 5 years, 621 pts underwent TAVR, of which 189 (30,4%) had previously diagnosed AF. 102pts were female, mean age of 82,6± 6,1 years. More than half (53%) had permanent AF, 28% paroxysmal AF and 19% persistent AF. During a mean follow up of 953 days, 8 (4,2%) pts suffered a major hemorrhagic event, two pts had ischemic arterial events (peripheral and mesenteric) and no venous thrombotic events were observed. As anticipated, event rate was high: at 1 year follow-up, 27 were admitted for cardiovascular events (3 with acute myocardial infarction and 4 with stroke). 26 pts died after 1-year (13,7%) and 30 died during available FUP (15,8%). The aforementioned AF mortality score was applied to our pts at baseline, before TAVR: 63%, 17.5% and 8.5% of patients were categorized as low, moderate or high risk. Patients in the high risk group (score>16) had a significantly higher rate of events during follow-up – figure1. Lower and intermediate group failed to show a clear separation in terms of risk estimation between them, which may be attributed to the paucity of events in these two groups. Conclusion AF and aortic stenosis are both burdensome diseases and AF increases the risk of events in TAVR population. We showed that a newly proposed score that stemmed from ENVISGE-AF can effectively select pts at high risk of mortality, in whom close clinical surveillance should be particularly rigorous.

Impact of proton pump inhibitor on quality of anticoagulant control and outcomes in atrial fibrillation patients treated with an oral anticoagulant in the COOL-AF registry

Abstract Introduction Proton pump inhibitor (PPI) is commonly prescribed in patients treated with antithrombotic therapy, assuming it will reduce bleeding risk irrespective of the risk of bleeding. Although PPI may reduce the risk of gastrointestinal bleeding in those treated with an oral anticoagulant, PPI may increase INR by accelerating warfarin absorption, thereby increasing the risk of bleeding. We aimed to assess the impact of PPI use on outcomes and quality of anticoagulant control in AF patients treated with OAC. Methods The COOL-AF registry was a nationwide prospective observational study enrolling AF patients from 27 hospitals in Thailand between 2014 and 2017. The registry aimed to evaluate antithrombotic patterns, quality of OAC control, and clinical outcomes. Clinical information of patients was collected every six months and until three years. Patients treated with oral anticoagulants (either warfarin or non-vitamin K antagonist OAC (NOAC)) were included in the present analysis. Patients receiving any PPI type and dosage at the registry entry were counted as PPI users. Poor anticoagulant control was defined as time to therapeutic range (TTR) less than 65%. The association between PPI use and outcomes, including GI bleeding, overall bleeding, all-cause mortality, and ischemic stroke or systemic embolization, were assessed in the Cox model adjusted for age, prior GI bleeding, chronic alcohol use, chronic kidney disease, liver disease, smoking, and baseline anemia. Subgroup analyses were performed in patients at high bleeding risk (HAS-BLED score ≥ 3), and in patients concomitantly treated with antiplatelet. Results Of 3,402 patients in the registry, 2568 (75.5%) were treated with OAC at baseline. The prevalence of females was 43.4%, with a mean age of 68.4 years. The majority of patients (91.1%) received warfarin. The incidence of major bleeding was 2.11 (1.79–2.48) per 100 person-years. PPI was used at baseline in 707 patients (20.8%). Compared with their counterpart, PPI was more frequently used in high-bleeding risk patients (27.3% vs. 18.1%, p < 0.001) and in those with concomitant antiplatelet therapy (37.5% vs. 17.1%, p < 0.001). The mean TTR was similar between PPI and non-PPI users (52.5% vs. 53.8%, p 0.37). PPI use was not associated with poor anticoagulant control (adjusted OR 1.12, 95% 0.89-1.40). The risk of GI bleeding in PPI users was similar to non-user (adjusted HR 1.01, 95%CI 0.59-1.75). The risk of all-cause mortality, ischemic stroke or systemic embolization, and overall bleeding was not different between PPI and non-PPI users. There was no significant interaction between PPI use and bleeding risk or concomitant antiplatelet therapy on adverse outcomes. Conclusion PPI use has no impact on major outcomes, including bleeding in AF patients treated with OAC. The practice of concomitant prescribing of PPI in patients treated with OAC is needed to be re-examined, given the potentially high impact of health care costs.PPI use and outcomes

Clinical characteristics of apixaban prescription in AF patients with single dose-reduction criterion: ASPIRE (efficacy and safety of apixaban in real-world practice in Korean frail patients with AF)

