Recommendations for the future management of thrombocytopenia in patients with liver cirrhosis: A modified RAND/UCLA appropriateness method.

OBJECTIVE: The lack of consensus and specific guidelines, and the introduction of new treatments in thrombocytopenia management in liver cirrhosis patients, required a series of recommendations by experts to improve knowledge on this disease. This study's aim was to improve the knowledge around thrombocytopenia in liver cirrhosis patients, in order to contribute to the generation of future evidence to improve the management of this disease. PATIENTS AND METHODS: A modified version of the RAND/UCLA appropriateness method was used. The scientific committee, a multidisciplinary team of 7 experts in managing thrombocytopenia in liver cirrhosis patients, identified the expert panel, and participated in elaborating the questionnaire. Thirty experts from different Spanish institutions were invited to answer a 48-item questionnaire covering 6 areas on a nine-point Likert scale. Two rounds were voted. The consensus was obtained if >77.7% of panelists reached agreement or disagreement. RESULTS: A total of 48 statements were developed by the scientific committee and then voted by the experts, resulting in 28 defined as appropriate and completely necessary, relating to evidence generation (10), care circuit, (8), hemorrhagic risk assessment, decision-making and diagnostic tests (14), professionals' role and multidisciplinary coordination (9) and patient education (7). CONCLUSIONS: This is the first consensus in Spain on the management of thrombocytopenia in liver cirrhosis patients. Experts indicated several recommendations to be carried out in different areas that could help physicians make better decisions in their clinical practice.

Hemorrhagic Safety of Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor without Interruption of Antiplatelet or Anticoagulant Therapy.

INTRODUCTION: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an incision-less ablative technique used to treat medically refractory tremor. Although intracerebral hemorrhage has not been reported with MRgFUS thalamotomy for the treatment of movement disorders, clinicians commonly interrupt active blood thinning medications prior to the procedure or offer gamma knife radiosurgery instead. However, MRgFUS uses focal thermoablation, and bleeding risk is likely minimal. This study aimed to evaluate the safety of MRgFUS thalamotomy in patients with essential tremor (ET) and tremor-dominant Parkinson's disease (PD) without interrupting anticoagulant or antiplatelet therapies. METHODS: This was a single-center retrospective case series of all patients with ET or PD undergoing MRgFUS from February 2019 through December 2022 (n = 96). Demographic variables and medications taken at the time of surgery were obtained. Our primary outcome was the type and frequency of hemorrhagic complications noted on the operative report or postoperative imaging. RESULTS: The mean age of patients was 74.2 years, and 26% were female. Forty patients were taking ≥1 antiplatelet or anticoagulant medications. No patient actively taking anticoagulant or antiplatelet therapies had a hemorrhagic complication during or <48 h after the procedure. CONCLUSION: The frequency of intra- or postoperative complications from MRgFUS was not higher in patients actively taking anticoagulant or antiplatelet therapies relative to those who were not. Our findings suggest that MRgFUS thalamotomy does not necessitate interrupting anticoagulant or antiplatelet therapies. However, given the limited number of patients actively taking these therapies in our cohort (n = 40), additional testing in large, prospective studies should be conducted to further establish safety.

Blood group O is a risk factor for delayed post-polypectomy bleeding.

BACKGROUND: Blood group O of ABO blood group system is considered as a risk factor for various bleeding events, but the relationship with endoscopic treatment-associated bleeding has yet to be investigated. This study aimed to evaluate whether blood group O is associated with delayed bleeding after colorectal endoscopic resection. METHODS: This was a retrospective observational study based on medical records at four university hospitals in Japan. We reviewed the records for consecutive patients who underwent colorectal endoscopic resection from January 2014 through December 2017. The primary outcome was the incidence of delayed bleeding, defined as hematochezia or melena, requiring endoscopy, transfusion, or any hemostatic intervention up to 28 days after endoscopic resection. Multivariate logistic regression analysis was performed to adjust the impact of blood group O on the delayed bleeding. RESULTS: Among 10,253 consecutive patients who underwent colorectal endoscopic resection during the study period, 8625 patients met the criteria. In total, delayed bleeding occurred in 255 patients (2.96%). The O group had significantly more bleeding events compared with the non-O group (A, B, and AB) (relative risk, 1.62 [95% confidence interval, 1.24-2.10]; P < 0.001). In multivariate logistic regression analysis, blood group O remained an independent risk factor for the bleeding (adjusted odds ratio, 1.60 [95% confidence interval, 1.18-2.17]; P = 0.002). CONCLUSIONS: Blood group O was associated with an increased risk of delayed bleeding in patients undergoing colorectal endoscopic resection. Preoperative screening for ABO blood group could improve risk assessments.

