Bleeding Outcomes Research Articles

Direct Oral Anticoagulants Versus Warfarin in Patients With Isolated Heparin-Induced Thrombocytopenia or Heparin-Induced Thrombocytopenia With Thrombosis.

No existing studies compare oral anticoagulants to treat heparin-induced thrombocytopenia with or without thrombosis (HIT/HITT). This retrospective study evaluated thrombotic and bleeding outcomes in adults treated for HIT/HITT with a direct oral anticoagulant (DOAC) or warfarin between 2012 and 2023 within the Ochsner Health System. Patients with mechanical heart valves, valvular atrial fibrillation, antiphospholipid syndrome, active malignancy, or venous thromboembolism (VTE) within the previous 6 months were excluded. The primary outcome was a composite of new or progressive VTE or arterial thromboembolism. Secondary outcomes included major and clinically relevant non-major bleeding, duration of hospitalization, time to platelet recovery, and incidence of skin necrosis, gangrene, and amputation. Forty-nine patients receiving a DOAC and 30 patients receiving warfarin were included. Baseline characteristics were similar between cohorts. There were non-statistically significant increased rates of both the primary outcome (8.9% vs. 4.3%, p = 0.65) and the composite bleeding outcome (32.7% vs. 23.3%, p = 0.37) in the DOAC cohort. Larger, prospective studies are needed to confirm these findings.

Use of Aspirin and Initial Cardiovascular and Bleeding Risk in Patients with Chronic Kidney Disease

Background: Despite the high cardiovascular risk in patients with chronic kidney disease (CKD), the role of aspirin in primary prevention remains unclear. This study aimed to investigate the association between aspirin initiation in adults with CKD without prior cardiovascular disease (CVD) and the first cardiovascular and bleeding events using Korean nationwide cohort data. Methods: Among individuals aged 40–79 years with an estimated glomerular filtration rate between 15 and 59 mL/min/1.73 m2 who underwent routine health examinations between 2011 and 2016, 15,861 individuals who were newly prescribed aspirin at a dose of 100 mg/day were matched with 79,305 aspirin non-users by propensity score matching. The primary efficacy outcome was a composite of nonfatal atherosclerotic CVD or cardiovascular death. The primary safety outcome was hospitalization due to intracranial or gastrointestinal bleeding. Results: During a mean follow-up of 6.9±2.9 years, the incidence rates for the primary efficacy outcome in aspirin users and non-users were 8.0 and 9.0 per 1,000 person-years, respectively. Aspirin therapy initiation was not associated with the primary efficacy outcome (hazard ratio [HR], 0.93; 95% confidence intervals [CI], 0.86-1.04). However, the primary safety outcome of major bleeding was more frequent in aspirin users than in non-users (6.7 versus 4.7 per 1,000 person-years). The HR for this outcome in aspirin users versus non-users was 1.45 (95% CI, 1.32-1.59). Conclusions: No association was observed between aspirin use and the risk of nonfatal atherosclerotic CVD or cardiovascular death in patients with CKD stages G3 and G4 without prior CVD. Aspirin use was associated with higher risk of major bleeding.

The Role of Systemic Inflammatory Indices in Predicting Composite Adverse Outcomes of Peripartum Hemorrhage Treated with Fibrinogen Concentrate

The Role of Systemic Inflammatory Indices in Predicting Composite Adverse Outcomes of Peripartum Hemorrhage Treated with Fibrinogen Concentrate

Postoperative bleeding outcome of fresh frozen plasma prime in pediatric cardiac surgery: A systematic review & meta-analysis.

Bleeding after cardiac surgeries holds risk of mortality and morbidity in pediatrics. This systematic review aimed to evaluate postoperative blood loss and blood transfusion requirements for pediatric patients undergoing cardiac surgery with fresh frozen plasma (FFP) priming. In 2024, the search reviewed four databases on randomized trials (RCTs) examining the impact of FFP prime intervention on 24-h postoperative blood loss and transfusion requirements in pediatric cardiac surgeries. The journals were appraised using Grading of Recommendation Assessment, Development, and Evaluation checklists, and random effects models estimated the effect size with a 95% confidence interval. Significance and study heterogeneity were indicated by p-values and I2. Of the screened 2070 articles, one high-quality and four moderate-quality RCTs involving 354 children were identified. No significant reduction in 24-h mean postoperative blood loss was found following FFP priming (mean difference MD: -0.78, 95% CI [-3.3 to 1.75], p = .55) in general pediatric cardiac surgeries. However, subgroup analysis showed significant decrease in blood loss for younger children (<7 months) or those with lower body weight (<6kg). There was no significant difference between groups in FFP (MD: -0.19, 95% CI [-0.42 to 0.05], p = .13) or red blood cell transfusion (MD: -0.25, 95% CI [-0.51 to 0.02], p = .07). Administering FFP as prime fluid in cardiac surgery did not reduce postoperative bleeding in general pediatric patients, but younger children (<7 months) and those with lower weight (<6kg) were the subjects who benefited from the FFP priming before surgery.

