Predictors of symptomatic intracranial haemorrhage in off-label thrombolysis: an analysis of the Safe Implementation of Treatments in Stroke registry.

BACKGROUND AND PURPOSE: Intravenous thrombolysis (IVT) is the only approved pharmacological treatment for acute ischemic stroke. Off-label IVT for ischemic stroke is common. We aimed to analyse its safety in a large database. METHODS: This was a retrospective analysis of the safe implementation of treatments in stroke (SITS) thrombolysis registry with regard to 11 off-label criteria according to the European licence for alteplase. Symptomatic intracranial haemorrhage (SICH) according to SITS was defined as primary safety endpoint and SICH according to the European Cooperative Acute Stroke Study (ECASS II) definition and the National Institute of Neurological Disorders and Stroke definition as secondary safety endpoints. Multivariable logistic regression analyses after replacing missing values using multiple imputations were performed. RESULTS: Patients from 793 centres in 44 countries were included, mainly (95%) in Europe. A total of 56 258 patients who were treated with intravenous alteplase were included. Median age was 71 (IQR 61-78) years and median National Institutes of Health Stroke Scale score was 12 (IQR 7-17). A total of 16 740 (30%) patients received off-label IVT and 1037 (1.8%) patients suffered from SICH according to the SITS definition (SICH SITS). Median percentage of missing values per variable was 0.4%. The only two off-label criteria constituting independent positive and negative predictors for SICH SITS were high blood pressure (odds ratio, 1.39; 95% confidence interval, 1.08-1.80; P = 0.012) and minor stroke (odds ratio, 0.51; 95% confidence interval, 0.33-0.78; P = 0.002). Very severe stroke, previous stroke and diabetes, age and high glucose levels were additional independent predictors of SICH according to the ECASS II and National Institute of Neurological Disorders and Stroke definitions. CONCLUSIONS: Thrombolysis appears to be safe with regard to SICH for most of the off-label criteria, especially for minor stroke, but is risky in patients with high blood pressure. Individual risk-benefit evaluation should be performed.

Questionnaire-Based Survey on Gastrointestinal Bleeding and Management of Antithrombotic Agents during Endoscopy Among Asian Countries.

OBJECTIVE: Guidelines on the management of antithrombotic therapy for endoscopic procedures vary among countries. Differences in the management of antithrombotic agents for endoscopic procedures between Western and Eastern countries have already been reported. However, no study has investigated the differences among Asian countries. The aim of this study was to examine the differences in the etiology of gastrointestinal bleeding and management of antithrombotic agents during endoscopic procedures between Japan and other Asian countries (OAC). METHODS: Questionnaires regarding gastrointestinal bleeding in clinical practice and management of antithrombotic agents during endoscopy were distributed to members of the International Gastroenterology Consensus Symposium Study Group. We analyzed the questionnaire answers and compared the results between Japan and OAC. RESULTS: The cause of and treatment methods for gastrointestinal bleeding differed between Japan and OAC. In Japan, the trend was to continue drugs at the time of biopsy and endoscopic therapy. Even in cases of discontinuation, the drug withdrawal period was as short as <3 days. Thrombotic complications caused by the withdrawal of antithrombotic agents were observed more frequently in Japan (34.78%) than in OAC (22.46%; p = 0.016). CONCLUSION: Due to differences in guidelines and complications associated with discontinuation of drugs, the antithrombotic withdrawal period in Japan tended to be shorter than that in OAC.

Biological standards for potency assignment to fibrinolytic agents used in thrombolytic therapy.

Thrombolytic drugs are used for the treatment of thrombotic disorders such as acute myocardial infarction, acute ischemic stroke, and pulmonary embolism. Biological standards are used for potency assignment to the range of fibrinolytic proteins used in thrombolytic therapy. The World Health Organization (WHO) International Standards are primary reference materials, calibrated in arbitrary units (international unit), assigned by collaborative study using the range of assay methods available at the time. Provided the standard and test material are equivalent, adhering to the principle of measuring like versus like, the exact nature of the assay method is unimportant. This approach has been applied successfully for several decades since the advent of fibrinolytic treatment, ensuring consistency for potency labeling and the correct dosing of patients. The emergence of generic biosimilar products and new recombinant variants poses a challenge to this system, where functional differences impact on the relative biological activity in different assay systems. A more demanding system of standardization may therefore be required on the basis of international reference materials with associated reference methods. WHO recognizes this, and where possible and practical is seeking to incorporate concepts of traceability, uncertainty, and commutability to International Standards. However, some caution is needed because limitations on the characterization of many complex biologicals remain real, and a flexible approach is required on the basis of real-world needs.