Comparison of Hemorrhagic Risk between Prasugrel and Clopidogrel: a Retrospective Study using Adverse Drug Event Reporting Databases.

Background: Prasugrel inhibits platelet aggregation more potently and exerts therapeutic action faster than clopidogrel. In the global phase III trial conducted in Western and South American countries that excluded Asian countries, prasugrel reduced ischemic events but increased hemorrhagic risk compared with clopidogrel in patients with acute coronary syndrome scheduled for percutaneous coronary intervention. In the Japanese phase III trial for similar patients, the efficacy of prasugrel compared with clopidogrel was comparable to the global trial, but the safety could not be confirmed because of an insufficient number of patients. Furthermore, given the strict enrollment criteria, the results of these trials may not be applicable to routine clinical practice. Accordingly, we compared the hemorrhagic risk of prasugrel and clopidogrel in real-world settings by analyzing adverse drug event reports in post-marketing stages provided by the Japanese regulatory authorities and the U.S. Food and Drug Administration (FDA). Methods: We analyzed a total of 3,970 reports for prasugrel (n = 518) or clopidogrel (n = 3,452) between 2014 and 2017 in the Japanese Adverse Drug Event Report (JADER) and a total of 91,914 reports for either prasugrel (n = 5,992) or clopidogrel (n = 85,922) between 2009 and 2019 in the FDA Adverse Event Reporting System (FAERS). Results: In JADER and FAERS, prasugrel was more frequently and significantly associated with hemorrhagic event reports than clopidogrel. After adjustment for known confounders including age, sex, and concomitant medications (aspirin, anticoagulants, and proton pump inhibitors), the hemorrhagic risk of prasugrel compared with clopidogrel remained significant (adjusted reporting odds ratios [95% CI] for total, intracranial, and gastrointestinal hemorrhagic events = 2.42 [1.97-2.96], 2.45 [1.85-3.24], and 2.27 [1.73-2.97] in JADER, and 2.21 [2.09-2.34], 1.21 [1.09-1.33], and 1.41 [1.29-1.54] in FAERS). Conclusions: The hemorrhagic risk was found to be greater with prasugrel than clopidogrel in real-world patients, including Japanese patients.

Anticoagulation decisions in elderly patients with stroke.

Primary and secondary prevention of stroke is often a challenge in elderly patients due to the increase in both thrombotic and hemorrhagic risks with age. In some cases, there is sufficient data in the elderly population to allow recommendations or anticoagulation decisions to be made, such as for the indication of anticoagulation to prevent stroke related to atrial fibrillation (AF) or the choice of oral anticoagulant therapy in this situation. In other situations, the less robust data leave some questions; this is the case for the delay to initiate an oral anticoagulant therapy after an AF-related ischemic stroke, for the management of antithrombotic treatment after a stroke of undetermined cause or after intracranial bleeding or in a high-risk bleeding situation associated with stroke in the elderly subject. These issues will be discussed in this paper.

[Fibrinolytics in lung thromboembolism. New alternatives for a controversial prescription]. / Fibrinolíticos en tromboembolismo de pulmón. Nuevas alternativas para una indicación controvertida.