Revisiting the Efficacy and Safety of Bivalirudin in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention: Insights From a Mixed Treatment Comparison Meta-Analysis of Randomized Trials.

Randomized trials of bivalirudin in patients with ST elevation myocardial infarction (STEMI) have yielded heterogeneous results. Our aim was to evaluate the efficacy and safety of four antithrombin regimens-unfractionated heparin (UFH), bivalirudin (stopped soon after percutaneous coronary intervention [PCI]), extended bivalirudin (continued for a few hours after PCI), and combined UFH and a Gp2b3a inhibitors (GPI) in patients who present with STEMI. A PubMed, EMBASE, and clinicaltrials.gov databases were searched for randomized clinical trials (RCTs) of the above antithrombin in patients with STEMI. The primary outcome was net adverse cardiovascular events (NACE). The primary ischemic endpoint was major adverse cardiovascular events (MACE), and the primary safety endpoint was major bleeding, and other endpoints included all-cause mortality and stent thrombosis. The primary analysis compared the effect of these antithrombin regimens in reference to UFH using a mixed treatment comparison meta-analysis. In the 14 RCTs evaluating 25,415 patients with STEMI, when compared to UFH monotherapy, extended bivalirudin lowered NACE (OR = 0.71 with 95% CI: 0.53-0.96; moderate level of confidence) driven by a significant decrease in major bleeding (OR = 0.42 with 95% CI: 0.26-0.68; high level of confidence) without any significant difference in MACE or all-cause mortality. When compared with UFH monotherapy, UFH+GPI reduced risk of MACE (OR = 0.76 with 95% CI: 0.60-0.97; high level of confidence) but at the expense of an increase in major bleeding (OR = 1.48 with 95% CI: 1.11-1.98; high level of confidence) with no difference in NACE or all-cause mortality. For major bleeding, extended bivalirudin infusion ranked #1, bivalirudin ranked #2, UFH monotherapy ranked #3, and combined UFH and GPI ranked #4. For NACE, extended bivalirudin infusion ranked #1, bivalirudin ranked #2, combined UFH and GPI ranked #3, and UFH monotherapy ranked #4. Cluster plots for MACE and major bleeding demonstrated that extended bivalirudin had the best balance for efficacy and safety. In patients undergoing PCI for STEMI, extended bivalirudin offers the best balance for primary ischemic (MACE) and safety (major bleeding) outcomes.

Sex Modifies the Severity and Outcome of Spontaneous Intracerebral Hemorrhage.

The limited existing evidence on sex differences in the clinical characteristics of patients with spontaneous, non-traumatic intracerebral hemorrhage (ICH) comes from small, single-center studies. Here, we performed an individual patient data meta-analysis of 3 randomized clinical trials and 1 multi-ethnic observational study of ICH to investigate the impact of sex on ICH severity and outcome. Inclusion criteria in our study were a neuroimaging-confirmed ICH. We evaluated whether sex was associated with ICH severity (hematoma volume and expansion) and poor functional outcomes (modified Rankin Scale >3) 3 or 6 months after the ICH. A total of 4,812 ICH patients were evaluated (mean age 62, 40% female). Males with ICH were younger, more likely to be smokers and have diabetes, and less likely to be on anticoagulants (all p < 0.05). In multivariable analyses, male sex was associated with non-lobar location (odds ratio [OR]: 1.63; 95% confidence interval [CI]: [1.39-1.92]; p < 0.001), larger hemorrhages (beta: 0.16 [0.08-0.23]; p < 0.001) and a higher risk of hematoma expansion (OR: 1.43 [1.20-1.71]; p < 0.001). Despite the larger hemorrhage volume and higher risk of expansion, male sex was associated with a 24% lower risk of poor outcomes (OR: 0.76 [0.64-0.90]; p = 0.002). Compared to females, males with ICH have larger bleeds and higher risk of hematoma expansion. Despite the larger bleeds and higher risk of hematoma expansion, males with ICH have lower risk of poor outcomes. Our results suggest that the biology and clinical trajectory are different in females and males with ICH, supporting sex-specific research in this condition. ANN NEUROL 2024.

Prediction of the outcome of intracerebral hemorrhage by blood neutrophil to lymphocyte ratio: a prospective observational study.

Intracerebral haemorrhage (ICH) is defined as bleeding within the brain parenchyma. Neutrophil lymphocyte ratio (NLR) is a dynamic parameter that can be affected by an underlying condition like microangiopathy (e.g. hemorrhagic stroke). The NLR value at the time of stress (e.g. ICH) could be a predictor among various other factors on the outcome of the disease. The aim of this study is to see if NLR could be a predictor of the outcome of the ICH. This is a prospective observational study conducted in the Department of Neurosurgery and Department of Neurology, from March 2020 to February 2021. The ICH cases presented to the emergency department within 24h of symptoms were included. The baseline haematological and biochemical investigations were sent and the noncontrast computed tomography (NCCT) head was done for the diagnosis of ICH. The NLR was measured. The ICH volume was calculated by ABC/2. Follow-up of the patient to measure outcome was done with a modified Rankin scale (mRS) on 30 days. Student's t-test was used to correlate NLR-mRS. Fischer's exact test was used for a categorical association of NLR to mRS. A total of 89 patients with ICH were enrolled in this study. In this study, 62.92% of patients had good outcomes (NLR of 4.88±3.06), whereas 37.08% of patients had bad outcomes (NLR of 9.09± 4.92). Statistically, higher NLR was significantly predictive of poorer outcomes. ICH causes stress in the body, which alters the value of NLR. Components of NLR are altered after haemorrhage due to a change in homeostasis of brain parenchyma. The NLR value obtained at the time of emergency department visits may help to predict the 30 days outcome of ICH.

Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial

The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation. We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7-14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing. Between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI -0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (pnon-inferiority=0·0003). Superiority was not identified (psuperiority=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, -0·004 to 0·006; p=0·78). Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation. British Heart Foundation.

Comparison of Intracranial Hemorrhage and Clinical Outcomes Among Patients Undergoing Mechanical Thrombectomy with and without Thrombolytic Therapy

Comparison of Intracranial Hemorrhage and Clinical Outcomes Among Patients Undergoing Mechanical Thrombectomy with and without Thrombolytic Therapy

Open Reduction and Internal Fixation Is a Feasible Alternative to Femoral Revision Arthroplasty in Geriatric Patients with Vancouver B2/3 Type Periprosthetic Fractures: A Study Analyzing In-Hospital Outcomes.

Purpose: The surgical management of periprosthetic femoral fractures is particularly challenging in geriatric patients due to physiological limitations. The choice between open reduction and internal fixation (ORIF) and hip revision arthroplasty for treating Vancouver B2 and B3 fractures remains controversial. This study aims to contribute further evidence by analyzing the in-hospital outcomes in geriatric patients with Vancouver B2/3 fractures. Methods: This retrospective study analyzed 133 patients treated for Vancouver B2/3 fractures at a level I trauma center from 2017 to 2023. Data were collected on preclinical characteristics, comorbidities, Vancouver classification, surgery-related parameters, and postoperative outcomes for an age- and gender-matched analysis. A subgroup analysis was also conducted on patients classified as American Society of Anesthesiologists (ASA) class 3 and 4. Results: Among the 133 patients, 85 suffered Vancouver B2 fractures and 48 Vancouver B3 fractures. Age-and-gender-matched analysis revealed that ORIF was more commonly performed in patients with higher ASA grades. A subgroup analysis of ASA 3 and 4 patients and an age-and-gender-matched analysis showed that ORIF resulted in shorter operation times and less blood loss. No significant differences were found in mortality or complication rates. Conclusions: ORIF is associated with shorter operation times, less bleeding, and comparable in-hospital outcomes in treating Vancouver B2/3 fractures in higher-risk geriatric patients compared to revision arthroplasty. The retrospective design and small sample size in the ORIF group are limitations of the study. Further studies with functional evaluation are still required.

Impact of procedural and patient-related risks on 1-year outcomes for patients with 1-month DAPT followed by P2Y12 inhibitor monotherapy after biodegradable-polymer drug-eluting stent implantation

Abstract Background While early de-escalation of dual antiplatelet therapy (DAPT) and P2Y12 inhibitor monotherapy following short DAPT are becoming standard treatments for patients after percutaneous coronary intervention (PCI), the impact of procedural and patient-related risks on clinical outcomes of PCI for patients receiving the above DAPT regimen has never been established. Purpose To evaluate the impact of procedural and patient-related risk factors on 1-year cardiovascular and bleeding outcomes in patients with 1-month DAPT followed by P2Y12 inhibitor monotherapy after biodegradable-polymer drug-eluting stent (BP-DES) implantation. Methods Using data from the multi-centre regional-wide REIWA registry, we assessed clinical outcomes according to each risk factor and compared between patients with and without either procedural or patient-related risk factors. The primary end point was net adverse clinical events (NACE), defined as a composite of cardiovascular outcomes (cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic or hemorrhagic stroke) and bleeding outcomes (TIMI major or minor bleeding), which was same with that for STOPDAPT-2 trial. Procedural risk was defined as a factor of complex PCI which was previously published and included the follows: treatment of three vessels, three or more lesions, three or more stents, bifurcation with two stents, long stenting (total stent length &amp;gt;60 mm) and target of chronic total occlusion. Additionally, patient-related risk factors were defined as chronic kidney disease, anaemia, peripheral vascular disease, heart failure and advanced age (≧75 years). Results Among 1,202 patients treated BP-DES with 1-month DAPT, 276 patients (23.0%) had at least one procedural factors and 510 patients (42.4%) had one or more patient-related risks. Compared with each risk factor, patients with patient-related risk factor were more likely to have higher NACE rates, whereas low NACE rates were observed in patients with each procedural risk factor (Figure 1). In addition, during 1-year follow-up, patients with patient-related risk factors had a significantly higher incidence of NACE compared with patients without such risks (4.90 % vs. 1.73 %, p = 0.002) (Figure 2). However, no significant differences in NACE rates was observed between patients with and without procedural risk factors (2.54% vs. 3.24%, p = 0.555). Conclusion In patients undergoing BP-DES implantation and 1 month DAPT followed by P2Y12 inhibitor monotherapy, patient-related risk factors had an impact on 1-year clinical outcomes, while procedural risk factors no longer had small impact on those outcomes.