Abstract Background/Introduction Previous observational studies reported that off-label underdosed apixaban might be associated with a higher risk of stroke. However, the real-world clinical practice data on the off-label underdosed apixaban in patients with atrial fibrillation (AF) who meet single dose reduction criteria remains scarce. Purpose This study aimed to evaluate the apixaban dosing pattern in patients with AF who met a single dose reduction criterion. The difference in clinical characteristics underlying the on-label and off-label underdose prescription of apixaban was also assessed. Methods The efficAcy and Safety of aPixaban In REal-world practice in Korean frail patients with AF (ASPIRE) study is a multicenter, prospective cohort study. This study included patients with AF having a single dose reduction criterion of apixaban. Study subjects were categorized into two groups according to apixaban dose (on-label 5 mg twice daily [on-label], or off-label underdose 2.5 mg twice daily [off-label]). We evaluated the difference in the clinical characteristics were evaluated. Additionally, the ‘marginal zone’ was defined as age between 75 and 80 years, weight between 60 and 65kg, and creatinine level between 1.2-1.5mg/dL. Results A total of 1997 patients were included in this analysis (mean age 74.3±7.8 years, women 55.8%); 591 (29.7%) patients were 80 years or older, 1250 (62.6%) patients had body weight 60 kg or below, and 156 (7.8%) patients had serum creatinine 1.5mg/dL or higher. Of these patients, 1022 (51.2%) patients were prescribed off-label underdose apixaban. The off-label group was older and had higher mean CHA2DS2-VASC score, Charlson Comorbidity Index, and HAS-BLED scores than the on-label group. Hypertension, heart failure, prior bleeding history, chronic kidney disease, anemia, and concomitant antiplatelet agent usage were more prevalent in the off-label group, but prior stroke history was more common in on-label group. In the age ≥ 80 years group, the marginal zone serum creatinine was more prevalent in off-label group (p=0.011). In the body weight ≤ 60 kg group, the prevalence of marginal zone bodyweight and serum creatinine were higher in off-label group (p<0.001 and p=0.02, respectively). In creatinine ≥ 1.5 mg/dL group, the proportion of marginal zone body weight were more common in off-label underdose group (p=0.001) (Figure). Conclusions Among AF patients with a single dose reduction criterion for apixaban, almost half of the patients were prescribed off-label underdose apixaban. Physicians were more likely to prescribe off-label underdose apixaban in patients with more frail characteristics, whereas on-label apixaban was preferred in patients with prior history of stroke. The clinical outcome of off-label underdose apixaban would be compared with the on-label standard dose in a future study.

Quality of anticoagulation and outcomes after mechanical aortic valve replacement in patients with atrial fibrillation: a nationwide cohort study

Abstract Background Mechanical aortic valve replacement (AVR) remains predominant treatment approach for younger patients in need of aortic valve operation. However, little is known about the success of the required Vitamin K Antagonist (VKA) treatment and its relation to adverse events. Purpose We assessed the quality of VKA treatment prior to ischemic events and major bleeding episodes after mechanical AVR in AF patients. Methods The registry-based FinACAF study combining data from several Finnish health care registers covers all patients diagnosed with atrial fibrillation (AF) during 2007–2018 in Finland. In the present study, we included patients undergoing mechanical AVR before or after the AF diagnosis. Hazard ratios (HR) of first-ever ischemic stroke, any bleeding, intracranial bleeding, and myocardial infarction (MI) after AVR were estimated with Fine-Gray model adjusted for known bleeding and stroke risk factors. Results We identified 1086 patients (27.1% female, median age 62.8 (IQR 56.2–68.3) years) with mechanical AVR and AF diagnosis, either before (58.8%) or after (41.2%) the operation, and without prior bleeding episode, ischemic stroke, or MI. Cumulative incidence estimates at 10 years after AVR were 12.8% for ischemic stroke, 27.9% for significant bleeding, 5.8% for intracranial hemorrhage (ICH), and 7.2% for MI. International Normalized Ratio (INR) was <2.0 during 27.9–33.9% of ischemic events and lower mean Time in Therapeutic Range (TTR) with INR target ≥2.0 was associated with subsequent higher stroke occurrence (standardized adjusted HR 1.23 (1.03–1.49) for lower TTR, p=0.030, Figure 1). INR was >3.5 during 23.4–24.3% of major bleeding events and lower mean TTR (INR target 2.0–3.5) was associated with subsequent bleeding episode (adjusted HR 1.20 (1.03–1.41), p=0.021, Figure 2). Mortality was high (10-year estimated survival 71.1%), and lower mean TTR (INR target 2.0–3.5) was associated with higher mortality (adjusted HR 1.56 (1.39–1.72), p<0.001). Conclusions Adverse events after mechanical AVR are frequent in AF patients and mortality is high. Suboptimal mean TTR appears to identify the patients at high risk for both bleeding episodes and ischemic stroke.Figure 1.Figure 2.

Abstract 17095: Change in Oral Anticoagulant Use for Atrial Fibrillation From 2013 to 2018 Among US Veterans and the Impact of Frailty

