Risk Of Serious Bleeding Research Articles

Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban

Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation. To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol. This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024. Diltiazem and metoprolol. The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting. The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26). In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Blocking tumor-platelet crosstalk to prevent tumor metastasis via reprograming glycolysis using biomimetic membrane-hybridized liposomes

Activated platelets promote tumor progression and metastasis through active interactions with cancer cells, especially in promoting epithelial-mesenchymal transition (EMT) of tumor cells and shedding tumor cells into the blood. Blocking platelet-tumor cell interactions can be a potential strategy to inhibit tumor metastasis. Platelet activation requires energy produced from aerobic glycolysis. Based on this, we propose a platelet suppression strategy by reprogramming glucose metabolism of platelets, which has an advantage over conventional antiplatelet treatment that has a risk of serious hemorrhage. We develop a biomimetic delivery system using platelet membrane-hybridized liposomes (PM-Lipo) for codelivery of quercetin and shikonin to simultaneously inhibit lactate transporter MCT-4 and a glycolytic enzyme PKM2 for achieving metabolic reprogramming of platelets and suppressing platelet activation. Notably, PM-Lipo can also inhibit glycolysis in cancer cells, which actually takes “two-birds-one-stone” action. Consequently, the platelet-tumor cell interactions are inhibited. Moreover, PM-Lipo can bind with circulating tumor cells and reduce their seeding in the premetastatic microenvironment. The in vivo studies further demonstrated that PM-Lipo can effectively suppress primary tumor growth and reduce lung metastasis without affecting inherited functions of platelets. Reprogramming glycolysis of platelets can remodel the tumor immune microenvironment, including suppression of Treg and stimulation of CTLs.

Bleeding Complications in COVID-19 Critically Ill ARDS Patients Receiving VV-ECMO Therapy.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) therapy is rapidly expanding worldwide, yet this therapy has a serious risk of bleeding. Whether coagulation-activating viral infections such as COVID-19 may have an impact on the risk of bleeding is largely unknown. This study conducted a monocentric investigation of severely affected COVID-19 patients receiving VV-ECMO therapy with regard to the occurrence and possible influences of minor and major bleeding and transfusion requirements. Among the 114 included study patients, we were able to assess more than 74,000 h of VV-ECMO therapy. In these, 103 major bleeding events and 2283 minor bleeding events were detected. In total, 1396 red blood concentrates (RBCs) were administered. A statistically significant correlation with the applied anticoagulation or demographic data of the patients was not observed. Contrary to the frequently observed thromboembolic complications among COVID-19 patients, patients with VV-ECMO therapy, even under low-dose anticoagulation, show a distinct bleeding profile, especially of minor bleeding, with a substantial need for blood transfusions. COVID-19 patients show a tendency to have frequent bleeding and require repeated RBC transfusions during VV-ECMO. This fact might not be solely explained by the mechanical alteration of ECMO or anticoagulation.

Dengue Fever Complicating Term Pregnancy Leading to Postpartum Hemorrhage

Dengue infection during the peripartum period is always a challenging situation for the obstetrician as well as other clinical departments involved in the management for these patients. The risk increases to a greater instant if the infection occurs during the third trimester as it possesses the risk of serious bleeding during parturition. In this case report, we will see the incidence and management of dengue fever in a peripartum female.

Clinical Outcomes in Elderly Atrial Fibrillation Patients at Increased Bleeding Risk Treated with Very-Low-Dose versus Regular-Dose Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study.

