Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

Ciprofloxacin and pegylated G-CSF combined therapy mitigates brain hemorrhage and mortality induced by ionizing irradiation.

Introduction: Brain hemorrhage was found between 13 and 16 days after acute whole-body 9.5 Gy 60Co-γ irradiation (IR). This study tested countermeasures mitigating brain hemorrhage and increasing survival from IR. Previously, we found that pegylated G-CSF therapy (PEG) (i.e., Neulasta®, an FDA-approved drug) improved survival post-IR by 20-40%. This study investigated whether Ciprofloxacin (CIP) could enhance PEG-induced survival and whether IR-induced brain hemorrhage could be mitigated by PEG alone or combined with CIP. Methods: B6D2F1 female mice were exposed to 60Co-γ-radiation. CIP was fed to mice for 21 days. PEG was injected on days 1, 8, and 15. 30-day survival and weight loss were studied in mice treated with vehicles, CIP, PEG, or PEG + CIP. For the early time point study, blood and sternums on days 2, 4, 9, and 15 and brains on day 15 post-IR were collected. Platelet numbers, brain hemorrhage, and histopathology were analyzed. The cerebellum/pons/medulla oblongata were detected with glial fibrillary acidic protein (GFAP), p53, p16, interleukin-18 (IL-18), ICAM1, Claudin 2, ZO-1, and complement protein 3 (C3). Results: CIP + PEG enhanced survival after IR by 85% vs. the 30% improvement by PEG alone. IR depleted platelets, which was mitigated by PEG or CIP + PEG. Brain hemorrhage, both surface and intracranial, was observed, whereas the sham mice displayed no hemorrhage. CIP or CIP + PEG significantly mitigated brain hemorrhage. IR reduced GFAP levels that were recovered by CIP or CIP + PEG, but not by PEG alone. IR increased IL-18 levels on day 4 only, which was inhibited by CIP alone, PEG alone, or PEG + CIP. IR increased C3 on day 4 and day 15 and that coincided with the occurrence of brain hemorrhage on day 15. IR increased phosphorylated p53 and p53 levels, which was mitigated by CIP, PEG or PEG + CIP. P16, Claudin 2, and ZO-1 were not altered; ICAM1 was increased. Discussion: CIP + PEG enhanced survival post-IR more than PEG alone. The Concurrence of brain hemorrhage, C3 increases and p53 activation post-IR suggests their involvement in the IR-induced brain impairment. CIP + PEG effectively mitigated the brain lesions, suggesting effectiveness of CIP + PEG therapy for treating the IR-induced brain hemorrhage by recovering GFAP and platelets and reducing C3 and p53.

Intracranial hemorrhage after a single dose of Yohimbine in a chronic user of clonidine.

INTRODUCTION: Yohimbine, an alpha-2 adrenoreceptor antagonist found in a variety of supplements, has been historically used to treat libido, erectile dysfunction, xerostomia, and as a weight loss enhancement. Yohimbine toxicity causes a sympathomimetic syndrome as demonstrated by the case below of a female who developed an intracranial hemorrhage (ICH) following an ingestion of yohimbine. CASE: This case follows a 39-year-old female who presented to the emergency department (ED) with complaints of nausea, emesis, and flushing following the ingestion of a female sexual enhancement supplement labeled to contain yohimbine (BioXgenic Nature's Desire) one hour prior. The patient took her prescribed 0.1 mg clonidine when the symptoms commenced. Upon arrival, the patient's blood pressure was 198/93. She developed neurological sequelae including a left-sided facial droop and weakness of her right extremities. A computed tomography scan demonstrated an acute basal ganglia hemorrhage with mild mass effect and mild subarachnoid hemorrhage. She was transferred to a regional referral hospital and discharged 16 days later to a rehabilitation center with persistent neurological sequelae. DISCUSSION: This patient exhibited sympathetic toxicity temporally associated with yohimbine ingestion. Our patient also had a variety of risk factors that increased the likelihood of a poor outcome with yohimbine. Chronic use of clonidine is known to down-regulate alpha-2 receptors. This leads to dependence of clonidine to maintain adrenergic homeostasis and could potentiate the effects of yohimbine. To compound effects, our patient was also taking bupropion and desvenlafaxine, which inhibit norepinephrine reuptake, likely worsening our patient's sympathomimetic response. Despite the temporal relationship of our patient's ICH and ingestion of yohimbine, a definitive relationship cannot be inferred due to our lack of confirmatory testing of yohimbine content and possibility of adulterants. The U.S. Food and Drug Administration (FDA) does not regulate the supplement market strictly, with multiple studies illustrating variation among ingredients of supplements despite stated quantities on the labels. CONCLUSION: Dietary supplements are not required by the FDA to undergo efficacy or safety testing, necessitating clear post-marketing communication regarding potential adverse events from various supplements. Users should be aware of yohimbine-containing products and the possible side effects of toxicity. It is crucial that physicians and patients be aware of possible drug-supplement interactions of yohimbine and the presentation of sympathomimetic syndromes.