Association of P2Y12 inhibitor pretreatment strategy with short and long term ischemic and bleeding outcomes in NSTE-ACS patients

Abstract Background and Aims Oral P2Y12 inhibitors form the basis of both short and long term antiplatelet therapy in NSTE-ACS patients. While reducing thrombogenic activity and ischemic risk is the basis of routine P2Y12 inhibitor pretreatment in NSTE-ACS patients, timing of treatment became controversial as a result of studies showing routine P2Y12 inhibitor pretreatment is associated with an increased risk of bleeding. Even though routine pretreatment is no longer recommended in the ESC guidelines, the inadequacies in RCTs combining all treatment modalities have been noted. Our study aims to determine the relationship between P2Y12 inhibitor pretreatment strategy and short and long-term ischemic and bleeding events. Methods The study was designed as a single-center, prospective and observational study. 2602 patients, aged between 18 and 85, diagnosed with NSTE-ACS in accordance with ESC guidelines were included in the study. 2189 patients were administered with P2Y12 inhibitor pretreatment while 413 patients weren't. Demographic data, CVD risk factors, ECG, echocardiography and laboratory findings at the time of admission, interventional procedural details, type of antiplatelet and anticoagulant treatment and application time were recorded. Patients were divided into two groups as pretreatment and no-pretreatment according to the time of administration of P2Y12 inhibitor loading dose. In the no-pretreatment group choice of P2Y12 inhibitor was left to operator in the cath lab before proceeding to PCI. Post-procedural in-hospital and long term follow up (1 year) were obtained through hospital and national registry systems and patient survey. Results In the no-pretreatment group 91.3% of patients underwent coronary angiography and PCI was performed in 51.8%. In patients proceeding to PCI, 58.5% were given clopidogrel and 41.5% were given a potent P2Y12 inhibitor. In the pretreatment group, clopidogrel was the drug of choice in 93.8% of patients. In the pretreatment group, the primary composite endpoint (MACE and bleeding events) were more common during in-hospital follow-up and this difference was due to a significant increase in both BARC class I &amp; II and class III, IV &amp; V bleedings (Table 1). In the long-term follow up, statistically significant difference was only seen in BARC class I &amp; II bleedings in the pretreatment group. There were no difference in MACE rates in neither in-hospital or long-term follow up (Table 2). Also in multivariate regression analysis, pretreatment with a P2Y12 inhibitor was found to be an independent predictor of short term primary composite endpoints and long-term all-cause mortality. Conclusion The results of our study investigating the effects of the P2Y12 inhibitor pretreatment strategy on ischemic and bleeding endpoints in NSTE-ACS patients showed that the pretreatment strategy did not lead to an improvement in MACE rates in in-hospital and long-term follow-up but caused on overall increase in bleeding events.Kaplan-Meier Survival Analysis

Edoxaban dose, frailty, and outcomes in patients with atrial fibrillation: the ETNA-AF-Europe 4-year follow-up

Abstract Background Frailty is a common reason to choose non-recommended (non-rec) doses of non-vitamin-K-antagonist oral anticoagulants in patients with atrial fibrillation (AF); however, it is not known how this practice affects stroke and bleeding outcomes. Purpose To assess clinical outcomes in frail patients with AF receiving non-rec vs recommended (rec) doses of edoxaban using 4-yr follow-up data from ETNA-AF-Europe. Methods The prospective, observational ETNA-AF-Europe study followed patients with AF receiving edoxaban for up to 4 yrs. In ETNA-AF-Europe, perceived frailty was based on investigators’ own clinical binary judgement in each patient. Objective frailty was determined using a simplified adaptation of the Rockwood’s Frailty Index. For objective frailty, patients with missing index were categorised as non-frail. Patients with perceived or objective frailty were combined for this analysis. Baseline characteristics and hazard ratios (HRs) with 95% confidence intervals (CIs) assessing risk of outcomes in frail patients prescribed non-rec vs rec edoxaban doses (i.e., non-rec 60mg vs rec 30mg and non-rec 30mg vs rec 60mg) are presented. Data were adjusted for age, sex, and derived versions of the CHA2DS2-VASc and HAS-BLED scores. Net clinical benefit was defined as any stroke/systemic embolic event (SEE), transient ischaemic attack, venous thromboembolic event, major bleeding, or cardiovascular death, whichever came first. Results Of 13164 patients, 1786 were frail (13.6%; perceived frailty [n=1410], age [IQR]: 82.0 [78.0-86.0] yrs, women: 57.9%; objective frailty [n=540], age [IQR]: 77.0 [71.0-82.0] yrs, women: 31.9%; both, n=164). Baseline characteristics are reported in Table 1. Risk of all-cause death was higher in frail patients treated with non-rec 30mg vs rec 60mg (HR [95% CI]: 1.44 [1.06,1.96]). The annualised rate [CI] of any stroke/SEE was non-significantly higher (HR [95% CI]:1.60 [0.80,3.20]) with non-rec 30mg (n=169; 2.25 [1.25,4.06]) vs rec 60mg (n=622; 1.54 [1.08,2.20]). There was, however, no association between treatment received and risk (HR [95% CI]) of major bleeding (1.19 [0.58,2.43]) or net clinical benefit (1.26 [0.84,1.87]) (Figure 1). In frail patients who received non-rec 60mg (n=183) vs rec 30mg (n=695), risk of any stroke/SEE (HR [95% CI]) was higher (2.15 [1.03,4.49]), but there were no significant differences in the risk (HR [95% CI]) of major bleeding (1.03 [0.52,2.01]), net clinical benefit (1.15 [0.78,1.71]), or all-cause death (0.79 [0.59,1.05]) (Figure 1). Conclusions In this large European AF registry, the presence of frailty should not drive dosing recommendations for edoxaban. In particular, when compared with the rec 60mg dose, the non-rec 30mg (reduced) dose, was associated with more all-cause death and no benefits on major bleeding.Baseline Characteristics