The ELDERCARE-AF trial showed that edoxaban at a very-low-dosage (VLD) of 15mg/day was more effective than a placebo at preventing stroke/systemic embolism without significantly increasing the risk of serious bleeding. We aimed to compare the effectiveness and safety for VLD non-vitamin K antagonist oral anticoagulants (NOACs) (edoxaban 15mg once daily, dabigatran 110 or 150 once daily, apixaban 2.5mg once daily, or rivaroxaban 10mg (without the diagnosis of chronic kidney disease) or less than 10mg once daily) versus regular-dosage (RD) NOACs (edoxaban 60/30mg once daily or other labeling-dosage NOACs) among a real-world cohort of elderly AF population similar to the ELDERCARE-AF cohort. In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database (NHIRD), we identified a total of 7294 and 4151 consecutive AF patients aged 80 years or older with a CHADS2 score≥2 who met the enrollment criteria (generally similar to ELDERCARE-AF) taking VLD and RD NOACs from June 1, 2012, to December 31, 2019, respectively. Propensity-score stabilized weighting (PSSW) was used to balance covariates across study groups. Patients were followed up from the first date of prescription for NOACs until the first occurrence of any study outcome, death, or until the end date of the study period (December 31, 2020). After PSSW, VLD NOAC was associated with a comparable risk of ischemic stroke/systemic embolism and major bleeding but a higher risk of major adverse limb events (MALEs) requiring lower limb revascularization or amputation (Hazard ratio [HR]:1.54, 95% confidential interval [CI]:1.09-2.18; p=0.014), venous thrombosis (HR:3.75,95%CI:1.56-8.97; p=0.003), and all-cause mortality (HR:1.21,95%CI:1.15-1.29; p<0.001) compared to RD NOACs. VLD NOACs showed worse outcomes in most net clinical benefits (NCOs). The main result was consistent based on on-treatment analysis or accounting for death as a competing risk. In general, the advantage of NCOs for the RD NOACs over VLD NOACs persisted in most high-risk subgroups, consistent with the main analysis (P for interaction>0.05). Use of VLD NOACs was associated with a greater risk of arterial and venous thrombosis, death as well as the composite outcomes, when compared to that of RD NOAC in high-risk elderly AF patients at increased bleeding risk. Thromboprophylaxis with RD NOAC is still preferable over VLD NOAC for the majority of elderly AF patients at increased bleeding risk.

Warfarin and Antibiotics: Drug Interactions and Clinical Considerations.

Warfarin administration poses a notable challenge in clinical practice due to the increased susceptibility of patients to major bleeding, particularly when co-administered with other medications capable of modulating its metabolic pathways. Among these medications, antibiotics have been recognized as potential agents that can either induce or inhibit cytochrome P450-2C9, thereby impacting the effects of warfarin. A wealth of evidence from numerous studies consistently supports an elevated risk of serious bleeding in patients concurrently receiving antibiotics and warfarin therapy. This narrative review elucidates the intricate interactions between warfarin and various antibiotic classes. Notably, significant increases in the International Normalized Ratio (INR) were observed among warfarin-treated patients receiving penicillin derivatives, fluoroquinolones, TMP-SMX, and macrolides. Conversely, investigations have also demonstrated a reduction in INR levels in patients on warfarin when exposed to rifampin, a potent inducer of cytochrome P-450. Intriguingly, cephalosporin antibiotics and amoxicillin/clavulanate, despite not interfering with the cytochrome P450 system, exhibited a positive association with increased INR values. The findings of this narrative review underscore the importance of diligent monitoring in patients on warfarin requiring concomitant antibiotic therapy, as this surveillance strategy proves pivotal in mitigating the risk of major bleeding complications. Additionally, for patients necessitating cytochrome P450 inhibitors such as penicillin derivatives, fluoroquinolones, TMP-SMX, and macrolides, the consideration of dose reduction in warfarin therapy may confer substantial benefits in reducing the occurrence of major bleeding events. Similarly, patients who are co-administered rifampin alongside warfarin necessitate vigilant monitoring, with a potential need for escalating warfarin doses to counteract the risk of a hypercoagulable state.

APTT-guided anticoagulation monitoring during ECMO support: A systematic review and meta-analysis

IntroductionThe initiation of the extracorporeal membrane oxygenation (ECMO) is associated with complex coagulatory and inflammatory processes and consequently needed anticoagulation. Systemic anticoagulation bears an additional risk of serious bleeding, and its monitoring is of immense importance. Therefore, our work aims to analyze the association of anticoagulation monitoring with bleeding during ECMO support. Material and methodsSystematic literature review and meta-analysis, complying with the PRISMA guidelines (PROSPERO-CRD42022359465). ResultsSeventeen studies comprising 3249 patients were included in the final analysis. Patients experiencing hemorrhage had a longer activated partial thromboplastin time (aPTT), a longer ECMO duration, and higher mortality. We could not find strong evidence of any aPTT threshold association with the bleeding occurrence, as less than half of authors reported a potential relationship. Finally, we identified the acute kidney injury (66%, 233/356) and hemorrhage (46%, 469/1046) to be the most frequent adverse events, while almost one-half of patients did not survive to discharge (47%, 1192/2490). ConclusionThe aPTT-guided anticoagulation is still the standard of care in ECMO patients. We did not find strong evidence supporting the aPTT-guided monitoring during ECMO. Based on the weight of the available evidence, further randomized trials are crucial to clarify the best monitoring strategy.