Introduction: Direct oral anticoagulants (DOACs) are superior to warfarin in both efficacy and safety regardless of frailty status. Data on prescribing patterns of different oral anticoagulants (OACs) in frail older adults are limited. Methods: We utilized the Veterans Health Administration clinical data, to identify those aged 65 and older with a diagnosis of non-valvular atrial fibrillation (AF) who initiated anticoagulation in 2013 and 2018. Frailty was assessed using the 31-item VA Frailty Index (VA-FI). Patients were stratified into 3 categories. VA-FI: frail (frailty index >0.2), pre-frail (frailty index 0.11-0.2), and non-frail (frailty index 0-0.1). Baseline data on prior stroke, CHA 2 DS 2 -VASc score, and bleeding were extracted. Descriptive statistics and logistic regression were used to examine association of frailty with choice of OAC. Results: Among 39,647 Veterans included from 2013 and 2018, mean age was between 71 to 76. 99% were male and 88% white race. From 2013 to 2018, DOACs use increased from 21% to 88%, while warfarin use decreased accordingly. Among the OACs, dabigatran was dominant (65%) in 2013 but apixaban was dominant (66%) in 2018. Increasing frailty was associated with reduced use of DOACs (p<0.001 in 2013 and 2018). Regardless of the choice of drug, the prior bleeding and prior stroke/transient ischemic attack were mostly seen in the frail population ranging between 54-60% and 20-21% respectively. CHA 2 DS 2 -VASc score averaged 3 for non-frail, and 4 for prefrail and frail patients regardless of the year. (Figure) Conclusion: Prior bleeding and stroke episodes were more common among the frail population. There was significant reduction in use of DOACs in both years with increasing frailty. Studying the impact of anticoagulant choice on clinical outcomes among frail older adults with non-valvular AF are needed.

Abstract 17169: Beyond CHA2DS2-VASc: Independent Predictors of Ischemic Stroke in Patients With Atrial Fibrillation

Introduction: Factors outside of the CHA 2 DS 2 -VASc score also contribute to stroke risk, and patients prescribed anticoagulants still face a residual stroke risk. Methods: A multivariable model to predict stroke risk was built using data from patients treated for atrial fibrillation (AF) at Duke between 2009 and 2018. The model was then refined in patients presenting with incident AF at 7 hospitals within the larger PCORnet database. Results: Of 43,896 patients with AF included in our multivariable model creation data set, median age was 71.6 years, 44.2% of patients were female, 17.4% were black, and median CHA 2 DS 2 -VASc was 3. DOAC was prescribed in 24.2%, warfarin in 28.7%, and 50.4% were not prescribed either anticoagulant. The 5-year incidence of ischemic stroke was 3.5%. In a multivariable model, patients who were black, had prior major bleeding, or who were prescribed aspirin or an SSRI were at increased risk for ischemic stroke regardless of type of anticoagulation, whereas lower eGFR did not increase the risk. The model was refined in the PCORnet database using 244,213 patients with incident AF, with additional identification of lower risk for patients with BMI >30 or recent cardiac surgery, and use of P2Y12 as a risk factor. Multivariable models showed substantial improvement in stroke prediction within both the Duke and PCORnet treatment cohorts, with improvement in C-indices to 69.6-75.7%, from baseline C-indices of 63.5%-68.7% for CHA 2 DS 2 -VASc alone among patients on DOAC, warfarin, or who were untreated. Conclusions: Lower BMI, prior major bleeding, antiplatelet (ASA or P2Y12) use, and black race were significantly associated with increased risk for ischemic stroke, independent of the commonly used CHA 2 DS 2 -VASc score. Future AF research should attempt to integrate these emerging risk factors with the existing CHA 2 DS 2 -VASc framework to improve the identification of patients at high risk of stroke and in greatest need of anticoagulation.

Abstract 14555: Early Predictors That Identify Patients With Significant Left Main and Three-Vessel Coronary Artery Disease in Non-ST Elevation Acute Coronary Syndrome: Validating the MADISON Score

Introduction: In patients with non-ST elevation acute coronary syndrome (NSTE-ACS), identifying those with a high probability of having high-risk disease such as left main (LM) or three-vessel disease (3VD) could influence decisions to preload with P2Y12 inhibitors and timing of coronary angiography. The MADISON score was developed to predict LM/3VD on coronary angiography in patients with NSTE-ACS. In this study, we validated the MADISON score using data from an external cohort. Methods: The MADISON score was first developed using a retrospective cohort of 1700 patients presenting with NSTE-ACS at the University of Wisconsin-Madison (UW) (2011-2018). Those with prior CABG, cardiac arrest/shock, and bleeding on initial presentation were excluded from the analysis. Multivariable estimates were employed and model performance was assessed using receiver operating characteristic curve analysis. The score was then validated using a retrospective Houston Methodist Hospital (HMH) cohort of 622 patients (2019-2022). Results: The MADISON score variables and their adjusted odds ratios (95% CI) are presented in Figure 1A. Risk categories and corresponding LM/3VD probabilities are presented in Figure 1B. In the UW cohort, the area under the curve (AUC) was 0.68 (0.65-0.71) (Figure 2A). Interestingly, the AUC was also 0.68 (0.64-0.72) in the HMH validation cohort (Figure 2B). Conclusions: The MADISON score performed well and similarly between 2 large, independent cohorts in predicting patients most likely to have LM/3VD. The MADISON score is a simple and practical tool to guide decisions. Prospective validation of the score is planned to evaluate its impact on clinical outcomes.

