Era Of Trials Research Articles

Comparison of New Glucose-Lowering Drugs on Risk of Heart Failure in Type 2 Diabetes: A Network Meta-Analysis

ObjectivesThe authors conducted a systematic review and network meta-analysis of placebo-controlled, randomized clinical trials in the post–Food and Drug Administration (FDA) guidance era to formally compare the effects of 3 new classes of glucose-lowering drugs on hospitalization for heart failure (HF) in type 2 diabetes mellitus. BackgroundThe 2008 FDA Guidance for Industry launched an era of cardiovascular outcome trials for new glucose-lowering drugs in T2DM, including glucagon-like peptide (GLP)-1 agonists, dipeptidyl peptidase (DPP)-4 inhibitors, and sodium glucose co-transporter (SGLT)-2 inhibitors. MethodsWe searched Embase, PubMed, Cochrane Library, and clinicaltrials.gov between December 1, 2008, and November 24, 2017, for randomized placebo-controlled trials, and performed network meta-analyses by Bayesian approach using Markov-chain Monte Carlo simulation method to compare the effects of glucose-lowering drugs on risk of HF hospitalization and estimate the probability that each treatment is the most effective. ResultsNine studies were identified, yielding data on 87,162 participants. In the network meta-analysis, SGLT-2 inhibitors yielded the greatest risk reduction for HF hospitalization compared with placebo (relative risk [RR]: 0.56; 95% CrI [credibility interval]: 0.43 to 0.72). Moreover, SGLT-2 inhibitors were associated with significant risk reduction in pairwise comparisons with both GLP-1 agonists (RR: 0.59; 95% CrI: 0.43 to 0.79) and DPP-4 inhibitors (RR: 0.50; 95% CrI: 0.36 to 0.70). Ranking of the classes revealed 99.6% probability of SGLT-2 inhibitors being the optimal treatment for reducing the risk of this outcome, followed by GLP-1 agonists (0.27%) and DPP-4 inhibitors (0.1%). ConclusionsCurrent evidence suggests that SGLT-2 inhibitors are more effective than either GLP-1 agonists or DPP-4 inhibitors for reducing the risk of hospitalization for HF in type 2 diabetes mellitus.

Lung volume reduction surgery in the post-National Emphysema Treatment Trial era.

Lung volume reduction surgery (LVRS) as means to improve the pulmonary function and quality of life of patients with chronic obstructive pulmonary disease (COPD) can be traced back to the 1950's and early work by Otto Brantigan. Joel Cooper revived this concept with pioneering work in the 1990's. His work, along with others, led to the National Emphysema Treatment Trial (NETT) which demonstrated a quality of life and survival benefit for certain subsets of patients with emphysema. While the outcomes of carefully selected patients are excellent, with proven benefits in both quality of life and overall survival, the volume of LVRS being performed remains low. The procedure is highly regulated in the United States and is only performed in Centers for Medicare and Medicaid Services (CMS) approved programs. Programs are required to follow the NETT selection criteria. The program at Columbia University Medical Center/New York Presbyterian Hospital remains active. Utilizing the NETT criteria, we continue to perform LVRS with no operative mortality and excellent long-term outcomes.

Intraoperative Aneurysm Rupture During Microsurgical Clipping: Risk Re-evaluation in the Post–International Subarachnoid Aneurysm Trial Era