IRight4Me: individualisation of P2Y12 inihibitors in the realworld practice - an interim report

Abstract Background The uptake of CYP2C19 testing has been limited, as clinicians opined majority of patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCI) should receive Ticagrelor per international guidelines. Remaining minority with high bleeding risk (HBR) would be on Clopidogrel from the outset. We set out to study how clinicians’ knowledge of CYP2C19 phenotype affects choice of P2Y12 inhibitors, and thus real-world clinical outcomes for ACS patients. We report the interim findings of bleeding at 6 months in the Ticagrelor-loaded subgroup. Methods Patients eligible for escalation or de-escalation were recruited into the study and tested for CYP2C19 polymorphism. CYP2C19 phenotype results and recommendations were revealed to outpatient clinicians, giving them the choice to keep or switch P2Y12 inhibitors. Bleeding outcomes were prospectively tracked and adjudicated by independent study team members. Results A total of 740 patients who have completed 6 months from index admission for ACS were used for this analysis. Overall adjudicated MACCE and bleeding rates were 3.46% (n = 27) and 12.7% (n=95) respectively. CYP2C19 Non-LoF (Loss-of-Function) patients who were de-escalated to Clopidogrel were least likely to bleed (Fig 1). Ticagrelor-only patients experienced almost twice the risk of bleeding than those who were de-escalated to Clopidogrel, regardless of phenotype status (15.1% vs 7.8%, Cox HR, p = 0.042). High bleeding risk (HBR) factors did not explain for differences in bleeding. The non-LoF patients on Ticagrelor (n = 173) experienced more than 2-fold risk of bleeding compared to those de-escalated to Clopidogrel (n = 71), adjusted HR 0.389, p = 0.059. MACCE rates were similar between these two groups at 2.41% for Non-LoF continued on Ticagrelor (n = 164) and 2.44% for Non-LoF switched to Clopidogrel (n = 81) respectively. Conclusion Our interim analysis shows that Ticagrelor is associated with significantly higher rates of bleeding which could be mitigated by de-escalation to Clopidogrel. Non-LoF patients who have been de-escalated to Clopidogrel could be at much lower risk of bleeding, without losing out on MACCE outcomes. CYP2C19 phenotype status has the potential to add more precision to decision-making. We expect to report final results of 1000 patients at the end of 12 months to fully assess the impact of phenotype-guided de-escalation on bleeding and MACCE.

The impact of body mass on cardiovascular outcomes in patients with acute coronary syndrome