Emicizumab Use in Infancy: A Survey of United States Pediatric Hemophilia Treatment Center Medical Directors

Introduction: Emicizumab, a bispecific antibody directed against activated factor IX and factor X, is a subcutaneous non-factor prophylactic option for individuals with hemophilia A (HA). The safety and efficacy of emicizumab has been demonstrated in both adult and pediatric patients. It was approved by the United States (U.S.) Food and Drug Administration for routine prophylaxis to prevent or reduce bleeding episodes in individuals with HA, ages newborn and older, both with (2017) and without (2018) factor VIII (FVIII) inhibitors. Despite this approval, data on emicizumab in infants are limited. The HAVEN 2 pediatric clinical trial had only two infants under 24 months of age, though interim analysis of the HAVEN 7 trial demonstrated emicizumab efficacy and safety in infants. Thus, the optimal use of emicizumab in infants under 12 months of age remains unclear. The objective of this study was to understand the rationale and treatment decisions regarding initiation of emicizumab prophylaxis in children under 12 months of age among pediatric Hemophilia Treatment Center (HTC) Medical Directors in the U.S. Methods: An electronic survey was conducted from April to May 2023 of U.S. HTC Medical Directors via REDCap. Invitations were sent to all individuals listed as HTC Directors at pediatric medical centers on the Center for Disease Control and Prevention database. The survey included two hemophilia patient case scenarios associated with 15 multiple-choice questions and additional free-text options. The first case was of a 9-month-old male with severe HA, without prior bleeding history or exposure to FVIII, who presented for his initial visit to an HTC. The second case was a 3-month-old male with severe HA receiving FVIII replacement therapy for an intracranial hemorrhage. This study was approved by the Baylor College of Medicine Institutional Review Board. Results: Overall, 33 of 97 (34%) pediatric HTC Medical Directors participated in the survey. One survey was minimally completed and excluded for a total of 32 surveys included in the final analysis. The majority of participants had over 15 years of experience caring for patients with HA (n=21, 65.6%) and represented HTCs with over 250 patients (n=22, 68.8%; Table 1). For previously untreated or minimally treated infants (Case 1), 96.9% of responses (n=31) stated they would consider starting emicizumab prophylaxis; 45.2% (n=14) would consider initiating it as young as 1 week of age. The most common reason cited for starting emicizumab in an infant was to prevent an intracranial hemorrhage (n=17, 53.1%) followed by the desire to avoid central line placement (n=7, 21.9%). The majority of respondents did not wait for a minimum number of factor exposure days prior to starting emicizumab (n=31, 96.9%) nor did they report regularly exposing infants to FVIII concentrate until 50 EDs are reached (n=29, 90.6%). After the initial loading phase, the majority of respondents selected an emicizumab dosing regimen of every 2 weeks (n=19, 59.4%). There was a varied approach to monitoring for inhibitor development after starting emicizumab; 40.6% (n=13) reported monitoring at regular intervals between every 6 to 24 months, whereas 46.8% (n=15) did not report following a set schedule and instead obtain FVIII inhibitor testing only after FVIII exposure (Table 2). For infants receiving FVIII replacement for treatment of an intracranial hemorrhage (Case 2), 96.9% (n=31) of participants stated they would transition to emicizumab as a prophylactic agent. Over half (n=16, 51.6%) stated they would initiate emicizumab during the treatment period for the hemorrhage rather than waiting until therapy completion. For providers that use emicizumab in moderate hemophilia, emicizumab was reported to be used routinely by 27.3% (n=6) and on a case-by-case basis in 40.9% (n=9, Table 2) in infants with moderate HA. Conclusion: Pediatric HTC Medical Directors in the U.S. report commonly utilizing emicizumab in infants under 12 months of age despite the lack of robust data in this age group. This practice is consistent with recommendations by the National Hemophilia Foundation's Medical and Scientific Advisory Council. With the completion of clinical trials focused on infants with HA, along with additional long-term outcomes data, more specific guidance around initiation, follow-up and monitoring may be available to inform the optimal management for these patients.

Trajectories of P2Y12 inhibitor adherence in patients with acute coronary syndromes.

P2Y12 inhibitors (P2Y12i) reduce cardiac events after acute coronary syndromes (ACS). However, suboptimal P2Y12i adherence persists. We aimed to examine P2Y12i non-adherence using group-based trajectory methods and to identify adherence predictors. We conducted a population-based, retrospective cohort study using administrative data in Ontario, Canada of patients ≥65 years admitted for ACS between April 2014 and March 2018 with a P2Y12i dispensed within 7 days of discharge. We used group-based trajectory models to characterize longitudinal 1-year adherence patterns. Predictors associated with each adherence trajectory were identified by multinomial logistic regression. We included 11 917 patients using clopidogrel and 9763 using ticagrelor, aged [mean ± SD]: 77.33 ± 8.31/73.59 ± 6.79 years; men: 56.2%/65.4%, respectively. We identified 3 longitudinal adherence trajectories, that differed by agent: 75% of clopidogrel and 68% of ticagrelor patients showed a consistently adherent trajectory, while 13%/17% were gradually, and 12%/15% were rapidly non-adherent, respectively (p < 0.001). Differing baseline characteristics in each cohort were associated with observed adherence trajectories. Concomitant atrial fibrillation and prior bleeding history were associated with non-adherence among clopidogrel users. Among ticagrelor users, women and older persons were more likely to be rapidly non-adherent, adherence declining steeply starting 1 month post-ACS. We identified distinct adherence trajectories for clopidogrel and ticagrelor post-ACS, with 3 out of 4 clopidogrel patients but only 2 out of 3 ticagrelor patients in the consistently adherent trajectory. Intensive interventions targeted to the period of steep adherence decline post-ACS, particularly for women and older persons initiating ticagrelor, and patients with atrial fibrillation on clopidogrel should be considered and investigated further.

