Outcome Differences between Intra-Arterial Iso- and Low-Osmolality Iodinated Radiographic Contrast Media in the Interventional Management of Stroke III Trial.

BACKGROUND AND PURPOSE: Intracarotid arterial infusion of nonionic, low-osmolal iohexol contrast medium has been associated with increased intracranial hemorrhage in a rat middle cerebral artery occlusion model compared with saline infusion. Iso-osmolal iodixanol (290 mOsm/kg H2O) infusion demonstrated smaller infarcts and less intracranial hemorrhage compared with low-osmolal iopamidol and saline. No studies comparing iodinated radiographic contrast media in human stroke have been performed, to our knowledge. We hypothesized that low-osmolal contrast media may be associated with worse outcomes compared with iodixanol in the Interventional Management of Stroke III Trial (IMS III). MATERIALS AND METHODS: We reviewed prospective iodinated radiographic contrast media data for 133 M1 occlusions treated with endovascular therapy. We compared 5 prespecified efficacy and safety end points (mRS 0-2 outcome, modified TICI 2b-3 reperfusion, asymptomatic and symptomatic intracranial hemorrhage, and mortality) between those receiving iodixanol (n = 31) or low-osmolal contrast media (n = 102). Variables imbalanced between iodinated radiographic contrast media types or associated with outcome were considered potential covariates for the adjusted models. In addition to the iodinated radiographic contrast media type, final covariates were those selected by using the stepwise method in a logistic regression model. Adjusted relative risks were then estimated by using a log-link regression model. RESULTS: Of baseline or endovascular therapy variables potentially linked to outcome, prior antiplatelet agent use was more common and microcatheter iodinated radiographic contrast media injections were fewer with iodixanol. Relative risk point estimates are in favor of iodixanol for the 5 prespecified end points with M1 occlusion. The percentage of risk differences are numerically greater for microcatheter injections with iodixanol. CONCLUSIONS: While data favoring the use of iso-osmolal iodixanol for reperfusion of M1 occlusion following IV rtPA are inconclusive, potential pathophysiologic mechanisms suggesting clinical benefit warrant further investigation.

Clinical trial design in the neurocritical care unit.

Clinical trials provide a robust mechanism to advance science and change clinical practice across the widest possible spectrum. Fundamental in the Neurocritical Care Society's mission is to promote Quality Patient Care by identifying and implementing best medical practices for acute neurological disorders that are consistent with the current scientific knowledge. The next logical step will be to foster rapid growth of our scientific body of evidence, to establish and disseminate these best practices. In this manuscript, five invited experts were impaneled to address questions, identified by the conference organizing committee as fundamental issues for the design of clinical trials in the neurological intensive care unit setting.

Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II: design, methods, and rationale.

The December 2003 report from the National Institute of Neurological Disorders and Stroke (NINDS) Workshop on priorities for clinical research in intracerebral hemorrhage (ICH) recommended clinical trials for evaluation of blood pressure management in acute ICH as a leading priority. The Special Writing Group of the Stroke Council of the American Heart Association in 1999 and 2007 emphasized the need for clinical trials to ensure evidence-based treatment of acute hypertensive response in ICH. To address important gaps in knowledge, we conducted a pilot study funded by the NINDS, Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) I Trial, during 2004-2008 to determine the appropriate level of systolic blood pressure (SBP) reduction. We now have initiated a multi-center, randomized Phase III trial, the ATACH II Trial, to definitively determine the efficacy of early, intensive, antihypertensive treatment using intravenous (IV) nicardipine initiated within 3 h of onset of ICH and continued for the next 24 h in subjects with spontaneous supratentorial ICH. The primary hypothesis of this large (N = 1,280), streamlined, and focused trial is that SBP reduction to ≤140 mm Hg reduces the likelihood of death or disability at 3 months after ICH, defined by modified Rankin scale score of 4-6, by at least 10% absolute compared to standard SBP reduction to ≤180 mm Hg. The ATACH II trial is a natural extension of numerous case series, the subsequent ATACH I pilot trial, and a preliminary, randomized, and controlled trial in this patient population funded by the Australian National Health and Medical Research Council. Both trials recently confirmed the safety and tolerability of both the regimen and goals of antihypertensive treatment in acutely hypertensive patients with ICH, as proposed in the present trial. The underlying mechanism for this expected beneficial effect of intensive treatment is presumably mediated through reduction of the rate and magnitude of hematoma expansion observed in approximately 73% of the patients with acute ICH. The Australian trial provided preliminary evidence of attenuation of hematoma expansion with intensive SBP reduction. The ATACH II trial will have important public health implications by providing evidence of, or lack thereof, regarding the efficacy and safety of acute antihypertensive treatment in subjects with ICH. This treatment represents a strategy that can be made widely available without the need for specialized equipment and personnel, and therefore, can make a major impact upon clinical practice for treating patients with ICH.