Intraoperative aneurysm rupture (IOAR) is a common complication during intracranial aneurysm (IA) surgery. In light of the paradigm shift regarding IA selected for clipping in the post-International Subarachnoid Aneurysm Trial (ISAT) era, we aimed to evaluate the risk factors and effects of IOAR in an institutional series of clipped ruptured IA (RIA) and unruptured IA (UIA). All IAs treated with microsurgical clipping at our institution between 2003 and 2016 were eligible for this study. Demographic, clinical, and radiographic factors were correlated with occurrence of IOAR in univariate and multivariate analyses. The effect on outcome was analyzed for RIA and UIA separately. Nine hundred and three clipped IAs were included in the final analysis (538 UIA and 365 RIA). IOAR occurred in 163 cases (18.1%), mostly during clipping of RIA (37.5% vs. 4.8%) In multivariate analysis, ruptured status (adjusted odds ratio [aOR], 10.46; P < 0.001), sack size (aOR, 1.05 per mm increase; P= 0.038) and IA location in the anterior communicating artery (aOR, 2.31; P < 0.001) independently predicted IOAR. For RIA cases, IOAR was also independently predicted by rebleeding before therapy (aOR, 3.11; P= 0.033) and clinical severity of subarachnoid hemorrhage (aOR, 1.18 per WFNS grade increase; P= 0.049). IOAR independently predicted poor outcome (aOR, 1.83; P= 0.042) after RIA surgery. In turn, IOAR affected only the risk for cerebral infarct (OR, 3.75; P= 0.003) and incomplete IA occlusion (OR, 3.45; P= 0.003) for UIA cases, but not the outcome (P= 0.263). IOAR was independently predicted by the ruptured status, location, and size of IA and by initial severity of aneurysmal bleeding and pretreatment rebleeding. The influence of IOAR differed between RIA and UIA cases.

Multivariable and Bayesian Network Analysis of Outcome Predictors in Acute Aneurysmal Subarachnoid Hemorrhage: Review of a Pure Surgical Series in the Post-International Subarachnoid Aneurysm Trial Era.

BACKGROUNDFollowing the International Subarachnoid Aneurysm Trial (ISAT), evolving treatment modalities for acute aneurysmal subarachnoid hemorrhage (aSAH) has changed the case mix of patients undergoing urgent surgical clipping.OBJECTIVETo update our knowledge on outcome predictors by analyzing admission parameters in a pure surgical series using variable importance ranking and machine learning.METHODSWe reviewed a single surgeon's case series of 226 patients suffering from aSAH treated with urgent surgical clipping. Predictions were made using logistic regression models, and predictive performance was assessed using areas under the receiver operating curve (AUC). We established variable importance ranking using partial Nagelkerke R2 scores. Probabilistic associations between variables were depicted using Bayesian networks, a method of machine learning.RESULTSImportance ranking showed that World Federation of Neurosurgical Societies (WFNS) grade and age were the most influential outcome prognosticators. Inclusion of only these 2 predictors was sufficient to maintain model performance compared to when all variables were considered (AUC = 0.8222, 95% confidence interval (CI): 0.7646-0.88 vs 0.8218, 95% CI: 0.7616-0.8821, respectively, DeLong's P = .992). Bayesian networks showed that age and WFNS grade were associated with several variables such as laboratory results and cardiorespiratory parameters.CONCLUSIONOur study is the first to report early outcomes and formal predictor importance ranking following aSAH in a post-ISAT surgical case series. Models showed good predictive power with fewer relevant predictors than in similar size series. Bayesian networks proved to be a powerful tool in visualizing the widespread association of the 2 key predictors with admission variables, explaining their importance and demonstrating the potential for hypothesis generation.

HPV-relatedness definitions for classifying HPV-related oropharyngeal cancer patient do impact on TNM classification and patients’ survival

BackgroundGiven the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8th edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value.Material and methodsThe aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7th edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16INK4a or HPV-mRNA), p16INK4a positivity alone or the combination of HPV-DNA/p16INK4a positivity as diagnostic tests.ResultsA total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16INK4a or HPV-mRNA), 83 (10.5%) were p16INK4a positive and 58 (7.4%) were double positive for HPV-DNA/p16INK4a. ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16INK4a-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria.ConclusionHPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients’ survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials.