The use of fibrinolytics in lung thromboembolism (PTE) is a subject under debate since its first description in the 1960s. This therapy, which can rapidly resolve the mechanical obstruction in the pulmonary artery, has the limiting of a high hemorrhagic risk. Precisely because of the prohibitive incidence of major and cerebral bleeding and the lack of benefit in survival, the use of systemic thrombolytics is only indicated in the small number of patients with severe PE and hemodynamic instability. In moderate-risk PE, even with right ventricular (RV) dysfunction, they are not indicated. In recent years, an alternative has arisen, by combining low doses of fibrinolytics released locally into the pulmonary artery through a catheter that may, or may not, be attached to ultrasound at the site of thrombosis. This way of administering thrombolytics can correct acute pulmonary hypertension and eliminate the thrombus without major or CNS bleeds. Although the published studies are very encouraging, the evidence is still poor, a laboratory of hemodynamics is required at all times and this procedure is not free of risks, with a considerable cost. At the moment, only a small number of patients with moderate PE and poor prognosis seem to have an indication for this new alternative.

Hemorrhagic Transformation in Patients With Ischemic Stroke and Atrial Fibrillation: To Anticoagulate or Not, That Is the Question.

The management of anticoagulation in patients with ischemic stroke and atrial fibrillation (AF) poses a critical dilemma due to the inherent risk of hemorrhagic transformation. This article presents the case of an 89-year-old male with AF and recurrent ischemic strokes, highlighting the complex challenge of deciding whether to initiate or withhold anticoagulation. After the initial ischemic stroke event, the patient started a direct oral anticoagulant. Subsequent imaging revealed hemorrhagic transformation, leading to the cessation of anticoagulation. Despite multiple hemorrhagic recurrences, balancing thrombotic and bleeding risks remained challenging. Mechanical thrombectomy was performed for a subsequent ischemic stroke due to an absolute contraindication for thrombolysis. The patient's intricate clinical course involved a multidisciplinary approach, resulting in a decision to cautiously resume low-dose anticoagulation combined with left atrial appendage closure. This decision was made after careful consideration of persistent thrombotic risk despite recurrent hemorrhages. The case underscores the complex management dilemma of anticoagulation in elderly patients with AF and recurrent strokes, emphasizing the need for a multidisciplinary approach and individualized decision-making in such challenging scenarios. Further research and guidelines are warranted to establish optimal strategies for (re)initiating anticoagulation in patients with recurrent hemorrhagic transformation.

A real-world multicenter study on left atrial appendage occlusion: The Italian multi-device experience.

Background: Transcatheter left atrial appendage occlusion (LAAO) has emerged as an alternative treatment for stroke prevention in patients with atrial fibrillation (AF) at high risk of thromboembolism, who cannot tolerate long-term oral anticoagulation (OAC). Questions persist regarding effectiveness and safety of this treatment and the optimal post-interventional antithrombotic regimen after LAAO. Methods: We retrospectively gathered data from 428 patients who underwent percutaneous LAAO in 6 Italian high-volume centres, aimed at describing the real-world utilization, safety, and effectiveness of LAAO procedures, also assessing the clinical outcomes associated with different antithrombotic strategies. Results: Among the entire population, 20 (4.7 %) patients experienced a combination of pericardial effusion and periprocedural major bleeding: 8 (1.9 %) pericardial effusion, 1 (0.3 %) fatal bleeding, and 3 (0.7 %) non-fatal procedural major bleeding. Patients were discharged with different antithrombotic regimens: dual (DAPT) (27 %) or single (SAPT) (26 %) antiplatelet therapy, OAC (27 %), other antithrombotic regimens (14 %). Very few patients were not prescribed with antithrombotic drugs (6 %). At a medium 523 ± 58 days follow-up, 14 patients (3.3 %) experienced all-cause death, 6 patients (1.4 %) cardiovascular death, 3 patients (0.7 %) major bleeding, 10 patients (2.6 %) clinically relevant non-major bleeding, and 3 patients (0.7 %) ischemic stroke. At survival analysis, with DAPT as the reference group, OAC therapy was associated with better outcomes. Conclusions: Our findings confirm that LAAO is a safe procedure. Different individualized post-discharge antithrombotic regimens are now adopted, likely driven by the perceived thrombotic and hemorrhagic risk. The incidence of both ischemic and bleeding events tends to be low.

Natural History and Predictors for Hemorrhage in Supratentorial Brain Arteriovenous Malformations.