The predictive model for risk of chemotherapy-induced thrombocytopenia based on antineoplastic drugs for solid tumors in eastern China

Chemotherapy-related thrombocytopenia (CIT) is a significant adverse event during chemotherapy, which can lead to reduced relative dose intensity, increased risk of serious bleeding and additional medical expenditure. Herein, we aimed to develop and validate a predictive nomogram model for prediction of CIT in patients with solid tumor. From Jun 1, 2018 to Sep 9, 2021, a total of 1541 patients who received 5750 cycles of chemotherapy were retrospectively enrolled. Cox regression analysis was performed to identify predictive factors to establish the nomogram model for CIT. The incidence of chemotherapy-induced thrombocytopenia was 21.03% for patient-based and 10.26% for cycles of chemotherapy. The top five solid tumors with CIT are cervix, gastric, bladder, biliary systemic, and ovarian. The incidence of chemotherapy dose delays in any cycle because of CIT was 5.39%. Multivariate analysis showed that tumor site, treatment line, AST, oxaliplatin, and capecitabine were significantly associated with CIT. Moreover, we established a nomogram model for CIT probability prediction, and the model was well calibrated (Hosme-Lemeshow P = 0.230) and the area under the receiver operating characteristic curve was 0.844 (Sensitivity was 0.625, Specificity was 0.901). We developed a predictive model for chemotherapy-induced thrombocytopenia based on readily available and easily assessable clinical characteristics. The predictive model based on clinical and laboratory indices represents a promising tool in the prediction of CIT, which might complement the clinical management of thrombocytopenia.

Outcomes of Transcatheter Aortic Valve Implantation Comparing Medtronic’s Evolut PRO and Evolut R: A Systematic Review and Meta-Analysis of Observational Studies

Transcatheter aortic valve implantation (TAVI) has become a broadly acceptable alternative to AV surgery in patients with aortic stenosis (AS). New valve designs are becoming available to address the shortcomings of their predecessors and improve clinical outcomes. A systematic review and meta-analysis was carried out to compare Medtronic's Evolut PRO, a new valve, with the previous Evolut R design. Procedural, functional and clinical endpoints according to the VARC-2 criteria were assessed. Eleven observational studies involving N = 12,363 patients were included. Evolut PRO patients differed regarding age (p < 0.001), sex (p < 0.001) and STS-PROM estimated risk. There was no difference between the two devices in terms of TAVI-related early complications and clinical endpoints. A 35% reduction of the risk of moderate-to-severe paravalvular leak (PVL) favoring the Evolut PRO was observed (RR 0.66, 95%CI, [0.52, 0.86] p = 0.002; I2 = 0%). Similarly, Evolut PRO-treated patients demonstrated a reduction of over 35% in the risk of serious bleeding as compared with the Evolut R (RR 0.63, 95%CI, [0.41, 0.96]; p = 0.03; I2 = 39%), without differences in major vascular complications. The evidence shows good short-term outcomes of both the Evolut PRO and Evolut R prostheses, with no differences in clinical and procedural endpoints. The Evolut PRO was associated with a lower rate of moderate-to-severe PVL and major bleeding.

L’aspirine a-t-elle une place dans la prévention cardiovasculaire primaire par la polypill ? Étude de simulation sur une population virtuelle réaliste