The ALIAS (ALbumin In Acute Stroke) Phase III randomized multicentre clinical trial: design and progress report.

High-dose human ALB (albumin) therapy is highly neuroprotective in animal models of ischaemic stroke. A recently completed 82-subject pilot-phase dose-escalation trial has shown that ALB is safe, with strong preliminary suggestions of possible efficacy. We are now proceeding to a large randomized, double-blinded, placebo-controlled multicentre trial funded by the NIH (National Institutes of Health), the ALIAS (Albumin In Acute Stroke) Phase III Trial, which is designed to ascertain definitively whether high-dose ALB therapy confers neuroprotection in subjects with acute ischaemic stroke treated within 5 h of stroke onset. The primary efficacy outcome measure is a favourable outcome, defined as an NIHSS (NIH Stroke Scale) score of 0-1 or a modified Rankin Scale score of 0-1 at 3 months post-randomization. Separate randomization (1:1) to ALB or placebo therapy will be carried out in two cohorts of 900 subjects each, one that receives standard-of-care thrombolytic therapy and the other that does not. Approx. 60 North American clinical sites will participate. Subject enrollment is expected to commence in July 2006.

Using the baseline CT scan to select acute stroke patients for IV-IA therapy.

BACKGROUND: Intra-arterial therapies for acute ischemic stroke are increasingly available. Intravenous therapy (IV) followed immediately by intra-arterial therapy (IA) has been shown to be safe, but such therapy is resource intensive. Selecting the best patients for this therapy may be accomplished with the use of baseline neuroimaging. METHODS: We used data from the IMS-1 and National Institute for Neurological Disorders and Stroke tissue plasminogen activator (tPA) stroke studies to compare outcomes among IV-IA tPA, IV-tPA, and placebo treatment stratified by the baseline CT scan appearance. The CT scans were scored using the Alberta Stroke Program Early CT (ASPECT) score and dichotomized into ASPECT score > 7 (favorable scan) and ASPECT score < or = 7 (unfavorable scan). Logistic regression was used to assess for an ASPECT score by treatment interaction. RESULTS: A total of 460 patients was included. Age and sex were similar among the 3 groups. The IV-IA tPA cohort had a higher median National Institutes of Health stroke scale (NIHSS) score (18 versus 17) compared with the IV tPA cohort. The proportion of patients with favorable CT scans (ASPECT score > 7) was lowest in the IV-IA tPA group. A multiplicative interaction effect was shown indicating that patients with an ASPECT score > 7 in the IV-IA cohort were more likely to have a good outcome compared with IV tPA and with placebo. Harm may accrue to patients treated with IV-IA therapy who have an unfavorable baseline CT scan appearance. CONCLUSIONS: Patients with a favorable baseline CT scan appearance are the most likely to benefit from IV-IA therapy. This hypothesis will be tested in the IMS-3 study.

Optimizing the ongoing search for new treatments for Parkinson disease: using futility designs.