Background/Objectives: Approximately half of the patients harboring supratentorial brain arterio-venous malformations (stAVMs) present with hemorrhage, and another considerable proportion suffer from epileptic seizures. An important milestone in the management of this vascular pathology is acknowledging their natural history, especially across long periods of time. The aim of this study was to assess the predictive factors for hemorrhage and for epileptic seizures as presenting symptoms in stAVMs. Methods: We retrospectively analyzed patients with stAVMs admitted to our institution between 2012 and 2022 and evaluated predictive factors for hemorrhage and the risk factors associated with epileptic seizures. Results: The cohort included 169 patients, 78 of them (46.2%) presenting with intracerebral hemorrhage (ICH). Seventy-seven (45.5%) patients suffered from epileptic seizures. The annual hemorrhagic rate was 1.28%/year. Unruptured lesions (p = 0.001, OR 3.1, 95% CI 1.6-6.2), superficial venous drainage (p = 0.007, OR 2.7, 95% CI 1.3-5.7) and large nidus size (p = 0.025, OR 4, 95% CI 1.2-13.5) were independently associated with seizures. Among unruptured lesions, superficial venous drainage (OR 2.6, p = 0.036, 95% CI 1.06-6.3) and frontal/temporal/parietal location (OR 2.7, p = 0.040, 95 CI% 1.04-6.9) significantly increased the risk of seizures as a presenting symptom in multivariate analysis. Patients younger than 18 (p = 0.003, OR 4.5, 95% CI 1.6-12.2), those with AVMs < 3 cm (p = 0.03, OR 2, 95% CI 1.07-3.9) or those with deep located AVMs (p = 0.035, OR 2.3, 95% CI 1.06-5.1) presented statistically more often with ICH in multivariate regression. Small size (HR 1.8, 95% CI 1.09-3, p = 0.022) and exclusively deep venous drainage (HR 2.2, 95% CI 1.2-4, p = 0.009) were independent predictors for ICH, in time-dependent birth-to-diagnosis analysis. After shifting the birth-to-diagnosis curve by 10 years, unique arterial feeder demonstrated a positive correlation with ICH presentation as well. Conclusions: Small AVMs, those with exclusively deep venous drainage, unique arterial feeder or deep location may pose higher hemorrhagic risks for the patient, and therapeutic strategies should be tailored accordingly. When managing unruptured brain AVMs, it is important to consider the risk of developing seizures, in addition to the lifelong risk of hemorrhage, in determining the optimal treatment approach for each patient.

Population Pharmacokinetics and Hemorrhagic Risk Analysis of Rivaroxaban in Elderly Chinese Patients With Nonvalvular Atrial Fibrillation.

Rivaroxaban is a popular direct factor Xa inhibitor used for anticoagulation therapy in patients with nonvalvular atrial fibrillation (NVAF). The aim of this study was to establish a population pharmacokinetic (PPK) model for rivaroxaban in elderly Chinese patients with nonvalvular atrial fibrillation, evaluate precision dosing regimens, and analyze hemorrhagic risk after rivaroxaban treatment. A 1-compartment population PK model with estimated glomerular filtration rate (eGFR), total bilirubin (TBIL), and ABCB1 rs1045642 as major covariates for apparent clearance was developed using the nonlinear mixed-effects model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates for the target range of therapeutic drug-monitoring concentrations (Cmax,ss and Cmin,ss ). The exposure to rivaroxaban was simulated and assessed through hemorrhagic risk evaluation. The results showed that the average probability of target attainment (PTA) for optimal dosing regimens with different covariate levels for the targeted Cmax,ss and Cmin,ss were 29.35% to 31.3% and 64.91% to 65.8%, respectively. A dosage of 10 mg of rivaroxaban in elderly Chinese patients with normal renal and liver function was appropriate. The area under the concentration-time curve estimated over 24 hours with precision dosing at steady state (AUC24,ss ) was statistically significantly associated with an increased risk of bleeding events (OR 1.0006, 95%CI 1.0003 to 1.001, P < .0001), and the bleeding risk increased by 1.82-fold for every 1000 µg*h/L increase in AUC24,ss . A lower dose is recommended for elderly patients with renal impairment to avoid overexposure and bleeding events. The PPK model could inform individualized dosing for elderly Chinese patients with nonvalvular atrial fibrillation receiving rivaroxaban anticoagulation therapy.