Safety of protocol violations in acute stroke tPA administration.

BACKGROUND: Intravenous (IV) tissue plasminogen activator remains the only approved therapy for acute ischemic stroke (AIS) in the United States; however, less than 10% of patients receive treatment. This is partially because of the large number of contraindications, narrow treatment window, and physician reluctance to deviate from these criteria. METHODS: We retrospectively analyzed consecutive patients who received IV thrombolysis at our stroke center for National Institute of Neurological Disorders and Stroke (NINDS) protocol violations and rates of symptomatic intracerebral hemorrhage (sICH). Other outcome variables included systemic hemorrhage, modified Rankin Scale at discharge, and discharge disposition. RESULTS: A total of 212 patients were identified in our stroke registry between 2009 and 2011 and included in the analysis. Protocol violations occurred in 76 patients (36%). The most common violations were thrombolysis beyond 3 hours (26%), aggressive blood pressure management (15%), elevated prothrombin time (PT) or partial thromboplastin time (PTT) (6.6%), minor or resolving deficits (4.2%), unclear time of onset (3.9%), and stroke within 3 months (3%). There were no significant differences in any of the safety outcomes or discharge disposition between patients with or without protocol violations. Controlling for age, National Institutes of Health Stroke Scale on admission, and glucose on admission, there was no significant increase in sICH (odds ratio: 3.8; 95% confidence interval: .37-38.72) in the patients who had protocol violations. CONCLUSIONS: Despite more than one third of patients receiving thrombolysis with protocol violations, overall rates of hemorrhage remained low and did not differ from those who did not have violations. Our data support the need to expand access to thrombolysis in AIS patients.

Catheter-based treatment of ilio-femoral deep vein thrombosis - an update on current evidence.

Ilio-femoral deep vein thrombosis (DVT) has a high rate of long-term morbidity in the form of the postthrombotic syndrome (PTS). Therefore, management of acute thrombosis should not only focus on the prevention of acute complications such as propagation or embolisation of the initial clot but also on preventing PTS and recurrent thrombosis. Contemporary catheter-based treatments of deep vein thrombosis have proven to be safe and effective in selected patients. Current guidelines recommend medical therapy with anticoagulation alone for all but the most severe, limb-threatening thrombosis. They additionally allow for consideration of catheter-based treatment in patients with acute DVT and low risk of bleeding complications to prevent PTS. Recent studies favoring interventional therapy have not been included in these guidelines. Data on long-term outcome is expected to be published soon, clarifying and very likely strengthening the role of catheter-based treatments in the management of acute ilio-femoral DVT.

Development and application of health outcome descriptors facilitated decision-making in the production of practice guidelines.

OBJECTIVE: Stakeholders involved in developing recommendations need to have a common understanding of health outcomes and the perspective of affected individuals. In this paper we report on the development and application of health outcome descriptors (HODs) to inform decision-making by panels developing guideline recommendations. STUDY DESIGN AND SETTING: Ten American Society of Hematology guideline panels addressing the management of venous thromboembolism developed HODs, rated their importance and health utility, applied them to prioritize outcomes, and to balance potential benefits and harms to formulate recommendations. RESULTS: It was feasible to involve 18 panelists in developing 127 HODs. There was high agreement (82%) across the ten panels about outcomes perceived as critical or important for decision-making. Panelists' utility ratings of the outcomes were strongly correlated with panelists' outcome importance ratings (Pearson's r=-0.88). HODs were incorporated into Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence-to-decision (EtD) frameworks to support a shared understanding of health outcomes in panel deliberations. CONCLUSION: HODs serve as a valuable tool to promote an explicit, common understanding of health outcomes during clinical guideline development and across different stakeholders. They are helpful across multiple steps of guideline development to facilitate panels' judgements, aiming to avoid variable implicit interpretations of health outcomes.

