Long-term outcomes after traumatic brain injury in elderly patients on antithrombotic therapy.

INTRODUCTION: Elderly patients receiving antithrombotic treatment have a significantly higher risk of developing an intracranial hemorrhage when suffering traumatic brain injury (TBI), potentially contributing to higher mortality rates and worse functional outcomes. It is unclear whether different antithrombotic drugs carry a similar risk. OBJECTIVE: This study aims to investigate injury patterns and long-term outcomes after TBI in elderly patients treated with antithrombotic drugs. METHODS: The clinical records of 2999 patients ≥ 65 years old admitted to the University Hospitals Leuven (Belgium) between 1999 and 2019 with a diagnosis of TBI, spanning all injury severities, were manually screened. RESULTS: A total of 1443 patients who had not experienced a cerebrovascular accident prior to TBI nor presented with a chronic subdural hematoma at admission were included in the analysis. Relevant clinical information, including medication use and coagulation lab tests, was manually registered and statistically analyzed using Python and R. In the overall cohort, 418 (29.0%) of the patients were treated with acetylsalicylic acid before TBI, 58 (4.0%) with vitamin K antagonists (VKA), 14 (1.0%) with a different antithrombotic drug, and 953 (66.0%) did not receive any antithrombotic treatment. The median age was 81 years (IQR = 11). The most common cause of TBI was a fall accident (79.4% of the cases), and 35.7% of the cases were classified as mild TBI. Patients treated with vitamin K antagonists had the highest rate of subdural hematomas (44.8%) (p = 0.02), hospitalization (98.3%, p = 0.03), intensive care unit admissions (41.4%, p < 0.01), and mortality within 30 days post-TBI (22.4%, p < 0.01). The number of patients treated with adenosine diphosphate (ADP) receptor antagonists and direct oral anticoagulants (DOACs) was too low to draw conclusions about the risks associated with these antithrombotic drugs. CONCLUSION: In a large cohort of elderly patients, treatment with VKA prior to TBI was associated with a higher rate of acute subdural hematoma and a worse outcome, compared with other patients. However, intake of low dose aspirin prior to TBI did not have such effects. Therefore, the choice of antithrombotic treatment in elderly patients is of utmost importance with respect to risks associated with TBI, and patients should be counselled accordingly. Future studies will determine whether the shift towards DOACs is mitigating the poor outcomes associated with VKA after TBI.

Atezolizumab-induced encephalitis with subdural hemorrhage and subarachnoid hemorrhage in a patient with hepatocellular carcinoma.

We report the case of a 76-year-old man who was diagnosed with advanced stage hepatocellular carcinoma and was treated with atezolizumab plus bevacizumab therapy. Two weeks after 1st dose, he presented with acute changes in consciousness followed by hypothermia. A cerebrospinal fluid test showed an elevated cell count, total protein, and albumin. Infectious, anatomical, endocrinal, and neoplastic etiologies were ruled out. Based on the findings, atezolizumab-induced encephalitis was suspected, and high dose steroid therapy was administered. The patient's conscious level and hypothermia recovered completely about 9 days after starting the steroids, and he recovered without any neurological sequelae. This case report reminds physicians that prompt administration of steroid treatment after early diagnosis of immune checkpoint inhibitor-related encephalitis is the key for patients to recover without apparent neurological sequelae.

Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates.