Developmental venous anomaly associated with dural arteriovenous fistula: Etiopathogenesis and hemorrhagic risk.

Introduction: Developmental venous anomalies (DVAs) have traditionally been defined as non-pathological congenital lesions. Compared to isolated DVAs, the association of DVAs with arteriovenous shunts seems to have a more adverse clinical connotation. In this review, we describe the association between DVA and dAVF and discuss the hemorrhagic risk. We also advance a hypothesis about the potential de novo formation of a DVA and challenge the dogma about their "developmental" or "congenital" nature. Methods: A systematic review of the literature on the association of DVA and dAVF was performed in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) guidelines. Results: A number of 678 papers was initially identified, but only 9 studies were included in the final qualitative analysis. Most of the patients presented with bleeding (56%), with a median GCS of 14 (range 10-15). In 56% of the cases the DVA had a supratentorial location. Supratentorial DVAs mostly drained in the superior sagittal sinus (80%), while all of infratentorial/combined DVAs drained in deep ependymal veins of the 4th ventricle. All the supratentorial dAVFs drained into the superior sagittal sinus, while the infratentorial/combined dAVFs mostly drained in the jugular bulb, Vein of Rosenthal, or transverse-sigmoid sinuses (75%). Most of the dAVFs were classified as Cognard type IIa + b (67%), while in a smaller number of cases type I (22%) and type V (11%). The dAVF was the target of treatment in each case and most patients underwent endovascular treatment (78%). The dAVF was completely occluded in 78% of cases and no periprocedural complications were reported. Conclusion: The clinical presentation, radiological findings, and treatment outcomes of DVAs and associated dAVFs have been discussed. Despite the general opinion that DVAs are benign congenital lesions, increasing epidemiological and radiological evidence supports a potential acquired origin, and the venous system seem to play a pivotal role in their post-natal genesis and development.

Future Perspectives to Improve CHA2DS2VASc Score: The Role of Left Atrium Remodelling, Inflammation and Genetics in Anticoagulation of Atrial Fibrillation.

In 10% of ischemic strokes, non-valvular atrial fibrillation (NVAF) is detected retroactively. Milder, or even asymptomatic forms of NVAF have shown high mortality, thrombotic risk, and deterioration of cognitive function. The current guidelines for the diagnosis and treatment of AF contain "grey areas", such as the one related to anticoagulant treatment in men with CHA2DS2-VASc score 1 and women with score 2. Moreover, parameters such as renal function, patient weight or left atrium remodelling are missing from the recommended guidelines scores. Vulnerable categories of patients including the elderly population, high hemorrhagic risk patients or patients with newly diagnosed paroxysmal episodes of atrial high rate at device interrogation are at risk of underestimation of the thrombotic risk. This review presents a systematic exposure of the most important gaps in evaluation of thrombotic and hemorrhagic risk in patients with NVAF. The authors propose new algorithms and risk factors that should be taken into consideration for an accurate thrombotic and hemorrhagic risk estimation, especially in vulnerable categories of patients.

Enoxaparin Posology According to Prothrombotic Status and Bleeding Risk in Hospitalized Patients with SARS-CoV-2 Pneumonia.

Some patients with COVID-19 have complex hypercoagulable abnormalities that are related to mortality. The optimal dosage of low molecular weight heparin in hospitalized patients with SARS-CoV-2 pneumonia is still not clear. Our objective is to evaluate the effects of adapting the dosage of low molecular weight heparin to thrombotic and bleeding risk scales in this setting. We performed a cohort, retrospective, observational, and analytical study at the Hospital Universitario of Jerez de la Frontera, with patients admitted with SARS-CoV-2 pneumonia from 1 October 2020 to 31 January 2021. They were classified according to whether they received prophylactic, intermediate, or therapeutic doses of enoxaparin. The primary endpoint was intrahospital mortality. Secondary endpoints were the need for invasive ventilation, thromboembolic events, bleeding, and the usefulness of thrombotic and bleeding scales. After binary logistic regression analysis, considering confounding variables, it was found that the use of enoxaparin at therapeutic doses was associated with lower mortality during admission compared to prophylactic and intermediate doses (RR 0.173; 95% CI, 0.038-0.8; p = 0.025). IMPROVE bleeding risk score correlated with a higher risk of minor bleeding (RR 1.263; 95% CI, 1.105-1.573; p = 0.037). In adult hospitalized patients with SARS-CoV-2 pneumonia presenting elevated D-dimer and severe proinflammatory state, therapeutic doses of enoxaparin can be considered, especially if bleeding risk is low according to the IMPROVE bleeding risk score.