The polypill strategy could become widely accepted in cardiovascular prevention due to reduced costs and its simplicity, which promote compliance. Aspirin is often included as a component of the polypill for primary prevention, but three powerful recent trials failed to show any favorable net benefit even in high-risk subgroups. Our objective is to estimate the net benefit associated with aspirin in primary cardiovascular prevention. We simulated the impact of different polypill compositions combining pravastatin, ramipril, hydrochlorothiazide, with or without aspirin, on a realistic French virtual population between 35 and 65 years old. We assessed how this impact on myocardial infarction and stroke varied according to gender, diabetes, and arterial hypertension. We identified the subgroup of individuals whose specific benefit from aspirin was greater than twice the risk of serious bleeding it induced. The absolute benefit associated with aspirin was reduced by co-prescriptions. No subgroup of women benefited from aspirin, and the subgroup of women with a clear net benefit represented 128 women out of 529,421. Men at high risk of cardiovascular death, or with diabetes and hypertension, had a benefit from aspirin exceeding the risk of bleeding induced, but this risk represented more than half of the benefit. No subgroup analyzed did show a benefit greater than twice the risk of bleeding. The proportion of men whose expected benefit from aspirin was greater than twice the risk of bleeding represented 3% of all men. An optimal polypill strategy in primary prevention between the ages of 35 and 65, combining three drugs but not aspirin, can hope to save two out of three strokes and more than one out of two myocardial infarctions. It would prevent a major cardiovascular accident every 16 to 193 individuals treated according to the subgroups considered. Until proven otherwise, aspirin has only a limited place in individuals between 35 and 65 years without a cardiovascular history. We showed how simulating therapeutic strategies on a realistic virtual population could be used for best applying available evidence.

Standardizing the Diagnostic and Therapeutic Approach to Newly Diagnosed Children with ITP: Prospective Data from the ITP Consortium of North America (ICON) Quality Improvement Initiative

Background Pediatric immune thrombocytopenia (ITP) is an acquired autoimmune disorder which leads to a low platelet count and increased risk of bleeding. Despite published treatment guidelines, there is practice variation among clinicians and institutions due to the low grade of available evidence. The recommended management of newly diagnosed children at low risk of serious bleeding is observation; despite this, these patients are often treated with medication. These medications are only transiently effective with potential for side effects and excess lab monitoring as well as associated with increased costs and overuse of healthcare resources due to hospital admissions and encounters for medication-related side effects. Our objective is to report prospective data from a quality improvement (QI) project of the Pediatric ITP Consortium of North America (ICON) that was initiated in 2020 to improve consistency in clinical practice using national ITP guidelines. DESIGN/METHODS Within the ICON QI subcommittee, a standardized clinical care pathway for newly diagnosed childhood ITP was developed based on the American Society of Hematology (ASH) 2019 guidelines. Sites initially completed a retrospective analysis documenting the pre-QI pathway management of children, ages 1-16 years, diagnosed with ITP from January to December 2019. After local dissemination of the clinical care pathway, clinicians at all participating sites reviewed the pathway at the time of managing newly diagnosed children and completed a short survey documenting a modified Buchanan-Adix bleeding score and management decisions. Chart review was completed six months following ITP diagnosis to collect data regarding additional treatment or hospitalization. For retrospective data, total patients include those with available data. Results Retrospective data were collected from 7 centers for 205 patients managed for newly diagnosed ITP. In this pre-intervention cohort, 0.5% of patients (1/204) had a bleeding score documented at their initial visit. Most patients (63%,129/204) received initial medication treatment including intravenous immunoglobulin (54%), corticosteroids (9%), and anti-D/other (3%); 37% (75/204) were initially observed. In the 6 months after diagnosis, 11% (23/205) were admitted to the hospital for management of ITP. The ITP QI pathway was implemented prospectively in the care of 126 patients from 7 centers between November 2020 and July 2022. Of these patients,100% (126/126) had a bleeding score documented at their initial visit [Grade 0 (2%), Grade 1 (26%), Grade 2 (27%), Grade 3 (45%), Grade 4 (0%)]. Initial treatment included close observation in the majority (63%, 79/125) and medication treatment in 37% [corticosteroids (22%, 28/125) and IVIG/anti-D (14%, 18/125)] (Figure 1). Most patients were managed per the pathway according to their bleeding score (80%, 93/117). The most common reasons that providers deviated from the pathway were parent preference (50%, 12/24) and provider concern about bleeding risk (29%, 7/24). Of those with low level grade 3 bleeding, in whom the pathway suggested close observation, 62% (21/34) were observed and 38% of patients (13/34) were treated with medication (Figure 2). For patients with high level grade 3 bleeding, in whom the pathway suggested medication treatment, all patients except one were treated with medication. Of the 66 patients with 6 month follow up data, only 2 patients (3%, 2/66) were admitted to the hospital. DISCUSSION For children with newly diagnosed ITP and a platelet count <20 x 109/L who have no or mild bleeding, ASH guidelines suggest observation rather than treatment with corticosteroids. Implementation of an ITP clinical care pathway based on bleeding score led to an increase in the number of children observed. In contrast to the pre-intervention cohort, most patients treated with medication received corticosteroids rather than IVIG as per ASH guidelines. Despite the increase in patients managed with close observation, just 3% were admitted to the hospital within the first 6 months of diagnosis compared to 11% of the retrospective cohort. Our findings suggest that the use of a clinical care pathway based on objective assessment of bleeding symptoms increases management with close observation when indicated in the treatment of childhood ITP without a subsequent increase in hospitalization and increases adherence to national guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 13639: Bivalirudin versus Heparin in Patients With STEMI Undergoing PCI: Individual-Patient-Data Pooled Analysis of the 6 Major Randomized Trials

