Background and Purpose— The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size. Methods— The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). Results— The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87–15.57). Conclusions— Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00235495.

This review surveys the efforts taken to achieve clinically efficacious protection of the ischemic brain and underscores the necessity of expanding our purview to include the essential role of cerebral perfusion and the collateral circulation. We consider the development of quantitative strategies to measure cerebral perfusion at the regional and local levels and the application of these methods to elucidate flow-related thresholds of ischemic viability and to characterize the ischemic penumbra. We stress that the modern concept of neuroprotection must consider perfusion, the necessary substrate upon which ischemic brain survival depends. We survey the major mechanistic approaches to neuroprotection and review clinical neuroprotection trials, focusing on those phase 3 multicenter clinical trials for acute ischemic stroke that have been completed or terminated. We review the evolution of thrombolytic therapies; consider the lessons learned from the initial, negative multicenter trials of endovascular therapy; and emphasize the highly successful positive trials that have finally established a clinical role for endovascular clot removal. As these studies point to the brain’s collateral circulation as key to successful reperfusion, we next review the anatomy and pathophysiology of collateral perfusion as it relates to ischemic infarction, as well as the molecular and genetic influences on collateral development. We discuss the current MR and CT-based diagnostic methods for assessing the collateral circulation and the prognostic significance of collaterals in ischemic stroke, and we consider past and possible future therapeutic directions.

Background Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial. Methods Ischemic stroke patients, aged 18–83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. Results Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01–5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3–26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). Conclusions ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. Trial Registration ClincalTrials.gov NCT00235495

BACKGROUND:In the ALIAS (Albumin in Acute Stroke) Part 2 Multicenter Trial, 85% of subjects received standard-of-care intravenous tissue plasminogen activator, and 21% received some form of endovascular thrombolysis. The overall rate of symptomatic intracranial hemorrhage was within the expected range but was higher in albumin-treated subjects than in saline-treated subjects.AIMS AND METHODS:Using the trial's Public Use Dataset, we analyzed factors contributing to symptomatic and asymptomatic intracranial hemorrhage in the 'safety sample' of 830 subjects.RESULTS:Four hundred sixteen subjects received albumin therapy, and 414 received saline. Intravenous tissue plasminogen activator was given to 68.2%; intravenous tissue plasminogen activator plus endovascular intervention in 16.4%; and endovascular therapy alone in 43%. Symptomatic intracranial hemorrhage occurred in 41 subjects - within the first 12 h in one-third of cases, and within the first day in ∼60%. Intravenous tissue plasminogen activator had been used in 78% of symptomatic intracranial hemorrhage subjects - no higher than in the overall cohort. In contrast, 48.8% of subjects with symptomatic intracranial hemorrhage had received endovascular therapy - a rate markedly higher than the 20.7% rate for the entire cohort (P = 0.0001). Sixty-eight point three percent of subjects with symptomatic intracranial hemorrhage had received albumin, and 31.7% saline (risk ratio 2.14, P = 0.025). Other factors associated with symptomatic intracranial hemorrhage were baseline NIHSS and ASPECTS scores and the SEDAN score. Forty-one point four percent of subjects with symptomatic intracranial hemorrhage died. The odds ratio for symptomatic intracranial hemorrhage was 3.89 (95% confidence interval 2.04-7.41) with endovascular therapy and 2.15 (confidence interval 1.08-4.25) with albumin.CONCLUSIONS:Endovascular thrombolysis was the major factor predisposing to symptomatic intracranial hemorrhage, and albumin contributed to this predisposition. The latter may be mediated by albumin's influence on platelet aggregation or collateral perfusion.