Validation of prediction tools for GI bleeding in patients on dual anti-platelet therapy after percutaneous coronary intervention

Background & AimsThe management of dual anti-platelet therapy (DAPT) after percutaneous coronary intervention (PCI) and gastrointestinal bleeding (GIB) remains a clinical dilemma. We sought to identify predictors of a GIB and a rebleed and to determine whether a rebleed increases the risk of major adverse cardiovascular events (MACE). MethodsIn this single-center retrospective study, patients undergoing PCI were identified. The primary and secondary endpoints were a GIB at 180 days, and a rebleed or MACE at 365 days. Logistic regression was used to identify predictors of GIB and rebleed. Cox Proportional Hazard modeling was used to determine whether rebleed can predict MACE. ResultsA total of 536 patients were included. On multivariable analysis, PCI for acute coronary syndrome was associated with 95% increased odds of GIB, p < 0.001. The P2Y12 inhibitor was continued in > 90% of patients, which trended towards significance for a rebleed, p < 0.10. The HAS-BLED score, including a labile INR and prior major bleeding, were strongly associated with a rebleed, p ≤ 0.009. A rebleed was associated with a 115% increased risk of MACE, p = 0.02. We derived a novel risk score, named the SIGE score, to predict a rebleed at 365 days with a high predictive accuracy, AUC 0.773 (95% CI: 0.702 – 0.845). ConclusionThe SIGE score may help to predict rebleeding, which was shown to be associated with an increased risk of MACE. Further external validation is needed.

Geographic variation in clinical outcomes and anticoagulation among medicare beneficiaries with non-valvular atrial fibrillation

Oral anticoagulants (OACs) have been used to prevent stroke/systemic embolism (SE) among patients with non-valvular atrial fibrillation (NVAF). To evaluate baseline clinical characteristics, incidence rates of stroke/SE and hospitalization for bleeding, and OAC use among elderly patients with NVAF in the US by geographic region. Patients with NVAF were selected from the US Centers for Medicare & Medicaid Services claims database (01JAN2013-31DEC2016). Twelve months of health plan enrollment was required before and after the NVAF diagnosis to evaluate baseline characteristics and outcomes, respectively. Each patient was assigned to a 3-digit zip code based on their primary residence, and geographic variation was visualized using ArcGIS Pro software. Over 2.8 million patients with NVAF were identified. Large geographic variation was observed in clinical characteristics, stroke/SE, hospitalization for bleeding, and OAC use among patients across the US. The zip codes with the highest mean CHA2DS2–VASc scores and frequency of prior bleeding also had the highest incidence of stroke/SE and hospitalization for bleeding. Across 3-digit zip codes, 35–63% of patients were untreated. Overall, the incidence of stroke/SE and hospitalization for bleeding were higher and OAC treatment was less frequent in zip codes located in the Southern US. Baseline clinical characteristics, incidence rates of stroke/SE and hospitalization for bleeding, and OAC usage vary considerably by 3-digit zip code in the US. The additional granularity provided in this study may help clinicians to identify small regions with high-risk of stroke/SE and hospitalization for bleeding and low use of OAC that may benefit from targeted care strategies.

Bleeding with intensive versus guideline antiplatelet therapy in acute cerebral ischaemia

Intensive antiplatelet therapy did not reduce recurrent stroke/transient ischaemic attack (TIA) events as compared with guideline treatment in the Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) trial, but did increase the frequency and severity of bleeding. In this pre-specified analysis, we investigated predictors of bleeding and the association of bleeding with outcome. TARDIS was an international prospective randomised open-label blinded-endpoint trial in participants with ischaemic stroke or TIA within 48 h of onset. Participants were randomised to 30 days of intensive antiplatelet therapy (aspirin, clopidogrel, dipyridamole) or guideline-based therapy (either clopidogrel alone or combined aspirin and dipyridamole). Bleeding was defined using the International Society on Thrombosis and Haemostasis five-level ordered categorical scale: fatal, major, moderate, minor, none. Of 3,096 participants, bleeding severity was: fatal 0.4%, major 1.5%, moderate 1.2%, minor 11.4%, none 85.5%. Major/fatal bleeding was increased with intensive as compared with guideline therapy: 39 vs. 17 participants, adjusted hazard ratio 2.21, 95% CI 1.24–3.93, p = 0.007. Bleeding events diverged between treatment groups in the 8–35 day period but not in the 0–7 or 36–90 day epochs. In multivariate analysis more, and more severe, bleeding events were seen with increasing age, female sex, pre-morbid dependency, increased time to randomisation, prior major bleed, prior antiplatelet therapy and in those randomised to triple vs guideline antiplatelet therapy. More severe bleeding was associated with worse clinical outcomes across multiple physical, emotional and quality of life domains.Trial registrationISRCTN47823388.