Background: Given differences in prior trial designs, the treatment tradeoffs between bivalirudin and heparin in patients with STEMI undergoing PCI remain uncertain. Study-level meta-analyses lack granularity to provide conclusive answers or assess subgroups. Methods: We performed an individual-patient-data pooled analysis from all 6 large (n&gt;1000) RCTs of bivalirudin vs heparin in STEMI pts undergoing PCI (BRIGHT, EUROMAX, HEAT-PPCI, HORIZONS-AMI, MATRIX, and VALIDATE-SWEDEHEART). The primary efficacy outcome was the 30-day rate of all-cause mortality. Subgroup analyses were performed according to planned use of glycoprotein IIb/IIIa inhibitors (GPI), and administration of a post-PCI bivalirudin infusion. Results: A total of 15,254 patients with STEMI undergoing PCI were included (7,306 randomized to bivalirudin and 7,948 to heparin [43.6% with planned GPI use]). Thirty-day mortality was not significantly different between bivalirudin vs heparin (aHR: 0.80; 95% CI: 0.64, 1.01); 30-day cardiac mortality was reduced with bivalirudin (aHR: 0.72; 95% CI: 0.57, 0.91). There was a higher risk of 30-day MI (aHR: 1.29, 95% CI: 1.02, 1.64) and stent thrombosis (aHR: 1.42; 95 % CI: 1.05, 1.91) but lower risk of serious bleeding (aHR: 0.57 (0.47, 0.68) with bivalirudin vs heparin. At 1 year, net adverse clinical events were reduced with bivalirudin (aHR: 0.84; 95% CI: 0.77, 0.93) (Table). All-cause mortality was reduced with bivalirudin when a post-PCI infusion was used. A high-dose post-PCI infusion mitigated the 30-day MI and ST risks, irrespective of planned GPI use with heparin. Conclusions: In patients with STEMI undergoing PCI, procedural anticoagulation with bivalirudin did not reduce all-cause mortality. Cardiac mortality and serious bleeding were reduced with bivalirudin at the cost of increased rates of MI and ST. Full analyses will be presented at AHA 2022.

Use of tramadol and the risk of bleeding complications in patients on oral anticoagulants: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to determine whether tramadol intake increases the risk of bleeding in patients receiving oral anticoagulants. This systematic review was registered on PROSPERO, CRD42022327230. We searched PubMed and Embase up to 14 April 2022, and references and citations of included studies were screened. Comparative and non-comparative studies exploring bleeding complications among adult patients on oral anticoagulants and tramadol were included. Risk of bias was assessed using an adaptation of the Drug Interaction Probability Scale for case reports and case series and the Newcastle-Ottawa Scale for comparative studies. A meta-analysis was performed for the risk of serious bleeding (leading to hospitalisation or death) associated with tramadol in patients on vitamin K antagonists. A total of 17 studies were included: 1 case series, 12 case reports, 2 case-control studies and 2 cohort studies. Most of the studies described tramadol-vitamin K antagonists' concomitant use; one case-control study also assessed dabigatran and rivaroxaban; one case report involved dabigatran. Among case reports/series, a total of 33 patients had a bleeding complication while using tramadol and an oral anticoagulant. The 4 comparative studies reported an increased bleeding risk during tramadol and vitamin K antagonist intake which was statistically significant in one study; the pooled risk ratio of serious bleeding was 2.68 [95% CI: 1.45 to 4.96; p < 0.001]. This systematic review confirms an association between tramadol use and risk of bleeding in patients on vitamin K antagonists. Evidence is too limited to assess whether this risk extends to patients on direct oral anticoagulants, and further studies are needed.