Preoperative predictors of high and low axillary nodal burden in Z0011 eligible breast cancer patients with a positive lymph node needle biopsy result

BackgroundZ0011 trial showed that early breast cancer patients with low axillary nodal burden, may be spared an axillary lymph node dissection with no survival compromise. Axillary lymph node dissection can be reserved for patients with a high axillary nodal burden. We aim to determine the preoperative factors that could distinguish between low and high axillary nodal burden in Z0011 eligible patients with a needle biopsy proven metastatic node. MethodPatients who fulfilled Z0011 trial criteria with a positive lymph node needle biopsy and had axillary lymph node dissection (ALND) were recruited. These patients were classified into low and high nodal burden subgroups, defined as having 1–2 and ≥3 metastatic lymph nodes, respectively. The clinical, radiological and pathological features between the 2 subgroups were compared. Results70 (40%) and 105 (60%) patients had low and high nodal burden respectively. The high nodal burden subgroup was more likely to have on ultrasound ≥3 abnormal lymph nodes (37.14% versus 4.29%) (P < 0.0001) and maximum cortical thickness >4 mm (31.43% versus 10.0%) (P = 0.0036). Multivariate analysis revealed abnormal lymph nodes ≥3 to have an odds ratio of 20.72 (95% CI 5.91–72.65) P < 0.0001. Conclusion≥3 abnormal lymph nodes on ultrasound was the most significant predictor of high nodal burden subgroup in Z0011 eligible patients with a positive lymph node needle biopsy. This information could allow this subgroup to proceed to an upfront ALND and avoid the need of a sentinel lymph node biopsy in the post Z0011 trial era.

Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system.

Cardiotoxic effects of chemotherapy and targeted drugs are ubiquitous and challenging in the field of oncology therapeutics. The broad spectrum of toxicities ranging from ischemic, hypertensive, cardiomyopathic, and arrhythmic complications can present as a significant challenge for clinicians treating cancer patients. If early diagnosis and intervention of cardiotoxic complications is missed, this can lead to delay or abrogation of planned treatment, which can potentially culminate to significant morbidity due to not only the cardiotoxic complications but also the progression of cancer. Hence, full knowledge of cardiovascular complications of chemotherapeutic agents, essential diagnostics tests to order, and appropriate management is paramount to oncologist, oncology pharmacists, and scientific clinical investigators. The aforementioned is particularly true in the current oncology era of plenteous early clinical trials studying several pathway/molecular-targeting agents with an increased cardiotoxic potential and the rapid expedited approval of those drugs by the FDA. Herein, we present a review discussing cardiotoxic effects of drugs and guidelines for management of the toxicities to assist the medical field in general managing patients with cancer.

263 (PB-058) - Preoperative predictors of high and low axillary nodal burden in Z0011 eligible breast cancer patients with a positive lymph node needle biopsy result

Abstract Background Z0011 trial showed that early breast cancer patients with low axillary nodal burden, may be spared an axillary lymph node dissection with no survival compromise. Axillary lymph node dissection can be reserved for patients with a high axillary nodal burden. We aim to determine the preoperative factors that could distinguish between low and high axillary nodal burden in Z0011 eligible patients with a needle biopsy proven metastatic node. Method Patients who fulfilled Z0011 trial criteria with a positive lymph node needle biopsy and had axillary lymph node dissection (ALND) were recruited. These patients were classified into low and high nodal burden subgroups, defined as having 1–2 and ≥3 metastatic lymph nodes, respectively. The clinical, radiological and pathological features between the 2 subgroups were compared. Results 70 (40%) and 105 (60%) patients had low and high nodal burden respectively. The high nodal burden subgroup was more likely to have on ultrasound ≥3 abnormal lymph nodes (37.14% versus 4.29%) (P 4 mm (31.43% versus 10.0%) (P = 0.0036). Multivariate analysis revealed abnormal lymph nodes ≥3 to have an odds ratio of 20.72 (95% CI 5.91–72.65) P Conclusion ≥3 abnormal lymph nodes on ultrasound was the most significant predictor of high nodal burden subgroup in Z0011 eligible patients with a positive lymph node needle biopsy. This information could allow this subgroup to proceed to an upfront ALND and avoid the need of a sentinel lymph node biopsy in the post Z0011 trial era.

The practical use of acetylsalicylic acid in the era of the ASPRE trial. Update and literature review.

It is now well established that acetylsalicylic acid - one of the most widely prescribed drugs today - has brought a new era in maternal-fetal medicine. The History of medicine mentions several antecedents. Extracts made from willow contained in clay tablets are reported in both ancient Sumer and Egypt. In 400 BC, Hippocrates referred to the use of salicylic tea to reduce fevers. In the 1950s, acetylsalicylic acid entered the Guinness Book of Records as the highest selling painkiller. There is little doubt that acetylsalicylic acid - one of the first drugs to enter common usage - remains one of the most researched drugs in the world.

Disparate compensation policies for research related injury in an era of multinational trials: a case study of Brazil, Russia, India, China and South Africa

BackgroundCompensation for research related injuries is a subject that is increasingly gaining traction in developing countries which are burgeoning destinations of multi center research. However, the existence of disparate compensation rules violates the ethical principle of fairness. The current paper presents a comparison of the policies of Brazil, Russia, India, China and South Africa (BRICS).MethodsA systematic search of good clinical practice guidelines was conducted employing search strategies modeled in line with the recommendations of ADPTE Collaboration (2007). The search focused on three main areas namely bibliographic data bases, clinical practice guidelines data bases and a restricted internet search. A manual search of references cited in relevant guideline documents was also conducted. The search terms, Medical Subject Headings (MeSH) and key words were developed for a PubMed platform and then adapted for all other data bases. The search terms were kept constant for each country with the only difference being the country name. The documents so obtained were subjected to systematic content analysis.ResultsThe study revealed that there is vast panoply of regulations which exist on a continuum. On one extreme is India with comprehensive regulations that are codified into law, and on the other end there is China which does not have specific laws regulating research related injuries. There are a number of differences and similarities such as mandatory insurance requirements, existence of no fault compensation, compensable injuries and the role of research ethics committees.ConclusionsIt is imperative to enact legislations that protect participants without stifling the research enterprise. There is need for consistency and ideally harmonization of such regulations at a global level. A model policy on compensation for research related injuries should borrow from the best aspects of the different country policies and should be informed by the cardinal ethics principles of autonomy, justice and beneficence.

Preoperative Axillary Ultrasound in the Selection of Patients With a Heavy Axillary Tumor Burden in Early-Stage Breast Cancer: What Leads to False-Positive Results?

To determine whether imaging and clinicopathologic features could predict false-positive axillary ultrasound (US) results in the selection of patients with breast cancer who had a heavy axillary tumor burden (≥3 tumor-involved nodes). Among 788 patients with histologically confirmed invasive breast cancer at Ruijin Hospital from October 2014 to September 2015, 162 patients (cT1-T2, cN0) with 167 axillae had suspicious axillary US findings. Ultrasound findings were considered suspicious for metastasis if cortical thickening of greater than 3 mm or effacement of the fatty hilum was present. The false-positive rate of suspicious axillary US results for identifying 3 or more positive lymph nodes in the final pathologic examination was calculated. Univariate and multivariate analyses were used to evaluate imaging and clinicopathologic factors related to the false-positive results. Axillary US showed a false-positive rate of 60.5% (101 of 167) in the patients with breast cancer and a heavy nodal burden. By logistic regression analyses, we found false-positive axillary US results more frequently in patients who had a T1 stage tumor (P = .005), an estrogen receptor/progesterone receptor-negative tumor (P < .001), solitary suspicious nodes identified on axillary US (P < .001), and a cortical thickness of the most suspicious lymph node of 3.5 mm or less (P = .015). Imaging and clinicopathologic features can be used to identify axillae with less than 3 metastatic nodes in patients with early-stage breast cancer who have positive axillary US results. In the post-American College of Surgeons Oncology Group Z0011 trial era, conducting a secondary evaluation either clinically or by axillary imaging before the use of a US-guided biopsy of suspicious nodes can potentially avoid the additional morbidity of axillary lymph node dissection and reduce the preoperative workload.

Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug-Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients.

Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated.Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added.Results: A potential clinically relevant 22% (95% CI, 9%-34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0-24h of cabazitaxel was 181 ng*h/mL (95% CI, 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209-261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising.Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541-6. ©2017 AACR.

Abstract 109: Trevo 2000: Results of the Largest Real-World Registry for Stent Retriever for Acute Ischemic Stroke

Objective: The Trevo Registry was designed to assess real world outcomes of the Trevo Retriever in patients experiencing ischemic stroke. It is the largest prospective study for acute stroke intervention, with 2010 patients enrolled and 90 day outcomes in 1873 patients. The primary endpoint is revascularization status based on post-procedure TICI score and secondary endpoints include 90-day mRS, 90-day mortality, neurological deterioration at 24 hours and device/procedure related adverse events. Methods: The study was a prospective, open-label, consecutive enrollment, multi-center, international registry of patients who underwent mechanical thrombectomy for acute stroke using the Trevo stent retriever as the initial device. Results: The median NIHSS at admission was 16 (IQR 11-20). Most patients (70.8%) were treated at &lt;= 6 hours from last known normal with a median procedure time of 50 minutes (32-77). The occlusion site was M1 or M2 in 73.9%. General anesthesia was employed in 43.5% of procedures. TICI 2b or 3 revascularization was 92.8% with an average of 1.7 passes with the device. Median NIHSS at 24 hours and discharge was 6 and 4 respectively. Fifty-five percent (55.2%) of patients had mRS ≤2 at 3 months and the overall mortality rate was 13.8%. Patients treated after 8 hours of symptom onset had a 95% revascularization rate and 51.2% mRS ≤2 at 3 months. The symptomatic ICH rate was 1.6%. Patients who met the revised AHA criteria for thrombectomy were found to have 59.5% mRS 0-2 at 90 days. Conclusions: The Trevo Retriever Registry represents the first real world data with stent retriever use in the era of clinical trials showing the overwhelming benefit of stent retrievers to treat acute ischemic stroke. Due to the fact that this data represents real world use of the Trevo Retriever, (e.g. subjects pre-stroke mRS &gt;1 (29%) and those treated 6-24 hours after stroke symptoms (29%), this data cannot be compared to the results from recent trials with restricted eligibility criteria. Future subgroup analysis of this large cohort will help to identify areas of future research to enhance outcomes further with this treatment modality.

Present Status and Perspectives on Future Roles of Japanese Clinical Research Coordinators.

BackgroundThe new Clinical Trials Act that recently came into effect in Japan emphasizes the reliability of investigator-initiated clinical trials. Although Japanese clinical research coordinators have been mainly engaged in operational roles in industry-initiated clinical trials for drug approval (registration trials), broadening their contribution to cover more types of clinical research may lead to quality improvement of clinical research. To ultimately establish a clinical research infrastructure that meets the needs of the new era of Clinical Trials Act, here we gathered basic information on how clinical research coordinators might make such contributions.MethodsWe conducted a survey using self-reporting questionnaires in clinical research-related personnel to examine present status and the perspectives toward broader contribution of clinical research coordinators. The study participants were attendee of group discussion of a clinical research-related meeting in Shikoku area of Japan held in August 2017.ResultsAmong 88 participants, 69 responded (response rate: 78.4%) and 68 respondents (98.6%) were engaged in support and management of clinical research. The main area of involvement was industry-initiated registration trials (48, 69.7%), and main roles of involvement were cooperators who plays roles under the guidance of investigators (41, 59.5%). When divided by occupation into clinical research coordinators (n = 41) and other clinical research-related personnel (n = 28), approximately half of the respondents in each group replied positively to wanting broader involvement of clinical research coordinators as a clinical research professional.ConclusionThe present study revealed that about half of the clinical research coordinators and other clinical research-related personnel view a broadening of involvement of clinical research coordinators in research activities positively. Accordingly, a structured practical program aimed at encouraging such involvement may help to expand and strengthen their contribution into the future. Whether greater involvement of clinical research coordinators in clinical research will help to ensure the reliability of investigator-initiated clinical research warrants further study.