Abstract Background Patients with acute coronary syndrome (ACS) and extreme body weights exhibit varying risks of bleeding and thrombotic outcomes. Furthermore, extreme body weights can influence the pharmacodynamic response to potent P2Y12 inhibitors (ticagrelor/prasugrel) and clopidogrel. Purpose This study aims to assess the impact of extreme body weights on cardiovascular outcomes, as well as the comparative efficacy and safety of potent P2Y12 inhibitors versus clopidogrel. Methods Data was extracted from the FORCE-ACS registry, a prospective, multicentre, registry, enrolling patients with ACS. Patients were stratified (in kg/m2) into the categories: underweight (body mass index [BMI] ≤20.0), normal weight (20.1–24.9), overweight (25.0–29.9), class 1 (30.0–34.9) and class 2 obesity (≥35.0). The primary thrombotic endpoint was major adverse cardiac events (MACE), a composite of cardiovascular death, myocardial infarction (MI), or stroke. The primary bleeding endpoint was defined as Bleeding Academic Research Consortium (BARC) 2, 3 or 5 bleeding. Cox proportional hazard models and Kaplan-Meier survival curves were used to estimate the risk of clinical events across the BMI categories. Restricted cubic splines were made to assess the continuous association of BMI with the risk of the primary endpoints, stratified for P2Y12-inhibitor therapy (potent vs. clopidogrel) and gender. Results The total included population consisted of 5,864 patients with ACS (mean age 65.2 years, 72.4% men), and were stratified into underweight (N=112 [2%]), normal weight (N=1,627 [28%]), overweight (N=2,697 [46%]), class 1 obesity (N=1,081 [18%]) and class 2 obesity (N=347 [6%]). Compared with normal weight (10.8%), the rate of primary bleeding outcome was higher in underweight (15.2%) patients, but lower in the overweight (8.9%), class 1 obesity (7.9%) and class 2 obesity (6.3%) categories. MACE occurred in 9.8% for the underweight group, 7.9% for normal weight, 7.0% for overweight, 8.0% for class, and 6.1% for class 2 obesity. After adjusting for confounding factors such as age, gender, cardiovascular risk factors, access site, and medical therapy, each unit increase in BMI was associated with a decreased bleeding risk (hazard ratio [HR] 0.97, 95% CI 0.95-0.99, p = 0.02), with no significant association found for MACE. Similar findings are demonstrated in the Kaplan Meier analysis (Figure 1A-1B). Subgroup analysis regarding bleeding risk and BMI did not show a significant interaction for potent P2Y12-inhibitor therapy versus clopidogrel and gender (P-value for interaction: 0.04 and 0.32, respectively)(Figure 2A-2D). Conclusions Our findings indicate a stronger correlation between BMI and bleeding risk compared to thrombotic risk, showing an increased risk for bleeding in patients with a low BMI. These results underscore the importance of careful monitoring and tailored interventions to mitigate bleeding risk in underweight patients.

Clinical outcomes of edoxaban treatment in atrial fibrillation patients with high bleeding risk: insights from the ETNA-AF-China 1-year follow-up

Abstract Background In China and many other countries, anticoagulated atrial fibrillation (AF) patients with high bleeding risk often raises clinical concern; the optimal dose of direct oral anticoagulants (DOACs) preventing stroke/systemic embolic events (SEE) in those population remains unclear. Purpose To assess the effectiveness and safety of edoxaban treatment in Chinese AF patients with high bleeding risk, and to compare 60 mg vs 30 mg dose in this real-world registry. Methods ETNA-AF-China is a prospective, observational study conducted in 89 centres across Chinese Mainland enrolling AF patients receiving edoxaban. This subgroup analysis was based on 1-year follow-up data. Patients were categorized to high bleeding risk group who had a DOAC score ≥6 (age, creatinine clearance, underweight, history of stroke/TIA/SEE, diabetes, hypertension, antiplatelet use, NSAIDs use, history of major/critical bleeding, liver disease) at baseline, or moderate-to-low bleeding risk group meeting criteria of DOAC score &amp;lt;6. The safety, effectiveness, and composite outcomes were reported by comparison between patient subgroups using Cox proportional hazards models. Results Of 4883 patients with 1-year follow-up, 1534 (31.4%, 60 mg: n=518, 30 mg: n=1016) were identified as high bleeding risk and 3349 (68.6%) as moderate-to-low bleeding risk. As expected, patients with high bleeding risk were more often elderly (48.2% ≥80 years), had lower body weight, worse renal function, higher CHA2DS2-VASc score than those with moderate-to-low risk (Figure 1). In both high risk and moderate-to-low risk subgroups, patients receiving 60 mg edoxaban were younger, with better renal function, lower CHA2DS2-VASc score compared with 30 mg. Annualised event rates of major bleeding (HR 2.95, 95%CI 1.62–5.36), all cause death (3.42, 2.29–5.09), CV death (3.27, 1.52–7.04), major adverse cardiac events (MACE, 2.61, 1.69–4.02) and all NCOs were significant higher in patients with high bleeding risk compared with moderate-to-low risk (Figure 2). After multivariable adjustment, edoxaban dose of 60 mg other than 30 mg were associated with significantly lower rates of all cause death (adjusted HR 0.41, 0.18–0.90) and lower trend of NCO3 (0.51, 0.28–0.92) and NCO4 (0.51, 0.30–0.88) by composite of stroke/SEE, major bleeding and death events in high risk subgroup; no significant difference between edoxaban doses and stroke or bleeding outcomes with cumulative low event rates were observed. Conclusion In routine clinical care, AF patients at high bleeding risk faces worse outcomes of death events, MACE, as well as the composite outcomes over moderate-to-low risk patients. Among patients with high bleeding risk, edoxaban use showed effectiveness and safety with overall low incidence, and potential better survival, composite endpoint benefit could be associated with 60mg. Further investigation is ongoing.