Abstract 11043: Clinical Safety Outcomes in Relation to Lipoprotein(a) Concentration: Insights from the FOURIER Trial

Background: Lipoprotein(a) is believed to play a causal role in atherogenesis. Drugs are in development that directly target Lp(a) and lower levels by &gt;75%. Thus, the safety of low Lp(a) levels is of importance. Methods: FOURIER randomized 27,564 patients w/ stable ASCVD to evolocumab (EVO) vs placebo on background statin (median f/up 2.2 y); EVO lowered Lp(a) levels by 27%. The relationships between Lp(a) levels, change in Lp(a) and 5 safety outcomes of interest based on prior reports (diabetes [DM], serious bleeding, hemorrhagic stroke, neurocognitive events, malignancy) were examined. Analyses were conducted in the overall population and by treatment arm. Multivariable models included age, sex, race, region, clinical predictors, high-intensity statin, ezetimibe, baseline hs-CRP, “Lp(a)-corrected” LDL-C, and treatment arm. Results: Lp(a) was assessed in 25,083 participants at baseline (median 37nM, range 5-1451) and 25,686 at week 12. There was no association between baseline or achieved Lp(a) levels and risk of serious bleeding, hemorrhagic stroke, neurocognitive events, or malignancy, even in the 3271 patients with Lp(a) levels ≤6nM. There was an inverse association between baseline Lp(a) levels and prevalent or incident DM [OR 1.09, 95%CI 1.07-1.12, for every 50nM lower Lp(a) below 250nM]. However, absolute change in Lp(a) with EVO was not associated with subsequent DM risk (HR 1.03, 0.91-1.16, per 50nM) and EVO did not increase the risk of DM irrespective of baseline Lp(a) (P int=0.97), even in participants in the top decile of baseline Lp(a) (HR 0.91, 0.51-1.62) in whom EVO reduced Lp(a) by 63nM. Conclusion: Lp(a) concentration and changes in Lp(a) were not associated with serious bleeding, hemorrhagic stroke, neurocognitive events, or malignancy. Levels were inversely correlated with having DM, but Lp(a) lowering over a median of 2.2 years with EVO did not further increase the risk. These findings provide new insights for ongoing trials of Lp(a)-lowering drugs.

Intracardiac Thrombosis in A Neonate: A Case Report

Background: Life-threatening intracardiac thrombosis is rare. Intracardiac thrombosis may affect neonates from the first months of life. Because of the potential risk of serious bleeding, the use of recombinant plasminogen activator (rt-PA) in neonates along with heparin is controversial. Case Report: We reported a 37- day- old term infant presented with fever, restlessness, malaise, and respiratory acidosis. Right atrial thrombose was identified by ECHO, results of laboratory tests, and examination. She was successfully treated with rt-PA and rivaroxaban. Conclusion: Early echocardiographic detection before the clot grows large and organized, allows complete, safe, and rapid thrombolysis with rt-PA and rivaroxaban.

Incidence of cardiovascular events in patients with atrial fibrillation anticoagulated with rivaroxaban after 2.5 years of follow-up: not all is stroke or bleeding