BACKGROUND: Since the approval of the oral factor Xa inhibitors, there have been concerns regarding the ability to neutralize their anticoagulant effects after intracranial hemorrhage (ICH). Multiple guidelines suggest using prothrombin complex concentrates (PCCs) in these patients on the basis of research that includes a limited number of patients with ICH. Given this, we aimed to evaluate the safety and efficacy of PCCs for factor Xa inhibitor-related ICH in a large, multicenter cohort of patients. METHODS: This was a multicenter, retrospective, observational cohort study of patients with apixaban- or rivaroxaban-related ICH who received PCCs between January 1, 2015, and March 1, 2019. The study had 2 primary analysis groups: safety and hemostatic efficacy. The safety analysis evaluated all patients meeting inclusion criteria for the occurrence of a thrombotic event, which were censored at hospital discharge or 30 days after PCC administration. Patients with intracerebral, subarachnoid, or subdural hemorrhages who had at least 1 follow-up image within 24 hours of PCC administration were assessed for hemostatic efficacy. The primary efficacy outcome was the percentage of patients with excellent or good hemostasis on the basis of the modified Sarode criteria. Secondary outcomes included an evaluation of in-hospital mortality, length of stay, infusion-related reactions, and thrombotic event occurrence during multiple predefined periods. RESULTS: A total of 663 patients were included and assessed for safety outcomes. Of these, 433 patients met criteria for hemostatic efficacy evaluation. We observed excellent or good hemostasis in 354 patients (81.8% [95% CI, 77.9-85.2]). Twenty-five (3.8%) patients had a total of 26 thrombotic events, of which 22 occurred in the first 14 days after PCC administration. One patient had documentation of an infusion-related reaction. For the full cohort of patients, in-hospital mortality was 19.0%, and the median intensive care unit and hospital lengths of stay were 2.0 and 6.0 days, respectively. CONCLUSIONS: Administration of PCCs after apixaban- and rivaroxaban-related ICH provided a high rate of excellent or good hemostasis (81.8%) coupled with a 3.8% thrombosis rate. Randomized, controlled trials evaluating the clinical efficacy of PCCs in patients with factor Xa inhibitor-related ICH are needed.

Aspirin Use and Risk of Subdural Hematoma: Updated Meta-Analysis of Randomized Trials.

BACKGROUND AND PURPOSE: Subdural hematomas are an uncommon, but a serious, bleeding complication of antithrombotic therapies. We update our previous inconclusive meta-analysis to better estimate the risk of subdural hematoma associated with aspirin use. METHODS: For the initial meta-analysis, nine randomized trials published between1980 and 2012 comparing aspirin with placebo/control were considered. Additional data from four large primary prevention trials were added. Two reviewers independently extracted data on subdural hematomas, with differences resolved by joint review and consensus. RESULTS: Numbers of subdural hematoma were available from thirteen randomized trials involving 155,554 participants comparing aspirin (dosage range 25 mg twice daily to 325 mg daily) to placebo (ten double-blind trials) or no aspirin (three trials). Participants included healthy healthcare providers, older people with vascular risk factors without manifest vascular disease, and those with atrial fibrillation or chronic angina. Pooling all trials, subdural hematomas were identified in 93 of 77,698 participants assigned to aspirin versus 62 of 77,856 participants assigned to placebo/no aspirin. By meta-analysis, the relative risk ratiometa of subdural hematoma associated with assignment to aspirin was 1.5 (95%CI 1.1, 2.0, p = 0.01; p = 0.9 for heterogeneity, I2 index = 0%). Based on recent primary prevention trials, subdural hematoma diagnosis averaged 1 per 3,125 people per year without aspirin use; the absolute increase associated with aspirin use was estimated as one additional subdural hematoma per 6,500 patients annually. CONCLUSIONS: This meta-analysis confirms that aspirin use increases the relative risk of subdural hematoma, but the absolute increased rate associated with aspirin therapy is very low for most people.

Warfarin Reinitiation After Intracranial Hemorrhage: A Case Series of Heart Valve Patients.

Patients with mechanical heart valves are at high thrombotic risk and require warfarin. Among those developing intracranial hemorrhage, limited data are available to guide clinicians with antithrombotic reinitiation. This 13-patient case series of warfarin-associated intracranial hemorrhages found the time to reinitiate antithrombotic therapy (17 days, interquartile range 21.5 days), and changes to international normalized ratio targets were variable and neither correlated with the type, location, or etiology of bleed, nor the valve and associated thromboembolic risk. The initial presentation significantly impacted prognosis, and diligent assessment and follow-up may support positive long-term outcomes.

Management of apixaban-associated subdural hematoma: a case report on the use of factor eight inhibitor bypassing activity.

OBJECTIVE: We report a case of a patient receiving apixaban who developed a spontaneous subdural hematoma and declining mental status that improved after administration of a single dose of factor eight inhibitor bypassing activity. DESIGN: Case report. SETTING: Comprehensive Stroke Center, Neurocritical Care Unit. PATIENT: A 76-year-old man presented to an outside facility with a chief complaint of headache and pain behind his right eye. A CT scan of his head revealed a subdural hematoma. The patient was transferred to our facility with worsening clinical status. INTERVENTIONS: After a confirmatory cranial CT scan revealed a worsening subdural hematoma with midline shift, a single dose of factor VIII inhibitor bypassing activity (25 U/kg) was administered. MEASUREMENTS AND MAIN RESULTS: Coagulation tests following the administration of factor VIII inhibitor bypassing activity and a follow-up CT scan confirmed hemostasis. The patient was discharged home with no focal deficits. CONCLUSIONS: Factor VIII inhibitor bypassing activity may be a viable, nonspecific reversal agent for life-threatening bleeding associated with apixaban.

Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension.

BACKGROUND: Antiproliferative strategies have emerged as a potential therapeutic option for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate the long-term efficacy and safety of imatinib. METHODS: This is an observational study of 15 patients with idiopathic PAH (n = 13) or PAH associated with connective tissue disease (n = 2) treated off-label with imatinib 400 mg daily. Pulmonary hypertension-specific therapy was established in all patients (triple therapy in 10, dual therapy in 3, and monotherapy in 2 patients). RESULTS: After 6 months, improvement in hemodynamics (p < 0.01), functional class (p = 0.035), and quality of life (p = 0.005) was observed. After a median follow-up of 37 months, there was a sustained improvement in functional class (p = 0.032), quality of life (p = 0.019), and echocardiographic parameters of right ventricular function (p < 0.05). Three patients (20%) presented with completely normal echocardiography, absent tricuspid regurgitation, and normal pro-brain natriuretic peptide levels, indicative of 'hemodynamic remission'. Of note, however, only 1 case was assessed by invasive hemodynamics. The overall 1- and 3-year survival was 100 and 90%, respectively. Two patients experienced a subdural hematoma (SDH), which in both cases resolved without sequelae. After careful consultation of the potential risks and benefits, all patients as well as a safety cohort of 9 subsequent cases decided to continue the imatinib therapy. After adjusting the target international normalized ratio (INR) to around 2.0, no further cases of SDH occurred during 50 patient-years. CONCLUSIONS: Long-term treatment with imatinib may improve the functional class and quality of life. Single cases might even attain hemodynamic remission. The occurrence of 5% SDH per patient-years is concerning. However, adjusting the INR to around 2.0 might obviate this complication.

Emergency neurosurgical care in patients treated with apixaban: report of 2 cases.

A debate has emerged regarding the safety profile of direct anticoagulants, which are increasingly prescribed for the prevention of thromboembolic events. Despite favorable safety data derived from controlled clinical trials, the absence of specific antidotes for the management of hemorrhagic complications represents a major challenge for emergency physicians. Here, we present the first report on patients treated with the direct factor Xa inhibitor apixaban and conditions requiring urgent neurosurgical intervention (intracerebral hemorrhage, n = 1; subdural hematoma, n = 1). Prothrombin complex concentrates were administered before surgery, and both patients had a favorable postsurgical course without bleeding or thromboembolic complications. Further studies are needed, but this approach seems to be suitable for the emergency management of apixaban-associated intracranial hemorrhage.

Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study.

BACKGROUND: By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). METHODS AND RESULTS: Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥ 800 dyne·s·cm(-5) symptomatic on ≥ 2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an open-label long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm(-5) (95% confidence interval, -502 to - 255; P<0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. CONCLUSIONS: Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common. Further studies are needed to investigate the long-term safety and efficacy of imatinib in patients with PAH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00902174 (core study); NCT01392495 (extension).

Vitamin K antagonists and risk of subdural hematoma: meta-analysis of randomized clinical trials.