Risk Profiles of New Users of Oral Anticoagulants Between 2011 and 2019 in Germany.

Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes over time among persons with non-valvular atrial fibrillation initiating treatment with different DOACs or phenprocoumon (vitamin K antagonist) between 2011 and 2019 in Germany. Using the German Pharmacoepidemiological Research Database (GePaRD; claims data of ~20% of the German population), we identified persons with a first dispensing of phenprocoumon or a DOAC and a diagnosis of non-valvular atrial fibrillation between August 2011 and December 2019. We described the morbidity of included patients prior to treatment initiation, stratified by year of treatment initiation. Overall, we included 448,028 new users (phenprocoumon: N = 118,117, rivaroxaban: N = 130,997, apixaban: N = 130,300, edoxaban: N = 38,128, dabigatran: N = 30,486). Comparing new DOAC users in 2019, the proportion with prior ischemic stroke was highest for dabigatran (17%) and lowest for rivaroxaban (8%). The proportion with prior major bleeding was also highest for dabigatran (25%) and lowest for edoxaban (20%). New users of apixaban were oldest and, eg, showed the highest prevalence of congestive heart failure. Changes over time were most pronounced for phenprocoumon. For example, among persons initiating phenprocoumon in 2012 vs 2019, the proportion with prior major bleeding increased from 18% to 35%; the proportion with renal disease increased from 20% to 36% and the proportion with liver disease from 18% to 24%. This study demonstrated differences in risk profiles between new users of different oral anticoagulants and substantial changes over time among new phenprocoumon users. These differences have to be considered in head-to-head comparisons of these drugs based on observational data, especially regarding potential unmeasured confounding.

A nomogram for predicting major gastrointestinal bleeding in patients treated with rivaroxaban

Background Rivaroxaban is a direct oral anticoagulant with the highest risk of anticoagulant-induced major gastrointestinal bleeding (MGIB). Currently, there is a lack of tools to identify patients at high risk of rivaroxaban-induced MGIB. Objective To establish a nomogram model to predict the risk of MGIB in patients receiving rivaroxaban. Methods Demographic information, comorbidities, concomitant medications, and laboratory test results were collected from 356 patients (178 diagnosed with MGIB) who were taking rivaroxaban between January 2013 and June 2021. Univariate and multivariate logistic regression analyses were used to identify the independent predictors of MGIB, and a nomogram was constructed based on these predictors. A receiver operating characteristic curve, Brier score, calibration plot, decision curve, and internal validation was used to evaluate the calibration, discrimination, and clinical usefulness of the nomogram. Results Age, haemoglobin level, platelet count, creatinine level, prior peptic ulcer disease, prior bleeding, prior stroke, proton pump inhibitor use, and antiplatelet agent use were independent predictors of rivaroxaban-induced MGIB. These risk factors were used to establish the nomogram. The area under the curve of the nomogram was 0.833 (95%CI, 0.782-0.866), the Brier score was 0.171, the internal validation accuracy was 0.73, and the kappa value was 0.46. Conclusion The nomogram demonstrated good discrimination, calibration, and clinical applicability. Therefore, it could accurately predict the risk of MGIB in patients treated with rivaroxaban.

Baseline characteristics of edoxaban treatment in routine clinical practice for patients with non-valvular atrial fibrillation in China (ETNA-AF-China)

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo (China) Holdings Co., Ltd, Shanghai, China. Background The effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) edoxaban for the treatment of patients with non-valvular atrial fibrillation (NVAF) have been investigated globally. Data from mainland China, however, is scarce. Purpose To report baseline characteristics of unselected NVAF patients receiving edoxaban in routine clinical practice. Methods ETNA-AF-China is a multi-center, prospective, observational study designed to evaluate effectiveness and safety of edoxaban for stroke preventions in 89 sites across mainland China with 2-year follow-up. Enrollment started on February 2021 and ended on October 2022. Patients having history of NVAF, prescribed edoxaban, and providing written informed consent were eligible. This descriptive analysis of the baselines data is based on a snapshot from November 2022. Results A total of 5,000 patients were enrolled and data of 4749 patients with full edoxaban treatment information at baseline were analyzed (60 mg: 2559, 30 mg: 2190). Overall, mean (SD) patient age was 70.2 (9.55) years, with 1660 (35.0 %) patients ≥ 75 years. Male patients constituted 57.0 %. The average calculated creatinine clearance rate, CHA2DS2-VASc scores and HAS-BLED scores were 71.3 (27.8) mL/min, 2.88 (1.41) and 1.83 (1.04), respectively. Patients with perceived frailty, history of stroke, history of bleeding comprised 6.46 %, 8.78 %, 2.21% of the overall population, respectively (Table). The majority of patients (79.0 %) received recommended dose according to label criteria, with similar percentages observed among economic regions (East, 81.5 %; Northeast, 78.4 %; Middle, 76.0 %; West, 76.8 %). A numerically larger percentage of patients receiving non-recommended 30 mg were categorised as high risk for either stroke or bleeding (presence of prior stroke, prior major bleeding or prior ICH, or a CHA2DS2-VASc score ≥ 4; 34.1 % vs 25.6 %), frail assessed by physician (10.6 % vs 3.3 %), and had stage 3 chronic renal disease (58.8 % vs 39.4 %) compared with patients receiving recommended 60 mg. Those prescribed a non-recommended 60 mg vs those with recommended 30 mg were less likely to be considered stroke or bleeding high risk (40.2 % vs 46.8 %), and advanced renal disease (≥ stage 4, 10.7% vs 13.8 %) (Figure). Conclusion In this real-world study, edoxaban was predominantly prescribed with elder NVAF patients, on dose of 60 mg. Most of Chinese patients adhered to edoxaban approved label and the deviation from dose recommendation appears to be influenced by physician’s consideration of patient’s characteristics (such as stroke or bleeding high risk). More data profiles of ETNA-AF-China concerning effectiveness and safety study are collecting at the follow-up period.