The role of Imaging and Radiation Oncology Core for precision medicine era of clinical trial.

Imaging and Radiation Oncology Core (IROC) services have been established for the quality assurance (QA) of imaging and radiotherapy (RT) for NCI's Clinical Trial Network (NCTN) for any trials that contain imaging or RT. The randomized clinical trial is the gold standard for evidence-based medicine. QA ensures data quality, preventing noise from inferior treatments obscuring clinical trial outcome. QA is also found to be cost-effective. IROC has made great progress in multi-institution standardization and is expected to lead QA standardization, QA science in imaging and RT and to advance quality data analysis with big data in the future. The QA in the era of precision medicine is of paramount importance, when individualized decision making may depend on the quality and accuracy of RT and imaging.

369 The TREVO Registry-Subgroup Analysis, Treatment Beyond 6 Hours

Abstract INTRODUCTION Current randomized trials demonstrating superiority of mechanical thrombectomy for the treatment of acute ischemic stroke for anterior circulation large vessel occlusion, have enrolled patients with symptom onset up to 6 hours. Outcomes of thrombectomy beyond 6 hours have not been well studied. The Trevo Registry is designed to assess real world outcomes of the Trevo Retriever in patients experiencing acute ischemic stroke. Trevo registry has currently enrolled 1431 patients with 90-day outcome data. Outcomes of patients treated beyond 6 hours of symptom onset were studied. METHODS The study design is a prospective, open-label, consecutive enrollment, multi-center, global registry of all patients who undergo mechanical thrombectomy for acute stroke using the Trevo stent retriever as the initial device. Enrollment is expected to reach 2000 subjects at up to 100 sites. Subgroup analysis of enrolled patients treated beyond 6 hours of symptom onset and with 90-day follow-up was performed. RESULTS &gt;As of March 24, 2017, a total of 1846 total patients were enrolled. Median NIHSS at admission was 15.5 (IQR 11–20). The majority of patients (67.4%) were treated at 6 hours or less from last known normal with a median procedure time of 50 minutes (8-286 minutes). In patients treated after 6 hours from time last known well, the revascularization rate was 93.7% with symptomatic ICH of 1.8% and 90-day mRS = 2 was 51.8%. Subgroup analysis of patients presenting within 6 hours and those presenting beyond 6 hours showed no significant difference in patient demographics or medical comorbidities. There was no difference in complication rate or 90-day outcome between the two groups. CONCLUSION The Trevo Retriever Registry represents the first look at real world data with stent retriever use in the era of clinical trials showing the overwhelming benefit of stent retrievers to treat acute ischemic stroke. This data represents real world use of the Trevo Retriever including those treated beyond 6 hours after stroke symptoms (33.8%), and this data adds to the results from recent trials with restricted eligibility criteria.

Intra-Arterial Alteplase Thrombolysis during Mechanical Thrombectomy for Acute Ischemic Stroke

Intra-arterial alteplase (IA tPA) is commonly used during mechanical thrombectomy for acute ischemic stroke in patients with large-vessel occlusion, but specific indications and applications for its use remain undefined. We analyzed 40 patients who underwent stent-retriever mechanical thrombectomy, 28 of whom received adjunctive IA tPA. To our knowledge, this is the largest cohort with this concomitant treatment reported in the literature in the post-mechanical thrombectomy trial era. Between patients with and without IA tPA, rates of hemorrhagic conversion, neurologic outcome, and mortality were equivalent, with a trend toward improved angiographic revascularization observed in the IA tPA group. IA tPA is a safe adjunct to mechanical thrombectomy, and more investigation is warranted to understand ideal indications and dosage methodologies.