Pulmonary Embolism in the Intensive Care Unit: Therapy in Subpopulations.

The optimal management of a submassive or massive pulmonary embolism (PE) during pregnancy is unclear because of a lack of large clinical trials. Evaluation of the patient who may be a candidate for more aggressive therapy includes the use of biomarkers and echocardiogram for risk stratification. PE Response teams (PERTs) have gained increasing acceptance by the medical community and are being implemented in hospitals in the United States and worldwide. PERTs bring together a team of specialists from different disciplines to enhance decision-making in the patient with acute submassive and massive PE.

Management of Right Ventricular Failure in Pulmonary Embolism.

Acute right ventricular failure remains the leading cause of mortality associated with acute pulmonary embolism (PE). This article reviews the pathophysiology behind acute right ventricular failure and strategies for managing right ventricular failure in acute PE. Immediate clot reduction via systemic thrombolytics, catheter based procedures, or surgery is always advocated for unstable patients. While waiting to mobilize these resources, it often becomes necessary to support the RV with vasoactive medications. Clinicians should carefully assess volume status and use caution with volume resuscitation. Right ventricular assist devices may have an expanding role in the future.

Clinical Practice and Guidelines for Managing Antithrombotics before and after Endoscopy: A National Survey Study.

Background/Aims: The proper handling of antithrombotics is critical, and this study aimed to assess guideline adherence in the management of antithrombotics before and after endoscopy. Methods: A survey questionnaire was developed. The respondents' demographic information was included, and the questionnaire was divided into the first section for forceps biopsy, the second for polypectomy, and the third for endoscopic submucosal dissection (ESD) in which aspirin, clopidogrel, combination therapy (aspirin and clopidogrel), warfarin, and direct oral anticoagulants (apixaban) were prescribed to imaginary patients. Results: A total of 415 endoscopists completed this survey (response rate of 6.2%, 415/6,673). The percentage of respondents who chose to proceed with biopsy for patients taking aspirin, those taking clopidogrel, those under combination therapy, those taking warfarin, and those taking apixaban was 89.4%, 74.2%, 61.0%, 38.6%, and 50.4%, respectively. Most respondents answered that they would discontinue aspirin, clopidogrel, and a combination of both drugs for 5 days before polypectomy or ESD (69.4%/76.9%, 83.6%/83.9%, and 53.3%/65.8%, respectively). The answers indicated that warfarin should be discontinued with heparin bridge therapy in high thromboembolic risk patients (polypectomy 70.1%, ESD 73.5%). Regarding apixaban use in polypectomy and ESD, 63.9% and 58.1% of respondents, respectively, chose answers consistent with the guidelines. Conclusions: The gap between the guidelines and clinical practice in the management of antithrombotics before and after endoscopy is considerable and should be addressed via educational strategies.

Is intravenous thrombolysis safe for acute ischemic stroke patients taking warfarin with INR 1.9?: A case report.

INTRODUCTION: Intravenous thrombolysis is not suitable for patients undergoing oral anticoagulants therapy, with INR > 1.7 or PT > 15 s. We described a case of intravenous thrombolysis in a patient with INR 1.9. PATIENT CONCERNS: A 66-year-old female patient was diagnosed with acute appendicitis complicated with atrial fibrillation. Seven days after admission, the patient suffered mixed aphasia with right limb asthenia. The NIHSS score was 11 points. and early infarction and hemorrhagic manifestations were not found in the emergency head CT. Thirty minutes after the onset of symptoms, NIHSS of patient increased from 11 to 14, but the INR was 1.92. DIAGNOSIS: Acute ischemic stroke. INTERVENTIONS: The IT therapy was recommended and all the therapy related risks were explained to the patient's parents. Briefly, the patient was given rTPA 38.5 mg. In addition to intravenous thrombolysis, VitK1 40 mg was simultaneously administered. OUTCOME: The patient's symptoms of drowsiness were improved. After 24 hours, all symptoms were stabilized with NIHSS of 2 points, there was a slight language obstruction, and no hemorrhagic transformation in head CT. Three months later, the review showed MRS score of 0, and the patient could take care of herself in daily life. CONCLUSION: The clinical guidelines are still the main reference for guiding clinical practice, and the main thrombolytic standards and contraindications for treatment still need to be conformed. On this basis, for individualized patients, clinicians must accurately judge the cause of acute stroke, to make optimal choice, reduce disability and mortality, and improve quality of life of patients.