Abstract Introduction Atrial fibrillation (AF) is not a benign arrhythmia, but is associated with an increase in mortality, above all related to the risk of suffering thromboembolic events, mainly stroke. The use of oral anticoagulants (OAC) reduces this risk, but increases the risk of serious bleeding. The DOACs have been shown to be superior to the classic vitamin K antagonists (VKAs). It is not as well known whether AF is associated with an increase in other serious cardiac events. Purpose The objective of this analysis was to assess the incidence of stroke, major bleeding, total mortality and major adverse cardiac events [MACE, defined as cardiac mortality (including death for coronary events, progressive heart failure death and sudden cardiac death), coronary revascularization, myocardial infarction] in a contemporary series of patients with AF anticoagulated with rivaroxaban. Methods To do this, we have analyzed a series of 1,433 patients with AF, anticoagulated with rivaroxaban for at least the previous 6 months, consecutively included in the first half of year 2017 in 79 Spanish centers (EMIR study), and followed for 2.5 years. Results Mean age was 74.2±9.7 years, 44.5% being women. Prevalence of diabetes was 27.1%, chronic renal failure 16.1%, coronary heart disease 16.4% and heart failure 22.7%. 2MACE score was 1.8±1.4, CHA2DS2-VASc was 3.5±1.5 and HAS-BLED 1.6±1.0. 77.1% of patients received 20 mg/ day of rivaroxaban and 22.9% 15 mg/day. After a follow-up of 2.5 years, the annual rate (events/100 patients/year) of myocardial infarction was 0.16 (all non-STEMI), coronary revascularization 0.28, cardiac death 0.63 (sudden 0.16, heart failure 0.41, other 0.06), overall MACE 1.07 and overall mortality 2.73, while the incidence of stroke was 0.57 / 100 patients / year (ischemic 0.35, haemorrhagic 0.22) and major bleeding 1.04 (gastrointestinal 0.63, intracranial 0.28). Conclusion In a current series of patients with AF anticoagulated with rivaroxaban, the incidence of embolic and hemorrhagic complications and mortality are low, while the incidence of serious cardiac events is significant, being overall similar to that of stroke and major bleeding. Attention must be paid to the prevention and diagnosis of these problems. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Bayer Hispania

Cardiovascular benefits outweigh risks in patients with atrial fibrillation in REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial)

Abstract Background/Introduction REDUCE-IT, a multinational, double-blind trial, randomized 8179 statin-treated patients with controlled low density lipoprotein cholesterol, elevated triglycerides, and cardiovascular (CV) risk, to icosapent ethyl (IPE) 4 grams/day or placebo. IPE reduced the primary (CV death, myocardial infarction [MI], stroke, coronary revascularization, hospitalization for unstable angina) and key secondary (CV death, MI, stroke) endpoints 25% and 26%, respectively (each p&amp;lt;0.0001), and individual components including stroke (28%), MI (31%), cardiac arrest (48%), and sudden cardiac death (31%) (all p≤0.01). With IPE, bleeding was greater (11.8% vs 9.9%; p=0.006), serious bleeding trended higher (2.7% vs 2.1%; p=0.06), and atrial fibrillation/flutter (AF/F) hospitalization endpoints increased (3.1% vs 2.1%; p=0.004). Purpose To evaluate the effects of IPE on the risk of CV events and safety measures in patients by either history of AF/F or in-study occurrence of positively adjudicated AF/F hospitalization. Methods Conduct post hoc efficacy and safety subgroup analyses of patients with or without either baseline history of AF/F or in-study adjudicated AF/F hospitalization, including hospitalization for ≥24 hours; AF/F not meeting endpoint criteria were reported as adverse events. Results Patients with (n=751; 9.2%) AF/F history at baseline (vs without; n=7428; 90.8%) (Figure 1), or those with (n=211; 2.6%) positively adjudicated in-study AF/F hospitalization endpoints (vs without; n=7968; 97.4%) (Figure 2), had higher event rates of primary, key secondary, and fatal or nonfatal stroke endpoints, but relative risk reductions with IPE were not significantly different (all interaction p-values [pint]=ns). Similar reductions were observed with IPE across the prespecified endpoint testing hierarchy in patients with or without AF/F history or in-study hospitalization endpoints. Patients with baseline AF/F history had similar relative risk for in-study occurrence of AF/F hospitalization with IPE versus placebo (pint=0.21) but had greater absolute risk (12.5% vs 6.3%, IPE vs placebo) vs patients without baseline AF/F history (2.2% vs 1.6%, IPE vs placebo); i.e., recurrent AF/F in those with a prior history of AF/F was more prevalent than de novo AF/F. Serious bleeding trended higher regardless of AF/F history or in-study AF/F hospitalization endpoints (all pint=ns); absolute risk of serious bleeding was greater in patients with AF/F history at baseline (7.3% vs 6.0%) vs those without a baseline history of AF/F (2.3% vs 1.7%), and serious bleeding also trended higher in patients with in-study AF/F hospitalization (8.7% vs 6.0%) vs without (2.5% vs 2.0%) [all IPE vs placebo]. Conclusion REDUCE-IT patients with AF/F history or in-study AF/F hospitalization endpoints had greater CV risk, but similar relative risk reduction in primary, key secondary, and fatal or nonfatal stroke endpoints with IPE. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Amarin Pharma, Inc.

