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data safety monitoring board [keywords]
- Adjudication-related processes are underreported and lack standardization in clinical trials of venous thromboembolism: a systematic review. [JOURNAL ARTICLE]
- J Clin Epidemiol 2013 Nov 27.
Although the use of an adjudication committee (AC) for outcomes is recommended in randomized controlled trials, there are limited data on the process of adjudication. We therefore aimed to assess whether the reporting of the adjudication process in venous thromboembolism (VTE) trials meets existing quality standards and which characteristics of trials influence the use of an AC.We systematically searched MEDLINE and the Cochrane Library from January 1, 2003, to June 1, 2012, for randomized controlled trials on VTE. We abstracted information about characteristics and quality of trials and reporting of adjudication processes. We used stepwise backward logistic regression model to identify trial characteristics independently associated with the use of an AC.We included 161 trials. Of these, 68.9% (111 of 161) reported the use of an AC. Overall, 99.1% (110 of 111) of trials with an AC used independent or blinded ACs, 14.4% (16 of 111) reported how the adjudication decision was reached within the AC, and 4.5% (5 of 111) reported on whether the reliability of adjudication was assessed. In multivariate analyses, multicenter trials [odds ratio (OR), 8.6; 95% confidence interval (CI): 2.7, 27.8], use of a data safety-monitoring board (OR, 3.7; 95% CI: 1.2, 11.6), and VTE as the primary outcome (OR, 5.7; 95% CI: 1.7, 19.4) were associated with the use of an AC. Trials without random allocation concealment (OR, 0.3; 95% CI: 0.1, 0.8) and open-label trials (OR, 0.3; 95% CI: 0.1, 1.0) were less likely to report an AC.Recommended processes of adjudication are underreported and lack standardization in VTE-related clinical trials. The use of an AC varies substantially by trial characteristics.
- Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. [JOURNAL ARTICLE]
- Lancet 2013 Nov 19.
The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy.Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181.Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management.The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up.National Institutes of Health, National Institute of Neurological Disorders and Stroke.
- A computerized system to diagnose and treat neonatal apnea using vibrotactile stimulation. [Journal Article]
- Conn Med 2013 Oct; 77(9):517-22.
To develop an appropriate apparatus for monitoring physiological signals and offering noninvasive automated mechanical stimulations for interrupting apneic events in neonates.Vibrotactile stimulation (VTS) maybe an effective, safer alternative to nursing hand stimulation in treating neonatal apnea. We therefore developed a new diagnostic and therapeutic instrument.The main components of the system are a computer running Windows XP using an AMD Athlon TM 64 processor, a neonatal physiological monitor (Model 511; CAS Medical Inc. in Branford, CT), a connector board, cable and data acquisition card (DAQ6602E), an amplifier, external lights, a tacaid vibrotactile stimulator (Audiological Engineering, Somerville, MA and a software application Labview 7.1, National Semiconductor Corporation). The device is a proof of concept at this point and has not undergone testing on neonatal patients. We have tested its ability to identify apneic events and appropriately administering vibrotactile stimulation on a 12-year-old boy with 10 simulated apnea events.Our device functioned 100% in (1) identification of "true apnea," (2) immediate VTS function, (3) accurate monitoring, and (4) safety.Our evaluation of this system demonstrates that under simulated conditions, pauses in breathing with associated decreased oxygen levels and heart rate are identified. This new medical device has potential to diagnose and treat neonatal apnea effectively and improve the quality of care.
- Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome: The VISTA-16 Randomized Clinical Trial. [JOURNAL ARTICLE]
- JAMA 2013 Nov 18.
IMPORTANCE Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE To determine the effects of sPLA2 inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES The primary efficacy measure was a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95% CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95% CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01130246.
- Interview: Data acquisition, tumor heterogeneity and precision medicine: future challenges for oncologic comparative effectiveness research. [Journal Article]
- J Comp Eff Res 2013 Jan; 2(1):17-21.
Al B Benson 3rd, MD, FACP, is a Professor of Medicine in the Division of Hematology/Oncology at Northwestern University's Feinberg School of Medicine in Chicago (IL, USA). He is also the Associate Director for Clinical Investigations for the Robert H Lurie Comprehensive Cancer Center. Benson earned his medical degree at the State University of New York at Buffalo, following which he completed an Internal Medicine Residency at the University of Wisconsin Hospitals in Madison (WI, USA). He was an Assistant Professor of Medicine at the University of Illinois and Co-Medical Director for the National Public Health Service in Champaign (IL, USA). He then served as a Clinical Oncology Fellow at the University of Wisconsin Clinical Cancer Center. Benson is a recipient of the American Society of Clinical Oncology (ASCO) Statesman Award (Fellow of ASCO). He has been a member of the ASCO Task Force on Quality of Cancer Care, the Co-Chair of ASCO's Stage II Colon Cancer Guidelines Panel and the Guidelines Panel for use of Radiofrequency Ablation for Colorectal Cancer Hepatic Metastases. He also is the Chair of both the Eastern Cooperative Oncology Group Gastrointestinal and Data Monitoring Committees. In addition, he is a past President of the Illinois Medical Oncology Society, past President for the Association of Community Cancer Centers, and a member of the Executive Committee and immediate past-chair of the Board of Directors of the National Comprehensive Cancer Network (NCCN). He is a member of the Board of the NCCN Foundation and ECOG Research and Education Foundation. He is the past President of the International Society of GI Oncology. Benson is a member of the Scientific Board of Directors of the Patient Advocate Foundation, the National Patient Advocate Foundation, Fight Colorectal Cancer and Friends of Cancer Research. Benson's research is primarily in the areas of gastrointestinal cancer clinical trials and cancer guideline development. Benson is an associate editor of the Journal of Comparative Effectiveness Research.