Many agents are being considered for treatment of Parkinson disease (PD). Given the large number of agents and the limited resources to evaluate new agents, it is essential to reduce the likelihood of advancing ineffective agents into large, long-term Phase III trials. Futility design methodology addresses this goal. The authors describe how a single-arm Phase II futility study uses a short-term outcome to compare a treatment group response to a predetermined hypothesized or historically based control response. The authors present advantages and limitations of futility designs along with examples derived from the data archive of a large Phase III efficacy study of treatments to delay PD progression, the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) trial. Using the same control progression rate and treatment effect assumptions used to power the original DATATOP trial, the authors calculated the number of subjects needed to conduct two 12-month futility studies. DATATOP was designed to enroll 800 patients. Using data on 124 consecutive subjects randomized into each of the DATATOP treatment groups, the authors identified tocopherol as futile and deprenyl as worthy of further study. Using Phase II information, DATATOP could have been simplified from a 2 x 2 factorial design to a comparison of deprenyl vs placebo. While not testing efficacy, futility designs provide a strategy for discarding treatments unlikely to be effective in Phase III. A limitation is the dependence on historical data or hypothesized outcomes for untreated controls. Futility studies may decrease the time to identify treatments unworthy of further pursuit and reduce subjects' exposure to futile treatments.

Age and alarm symptoms do not predict endoscopic findings among patients with dyspepsia: a multicentre database study.

INTRODUCTION: Symptoms of dyspepsia are common but most patients do not have major upper gastrointestinal pathology. Endoscopy is recommended for dyspeptic patients over the age of 45, or those with certain "alarm" symptoms. We have evaluated the effectiveness of age and "alarm" symptoms for predicting major endoscopic findings in six practising endoscopy centres. METHODS: Clinical variables of consecutive patients with dyspepsia symptoms undergoing upper endoscopy examinations were recorded using a common endoscopy database. Patients who had no previous upper endoscopy or barium radiography were included. Stepwise multivariate logistic regression was used to identify predictors of endoscopic findings. The accuracy of these for predicting endoscopic findings was evaluated with receiver operating characteristic analysis. The sensitivity and specificity of age thresholds from 30 to 70 years were evaluated. RESULTS: Major pathology (tumour, ulcer, or stricture) was found at endoscopy in 787/3815 (21%) patients with dyspepsia. Age, male sex, bleeding, and anaemia were found to be significant but weak independent predictors of endoscopic findings. A multivariate prediction rule based on these factors had poor predictive accuracy (c statistic=0.62). Using a simplified prediction rule of age > or =45 years or the presence of any "alarm" symptom, sensitivity was 87% and specificity was 26%. Increasing or decreasing the age cut off did not significantly improve the predictive accuracy. CONCLUSIONS: Age and the presence of "alarm" symptoms are not effective predictors of endoscopic findings among patients with dyspepsia. Better clinical prediction strategies are needed to identify patients with significant upper gastrointestinal pathology.

Quantitative real-time RT-PCR detection of breast cancer micrometastasis using a multigene marker panel.

Real-time RT-PCR is a relatively new technology that uses an online fluorescence detection system to determine gene expression levels. It has the potential to significantly improve detection of breast cancer metastasis by virtue of its exquisite sensitivity, high throughput capacity and quantitative readout system. To assess the utility of this technology in breast cancer staging, we determined the relative expression levels of 12 cancer-associated genes (mam, PIP, mamB, CEA, CK19, VEGF, erbB2, muc1, c-myc, p97, vim and Ki67) in 51 negative-control normal lymph nodes and in 17 histopathology-positive ALNs. We then performed a receiver operating characteristic (ROC) curve analysis to determine the sensitivity and specificity levels of each gene. Areas under the ROC curve indicated that the most accurate diagnostic markers were mam (99.6%), PIP (93.3%), CK19 (91.0%), mamB (87.9%), muc1 (81.5%) and CEA (79.4.0%). mam was overexpressed in 16 of 17 lymph nodes known to contain metastatic breast cancer at levels ranging from 22- to 2.8 x 10(5)-fold above normal mean expression, whereas PIP was overexpressed from 30- to 2.2 x 10(6)-fold above normal in 13 lymph nodes. Real-time RT-PCR analysis of pathology-negative LN from breast cancer patients revealed evidence of overexpression of PIP (6 nodes), mam (3 nodes) and CEA (1 node) in 8 of 21 nodes (38%). Our results provide evidence that mam, PIP, CK19, mamB, muc1 and CEA can be applied as a panel for detection of metastatic and occult micrometastatic disease.