Neuroimaging in acute posterior cerebral artery infarction.

BACKGROUND: The role of neuroimaging in acute posterior cerebral artery (PCA) territory infarction is less well appreciated compared with the anterior cerebral circulation because PCA infarction occurs less frequently and more often is associated with limited neurologic deficit not qualifying for thrombolytic therapy. On occasion, however, hemiparesis and/or visual field defect accompanies PCA infarction that would warrant thrombolytic therapy. REVIEW SUMMARY: As neuroimaging plays a central role in the diagnosis and treatment of acute stroke in the thrombolytic era, a series of case studies is presented to illustrate the role of computed tomography and magnetic resonance imaging in the setting of acute PCA infarction. CONCLUSION: Familiarity with the neuroimaging features of acute PCA infarction can facilitate management in those select patients that qualify for thrombolytic therapy.

Prevalence and Clinical Intentions of Antithrombotic Therapy on Discharge to Hospice Care.

BACKGROUND: There are no guidelines for antithrombotic therapy on admission to hospice care. Antithrombotic therapy may offer some benefit in these patients, but is also associated with well-described risks. OBJECTIVE: We quantified the frequency and characteristics of patients prescribed antithrombotic therapy on discharge from acute care to hospice care. DESIGN: Retrospective cohort study. Settings/Subjects: Adult (age> = 21 years) patients discharged from acute care to hospice care between January 1, 2010 and June 30, 2014. MEASURES: Our primary outcome of interest was receiving an outpatient prescription for antithrombotic therapy on discharge to hospice care. RESULTS: Among 1141 eligible patients, 77 (6.7%) patients received a prescription for antithrombotic therapy on discharge to hospice care, most frequently, aspirin (57.1%), enoxaparin (26.0%), and warfarin (20.8%). Patients actively treated for deep vein thromboembolism or pulmonary embolism, or with a history of atrial fibrillation or aortic/mitral valve replacement were significantly more likely to receive antithrombotic therapy. Patients with a history of cancer, cerebrovascular disease, or liver disease were significantly less likely to receive antithrombotic therapy (p < 0.05 for all). Among patients who received antithrombotic therapy, 22% were not receiving antithrombotic therapy before the index admission. Among patients previously receiving antithrombotic therapy, 55% continued on the same medication, of which 54.5% did not have any documented rationale for continuation. CONCLUSIONS: Prescriptions for antithrombotic therapy were infrequent and often lacked a documented rationale. Further research is needed on the safety and effectiveness of antithrombotic therapy in hospice care and what drives current medication decisions in the absence of these data.

The Prophylaxis of Venous Thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is the third most common cardiovascular condition, after myocardial infarction and stroke. Prophylactic measures in accordance with current guidelines can significantly reduce the risk of VTE and the associated morbidity and mortality. Until now, the German interdisciplinary, evidence- and consensus-based (S3) clinical practice guideline on VTE prophylaxis was based on a complete review of all pertinent literature available in MEDLINE up to January 2008. More recent publications and drug approvals have made a thorough revision necessary. METHODS: A systematic search was carried out in the MEDLINE and Embase databases for publications that appeared from 1 January 2008 to 7 August 2013. Updates of 5 national and international reference guidelines and 2 new Health Technology Assessment (HTA) reports were considered as well. A structured consensus-finding process was carried out with delegates from 27 scientific medical societies and from the Union of Medical Specialist Associations. RESULTS: 46 randomized controlled trials (RCTs) were included for critical appraisal. New findings led to re-evaluation of the value of compression stockings in combination with pharmacological prophylaxis (open recommendation), and suggest equal value of non-vitamin K antagonist oral anticoagulants (NOACs) and low molecular weight heparins (LMWH) or fondaparinux in elective hip and knee replacement (strong recommendation). For patients undergoing hip fracture surgery, we recommend LMWH or fondaparinux. CONCLUSION: Further research is needed to assess the value of NOACs for pharmacological prophylaxis in orthopedic/trauma patients undergoing surgical procedures other than the ones mentioned above, and into the benefit and harm of new devices available for mechanical prophylaxis. The stringent implementation of basic measures such as early mobilization, movement exercises, and patient instruction is a key point to prevent venous thrombo - embolism.

Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen.

BACKGROUND: The treatment of patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin sodium therapy is a common clinical problem. We investigated the efficacy and safety of a standardized periprocedural anticoagulation regimen with low-molecular-weight heparin. METHODS: We studied 650 consecutive patients with a mechanical heart valve, chronic atrial fibrillation, or embolic stroke who required interruption of warfarin therapy because of an invasive procedure. Warfarin was stopped 5 or 6 days before the procedure, and patients received subcutaneous dalteparin sodium, 100 IU/kg twice daily, starting 3 days before the procedure. The risk of postprocedural bleeding determined postprocedural anticoagulant management. In patients undergoing a non-high-bleeding-risk procedure who had adequate postprocedural hemostasis, warfarin was resumed on the evening of the procedure, and dalteparin sodium, 100 IU/kg twice daily, was resumed on the next day and continued until the international normalized ratio was 2.0 or more. If postprocedural hemostasis was not secured, the resumption of dalteparin was delayed. In patients undergoing a high-bleeding-risk procedure, warfarin was resumed on the evening of the procedure, but dalteparin was not given after the procedure. RESULTS: Patients were followed up during the preprocedural and postprocedural period for a mean of 13.8 days (range, 10-18 days). In 542 patients who underwent a non-high-bleeding-risk procedure, there were 2 thromboembolic events (0.4%), 4 major bleeding episodes (0.7%), and 32 episodes of increased wound-related blood loss that precluded postprocedural dalteparin administration (5.9%). In 108 patients who underwent a high-bleeding-risk procedure, there were 2 deaths (1.8%) possibly due to thromboembolism and 2 major bleeding episodes (1.8%). CONCLUSIONS: In patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin therapy, a standardized periprocedural anticoagulant regimen with low-molecular-weight heparin is associated with a low risk of thromboembolic and major bleeding complications.

Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis.

BACKGROUND: The benefit-to-risk ratio of vitamin K antagonists (VKA), relative to active comparators, especially low-molecular-weight heparins (LMWH), for preventing venous thromboembolism in patients undergoing major orthopedic surgery is debated. OBJECTIVES: We performed a meta-analysis of all randomized trials in orthopedic surgery comparing adjusted doses of VKA to control treatments. PATIENTS AND METHODS: An exhaustive literature search, both manual and computer-assisted, was performed. Studies were selected on the basis of randomization procedure (VKA vs. a control group). At least one of the following outcome measures was to be evaluated: deep vein thrombosis (DVT), pulmonary embolism (PE), death, major hemorrhage or wound hematoma. Four reviewers assessed each article to determine eligibility for inclusion and outcome measures. RESULTS: VKAs were more effective than placebo or no treatment in reducing DVT [567 patients, relative risk (RR) = 0.56, 95% confidence interval (CI) 0.37, 0.84, P < 0.01] and clinical PE (651 patients, RR = 0.23, 95% CI 0.09, 0.59, P < 0.01). These results were obtained at the cost of a higher rate of wound hematoma (162 patients, RR = 2.91, 95% CI 1.09, 7.75, P = 0.03). VKAs were also more effective than intermittent pneumatic compression (534 patients, RR = 0.46, 95% CI 0.25, 0.82, P = 0.009) in preventing proximal DVT. In contrast, VKAs were less effective than LMWH in preventing total DVT and proximal DVT (9822 patients, RR = 1.51, 95% CI 1.27, 1.79, P < 0.001; and 6131 patients, RR = 1.51, 95% CI 1.04, 2.17, P = 0.028, respectively). The differences between VKA and LMWH in major hemorrhage and wound hematoma were not significant. CONCLUSIONS: In patients undergoing major orthopedic surgery, VKAs are less effective than LMWH, without any significant difference in the bleeding risk.