- ST Elevation Myocardial Infarction Treated by RADIAL or Femoral Approach in a Multicenter Randomized Clinical Trial : The STEMI-RADIAL Trial. [JOURNAL ARTICLE]
- J Am Coll Cardiol 2013 Nov 6.
To compare radial and femoral approaches in patients presenting with ST-elevation myocardial infarction (STEMI) and undergoing primary percutaneous coronary intervention (PCI) by high-volume operators experienced in both access-sites.The exact clinical benefit of the radial compared to the femoral approach remains controversial.STEMI-RADIAL (ST Elevation Myocardial Infarction treated by RADIAL or femoral approach) was a randomized, multicenter trial. Seven hundred and seven patients referred for STEMI < 12 hours of symptom onset were randomized in 4 high-volume radial centers. The primary endpoint was the cumulative incidence of major bleeding and vascular access site complications at 30 days. The rate of net adverse clinical events (NACE) was defined as a composite of death, myocardial infarction, stroke and major bleeding/vascular complications. Access site crossover, contrast volume, duration of intensive care stay and death at 6 months were secondary endpoints.The primary endpoint occurred in 1.4% in the radial group (n=348) and 7.2% in the femoral group (n=359), (p=0.0001). The NACE rate was 4.6% vs. 11.0% (p=0.0028), respectively. Crossover from radial to femoral approach was 3.7%. Intensive care stay was significantly reduced in the radial group (2.5±1.7 vs. 3.0±2.9 days, p=0.0038) as well as contrast utilization (170±71 vs. 182±60 ml, p=0.01). Mortality in the radial and femoral groups was 2.3% vs. 3.1% (p= 0.64) at 30 days, and 2.3% vs. 3.6% (p=0.31) at 6 months, respectively.In patients with STEMI undergoing primary PCI by operators experienced in both access-sites, the radial approach was associated with significantly lower incidence of major bleeding and access site complications and superior net clinical benefit. These findings support the use of the radial approach in primary PCI as first choice after proper training.clinicaltrials.gov Identifier: NCT01136187.
- Cardiac rhythm device surgery with uninterrupted oral anticoagulation. [Journal Article]
- Future Cardiol 2013 Nov; 9(6):763-6.
Evaluation of: Birnie DH, Healey JS, Wells GA et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N. Engl. J. Med. 368, 2084-2093 (2013). Current guidelines recommend interrupting anticoagulation and bridging therapy with heparin or low-molecular-weight heparin for cardiac rhythm device surgeries in patients with high thrombotic risk. However, there are some studies that suggest continuing warfarin may be safe. The study by Birnie et al. investigates this important clinical question in a randomized controlled trial setting. They randomly assigned 681 patients with high thrombotic risk (5% or more per year), in 18 centers, to receive either stopping warfarin combined with heparin bridging (standard of care) or continued uninterrupted warfarin therapy for cardiac rhythm device surgery. The trial was terminated after a second prespecified interim analysis by the data and safety monitoring board. Clinically significant device-pocket hematoma was noted in 12 out of 343 patients (3.5%) in the uninterrupted warfarin group, compared with 54 out of 338 (16.0%) in the heparin-bridging group (relative risk: 0.19; 95% CI: 0.10-0.36; p < 0.001). Uninterrupted warfarin was associated with better patient satisfaction, and there was no significant difference in thromboembolic or surgical complications between the two groups. These results demonstrate that device surgeries can be safely performed with continued warfarin, and bridging with heparin is associated with high risk of device-pocket hematoma.
- Clinical Experience Using a Remote Control Injection System in Vertebroplasty: Feasibility, Safety and Cement Leakage of Osteoporotic and Malignant Compression Fractures. [JOURNAL ARTICLE]
- J Spinal Disord Tech 2013 Oct 16.
A retrospective study.Cement leakage is a frequent occurrence in vertebroplasty and is also the main source of complications. Continuous radiographic evaluation is mandatory in order to detect cement leakage during injecting cement into vertebral body, while the operator is subjected to X-ray radiation exposure.To evaluate the feasibility and safety in vertebroplasty performed for patients and operators in treatment of osteoporotic and malignant vertebral compression fractures using a remote control injection system.Institutional review board approval was obtained for this retrospective study. A clinical charts and postoperative radiographs were conducted in 74 patients (114 levels) who had undergone vertebroplasty. The study group included 46 cases (71 levels) of benign osteoporotic fractures and 28 cases (43 levels) of different malignant metastatic lesions. Under fluoroscopic guidance, cement was injected using a remote control injection system while the operator standing outside the radiation field. The location and degree of leakage at each treated level were recorded.Cement leakage rate reached 47.4% across all treated levels. No severe leakage in any location was observed. A total of 35 leakages were detected in 71 levels and 24 leakages were detected in 43 levels in the benign and malignant fractures group, respectively. The overall rate of cement leakages and the location of the leakages were not statistically different between the benign and malignant fractures group (P=0.60, P=0.45). With the operator standing outside the radiation field to inject cement, the radiation dose to operators was avoided during cement injection.Vertebroplasty using a remote control injection system was feasible and safe in treatment of osteoporotic and malignant compression fractures. The cement injection system had potential benefits to decrease the leakage rate in treating malignant fractures and eliminate injection dose to operators under lateral fluoroscopic monitoring.
- Data and safety monitoring boards: academic credit where credit is due? [Journal Article]
- JAMA 2013 Oct 16; 310(15):1563-4.
- Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. [Journal Article, Research Support, Non-U.S. Gov't]
- JAMA 2013 Nov 27; 310(20):2174-83.
Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia.To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis.An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized.Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care.Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients.After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977).Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke.clinicaltrials.gov Identifier: NCT00774631.