Effects of the ABC pathway on clinical outcomes in a secondary prevention population of Chinese patients with atrial fibrillation: A report from the Optimal Thromboprophylaxis in Elderly Chinese Patients with Atrial Fibrillation (ChiOTEAF) registry.

The atrial fibrillation better care (ABC) pathway is a simple, comprehensive framework that facilitates provision of integrated care for atrial fibrillation (AF) patients. We evaluated management of AF patients in a secondary prevention cohort using the ABC pathway and examined the impact of ABC adherence on clinical outcomes. The Chinese Patients with Atrial Fibrillation registry is a prospective registry conducted in 44 sites across China between October 2014 and December 2018. The primary outcome was the composite of all-cause mortality/any thromboembolism (TE), all-cause death, any TE and major bleeding at 1 year. Of the 6420 patients, 1588 (24.7%) had a prior stroke or transient ischemic attack and were identified as the secondary prevention cohort. After excluding 793 patients due to insufficient data, 358 (22.5%) were ABC compliant and 437 (27.5%) ABC noncompliant. ABC adherence was associated with a significantly lower risk of the composite outcome of all-cause death/TE, odds ratio (OR) 0.28 (95% confidence interval [CI]: 0.11-0.71) and all-cause death, OR 0.29 (95% CI: 0.09-0.90). Significant differences were not observed for TE, OR 0.27 (95% CI: 0.06-1.27) and major bleeding, OR 2.09 (95% CI: 0.55-7.97). Age and prior major bleeding were significant predictors of ABC noncompliance. Health-related quality of life (QOL) was higher in the ABC compliant group versus the noncompliant group (EQ score 0.83 ± 0.17 vs. 0.78 ± 0.20; p = .004). ABC pathway adherence in secondary prevention AF patients was associated with a significantly lower risk of the composite outcome of all-cause death/TE and all-cause death, as well as better health-related QOL.

PO-02-201 OUTCOMES OF RADIOFREQUENCY ABLATION OF ATRIAL FIBRILLATION IN OCTOGENARIANS IN A MULTICENTER REGISTRY (REAL-AF)

Catheter ablation for atrial fibrillation (AF) has significantly increased in prevalence, including in an elderly population. However, some studies suggest that outcomes of AF ablation may be inferior in elderly patients. Real-world, multi-center data is minimal and may provide more insight on this possibility. To compare the outcomes of octogenarians versus non-octogenarians undergoing catheter ablation of AF in high volume centers. Patients undergoing radiofrequency ablation of AF were prospectively enrolled in a multi-center registry (REAL-AF) from January 2018 to May 2021. The cohort was divided into 2 groups, patients ≥ 80 years old (octogenarians) and patients < 80 years old (non-octogenarians). Baseline characteristics and procedural data were collected prospectively on all patients. Routine ambulatory monitoring was performed at 6- and 12-months and additionally as needed based on symptoms. Efficacy was assessed at 12 months. The primary outcome was freedom from symptomatic atrial arrhythmias lasting greater than 30 seconds after a 90-day blanking period. 71 patients were included in the octogenarian group and 1,134 patients in the non-octogenarian group. The proportion of patients with persistent AF was similar between the groups. Octogenarians were more likely to have lower BMI, hypertension, prior bleeding, and left atrial scar as assessed by electro-anatomic mapping system (EAM). Left ventricular ejection fraction and left atrial volume as measured on EAM were also similar among the groups. There was a trend towards increased recurrence of atrial arrhythmias in octogenarians (table 1). At 12 months, octogenarians were more likely to be on anti-arrhythmic drugs as well. However, there was no difference in procedure-related complications between the groups. When controlled for left atrial scar burden, there was no difference in outcomes between the two groups. Octogenarians undergoing ablation of atrial fibrillation are more likely to have recurrent atrial arrhythmias than younger patient; this difference seems to be associated with an increased likelihood of abnormal left atrial voltage in the elderly patients. Although octogenarians are considered a frail population, AF ablation maintained similar safety profiles and arrhythmia related healthcare utilization rates when compared to a younger population.

Aortic Stenosis and Outcomes in Patients With Atrial Fibrillation: A Nationwide Cohort Study.