BACKGROUND AND PURPOSE: Subdural hematomas are an important bleeding complication of anticoagulation. We quantify the risk of subdural hematoma associated with anticoagulation with vitamin K antagonists (VKAs) compared with other oral antithrombotic therapies. METHODS: Randomized trials were identified from the Cochrane Central Register of Controlled Trials and were included if published since 1980 and compared oral VKAs with antiplatelet therapy or with direct-acting oral anticoagulants. Two reviewers independently extracted data with differences resolved by joint review. RESULTS: Nineteen randomized trials were included that involved 92 156 patients and 275 subdural hematomas. By meta-analysis, VKAs were associated with a significantly increased risk of subdural hematoma (odds ratios, 3.0; 95% confidence interval, 1.5-6.1) compared with antiplatelet therapy (9 trials, 11 603 participants). The risk of subdural hematoma was also significantly higher with VKAs versus factor Xa inhibitors (meta-analysis odds ratios, 2.9; 95% confidence interval, 2.1-4.1; 5 trials, 49 687 patients) and direct thrombin inhibitors (meta-analysis odds ratios, 1.8; 95% confidence interval, 1.2-2.7; 5 trials, 30 866 patients) versus VKAs. The absolute rate of subdural hematoma among 24 485 patients with atrial fibrillation treated with VKAs pooled from 6 trials testing direct-acting oral anticoagulants was 2.9 (95% confidence interval, 2.5-3.5) per 1000 patient-years. CONCLUSIONS: VKA use significantly increases the risk of subdural hematoma by ≈3-fold relative to antiplatelet therapy. Direct-acting oral anticoagulants are associated with a significantly reduced risk of subdural hematomas versus VKAs. Based on indirect comparisons to VKAs, the risks of subdural hematoma are similar with antiplatelet monotherapies and factor Xa inhibitors.

Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG(®)) to guide decision-making.

Novel oral anticoagulants present challenges and uncertainties in the management of hemorrhagic emergencies. An 84-year-old man taking dabigatran presented with a subdural hematoma requiring neurosurgical intervention. Routine coagulation assays were prolonged at admission and following administration of Factor VIII Inhibitor Bypassing Activity (FEIBA). Thromboelastography (TEG(®)) was utilized to assess clot dynamics prior to placement of a subdural drain, which was safely inserted despite a prolonged thrombin time (TT). Exclusive reliance on the TT may delay necessary interventions. TEG(®) may be a valuable tool to investigate hemostasis in patients on dabigatran requiring emergent procedures.

Subdural haemorrhage is associated with recent morphine treatment in patients with cancer: a retrospective population-based nested case-control study.

BACKGROUND: This study investigated the relationship between recent morphine use and risk of subdural haemorrhage (SDH) in patients with cancer. METHODS: This study identified a malignancy cohort of 25,322 patients who had never received morphine treatment. In this malignancy cohort, 200 patients who subsequently developed SDH were designated as the SDH group. Control-group patients without SDH were selected from the malignancy cohort and were matched ∼4:1 to each SDH case for age, sex, year of cancer diagnosis and index year. Morphine use was designated as 'recent' if the prescription duration covered the index date or ended within 6 months before the index date. Logistic regression was used to estimate odds ratios and 95% confidence intervals and a multivariable model was applied to control for age, sex and cerebrovascular disease. RESULTS: Compared with non-morphine users, patients with cancer who received morphine within 6 months of the index date exhibited a 2.58-fold (95% CI = 1.23-5.39) increase in the risk of developing SDH. The risk of SDH development increased as the duration of morphine treatment increased. CONCLUSION: The incidence of SDH in patients with cancer in Taiwan is associated with recent morphine treatment (≤6 months) and is dependent on the duration of morphine use.

Ventriculostomy associated haemorrhage: a complication of anti-platelet therapy during coiling.

A young man with Fisher grade IV subarachnoid haemorrhage (SAH) underwent aneurysm coiling following external ventriculostomy. Coiling was complicated by thrombus formation and parent vessel occlusion necessitating anti-platelet therapy. Several hours after anti-platelet therapy, catastrophic haemorrhage associated with the ventriculostomy tract occurred. Timing and location of haemorrhage suggest combined anti-platelet therapy and ventriculostomy may have been causal. The literature on ventriculostomy haemorrhage rates and risks with concomitant anti-platelet therapy are reviewed. Where endovascular coiling is being considered, the possibility of ventriculostomy-related haemorrhage should be considered and should influence subsequent treatment decisions.

Aspirin therapy and risk of subdural hematoma: meta-analysis of randomized clinical trials.