High versus low fixed-dose four factor-prothrombin complex concentrate for warfarin reversal in patients with intracranial hemorrhage.

BACKGROUND: Four-factor prothrombin complex concentrate 4F-PCC is the standard of care for warfarin reversal in patients with major bleed or requiring urgent surgery. Although the 4F-PCC dose is weight and international normalized ratio (INR) based, for practical purposes, a fixed-dose approach has been explored, especially for rapid reversal. We report our experience using two different fixed-dose 4F-PCC for warfarin reversal in patients presenting with intracranial hemorrhage (ICH). STUDY DESIGN AND METHODS: We completed a retrospective chart review comparing high (4000 units) versus low (2000 units) dose 4F-PCC by evaluating patient characteristics, laboratory data, and pre-and post-4F-PCC brain imaging. RESULTS: There was no significant difference between patient characteristics or INR correction (≤1.5) between the two groups. Eighty percent (12/15) of patients who received the low dose 4F-PCC had either improved or stable brain imaging as compared to 88% (14/16) of patients who received the high dose PCC. When the eight patients (4 from each arm of the study) who required neurosurgery were excluded, only two patients in each arm had worse imaging after 4F-PCC. CONCLUSION: There was no significant difference between the INR correction and the brain imaging changes in patients with an ICH who received either the high or the low fixed-dose 4F-PCC for warfarin reversal.

Effect of Traditional Chinese Medicine on Long-Term Outcomes of Snakebite in Taiwan.

Herein, we review the characteristics of the six predominant venomous snakes in Taiwan and the effects of traditional Chinese medicine on the long-term outcomes of snakebite venom. We electronically searched databases, including PubMed, ClinicalKey, China National Knowledge Infrastructure, National Digital Library of Theses and Dissertations in Taiwan, and Airiti Library, from their inception to November 2019 by using the following Medical Subject Headings' keywords: snakebite, long-term, chronic, Chinese medicine, CAM, herb, and Taiwan. The most common long-term effects of snakebite envenomation include "migraine-like syndrome", brain injuries caused by hypoxia or intracranial hemorrhage, and chronic kidney disease. In addition, hypopituitarism is also worth mentioning. Traditional Chinese medicine can potentially be used in a complementary or alternative treatment for these effects, but additional studies are needed.

Real-world utilization of andexanet alfa.

OBJECTIVE: In 2018, the FDA approved andexanet alfa for the reversal of life-threatening hemorrhages in patients anticoagulated with apixaban or rivaroxaban. Yet, cost-effective factor Xa inhibitor reversal remains controversial. The objective of this study was to describe real world utilization of andexanet alfa. METHODS: This was a retrospective case series of patients receiving andexanet alfa between July 28, 2018 and April 29, 2019 at a large academic health system. Baseline demographics, anticoagulant type and reversal, as well as brain imaging were collected. Primary endpoints were stability of hematoma for intracranial hemorrhage (ICH), and hemostatic effectiveness for patients undergoing surgical procedures. Secondary endpoints were thromboembolism and 30 day mortality. RESULTS: Of the 25 patients evaluated, 13 received andexanet alfa for ICH. Eleven of the 13 had follow-up imaging available and stability was observed in 90.9%. Three patients received andexanet alfa for reversal prior to surgical procedures, and 100% hemostatic effectiveness was achieved. Nine patients received andexanet alfa for reversal of extracranial bleeding, including gastrointestinal bleed (n=4). There were no thrombotic events in our cohort, and 30 day mortality was 24%. Sixty-four percent of patients would have met exclusion criteria for the ANNEXA-4 trial. CONCLUSION: This is the largest series to date describing real-world utilization of andexanet alfa. Our series showed hemostatic efficacy in 90.9% of patients with ICH, and 100% in patients undergoing surgical procedures. There were no thrombotic complications. Yet, larger and comparative studies are needed to clarify the optimal agent and patient selection for reversal of factor Xa inhibitors.

Efficacy of trazodone for treating paroxysmal sympathetic hyperactivity presenting after thalamic hemorrhage: A case report.

Paroxysmal sympathetic hyperactivity (PSH) is a clinical condition characterized by abnormal paroxysmal surges in sympathetic nervous system activity. PSH is known to occur after severe head injury and hypoxic encephalopathy. Cases of PSH that develop after stroke have been reported worldwide; however, PSH is not commonly reported in the field of stroke research in Japan. Some studies have suggested that gabapentin may improve the symptoms of PSH. To our knowledge, this is the first case report demonstrating the efficacy of trazodone for the treatment of PSH that developed after thalamic hemorrhage. A 45-year-old woman presented to our clinic with headache and paralysis of the left side of her body after experiencing right thalamic hemorrhage; a conservative treatment was initiated at our hospital. Immediately upon hospitalization, she developed high fever, tachycardia, tachypnea, constipation, and overactive bladder and had breathing difficulties. Blood sampling revealed elevated levels of myocardial escape enzymes; however, coronary angiography did not show any significant stenosis or occlusion. The patient's symptoms improved after the administration of trazodone. She was diagnosed with catecholamine cardiomyopathy associated with PSH after intracranial hemorrhage and was subsequently transferred to a recovery and rehabilitation hospital unit where the oral administration of trazodone continued. Prolonged PSH contributes significantly to the impairment of daily activities in patients with stroke; therefore, early diagnosis and treatment are critical. Here, we report on the efficacy of trazodone as an effective treatment option for improving clinical outcomes and reducing the stay in the stroke care unit.

Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke.

Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.

Vitamin K deficiency bleeding in an apparently healthy newborn infant: the compelling need for evidence-based recommendation.

BACKGROUND: Vitamin K is a key point for guarantee normal blood clotting and its level in newborns is commonly low, so a supplementation after delivery is mandatory. Vitamin K prophylaxis in newborns is still an open field of debate: many types of protocol have been proposed in different years and Countries, and sometimes with great variability inside the same Nation (for instance, in Italy a national consensus is not available, so different protocols are employed). Recommendations include different protocols for healthy newborns born at term, but the unpreventable presence of bleeding favouring factors (i.e. blood vessels malformations) or limiting intestinal absorption of liposoluble vitamins (i.e. cholestasis), which could be unrecognized or subclinical in the perinatal period, rises some concerning about the most precautionary route of administration and the timing of further doses after the first one given at birth. The purpose of this report is to underline the most recent evidences available in literature and to arise a debate about this topic, in order to stimulate the production of evidence-based guidelines concerning the prophylaxis with vitamin K1 in newborn infants, considering that many bleeding risk factors are not recognizable at birth. CASE PRESENTATION: We are hereby presenting an emblematic case concerning the risk of intracranial bleeding in an apparently healthy newborn: the described infant did not show any pathological elements in pregnancy history or perinatal life which suggest a possible increased risk of bleeding and the needing of a particular approach in the administration of vitamin K1, but at the end of the first week of life presented an intracranial bleeding with neurological symptoms that required treatment for vitamin K deficiency. CONCLUSIONS: Univocal recommendations about vitamin K prophylaxis are not available and the contrast between oral and intramuscular routes persists unsolved. The difficulty to certainly identify an infant eligible for oral administration of vitamin K1 at birth suggests that the intramuscular route should be preferred. How to prosecute the supplementation in the first months of life is still an open topic of debate.

Rho Kinase Inhibition Blunts Lesion Development and Hemorrhage in Murine Models of Aggressive Pdcd10/Ccm3 Disease.

Background and Purpose- Previously, murine models Krit1 +/- Msh2 -/- and Ccm2 +/- Trp53 -/- showed a reduction or no effect on cerebral cavernous malformation (CCM) burden and favorable effects on lesional hemorrhage by the robust Rock (Rho-associated protein kinase) inhibitor fasudil and by simvastatin (a weak pleiotropic inhibitor of Rock). Herein, we concurrently investigated treatment of the more aggressive Pdcd10/Ccm3 model with fasudil, simvastatin, and higher dose atorvastatin to determined effectiveness of Rock inhibition. Methods- The murine models, Pdcd10 +/- Trp53 -/- and Pdcd10 +/- Msh2 -/-, were contemporaneously treated from weaning to 5 months of age with fasudil (100 mg/kg per day in drinking water, n=9), simvastatin (40 mg/kg per day in chow, n=11), atorvastatin (80 mg/kg per day in chow, n=10), or with placebo (n=16). We assessed CCM volume in mouse brains by microcomputed tomography. Lesion burden was calculated as lesion volume normalized to total brain volume. We analyzed chronic hemorrhage in CCM lesions by quantitative intensity of Perls staining in brain sections. Results- The Pdcd10 +/- Trp53 -/- /Msh2 -/- models showed a mean CCM lesion burden per mouse reduction from 0.0091 in placebos to 0.0042 ( P=0.027) by fasudil, and to 0.0047 ( P=0.025) by atorvastatin treatment, but was not changed significantly by simvastatin. Hemorrhage intensity per brain was commensurately decreased by Rock inhibition. Conclusions- These results support the exploration of proof of concept effect of high-dose atorvastatin on human CCM disease for potential therapeutic testing.

Effects of ginkgo biloba extract on the cognitive function and expression profile of inflammatory factors in a rat model of hemorrhagic stroke.

Hemorrhagic stroke is a major risk factor for cognitive impairment. Our study aimed to measure the effect of ginkgo biloba extract (EGB761) on the cognitive ability and inflammatory expression in hemorrhagic stroke model SD rats and to analyze their relationship. Forty SD rats were divided randomly into an SD group (normal control SD rats), an SD+EGB761 group (normal control SD rats supplemented with 45 mg/kg EGB761), a CO group (hemorrhagic stroke model SD rats using collagenase), and a CO+EGB761 group (hemorrhagic stroke model SD rats supplemented with 45 mg/kg EGB761) consisting of 10 rats, respectively. The Y-electric maze test was selected to measure the cognitive function in four groups. Furthermore, enzyme-linked immunosorbent assay and real-time PCR were, respectively, applied for detecting the protein and gene expression profiles of inflammatory factors in primary cultured microglia. Compared with rats in the SD group, the average time of electrical simulation for mastering criteria was prolonged in the CO group (P<0.05). Furthermore, expression levels of proinflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α and anti-inflammatory cytokines IL-4, IL-10, and tumor necrosis factor-ß were significantly increased and decreased, respectively, in rats of the CO group compared with the SD group (P<0.05). The results of electrical simulation time, inflammatory factors protein, and gene expression profile in rats of the CO+EGB761 group compared with the CO group were opposite to above contrast (P<0.05). Ginkgo biloba extract could alleviate the cognitive dysfunction after hemorrhagic stroke in SD rats; this is associated with regulating the expression of inflammatory factors secreted by microglia.

Protective effects of the astaxanthin derivative, adonixanthin, on brain hemorrhagic injury.

Astaxanthin is beneficial for human health and is used as a dietary supplement. The present study was performed in order to examine the protective effects of the astaxanthin derivative, adonixanthin, against cell death caused by hemoglobin, collagenase, lipopolysaccharide, and hydrogen peroxide, which are associated with hemorrhagic brain injury. In an in vitro study, adonixanthin exerted cytoprotective effects against each type of damage, and its effects were stronger than those of astaxanthin. The increased production of reactive oxygen species in human brain endothelial cells in the hemoglobin treatment group was inhibited by adonixanthin. Moreover, adonixanthin suppressed cell death in SH-SY5Y cells. In an in vivo study, the oral administration of adonixanthin improved blood-brain barrier hyper-permeability in an autologous blood ICH model. We herein demonstrated for the first time that adonixanthin exerted protective effects against hemorrhagic brain damage by activating antioxidant defenses, and has potential as a protectant against intracerebral hemorrhage.

Focused Update on Pharmacologic Management of Hypertensive Emergencies.

PURPOSE OF REVIEW: Hypertensive emergency is defined as a systolic blood pressure > 180 mmHg or a diastolic blood pressure > 120 mmHg with evidence of new or progressive end-organ damage. The purpose of this paper is to review advances in the treatment of hypertensive emergencies within the last 5 years. RECENT FINDINGS: New literature and recommendations for managing hypertensive emergencies in the setting of pregnancy, stroke, and heart failure have been published. Oral nifedipine is now considered an alternative first-line therapy, along with intravenous hydralazine and labetalol for women presenting with pre-eclampsia. Clevidipine is now endorsed by guidelines as a first-line treatment option for blood pressure reduction in acute ischemic stroke and may be considered for use in intracranial hemorrhage. Treatment of hypertensive heart failure remains challenging; clevidipine and enalaprilat can be considered for use in this population although data supporting their use remains limited.

Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study.

Oral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for the management of Xa-inhibitor-associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53-77), moderate in 20% (95% CI, 10-30) and poor/none in 15% (95% CI, 6-24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.

Baicalin Attenuates Blood-Brain Barrier Disruption and Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke Rats with Delayed t-PA Treatment: Involvement of ONOO--MMP-9 Pathway.

Tissue plasminogen activator (t-PA) has a restrictive therapeutic window within 4.5 h after ischemic stroke with the risk of hemorrhagic transformation (HT) and neurotoxicity when it is used beyond the time window. In the present study, we tested the hypothesis that baicalin, an active compound of medicinal plant, could attenuate HT in cerebral ischemia stroke with delayed t-PA treatment. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 4.5 h and then continuously received t-PA infusion (10 mg/kg) for 0.5 h and followed by 19-h reperfusion. Baicalin (50, 100, 150 mg/kg) was administrated via femoral vein at 4.5 h after MCAO cerebral ischemia. Delayed t-PA infusion significantly increased the mortality rate, induced HT, blood-brain barrier (BBB) damage, and apoptotic cell death in the ischemic brains and exacerbated neurological outcomes in cerebral ischemia-reperfusion rats at 24 h after MCAO cerebral ischemia. Co-treatment of baicalin significantly reduced the mortality rates, ameliorated the t-PA-mediated BBB disruption and HT. Furthermore, baicalin showed to directly scavenge peroxynitrite and inhibit MMP-9 expression and activity in the ischemic brains with the delayed t-PA treatment. Baicalin had no effect on the t-PA fibrinolytic function indicated by t-PA activity assay. Taken together, baicalin could attenuate t-PA-mediated HT and improve the outcomes of ischemic stroke treatment possibly via inhibiting peroxynitrite-mediated MMP-9 activation.

Four-factor prothrombin complex concentrate for life-threatening bleeds or emergent surgery: A retrospective evaluation.

PURPOSE: Previous trials investigating usage of four-factor prothrombin complex concentrate (4F-PCC) excluded patients with various thrombotic risk factors. The objective of this study was to evaluate the safety and effectiveness of 4F-PCC in a real-world setting based on an institutional protocol that does not have strict exclusion criteria. METHODS: This was a retrospective study of adult patients who received 4F-PCC. The primary outcome was a confirmed thromboembolism within 14 days after 4F-PCC administration. Secondary outcomes included international normalized ratio (INR) correction to <1.5 at first draw and incidence of INR rebound for patients undergoing reversal of warfarin and hemostatic effectiveness for patients experiencing a bleed. RESULTS: Ninety-three patients received 4F-PCC. Sixty-three (67.7%) were reversed for bleeding and 30 (32.3%) for surgery. Eleven patients (11.8%) developed a thromboembolism within 14 days. The median (interquartile range) time to event was 5 (2-7) days. Significant risk factors were heparin-induced thrombocytopenia (P= .01) and major surgery within 14 days (P= .02), as well as the presence of >6 thrombotic risk factors (P= .01). For patients post-warfarin reversal, 45/63 (71.4%) achieved INR correction at first draw, 55/63 (87.3%) achieved INR correction within 24 hours, and 14/55 (25.5%) experienced INR rebound. Of these 14 patients, 8 (57.1%) did not receive concomitant vitamin K. CONCLUSIONS: 4F-PCC was associated with a notable thromboembolic risk. All patient-specific risk factors should be considered prior to administration. 4F-PCC remains a useful agent for warfarin reversal. Lack of concomitant vitamin K may contribute to INR rebound.

Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors.

BACKGROUND: Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers. METHODS: In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication. RESULTS: The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up. CONCLUSIONS: On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Rivaroxaban and intracranial haemorrhage after mild traumatic brain injury: A dangerous combination?

OBJECTIVES: Despite several advantages of the novel anticoagulant rivaroxaban compared with vitamin K antagonists (VKA), its lack of specific antidotes to reverse anticoagulant effects may increase the risk profile of patients with bleeding complications. The purpose of this study was to analyze the effects of pre-injury treatment with rivaroxaban on patients with mild traumatic brain injury (TBI) and traumatic intracranial haemorrhage (tICH). METHODS: A total of 70 patients with tICH after mild TBI were included in this retrospective analysis and were categorized into three groups: group A (no antithrombotics n=37), group B (antiplatelet medication n=22, VKA=5), and group C (rivaroxaban n=6). Medical charts were reviewed for baseline characteristics, laboratory values, intracranial haemorrhage, repeated computed tomography (CT) scans, re-haemorrhage, Glasgow Coma Scale (GCS) scores and in-hospital mortality. RESULTS: No significant differences were observed for baseline characteristics. The rate of re-haemorrhage was significantly higher in group C (50%) than in group A (11%) (p<0.05). Two patients died and both had been treated with rivaroxaban which resulted in a significantly higher mortality rate of 33% in group C compared with groups A (0%) and B (0%). No significant differences were observed for GCS at discharge and length of hospital stay between survivors of groups A-C. CONCLUSIONS: Despite major limitations of retrospective design and small patient numbers, our results suggest that rivaroxaban may exacerbate intracranial haemorrhage in patients with mild TBI. Further studies are needed to characterize the risk profile of this drug in patients with tICH.