Effect of tranexamic acid in vascular surgery- a sub-study of the POISE-3 randomized clinical trial

Abstract Background/Introduction In the POISE-3 trial involving patients undergoing noncardiac surgery, tranexamic acid (TXA) reduced the incidence of the composite outcome of life-threatening bleeding, major bleeding, or bleeding into a critical organ at 30 days. Bleeding is a major issue in vascular surgery. However, TXA use may be limited due to concerns about its safety in this high-risk population. With 1,399 participants in POISE-3 undergoing vascular surgery, this is the largest trial assessing TXA's efficacy in this population. Purpose In this post hoc subgroup analysis, we aimed to investigate the interaction between surgery type (vascular/non-vascular) and the effects of TXA vs placebo on bleeding and cardiovascular (CV) safety outcomes in the POISE-3 population. Methods: Eligible patients were ≥45 years, undergoing inpatient noncardiac surgery, and at risk for bleeding and CV complications. Patients were randomised (1:1) to TXA 1 gm IV bolus at start and end of surgery (total 2 gm) or placebo. We used Cox proportional hazards models incorporating tests for interaction to analyse time to the first occurrence of the composite bleeding outcome, and the CV safety outcome (composite of myocardial injury after noncardiac surgery, non-hemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism) at 30 days. Estimates of hazard ratios (HR) with 95% confidence intervals (CI) were calculated for each subgroup with the interaction P value. Results 9,468 of 9535 (99.3%) POISE-3 patients are included in this analysis; 1399 of whom underwent vascular surgery (699 TXA, 700 placebo). Majority (89.8%) of the vascular surgeries were aorto-iliac, peripheral vascular and extracranial surgeries. In the vascular surgery group, 12.6% of patients receiving TXA experienced the composite bleeding outcome versus 14.7% with placebo (HR 0.85, 95% CI 0.64-1.13). For non-vascular surgery patients, these rates were 8.6% with TXA and 11.3% with placebo (HR 0.74, 95% CI 0.65-0.86), with an interaction P value of 0.42. In vascular surgery patients, the CV safety outcome occurred in 20.2% with TXA versus 18.1% with placebo (HR 1.12, 95% CI 0.88-1.42). In the non-vascular surgery group, both TXA and placebo arms showed a 13.1% incidence rate (HR 1.00, 95% CI 0.89-1.13), with an interaction P value of 0.43. Conclusion In vascular surgery patients, there were higher rates of bleeding and cardiovascular events compared to those undergoing non-vascular surgeries; however, there was no significant interaction between the effects of TXA and the type of surgery. The overall POISE-3 trial provides the best estimate of effect with TXA for all patients including those undergoing vascular surgery. The main limitation is that this subgroup analysis was not pre-specified.

Post-PCI anticoagulation with unfractionated heparin in acute coronary syndrome: insight from the STOPDAPT-3 trial

Abstract Background The guidelines recommend the post-procedural anticoagulation should be discontinued after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) except for the specific indications.(1) However, these guideline recommendations were not well supported by data, and therefore, post-PCI parental anticoagulation has been commonly implemented in patients with ACS in the previous studies.(2-5) Purpose To clarify the preference and clinical situations of post-PCI unfractionated heparin (UFH) in ACS patients and to explore the influence of post-PCI UFH on cardiovascular and bleeding outcomes. Methods STOPDAPT-3 trial is a randomized controlled trial to demonstrate the efficacy and safety of the aspirin-free prasugrel monotherapy strategy compared to the conventional dual antiplatelet therapy after PCI in patients with high-bleeding risk or ACS.(6) Data on periprocedural heparin use and its doses were vigorously collected. The current study population was the ACS patients enrolled in the STOPDAPT-3 without use of mechanical circulatory support devices. The two co-primary endpoints were the bleeding outcome defined as the BARC 3 or 5 criteria and the cardiovascular outcome defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke. Outcomes were assessed at 30 days from index PCI. Results Among 4088 ACS study patients, 2339 (57.2%) patients received post-PCI UFH. Median dose of UFH was 7.1 (IQR 6.0-8.8) units/kg/hour and the median duration was 25 (IQR 24-48) hours. As many as 57.7% of patients received 10000 units/day of heparin after PCI irrespective of body weight. STEMI patients more frequently received post-PCI UFH compared to NSTE-ACS (72.3% and 38.8%, P&amp;lt;0.001) and the patients with intraprocedural adverse angiographic findings such as thrombus, slow-flow, no-reflow, or final TIMI flow &amp;lt;=2 also more frequently received post-PCI UFH than those without (67.6% and 47.5%, P&amp;lt;0.001). Post-PCI UFH was associated with a significantly increased risk of bleeding endpoint (4.75% and 2.52%, adjusted HR 1.69 [95%CI 1.15-2.46], P=0.007) and a numerically increased risk of cardiovascular endpoint (3.16% and 1.72%, adjusted HR 1.56 [95%CI 0.98-2.46], P=0.06). Even in the patients with intraprocedural adverse angiographic findings, post-PCI UFH did not show a clear benefit for cardiovascular endpoint (3.15% and 1.72%, adjusted HR 1.73 [95%CI 0.88-3.41]. P=0.11). Conclusion(s) Post-PCI anticoagulation with UFH was frequently implemented in ACS patients enrolled in the latest large Japanese clinical trial. Post-PCI UFH use was associated with harm in terms of bleeding without a benefit in reducing cardiovascular events.