Inflammatory Bowel Disease and Acute Coronary Syndromes: From Pathogenesis to the Fine Line Between Bleeding and Ischemic Risk.

Inflammatory bowel disease (IBD) is a pathological condition that first involves the gastrointestinal wall but can also trigger a systemic inflammatory state and thus extraintestinal manifestations. Systemic inflammation is probably secondary to the passage of bacterial products into the bloodstream because of altered intestinal permeability and the consequent release of proinflammatory mediators. Inflammation, through several diverse pathophysiological pathways, determines both a procoagulative state and systemic endothelial dysfunction, which are both deemed to be responsible for venous and arterial thromboembolic adverse events. The management of systemic thrombotic complications is particularly challenging in this category of patients, who also present a high bleeding risk; what is more, both bleeding and thrombotic risks peak during the active phases of the disease. The literature suggests that treating physicians have been, so far, more heavily influenced by concerns about bleeding than by the thrombotic risk. Despite the absence of data provided by large cohorts or randomized studies, the high risk of arterial and venous atherothrombosis in patients with IBD seems unquestionable. Moreover, several reports suggest that when arterial thromboembolism involves the coronary vessels, causing acute coronary syndromes, ischemic complications from antithrombotic drug undertreatment are frequent and severe. This review aims to shed light on the tricky balance between the ischemic and hemorrhagic risks of patients with IBD and to highlight how difficult it is for clinicians to define a tailored therapy based on a case-by-case, careful, and unprejudiced clinical evaluation.

Acute coronay syndrome in a patient with severe hemophilia A: Dificult decisions.

Hemophilia A is an inherited coagulation disease characterized by factor VIII (FVIII) deficiency and is associated with high hemorrhagic risk, especially in its severe forms. As the average life expectancy of patients with hemophilia has increased, so has the prevalence of acute coronary events. There is however limited experience in dealing with them. The strategy of acting on acute coronary events in patients with hemophilia, as demonstrated in the present case, is a real challenge, not only due to the need for antiplatelet therapy (which is essential in the prevention of stent thrombosis, but increases hemorrhagic risk), but also due to the lack of specific recommendations related to the most adequate and safe replacement therapy in these situations. The authors describe the case of a 48-year-old man with unstable angina and a previous diagnosis of severe hemophilia A who underwent percutaneous coronary intervention under FVIII therapy without hemorrhagic complications.

Iliocava junction to L4-L5 disc anatomical relationship in L5-S1 isthmic spondylolisthesis.

BACKGROUND: Anterior lumbar interbody fusion finds a place in L5-S1 isthmic spondylolisthesis (ISPL) treatment. Extension of this arthrodesis at L4-L5 level is sometimes required. Anterior approach of the L4L5 disc is considered difficult due to the anatomical relationship between the iliocava junction (ICJ) and the spine. HYPOTHESIS: Does the lumbosacral deformation induced by ISPL allows anterior approach of L4-L5 disc between the iliac? STUDY DESIGN: Retrospective radiographic analysis of consecutive patients. METHODS: This retrospective imaging study of a continuous series of 97 patients treated for an L5-S1 ISPL involved radiological parameters specific to ISPL and pelvic-sagittal balance. The distance between the ICJ and the L4 lower endplate was measured in millimeters. The factors influencing this distance were sought in order to identify a predictive model of high ICJ. RESULTS: The ICJ took a cranial position with respect to the L4-L5 disc with an average distance of 1.8mm±16.4. This distance was statistically higher in the case of high-grade ISPL (p<0.01). The high ICJ position was correlated with a high Taillard index (r=0.39; CI95% [0.13; 0.61]; p<.001) and a low lumbar-sacral angle (LSA) (r=-0.33; CI95% [-0.56; -0.06]; p<0.01). Among the parameters specific to spino-pelvic statics, pelvic incidence, pelvic tilt and lumbar lordosis had similar correlations (r>0.30). CONCLUSION: ISPL induces a geometric deformation of the lumbosacral hinge which modifies its anatomical relations with the ICJ. The anterior approach technique of L4-L5 disc in the presence of an L5-S1 ISPL is possible between the iliac veins for the large displacement and low LSA forms. LEVEL OF EVIDENCE: IV, retrospective analysis.