BACKGROUND: Subdural hematomas are an important bleeding complication of antithrombotic therapies. We sought to characterize the risk of subdural hematoma associated with antiplatelet therapy. METHODS: Trials were gathered from the Cochrane Central Register of Controlled Trials and from recent meta-analyses of trials regarding antiplatelet therapy for the primary prevention of stroke. Randomized trials published since 1980 comparing antiplatelet therapy with placebo or control and reporting subdural hematoma were included in the analysis. For recent large trials that did not report subdural hematomas, unpublished results were sought. Two reviewers independently extracted data on study design and subdural hematomas, with differences resolved by joint review and consensus. RESULTS: Four published trials were identified that compared aspirin with placebo/control involving 6565 participants (mean age 66 years) with 8 total subdural hematomas. Unpublished data from 5 aspirin trials with 90,689 participants reported 18 total subdural hematomas. The incidence of subdural hematomas varied from 0.02 per 1000 patient-years for primary prevention trials of middle-aged health professionals to 1 to 2 per 1000 patient-years for older patients with atrial fibrillation. Pooled data from all 9 trials revealed an odds ratio of 1.6 (95% confidence interval 0.8-3.5; heterogeneity P = .8; I(2) index 0%) for antiplatelet therapy and risk of subdural hematoma. CONCLUSIONS: Based on the limited available data, it is uncertain whether aspirin therapy increases the risk of subdural hematoma: the observed 1.6-fold increased risk was not statistically significant. The incidence of subdural hematoma during aspirin therapy is low but varies widely depending upon the age of the patient population.

Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no known efficacious therapy. Imatinib is a tyrosine kinase inhibitor with potential efficacy to treat fibrotic lung disease. OBJECTIVES: To investigate the safety and clinical effects of imatinib in patients with IPF. METHODS: We studied 119 patients in an investigator-initiated, multicenter, multinational, double-blind clinical trial to receive imatinib or placebo for 96 weeks. MEASUREMENTS AND MAIN RESULTS: Over 96 weeks of follow-up, imatinib did not differ significantly from placebo (log rank P = 0.89) for the primary endpoint defined as time to disease progression (10% decline in percent predicted FVC from baseline) or time to death. There was no effect of imatinib therapy on change in FVC at 48, 72, or 96 weeks (P > or = 0.39 at all time points) or change in diffusing capacity of carbon monoxide at 48, 72, or 96 weeks (P > or = 0.26 at all time points). Change in resting Pa(O(2)) favored imatinib therapy at 48 weeks (P = 0.005) but not at 96 weeks (P = 0.074). During the 96-week trial there were 8 deaths in the imatinib group and 10 deaths in the placebo group (log rank test P = 0.64). Thirty-five (29%) patients discontinued the study without reaching the primary endpoint (imatinib, 32%; placebo, 27%; P = 0.51). Serious adverse events (SAEs) were not more common in the imatinib group (imatinib, 18 SAEs in 17 patients; placebo, 19 SAEs in 18 patients). CONCLUSIONS: In a randomized, placebo-controlled trial of patients with mild to moderate IPF followed for 96 weeks, imatinib did not affect survival or lung function. Clinical trial registered with www.clinicaltrials.gov (NCT00131274).

Successful dabigatran reversal after subdural hemorrhage using idarucizumab in a mobile stroke unit: A case report.

RATIONALE: Idarucizumab is a specific reversal agent for patients with bleeding related to the anticoagulant dabigatran. There are no prior descriptions of Idarucizumab administration in the prehospital setting for intracranial hemorrhage. PATIENT CONCERNS: An 82-year-old woman treated with dabigatran for atrial fibrillation developed acute focal weakness. This led to activation of emergency medical services and assessment in the mobile stroke unit (MSU). DIAGNOSIS: Computed tomography of the brain performed in the MSU revealed an acute subdural hematoma. INTERVENTIONS: The patient was treated with Idarucizumab in the MSU. OUTCOMES: The subdural hematoma was treated with a burr hole evacuation and the patient was discharged to a rehabilitation facility without residual focal neurological deficits. LESSONS: Idarucizumab can be used safely and effectively to treat dabigatran-associated intracranial hemorrhage in the prehospital setting.

Bilateral subdural hemorrhage as a possible adverse event of gefitinib in a patient with non-small cell lung cancer.

Gefitinib, a selective inhibitor of epidermal growth factor receptor tyrosine kinase is an effective agent used in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Adverse drug reactions were frequently observed in the skin, gastrointestinal tract, and liver, but they were generally mild in severity and reversible. Therefore, gefitinib has been regarded as a relatively safe agent. As a serious adverse effect, however, acute lung injury has been reported. The present report describes a patient with NSCLC who developed bilateral subdural hemorrhage as a possible adverse drug reaction after gefitinib therapy. We expect that this case may provide a reference for clinicians being involved in the treatment with gefitinib.