Association between cigarette and alcohol consumption and Raynaud's phenomenon.

The association between alcohol and cigarette consumption and Raynaud's Phenomenon (RP) was examined by using data from an American-French collaborative, cross-sectional, epidemiological study in five geographically varied regions (Charleston, South Carolina, USA; and Grenoble, Tarentaise, Nyons, and Toulon, France). Using logistic regression models that take into account the sampling weights, the association was examined stratified by gender and adjusted for age, body mass index, self-perceived health, and education. Overall, neither cigarette nor alcohol consumption showed a significant association with RP. In men, however, a V-shaped relationship between drinking and RP was observed, with mild consumption (1 to 7 drinks per week) exhibiting a protective effect over abstinence, whereas occasional (less than 1 drink per week), moderate (8 to 18 drinks per week) and heavy consumption (more than 18 drinks per week) did not. Among the participants with RP, no significant association was observed between RP attack frequencies and the amount of either alcohol or cigarette consumption. These negative findings suggest that having RP is not strongly affected by alcohol or cigarette consumption.

Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction.

BACKGROUND & AIMS: Patients with sphincter of Oddi dysfunction are at high risk of developing pancreatitis after endoscopic biliary sphincterotomy. Impaired pancreatic drainage caused by pancreatic sphincter hypertension is the likely explanation for this increased risk. A prospective, randomized controlled trial was conducted to determine if ductal drainage with pancreatic stenting protects against pancreatitis after biliary sphincterotomy in patients with pancreatic sphincter hypertension. METHODS: Eligible patients with pancreatic sphincter hypertension were randomized to groups with pancreatic duct stents (n = 41) or no stents (n = 39) after biliary sphincterotomy. The primary measured outcome was pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: Pancreatic stenting significantly decreased the risk of pancreatitis from 26% to 7% (10 of 39 in the no stent group and 3 of 41 in the stent group; P = 0.03). Only 1 patient in the stent group developed pancreatitis after sphincterotomy, and 2 others developed pancreatitis at the time of stent extraction. Patients in the no stent group were 10 times more likely to develop pancreatitis immediately after sphincterotomy than those in the stent group (relative risk, 10.5; 95% confidence interval, 1.4-78.3). CONCLUSIONS: Pancreatic duct stenting protects significantly against post-ERCP pancreatitis in patients with pancreatic sphincter hypertension undergoing biliary sphincterotomy. Stenting of the pancreatic duct should be strongly considered after biliary sphincterotomy for sphincter of Oddi dysfunction; pancreatic sphincter of Oddi manometry identifies which high-risk patients may benefit from pancreatic stenting.

The effectiveness of a magnetized water oral irrigator (Hydro Floss) on plaque, calculus and gingival health.

The purpose of this study was to evaluate the effects of a magnetized water oral irrigator on plaque, calculus and gingival health. 29 patients completed this double-blind crossover study. Each patient was brought to baseline via an oral prophylaxis with a plaque index < or = 1 and a gingival index < or = 1. Subjects used the irrigator for a period of 3 months with the magnet and 3 months without the magnet. After each 3 month interval, data were collected using the plaque index, gingival index, and accretions index. The repeated measures analysis on plaque, gingival and calculus indices yielded a statistically-significant period effect for PlI (p=0.0343), GI (p=0.0091), and approached significance for calculus (p=0.0593). This meant that the effect of irrigation resulted in a decrease of all indices over time. Therefore, the treatment effect on each index was evaluated using only the measurements obtained at the end of the first period (i.e., assuming a parallel design). Irrigation with magnetized water resulted in 64% less calculus compared to the control group. The reduction was statistically significant (p< or =0.02). The reduction by 27% in gingival index was not statistically significant. The reduction in plaque was minimal (2.2%). A strong positive correlation between the plaque index and the Watt accretion index was observed. The magnetized water oral irrigator could be a useful adjunct in the prevention of calculus accumulation in periodontal patients, but appears to have minimal effect on plaque reduction. The results indicated a clinical improvement in the gingival index, but this was not a statistically significant finding.