Labile PT-INR in a Covid-19 Patient Under Long-term Vitamin K Antagonist Therapy: a Case Report.

The COronaVIrus Disease-19 (COVID-19) has been associated with thromboembolic complications, but evidence on its impact on hemorrhagic risk are still scarce. We describe a case of COVID-19 with hemorrhagic complication in the post-acute phase of the disease. The patient was a 93-year-old woman admitted to a post-acute care unit for COVID-19 patients in northern Italy. The patient's medical history included moderate cognitive impairment, atrial fibrillation under oral anticoagulation (warfarin 2.5 mg and 3.75 mg on alternate days, showing stable PT-INR values since October 2018), and arterial hypertension. The patient was affected by COVID-19, treated with supportive therapy. In the post-acute phase of the disease, the patient presented with melena and showed a marked elevation of PT-INR of 25.1. She was treated with venous infusion of three-factor prothrombin complex concentrate and vitamin K until PT-INR reduction. After 5 days, blood analyses revealed normal hemoglobin, PT-INR 2.15, and a slight alteration of liver function. This case supports a strong impact of the infection on the coagulative pattern not only pro-thrombotically but also by increasing hemorrhagic risk. Special attention should therefore be paid to COVID-19 patients under anticoagulation with vitamin K antagonist and a shift to heparin treatment until illness resolution may be a safe option in these individuals.

Low-Dose Acetylsalicylic Acid in Chronic Subdural Hematomas: A Neurosurgeon's Sword of Damocles.

Background: The possible influence of different antithrombotic drugs on outcome after neurosurgical treatment of chronic subdural hematoma (CSDH) is still unclear. Nowadays, no randomized clinical trials are available. A metanalysis including 24 studies for a total of 1,812 pooled patients concluded that antiplatelets and anticoagulations present higher risk of recurrences. On the other hand, several studies highlighted that antithrombotic suspension, timing of surgery, and resumption of these drugs are still debated, and patients taking these present higher risk of thromboembolic events with no excess risk of bleed recurrences or worse functional outcome. Our assumption is that the real hemorrhagic risk related to antithrombotic drug continuation in CSDH may be overrated and the thromboembolic risk for discontinuation underestimated, especially in patients with high cardiovascular risk. Methods: A comprehensive literature review with the search terms "acetylsalicylic acid" and "chronic subdural x" was performed. Clinical status, treatment, time of drug discontinuation, complications (in particular, rebleeding or thromboembolic events), and clinical and radiological outcome at follow-up were evaluated. Results: Five retrospective studies were selected for the review, three of them reporting specifically low-dose acetylsalicylic intake and two of them general antithrombotic drugs for a total of 1,226 patients. Only two papers reported the thromboembolic rate after surgery; in one paper, it is not even divided from other cardiac complications. Conclusion: The literature review does not clarify the best management of low-dose acetylsalicylic in CSDH patients, in particular, concerning the balance between thromboembolic event rates and rebleeding risks. We do believe that CSDH precipitates the worsening of comorbidities with a resulting increased mortality. Further studies clearly evaluating the thromboembolic events are strongly needed to clarify this topic. In this perspective paper, we discuss the difficult choice of low-dose acetylsalicylic acid (LDAA) management in patients suffering from chronic subdural hematoma (CSDH). The balance between hemorrhagic and thromboembolic risks often represents a sword of Damocles for neurosurgeons, especially when dealing with patients with high cardiovascular risk. No guidelines are currently available, and a survey by Kamenova et al. showed that most neurosurgeons discontinue LDAA treatment for at least 7 days in the perioperative period of surgical evacuation of CSDH, even though recent studies show that early LDAA resumption might be safe. Thrombosis prophylaxis is administered by only 60%, even though patients with CSDH are at high risk of developing thromboembolic complications. We would like to bring attention to this controversial issue.