VISUOMOTOR INTEGRATION IN PRESYMPTOMATIC FAMILIAL ALZHEIMER’S DISEASE

As we enter an era of prevention trials for Alzheimer's disease (AD), it is vital to have sensitive cognitive tests that can identify and track subtle cognitive decline in preclinical AD. A circle-tracing task has identified visuomotor integration deficits in presymptomatic mutation carriers for Huntington's disease. As there is some evidence that visuomotor integration is impaired in early AD, we tested for similar deficits in presymptomatic individuals carrying mutations for autosomal dominant familial AD (FAD). Thirty-one participants at risk of FAD were recruited: 19 presymptomatic mutation carriers (MC) and 12 non-carriers (NC). MC were on average 7.0 years from expected symptom onset and were well matched with NC for mean age and performance on standard cognitive tests (Table). Participants completed 12 45-second circle-tracing trials, half with serial-subtraction, using a stylus to trace as quickly and accurately as possible round an annulus on a tablet screen. Six trials were ‘direct’: participants could see their arm and their tracing path on the tablet. Six trials were ‘indirect’: the participant's arm was covered by a box, but they could view a copy of the annulus and their tracing path on a monitor positioned behind the tablet (Figure 1). Outcome variables were tracing speed (number of rotations) and error rate (number of deviations outside the annulus per rotation). GEE models were used to compare outcomes between groups after adjustment for age, gender and education. As expected, the indirect condition was more difficult than the direct condition, with slower tracing (p<0.001) and higher error rates (p<0.01). There was no evidence of an interaction between mutation status and task condition. Across both conditions, MC made more errors than NC (difference=0.297 (95% CI 0.062–0.532), p=0.013) (Figure 2); there was no significant difference in tracing speed. Within MC, error rate did not correlate with years to expected onset. Subtle deficits in visuomotor integration are an early feature of cognitive decline that can be detected in presymptomatic FAD. These deficits may appear at a similarly early stage to subtle memory decline. Computerised tasks measuring visuomotor integration may be suitable outcome measures in AD prevention trials. Set-up of the circle-tracing task (reprinted from Figure 1A in Say et al., Visuomotor integration deficits precede clinical onset in Huntington's disease. Neuropsychologia 2011, Vol. 49, No. 2, 264–270, Elsevier). In the indirect condition the participant's arm was covered by a box, not shown here. Comparison of mutation carriers and non-carriers for speed and accuracy on the Direct and Indirect conditions of the circle-tracing task. Error bars show 95% confidence intervals for the mean. Asterisk shows significant difference between the groups.

National Patterns of Carotid Revascularization in the Pre- and Post- Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) Era (S36.001)

National Patterns of Carotid Revascularization in the Pre- and Post- Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) Era (S36.001)

Implantable cardioverter defibrillator use for primary prevention in ischaemic and non-ischaemic heart disease-indications in the post-DANISH trial era: results of the European Heart Rhythm Association survey.

Implantable cardioverter-defibrillator (ICD) is the standard of care for prevention of sudden cardiac death (SCD) in high-risk patients. For primary prevention of SCD, in patients with ischaemic heart disease, there is more robust data on the effect of ICD therapy compared with patients with non-ischaemic heart disease, but current real-life practice may differ substantially. The aim of this European Heart Rhythm Association survey was to evaluate the clinical practice regarding implantation of ICD for primary prevention among European countries in patients with non-ischaemic and ischaemic heart disease. Furthermore, we wanted to investigate the impact of the results of the recently published DANISH trial on clinical practice among European countries. In total, 48 centres from 17 different countries responded to the questionnaire. The majority did not implant ICD for primary prevention on a regular basis in patients with non-ischaemic heart disease despite current guidelines. Also, centres have changed their indications after the recent report on the efficacy of ICD in these patients. In patients with ischaemic heart disease, the guidelines for primary prevention ICD were followed on a regular basis, and no relevant change in indications were reported.