Anti-GPIIb/IIIa drugs: current strategies and future directions.

Three platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been approved as adjunctive therapy to decrease the ischemic complications of percutaneous coronary interventions (PCI) and/or unstable angina. They include the chimeric murine/human monoclonal antibody 7E3 Fab fragment (abciximab), a cyclic heptapeptide based on the KGD amino acid sequence (eptifibatide), and a nonpeptide mimetic of the RGD sequence (tirofiban). The agents are very effective in providing both short-term and long-term benefit after PCI, and one agent has also demonstrated a progressive long-term mortality benefit. The long-term mortality benefit is highly cost-effective when compared to other medical interventions. The benefits in treating unstable angina without PCI are less dramatic and robust, with some agents providing no benefit. Severe thrombocytopenia is an infrequent, but potentially serious, complication of therapy with all of the agents. The risk of major bleeding is increased only minimally or not at all by the drugs. Currently, a number of new indications for GPIIb/IIIa antagonists are under study, including acute myocardial infarction (+/- thrombolytic therapy, +/- PCI) and stroke. In addition to their impact on improving outcome, the results of clinical trials with these agents provide crucial insights into the contribution of GPIIb/IIIa-mediated platelet function in the pathophysiology of thrombotic vascular disease.

Heparins and venous thromboembolism: current practice and future directions.

Unfractionated heparin (UFH) in adjusted doses and low-molecular-weight heparins (LMWH) in fixed doses are the chosen therapy for the initial treatment of venous thromboembolism. The use of UFH protocols ensures that virtually all patients will promptly achieve the therapeutic range for the activated partial thromboplastin time. However, proper use of UFH requires considerable expertise, can cause inconvenience and has limitations. Unmonitored therapy with subcutaneous LMWH is at least as effective and safe as adjusted-dose UFH, is associated with a considerable reduction of mortality in cancer patients, and permits the treatment of suitable patients in an outpatient setting. LMWH in high prophylactic doses is more effective than UFH and oral anticoagulants for prevention of postoperative venous thrombosis in major orthopedic surgery. Whether thromboprophylaxis should be continued for a few additional weeks after hospital discharge is controversial. LMWH and UFH are equally effective for prevention of postoperative deep-vein thrombosis in cancer patients. In a recent controlled randomized trial, enoxaparin in high prophylactic doses was an effective and safe measure of thromboprophylaxis in ordinary bedridden patients. The efficacy and safety of pentasaccharide (the smallest antithrombin binding sequence of heparin) in the treatment and prevention of venous thromboembolic disorders is currently under investigation.

The role of low-molecular-weight heparins in arterial diseases: optimizing antithrombotic therapy.

On the basis of current evidence, all patients with acute coronary syndromes should receive optimized medical therapy, whether or not they ultimately undergo an invasive revascularization procedure, to improve both clinical outcomes and cost effectiveness. While standard aspirin and unfractionated heparin (UFH) have improved short-term outcomes, they do not eliminate the risk of recurrent ischemic episodes. The recent introduction of platelet fibrinogen receptor antagonists and low-molecular-weight heparins (LMWHs) has offered an opportunity to develop more aggressive antithrombotic regimens. The LMWHs have been thoroughly evaluated in unstable angina and non-Q wave myocardial infarction (UA/NQMI), and have demonstrated improved efficacy compared to standard UFH, without an increase in major complications caused by bleeding. Experience has also been gathered using LMWHs in other arterial diseases (such as pregnant patients with prosthetic heart valves) and as an adjunctive therapy with thrombolytics for acute myocardial infarction. Lastly, studies are currently underway evaluating LMWHs in patients with atrial fibrillation.