The FAST-MI 2005-2010-2015 registries in the light of the COMPASS trial: The COMPASS criteria applied to a post-MI population.

BACKGROUND: The COMPASS trial assessed the impact of adding low dose rivaroxaban to aspirin in selected patients (pts). After an acute myocardial infarction (MI), when dual antiplatelet treatment is no longer needed, patients might be eligible for aspirin/rivaroxaban co-therapy. The characteristics and risks of such a population are unclear. METHODS: Data were extracted from the FAST-MI 2005, 2010 and 2015 nationwide French registries. Characteristics and long-term mortality were compared according to COMPASS eligibility and between registry and trial populations. RESULTS: Among 9954 patients alive and free of events at one year, 4402 (44%) were classified as COMPASS-Like (i.e. meeting COMPASS inclusion and without exclusion criteria), 1720 (17%) COMPASS-Excluded (i.e. meeting any exclusion criterion) and 3832 (39%) Non-COMPASS (i.e. meeting neither COMPASS inclusion nor exclusion criteria). COMPASS-Like patients were at higher risk and had higher 5-year mortality compared with Non-COMPASS patients. COMPASS-Excluded patients had the highest mortality. COMPASS enrichment criteria defined a population at increased risk of death: eligible pts. had 40% higher 5-year adjusted mortality (Hazard Ratio = 1.40 [1.15; 1.70]), while excluded pts. had 57% higher risk (Hazard Ratio = 1.57 [1.25; 1.97]). Patients meeting the COMPASS criteria one year after MI differed from those included in the randomized trial. CONCLUSIONS: Based on the population included in the French FAST-MI registries, enrichment criteria used in COMPASS defined a population representing 44% of the overall population of MI patients surviving to one year, and these patients are at high risk of 5-year mortality. They were at higher risk compared to chronic stable vascular patients enrolled in the trial. Registered with Clinicaltrials.gov under the number: NCT00673036.

Optimal delay time to initiate anticoagulation after ischemic stroke in atrial fibrillation (START): Methodology of a pragmatic, response-adaptive, prospective randomized clinical trial.

RATIONALE: An estimated 15% of all strokes are associated with untreated atrial fibrillation. Long-term secondary stroke prevention in atrial fibrillation is anticoagulation, increasingly with non-vitamin K oral anticoagulants. The optimal time to initiate anticoagulation following an atrial fibrillation-related stroke that balances hemorrhagic conversion with recurrent stroke is not yet known. AIMS: To determine if there is an optimal delay time to initiate anticoagulation after atrial fibrillation-related stroke that optimizes the composite outcome of hemorrhagic conversion and recurrent ischemic stroke. SAMPLE SIZE ESTIMATES: The study will enroll 1500 total subjects split between a mild to moderate stroke cohort (1000) and a severe stroke cohort (500). METHODS AND DESIGN: This study is a multi-center, prospective, randomized, pragmatic, adaptive trial that randomizes subjects to four arms of time to start of anticoagulation. The four arms for mild to moderate stroke are: Day 3, Day 6, Day 10, and Day 14. The time intervals for severe stroke are: Day 6, Day 10, Day 14, and Day 21. Allocation involves a response adaptive randomization via interim analyses to favor the arms that have a better risk-benefit profile. STUDY OUTCOMES: The primary outcome event is the composite occurrence of an ischemic or hemorrhagic event within 30 days of the index stroke. Secondary outcomes are also collected at 30 and 90 days. DISCUSSION: The optimal timing of direct oral anticoagulants post-ischemic stroke requires prospective randomized testing. A pragmatically designed trial with adaptive allocation and randomization to multiple time intervals such as the START trial is best suited to answer this question in order to directly inform current practice on this question.