Comparative analysis of vitamin K antagonists and direct oral anticoagulants for left ventricular thrombus management: a retrospective study utilising TriNetX

Abstract Introduction Despite progress in cardiovascular medicine, guidelines for addressing left ventricular thrombus (LVT) remain limited. Furthermore, incorporating oral anticoagulants into dual antiplatelet therapy for acute myocardial infarction (MI) adds complexity to treatment decisions. While conventional guidance favors vitamin K antagonists (VKAs), emerging evidence suggests favorable outcomes with direct oral anticoagulants (DOACs). Purpose This study aims to assess the safety and efficacy of DOACs versus VKAs in managing LVT among patients with and without recent acute coronary syndrome (ACS). Methods This was a retrospective observational study conducted within TriNetX, a global federated health research network with access to electronic medical records (EMRs) from participating health care organizations including academic medical centres and community hospitals covering approximately 70 million individuals, mainly in the United States. The search was conducted on 26th Februrary 2024 with a study cohort comprising patients with LV thrombus treated with either DOAC or VKA between 1st December 2013 to 1st December 2023. Subgroup analyses were conducted for patients with ACS within one month and those without ACS within a month of treatment. Cohort data were subject to propensity matching (PSM) for age, gender, ethnicities, medical and drug history. Risk analysis and Kaplan-Meier survival analysis were computed for each subgroup at 90 days since the indexed event. Results Following PSM, a total of 39,770 patients were included and 14,302 were in the ACS group and 24,162 in the non-ACS group. DOAC treatment exhibited favourable outcomes for stroke, bleeding, and systemic embolism (p&amp;lt;0.05) compared to VKA in the overall cohort (Table 1). In the ACS group, DOAC was linked to a reduced risk of stroke and systemic embolism (p&amp;lt;0.05) but not bleeding (p=0.066). In the non-ACS group, DOAC was associated with a decreased risk of stroke and bleeding (p&amp;lt;0.05) but not systemic embolism (p=0.113). Across all groups, there were no disparities in overall all causes of mortalities. Conclusion DOACs demonstrated better safety and efficacy outcomes when compared to VKAs in LVT treatment. Interestingly, DOACs utilisation within the ACS context resulted in a diminished risk of embolic complications without the benefit of reduced bleeding risk seen in patients without ACS, suggesting potential implications of triple therapy within first month of ACS treatment, removing the bleeding risk reduction of DOACs. This shows a fundamental difference in LVT between the 2 groups of patients so future studies should aim to differentiate between the 2.

Predictors and outcomes of intracranial hemorrhage in 58,000 patients with atrial fibrillation on oral anticoagulation: insights from COMBINE-AF

Abstract Background Among anticoagulated patients with atrial fibrillation (AF), intracranial hemorrhage (ICH) is the leading cause of bleeding-related death and disability. The COMBINE-AF database has patient-level data from four major randomized-controlled trials [ROCKET-AF (rivaroxaban), RE-LY (dabigatran), ENGAGE-TIMI 48 (edoxaban), ARISTOTLE (apixaban)] of direct oral anticoagulants (DOACs) versus warfarin in patients with AF. Purpose/Methods We investigated the rates, predictors, and mortality of ICH in patients randomized to DOAC (rivaroxaban, dabigatran, edoxaban, apixaban) or warfarin. ICH was subclassified as subdural or non-subdural (intracerebral, intraventricular, subarachnoid, epidural). Multivariable Cox models were used to identify predictors of ICH. Frequencies and fatality rates of ICH were calculated and displayed as Kaplan-Meier curves. Results In COMBINE-AF, there were 58,634 patients randomized to either DOAC (n=29,362) or warfarin (n=29,272). The mean age was 70.5 years, 37% were female, and 81% were White. The mean CHA2DS2-VASc score was 2.6, 43% of patients had a history of smoking, 31% had diabetes, and 29% had prior stroke/TIA. After a mean of 32 months, ICH occurred in 593 patients (1.01%, 0.58 per 100-patient years, 95% CI [0.54, 0.63]). The most significant independent predictors of ICH in order of importance were: treatment with warfarin, older age, prior stroke/TIA, enrollment in Asia, antiplatelet use at randomization, and history/risk of falls (Figure 1). Mortality after ICH was 48.4% (287/593 participants), with a majority of deaths (82%) occurring within 30 days of ICH event. Non-subdural ICH was more common than subdural ICH (73% vs 25%) and had a higher risk of death (Figure 2). Participants randomized to DOAC had a lower risk of both subdural and non-subdural ICH than those treated with warfarin; however, mortality rates after ICH were similar regardless of anticoagulant type. Conclusion ICH is an uncommon but devastating complication of oral anticoagulation in patients with atrial fibrillation. The mortality rate following ICH is high, particularly following non-subdural ICH. To reduce the risk of ICH, clinicians should consider using DOACs over warfarin and carefully evaluate the need for antiplatelet therapy, particularly in patients with other significant predictors of ICH such as prior stroke, advanced age, residence in Asia, and history of falls.Predictors of Intracranial Hemorrhage90-Day Mortality after ICH