Digital vascular responses to cooling in subjects with cold sensitivity, primary Raynaud's phenomenon, or scleroderma spectrum disorders.

OBJECTIVE: To define differences in digital vascular responses to cooling and to determine their usefulness for the differential diagnosis of 4 groups of subjects: patients with primary Raynaud's phenomenon (RP) (n = 96), patients with RP associated with scleroderma (systemic sclerosis, SSc) spectrum disorders (SSc spectrum RP) (n = 108), subjects complaining of cold sensitivity of the fingers (n = 88), and RP negative controls (n = 120). METHODS: Digital systolic blood pressure, digital blood flow, and digital skin temperature were measured in a temperature controlled room at 18 or 23 degrees C; the effect of local finger cooling was tested at 30, 20, 15, and 10 degrees C. RESULTS: Digital blood pressure responses clearly differentiate the 4 diagnostic groups from each other. By contrast, blood flow and skin temperature measurements, although showing different group means, fail to reach statistical significance due to a large variance. Digital pressure responses have high sensitivity and specificity for distinguishing not only between patients with RP and controls, but also between the 2 types of RP. A relative digital systolic pressure (digital systolic pressure over brachial systolic pressure) of less than 70% at low local finger cooling temperatures (15 and 10 degrees C) has a sensitivity of 97.1% in differentiating SSc spectrum RP from primary RP. A zero reopening pressure shows a specificity of 100% at 30 degrees C and 81.7% at 20 degrees C to separate the 2 groups. The zero reopening pressure is seldom associated with clinically visible RP (10.3% among SSc spectrum RP, 4.3% among primary RP). Although the study was not designed to investigate drug effects, our data from patients who failed to abstain from vasodilators, as instructed, show they have a protective effect at 15 and 10 degrees C. CONCLUSION: The digital pressure response to cooling is a useful test for RP and cold sensitive subjects. It has high sensitivity and specificity to differentiate between SSc spectrum RP and primary RP and between primary RP and cold sensitive subjects. Our preliminary data on vasodilator use suggest that the digital pressure response to cooling may also be useful in RP treatment studies.

Propranolol metabolism in normal subjects: association with sex steroid hormones.

The objective of this study was to determine the potential role of circulating testosterone and estradiol in regulation of the activity of the sex-dependent pathways of propranolol metabolism (i.e., alpha-naphthoxylactic acid and propranolol glucuronide). The pharmacokinetics of a single 80 mg oral dose of propranolol and the plasma levels of the sex steroid hormones were therefore determined in normal volunteers. In 33 young men there was a positive correlation between the testosterone levels and the propranolol clearances through both alpha-naphthoxylactic acid (p < 0.001) and propranolol glucuronide (p < 0.002), as well as the total clearance (p < 0.05), but not through aromatic ring hydroxylation. Testosterone cypionate administration led to an increased clearance of propranolol through alpha-naphthoxylactic acid in nine of the 11 men studied, further supporting a stimulatory effect of testosterone on propranolol metabolism. In 23 young women there was no significant association between the circulating levels of either estradiol or testosterone and any of the clearances of propranolol. These observations may be clinically relevant for propranolol therapy and may provide improved insight into the influence of gender and circulating gonadal hormones on drug metabolism in humans.

Sex differences in declining cohort death rates from heart disease.

We examined cohort mortality from heart disease (HD) at ages 40 and over for White men and women in the United States between 1945 and 1975. For each successive birth cohort from 1886 to 1890 and 1906 to 1910, female HD mortality rates exhibit a continuous decline with parallel slopes which shows no sign of abating in recent years. Among men, cohort HD mortality rates were increasing prior to 1965; since 1965, there has been a reversal of prior trends, i.e., each successive cohort has shown a decrease in HD mortality rates. None of the various hypotheses put forward to explain the recent decline in HD mortality provides a cogent explantation for the differential effects in men and women.