Background Patients with aortic stenosis (AS) have been underrepresented in the trials evaluating direct oral anticoagulants (DOACs) in atrial fibrillation (AF). We aimed to assess whether AS impacts outcomes in patients with AF and estimate the effects of DOACs versus warfarin in patients with AF and AS. Methods and Results The registry-based FinACAF (Finnish Anticoagulation in Atrial Fibrillation) study covered all patients with AF diagnosed during 2007 to 2018 in Finland. Hazard ratios (HRs) of first-ever gastrointestinal bleeding, intracranial bleeding, any bleeding, ischemic stroke, and death were estimated with cause-specific hazards regression adjusted for anticoagulant exposure variables. We identified 183 946 patients (50.5% women; mean age, 71.7 [SD, 13.5] years) with incident AF without prior bleeding or ischemic stroke, of whom 5231 (2.8%) had AS. The crude incidence rate of all outcomes was higher in patients with AS than in patients without AS. After propensity score matching, AS was associated with the hazard of any bleeding, gastrointestinal bleeding, and death but not with intracranial bleeding or ischemic stroke (adjusted HRs, 1.36 [95% CI, 1.25-1.48], 1.63 [95% CI, 1.43-1.86], 1.32 [95% CI, 1.26-1.38], 0.96 [95% CI, 0.78-1.17], and 1.11 [95% CI, 0.99-1.25], respectively). Among patients with AS, DOACs were associated with a lower risk of ischemic stroke when compared with warfarin, while bleeding and mortality did not differ between DOACs and warfarin. Conclusions AS is associated with substantially higher risk of gastrointestinal bleeding in patients with AF. DOACs may be more effective in preventing ischemic stroke than warfarin in patients with AF and AS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04645537.

The Canadian WATCHMAN Registry for Percutaneous Left Atrial Appendage Closure

BackgroundAccess to left atrial appendage closure (LAAC) in Canada is limited, due to funding restrictions. This work aimed to assess Canadian clinical practice on patient selection, postprocedural antithrombotic therapy, and safety and/or efficacy with WATCHMAN device implantation. MethodsSeven Canadian centres implanting the WATCHMAN device participated in this prospective multicentre, observational registry. All procedures were done under general anesthesia with transesophageal echocardiography guidance. Patients were prospectively followed for 2years. The long-term stroke rate was compared with the expected rate based on the CHA2DS2-VASc score. ResultsA total of 272 patients who underwent LAAC with the WATCHMAN device between December 2013 and August 2019 (mean age: 75.4 years [standard deviation {SD}: 8.75]; male, 63.2%; CHA2DS2-VASc score: 4.35 [SD: 1.64]; HAS-BLED score: 3.55 [SD: 0.94]) were included. Most patients (90.4%) had prior history of bleeding (major, 80.5%; minor, 21.7%). The WATCHMAN device was successfully implanted in 269 patients (98.9%), with a few procedure-related complications, including 5 pericardial effusions requiring drainage (1.8%), and 1 death (0.4%; 22 days post-LAAC from respiratory failure). Post-LAAC antithrombotic therapy included dual antiplatelet therapy in 70.6%, single antiplatelet therapy in 18.4%, and oral anticoagulation in 13.6%. During the follow-up period (mean: 709.7 days [SD: 467.2]), an 81.4% reduction of the ischemic stroke rate occurred, based on the expected rate from the CHA2DS2-VASc score (6.0% expected vs 1.1% observed). Device-related thrombus was detected in 1.8%. ConclusionsThe majority of Canadian patients who underwent LAAC had oral anticoagulation contraindication due to prior bleeding, and most were safely treated with antiplatelet therapy post-LAAC, with a low device-related thrombus incidence. Long-term follow-up demonstrated that LAAC achieved a significant reduction in ischemic stroke rate.

Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation andCancer.

The prevention of stroke in patients with atrial fibrillation (AF) and cancer is challenging because patients are at increased bleeding and thrombotic risk. The authors sought to assess left atrial appendage occlusion (LAAO) as a safe and effective strategy for reducing stroke at no increased bleeding risk in cancer patients with AF. We reviewed patients with nonvalvular AF who underwent LAAO at Mayo Clinic sites from 2017 to 2020 and identified those who had undergone prior or current treatment for cancer. We compared the incidence of stroke, bleeding, device complications, and death with a control group who underwent LAAO without malignancy. Fifty-five patients were included; 44 (80.0%) were male, and the mean age was 79.0 ± 6.1 years. The median CHA2Ds2-VASc score was 5 (Q1-Q3: 4-6), with 47 (85.5%) having a prior bleeding event. Over the first year, ischemic stroke occurred in 1 (1.4%) patient, bleeding complications in 5 (10.7%) patients, and death in 3 (6.5%) patients. Compared with controls who underwent LAAO without cancer, there was no significant difference in ischemic stroke (HR: 0.44; 95% CI: 0.10-1.97; P = 0.28), bleeding complication (HR: 0.71; 95% CI: 0.28-1.86; P = 0.19), or death (HR: 1.39; 95% CI: 0.73-2.64; P = 0.32). Within our cohort, LAAO in cancer patients was achieved with good procedural success and offered a reduction in stroke at no increased bleeding risk similar to noncancer patients.