Association Between Use of Pharmacokinetic-Interacting Drugs and Effectiveness and Safety of Direct Acting Oral Anticoagulants: Nested Case-Control Study.

Concomitant use of direct oral anticoagulants (DOACs) and medications with inhibition/induction effect on P‐gp/CYP3A might increase risk of bleeding/treatment failure, respectively. We designed a nested case‐control study within a Clalit cohort of patients with atrial fibrillation (AF) and a cohort of patients with venous thromboembolism, new users of a DOAC (January 1, 2010 to August 24, 2020). Propensity scores were constructed from demographic/clinical characteristics, and medications at cohort entry. Each case of: (i) serious bleeding event; (ii) stroke/systemic emboli (SE) in patients with AF; (iii) recurrent thromboembolism in patients with thromboembolism, was matched by age, sex, length of follow‐up, year of cohort entry, DOAC type, and DOAC indication, to up to 20 controls. Within 89,284 patients with AF and venous thromboembolism and 126,302 patient‐years of follow‐up, there were 1,587 serious bleeding events. Risk of serious bleeding increased in association with concurrent prescription of P‐gp/CYP3A4 inhibitors. Specifically, higher bleeding risk was associated with dabigatran‐verapamil, rivaroxaban‐verapamil, and rivaroxaban‐amiodarone concurrent prescriptions: adjusted odds ratios (ORs) 2.29 (1.13–4.60), 2.18 (1.07–4.40), and 1.68 (1.14–2.49), respectively. There were 1,116 events of stroke/SE, in 79,302 DOAC‐treated patients with AF and 118,124 patient‐years of follow‐up. Concomitant use of phenytoin, carbamazepine, valproic acid, or levetiracetam was associated with risk for stroke/SE: adjusted OR 2.18 (1.55–3.10). Risk of recurrent venous thromboembolism could not be assessed due to the low number of cases. Concurrent prescriptions of dabigatran or rivaroxaban with verapamil, and of rivaroxaban with amiodarone, are associated with increased risk for serious bleeding. Higher risk for stroke/SE in patients with AF is associated with concurrent prescriptions of DOACs with phenytoin, carbamazepine, valproic acid, or levetiracetam.

Use of antithrombotic therapy for secondary prevention in patients with stable atherosclerotic cardiovascular disease: Insights from the COordinated National Network to Engage Cardiologists in the antithrombotic Treatment of patients with CardioVascular Disease (CONNECT‐CVD) study

Although acetylsalicylic acid is the most commonly used antithrombotic agent for the secondary prevention of cardiovascular events, residual atherothrombotic risk has prompted a guideline recommendation for the addition of dual antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) in high vascular risk patients. Accordingly, the CONNECT CVD quality enhancement initiative provides a contemporary "snapshot" of the clinical features and antithrombotic management of atherosclerotic cardiovascular disease (ASCVD) patients in Canada. Canadian cardiologists (49 cardiologists from six provinces) undertook a retrospective chart audit of 10 ASCVD patients in their outpatient practice who met the Cardiovascular Outcomes for People Using Anticoagulation Strategy-like criteria from May 2018 to April 2019. Of the 492 (two cardiologists provided 11 patients) enroled, average age was 70years, 25% were female, 39% had diabetes and 20% had atrial fibrillation. Prior revascularisation was common (percutaneous coronary artery intervention 61%, coronary artery bypass graft 39%), with 31% having multivessel disease. A total of 47% of patients had a Reduction of Atherothrombosis for Continued Health bleeding score of ≥11 (~2.8% risk of serious bleeding at 2years). Single antiplatelet therapy (SAPT) alone was most commonly used (62%), while 22% were on DAPT alone. In total, 22% were on oral anticoagulation (OAC), with 16% being on non-vitamin K oral anticoagulant alone, 5% on DPI and 1% received triple therapy. In contemporary Canadian clinical practice of stable ASCVD patients, a large number of patients receive antithrombotic therapy other than SAPT. Further efforts are required to guide the appropriate selection of patients in whom more potent antithrombotic therapies may safely reduce residual risk.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist