Maria I. Aguilar

Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion.

Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.

Stroke Team Remote Evaluation Using a Digital Observation Camera in Arizona The Initial Mayo Clinic Experience Trial

Background and Purpose— Telemedicine techniques can be used to address the rural–metropolitan disparity in acute stroke care. The Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC) trial reported more accurate decision making for telemedicine consultations compared with telephone-only and that the California-based research network facilitated a high rate of thrombolysis use, improved data collection, low risk of complications, low technical complications, and favorable assessment times. The main objective of the STRokE DOC Arizona TIME (The Initial Mayo Clinic Experience) trial was to determine the feasibility of establishing, de novo, a single-hub, multirural spoke hospital telestroke research network across a large geographical area in Arizona by replicating the STRokE DOC protocol. Methods— Methods included prospective, single-hub, 2-spoke, randomized, blinded, controlled trial of a 2-way, site-independent, audiovisual telemedicine system designed for remote examination of adult patients with acute stroke versus telephone consultation to assess eligibility for treatment with intravenous thrombolysis. The primary outcome measure was whether the decision to give thrombolysis was correct. Secondary outcomes were rate of thrombolytic use, 90-day functional outcomes, incidence of intracerebral hemorrhages, and technical observations. Results— From December 2007 to October 2008, 54 patients were assessed, 27 of whom were randomized to each arm. Mean National Institutes of Health Stroke Scale score at presentation was 7.3 (SD 6.2) points. No consultations were aborted; however, technical problems (74%) were prevalent in the telemedicine arm. Overall, the correct treatment decision was established in 87% of the consultations. Both modalities, telephone (89% correct) and telemedicine (85% correct), performed well. Intravenous thrombolytic treatment was used in 30% of the telemedicine and telephone consultations. Good functional outcomes at 90 days were not significantly different. There were no statistically significant differences in mortality (4% in telemedicine and 11% in telephone) or rates of intracerebral hemorrhage (4% in telemedicine and 0% in telephone). Conclusions— It is feasible to extend the original STRokE DOC trial protocol to a new state and establish an operational single-hub, multispoke rural hospital telestroke research network in Arizona. The trial was not designed to have sufficient power to detect a difference between the 2 consultative modes: telemedicine and telephone-only. Whether by telemedicine or telephone consultative modalities, there were appropriate treatment decisions, high rates of thrombolysis use, improved data collection, low rates of intracerebral hemorrhage, and equally favorable time requirements. The learning curve was steep for the hub and spoke personnel of the new telestroke network, as reflected by frequent technical problems. Overall, the results support the effectiveness of highly organized and structured stroke telemedicine networks for extending expert stroke care into rural remote communities lacking sufficient neurological expertise.

Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, Part 1: Prevention

Oral anticoagulant therapy with coumarins is widelyused for the prevention and treatment of venous andarterial thrombosis. The most common complication ofvitamin K antagonist therapy is bleeding, with majorbleeding events occurring in 1–3% of patients annually.Although a number of potential predictors for bleedinghave been described, little research is available to pro-vide evidence-based guidelines for the prevention ofbleeding. To address this knowledge gap, we assembleda panel of international experts and posed a series offocused clinical questions. The experts were asked toperform a systematic literature review and summarize theresults of that review within the context of their clinicalquestion. In many cases, data were lacking and theexperts were asked to supplement their answer with clin-ical expertise. To minimize bias the reviews were vettedby three internationally recognized scholarly bodies. Ourgoal in this project is to provide ‘‘best evidence’’ forclinicians faced with the problem of minimizing the riskof bleeding in patients on vitamin K antagonist therapy.The number of patients receiving vitamin K antagonisttherapy increases annually and probably exceeds three mil-lion in the United States. Despite monitoring and carefuldose adjustment, the time spent in the therapeutic Interna-tional Normalized Ratio (INR) range varies from below 47%to a maximum of 81% of the time [1]. Major bleedingevents occur in up to 3% of ‘‘standard risk’’ patients treatedwith an oral vitamin K antagonist in one year. Despite thehigh frequency of use of vitamin K antagonists, very littleresearch has been performed examining techniques toreduce the risk of bleeding. In particular, the role of clinicalbleeding prediction rules is uncertain and further study ofthe role of drug and food interactions, the impact of patienteducation, the risk to benefit ratio of combining differentantithrombotic drugs, the role of pharmacogenomic testing,and on the optimal management of patients presentingwith elevated INR values is required. However, despitethese needs clinicians are still required to initiate andmonitor vitamin K antagonists while mitigating the risks ofbleeding and thrombosis. This article provides recommen-dations designed to assist clinicians in estimating andmanaging bleeding risk in patients receiving oral vitamin Kantagonists.Clinical questions were formulated by three of theauthors (WA, MC, DG) and authors were selected basedon their published experience. In each case, a North Ameri-can and Italian expert were asked to co-author theresponse to the question. The authors were asked to per-form a comprehensive literature review and make specificrecommendations on the basis of this review in concertwith their clinical experience. Given the anticipated lack ofevidence, the recommendations are largely opinion-based.To increase the rigor of the recommendations, each sectionwas carefully reviewed by members of the Italian Societyfor Studies on Haemostasis and Thrombosis, the Federa-tion of Centers for the Diagnosis of Thrombosis and Sur-veillance of Antithrombotic Therapies, and the Anticoagula-tion Forum.To provide readers with information on the strength of therecommendations, we have asked the authors to use theAmerican College of Chest Physicians GRADE system toevaluate the quality of the recommendations [2]. In thissystem, grades of 1A, 1B, 1C, 2A, 2B, and 2C are possible.A 1A recommendation is a strong recommendation basedon evidence from randomized trials or exceptional qualityobservational data which is thought to apply to mostpatients, in most circumstances. A 2C recommendation is avery weak recommendation, based on poor quality evi-dence, and for which there is doubt as to which patientsthe recommendation applies. Our goal with this project is toboth provide guidance to clinicians and to stimulate addi-tional research designed to improve the quality of evidenceon which treatments for vitamin K antagonist associatedbleeding are based.Clinical Scenario 1A 79-year-old woman with atrial fibrillation and well-con-trolled hypertension is assessed for anticoagulant therapy.She has no history of diabetes, congestive heart failure,stroke, or transient ischemic attack (TIA). Two years agoshe had an upper gastrointestinal bleed treated with a pro-

Statins and Intracerebral Hemorrhage: Collaborative Systematic Review and Meta-analysis

Background— A recent large, randomized trial suggested that statins may increase the risk of intracerebral hemorrhage. Accordingly, we systematically reviewed the association of statins with intracerebral hemorrhage in randomized and observational data. Methods and Results— We screened 17 electronic bibliographic databases to identify eligible studies and consulted with experts in the field. We used DerSimonian-Laird random-effects models to compute summary risk ratios with 95% confidence intervals. Randomized trials, cohort studies, and case-control studies were analyzed separately. Only adjusted risk estimates were used for pooling observational data. We included published and unpublished data from 23 randomized trials and 19 observational studies. The complete data set comprised 248 391 patients and 14 784 intracerebral hemorrhages. Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (risk ratio, 1.10; 95% confidence interval, 0.86–1.41), cohort studies (risk ratio, 0.94; 95% confidence interval, 0.81–1.10), or case-control studies (risk ratio, 0.60; 95% confidence interval, 0.41–0.88). Substantial statistical heterogeneity was evident for the case-control studies (I2=66%, P=0.01), but not for the cohort studies (I2=0%, P=0.48) or randomized trials (I2=30%, P=0.09). Sensitivity analyses by study design features, patient characteristics, or magnitude of cholesterol lowering did not materially alter the results. Conclusions— We found no evidence that statins were associated with intracerebral hemorrhage; if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs.Background— A recent large, randomized trial suggested that statins may increase the risk of intracerebral hemorrhage. Accordingly, we systematically reviewed the association of statins with intracerebral hemorrhage in randomized and observational data.nnMethods and Results— We screened 17 electronic bibliographic databases to identify eligible studies and consulted with experts in the field. We used DerSimonian-Laird random-effects models to compute summary risk ratios with 95% confidence intervals. Randomized trials, cohort studies, and case-control studies were analyzed separately. Only adjusted risk estimates were used for pooling observational data. We included published and unpublished data from 23 randomized trials and 19 observational studies. The complete data set comprised 248 391 patients and 14 784 intracerebral hemorrhages. Statins were not associated with an increased risk of intracerebral hemorrhage in randomized trials (risk ratio, 1.10; 95% confidence interval, 0.86–1.41), cohort studies (risk ratio, 0.94; 95% confidence interval, 0.81–1.10), or case-control studies (risk ratio, 0.60; 95% confidence interval, 0.41–0.88). Substantial statistical heterogeneity was evident for the case-control studies (I2=66%, P =0.01), but not for the cohort studies (I2=0%, P =0.48) or randomized trials (I2=30%, P =0.09). Sensitivity analyses by study design features, patient characteristics, or magnitude of cholesterol lowering did not materially alter the results.nnConclusions— We found no evidence that statins were associated with intracerebral hemorrhage; if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs.nn# Clinical Perspective {#article-title-52}

Smartphone Teleradiology Application Is Successfully Incorporated Into a Telestroke Network Environment

Background and Purpose— ResolutionMD mobile application runs on a Smartphone and affords vascular neurologists access to radiological images of patients with stroke from remote sites in the context of a telemedicine evaluation. Although reliability studies using this technology have been conducted in a controlled environment, this study is the first to incorporate it into a real-world hub and spoke telestroke network. The study objective was to assess the level of agreement of brain CT scan interpretation in a telestroke network between hub vascular neurologists using ResolutionMD, spoke radiologists using a Picture Archiving and Communications System, and independent adjudicators. Methods— Fifty-three patients with stroke at the spoke hospital consented to receive a telemedicine consultation and participate in a registry. Each CT was evaluated by a hub vascular neurologist, a spoke radiologist, and by blinded telestroke adjudicators, and agreement over clinically important radiological features was calculated. Results— Agreement (&kgr; and 95% CI) between hub vascular neurologists using ResolutionMD and (1) the spoke radiologist; and (2) independent adjudicators, respectively, were: identification of intracranial hemorrhage 1.0 (0.92–1.0), 1.0 (0.93–1.0), neoplasm 1.0 (0.92–1.0), 1.0 (0.93–1.0), any radiological contraindication to thrombolysis 1.0 (0.92–1.0), 0.85 (0.65–1.0), early ischemic changes 0.62 (0.28–0.96), 0.58 (0.30–0.86), and hyperdense artery sign 0.40 (0.01–0.80), 0.44 (0.06–0.81). Conclusions— CT head interpretations of telestroke network patients by vascular neurologists using ResolutionMD on Smartphones were in excellent agreement with interpretations by spoke radiologists using a Picture Archiving and Communications System and those of independent telestroke adjudicators using a desktop viewer. Clinical Trial Registration Information— www.clinicaltrials.gov unique identifier NCT00829361.

Spontaneous intracerebral hemorrhage.

Spontaneous intracerebral hemorrhage (sICH) is defined as bleeding within the brain parenchyma, and occurs twice as commonly as subarachnoid hemorrhage, but is equally as deadly. Risk factors for sICH include hypertension, advanced age, leukoaraiosis, prior ICH, renal failure, use of anticoagulant drugs, and cerebral amyloid angiopathy. When a patient is clinically suspected of having sICH, head computed tomography scan is the standard diagnostic tool. However, newer magnetic resonance neuroimaging techniques may aid in determining the underlying pathology and aid in prognosis. Supportive care and blood pressure management are important in the care of patients with sICH. Ongoing research is aimed at determining a safe blood pressure goal that may also prevent expansion of hemorrhage. Hemostatic medications and neuroprotectants have thus far not shown clinical improvement. Although several neurosurgical trials have failed to demonstrate benefit for surgical evacuation of sICH, multiple research trials are ongoing investigating acute blood pressure control, deep or basal ganglionic hemorrhage evacuation via minimally invasive approach (MISTIE; http://mistietrial.com/default.aspx), lobar ICH evacuation (STICH; II http://research.ncl.ac.uk/stich/), and intraventricular thrombolysis with tissue plasminogen activator (tPA) (CLEAR III; http://biosgroup-johnshopkinsmedicine.health.officelive.com/default.aspx).

Anticoagulation in atrial fibrillation: selected controversies including optimal anticoagulation intensity, treatment of intracerebral hemorrhage

Clinical trials during the past 20xa0years have revolutionized the antithrombotic management of atrial fibrillation. Based on consideration of 30 randomized trials involving 29,017 participants, adjusted-dose warfarin remains the most efficacious prophylaxis against stroke for atrial fibrillation patients at moderate-to-high risk (compared with antiplatelet agents, warfarin reduces stroke by about 40%). The optimal INR for prevention of stroke for most atrial fibrillation patients is probably 2.0–2.5; INRs of 1.6–1.9 provide substantial protection, 80–90% of that afforded by higher intensities. Warfarin-associated intracerebral hemorrhage is an increasing problem as more elderly patients with atrial fibrillation are anticoagulated. Modest reductions in blood pressure results in large decreases in this most dreaded complication of warfarin; anticoagulation of elderly atrial fibrillation patients should be accompanied by a firm commitment to control hypertension. Warfarin-associated intracerebral hemorrhage has a 50% early mortality. A wide range of acute treatments to urgently reverse anticoagulation have been recommended by experts, but prevention is a far better option than treatment of this devastating problem.

Albuminuria and the risk of incident stroke and stroke types in older adults

Background: The kidney biomarker that best reflects risk of stroke is unknown. We sought to evaluate the association of stroke with 3 kidney biomarkers: albuminuria, cystatin C, and glomerular filtration rate. Methods: These 3 biomarkers were determined in 3,287 participants without history of stroke from the Cardiovascular Health Study, a longitudinal cohort study of men and women age 65 years and older from 4 US communities. The biomarkers were albuminuria ascertained using urinary albumin-to-creatinine ratio (UACR) from morning spot urine, creatinine-based estimated glomerular filtration rate (eGFR), and cystatin C. Outcomes were incident stroke (any, ischemic, or hemorrhagic) during follow-up between 1996 and 2006. Results: A total of 390 participants had an incident stroke: 81% ischemic, 12% hemorrhagic, and 7% unclassified. In adjusted Cox regression models, UACR was more strongly related to any stroke, ischemic stroke, and hemorrhagic stroke than eGFR and cystatin C. The hazard ratio (HR) of any stroke comparing the top to bottom quintile of UACR was 2.10 (95% confidence interval [CI] 1.47–3.00), while HR for eGFR was 1.29 (95% CI 0.91–1.84) and for cystatin C was 1.22 (95% CI 0.85–1.74). When considering clinically relevant categories, elevated UACR was associated with increased hazard of any stroke and ischemic stroke regardless of eGFR or cystatin C categories. Conclusions: UACR was the kidney biomarker most strongly associated with risk of incident stroke. Results in this elderly cohort may not be applicable to younger populations. These findings suggest that measures of glomerular filtration and permeability have differential effects on stroke risk.

Telemedicine versus telephone for remote emergency stroke consultations: a critically appraised topic.

Background:The rate of patients being treated with thrombolytic therapy is low, in part, due to a shortage of vascular neurologists, especially in rural communities. Two-way audio-video communication through telemedicine has been demonstrated to be a reliable method to assess neurologic deficits due to stroke and maybe more efficacious in determining thrombolytic therapy eligibility than telephone-only consultation. Objective:To determine the efficacy of telemedicine versus telephone-only consultations for decision making in acute stroke situations. Methods:The objective was addressed through the development of a structured, critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarian, and clinical content experts in the fields of vascular neurology, emergency medicine, and telemedicine. Participants started with a clinical scenario and a structured question, devised search strategies, located and compiled the best evidence, performed a critical appraisal, synthesized the results, summarized the evidence, provided commentary, and declared bottom-line conclusions. Results:A single randomized, blinded, prospective trial comparing telephone-only consultations to telemedicine consultations for acute stroke was selected and appraised. Correct acute stroke treatment decisions were made more often in the telemedicine group versus the telephone-only group (98% vs. 82%, [number needed to assess = 6]). Stroke telemedicine when compared with telephone-only consultations was more sensitive (100% vs. 58%), more specific (98% vs. 92%), had a more favorable positive likelihood ratio (LR: 41 vs. 7) and negative likelihood ratio (LR: 0 vs. 0.5), and had higher predictive values (positive predictive value 94% vs. 76%, and negative predictive value 100% vs. 84%) for the determination of thrombolysis eligibility. Conclusion:Stroke telemedicine when compared with telephone-only consultations is an effective method to determine thrombolysis eligibility for acute stroke patients who do not have immediate access to a stroke neurologist.

Update in Intracerebral Hemorrhage

Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is defined as bleeding within the brain parenchyma. Intracranial hemorrhage includes bleeding within the cranial vault and encompasses ICH, subdural hematoma, epidural bleeds, and subarachnoid hemorrhage (SAH). This review will focus only on ICH. This stroke subtype accounts for about 10% of all strokes. The hematoma locations are deep or ganglionic, lobar, cerebellar, and brain stem in descending order of frequency. Intracerebral hemorrhage occurs twice as common as SAH and is equally as deadly. Risk factors for ICH include hypertension, cerebral amyloid angiopathy, advanced age, antithrombotic therapy and history of cerebrovascular disease. The clinical presentation is “stroke like” with sudden onset of focal neurological deficits. Noncontrast head computerized tomography (CT) scan is the standard diagnostic tool. However, newer neuroimaging techniques have improved the diagnostic yield in terms of underlying pathophysiology and may aid in prognosis. Intracerebral hemorrhage is a neurological emergency. Medical care begins with stabilization of airway, breathing function, and circulation (ABCs), followed by specific measures aimed to decrease secondary neurological damage and to prevent both medical and neurological complications. Reversal of coagulopathy when present is of the essence. Blood pressure management can be key and continues as an area of debate and ongoing research. Surgical evacuation of ICH is of unproven benefit though a subset of well-selected patients may have improved outcomes. Ventriculostomy and intracranial pressure (ICP) monitoring are interventions also used in this patient population. To date, hemostatic medications and neuroprotectants have failed to result in clinical improvement. A multidisciplinary approach is recommended, with participation of vascular neurology, vascular neurosurgery, critical care, and rehabilitation medicine as the main players.