In the ALIAS2 Trial, 841 subjects were randomized 1:1 to treatment with either 25% albumin (ALB, 2 g/kg) or normal saline within 5 hours of stroke onset, and the primary outcome (NIHSS 0-1 and/or modified Rankin scale 0-1) was assessed at 90 days. While overall outcomes did not differ by treatment (44% for both groups), we observed a steadily improving favorable rate in the saline-placebo arm but not in the ALB arm over the trial’s 3.5 year course. This was further analyzed here. Methods and Findings: Logistic regression confirmed a significant randomization-order x treatment interaction (p<0.001). Thus, at the first pre-specified interim analysis of N=275 subjects, favorable outcome was seen in 44.8% with ALB but only 30.3% with saline (relative benefit 1.48, p=0.0028), while at the second interim analysis of N=550 subjects, the saline rate had risen to 37.5% while the ALB rate remained steady at 44.6% (relative benefit 1.21, p=0.0176). This trend-over-time in saline subjects was highly significant (Jonckheere-Terpstra (J-T) test, p=0.001; Pearson coefficient r=0.792), but there was no such trend in ALB subjects (J-T p=1.000). Simulation analysis confirmed that the saline trend could not have arisen by chance (p=0.0007). Importantly, intravenous tPA use also increased significantly during the trial in both ALB and saline subjects (initial rate 74%, final rate 95%, p<0.0001). Separate logistic regression analyses revealed a highly significant effect of IV tPA use on outcome in saline subjects (odds ratio 2.8, 95% CI 1.5-5.3, p=0.001) but only a marginal effect in ALB subjects (odds ratio 1.7, p=0.06). Conclusion: ALB treatment appears to have conferred a stable (and desirable) therapeutic “ceiling effect” throughout the trial (in the absence of significant toxicity), while saline subjects (who were unable to benefit from ALB) were susceptible to improved outcome from increasing tPA use as the trial progressed.

BACKGROUND:In animal models of ischaemic stroke, 25% albumin reduced brain infarction and improved neurobehavioural outcome. In a pilot clinical trial, albumin doses as high as 2 g/kg were safely tolerated. We aimed to assess whether albumin given within 5 h of the onset of acute ischaemic stroke increased the proportion of patients with a favourable outcome. METHODS:We did a randomised, double-blind, parallel-group, phase 3, placebo-controlled trial between Feb 27, 2009, and Sept 10, 2012, at 69 sites in the USA, 13 sites in Canada, two sites in Finland, and five sites in Israel. Patients aged 18-83 years with ischaemic (ie, non-haemorrhagic) stroke with a baseline National Institutes of Health stroke scale (NIHSS) score of 6 or more who could be treated within 5 h of onset were randomly assigned (1:1), via a central web-based randomisation process with a biased coin minimisation approach, to receive 25% albumin (2 g [8 mL] per kg; maximum dose 750 mL) or the equivalent volume of isotonic saline. All study personnel and participants were masked to the identity of the study drug. The primary endpoint was favourable outcome, defined as either a modified Rankin scale score of 0 or 1, or an NIHSS score of 0 or 1, or both, at 90 days. Analysis was by intention to treat. Thrombolytic therapies were permitted. This trial is registered with ClinicalTrials.gov, number NCT00235495. FINDINGS:422 participants were randomly assigned to receive albumin and 419 to receive saline. On Sept 12, 2012, the trial was stopped early for futility (n=841). The primary outcome did not differ between patients in the albumin group and those in the saline group (186 [44%] vs 185 [44%]; risk ratio 0·96, 95% CI 0·84-1·10, adjusted for baseline NIHSS score and thrombolysis stratum). Mild-to-moderate pulmonary oedema was more common in patients given albumin than in those given saline (54 [13%] of 412 vs 5 [1%] of 412 patients); symptomatic intracranial haemorrhage within 24 h was also more common in patients in the albumin group than in the placebo group (17 [4%] of 415 vs 7 [2%] of 414 patients). Although the rate of favourable outcome in patients given albumin remained consistent at 44-45% over the course of the trial, the cumulative rate of favourable outcome in patients given saline rose steadily from 31% to 44%. INTERPRETATION:Our findings show no clinical benefit of 25% albumin in patients with ischaemic stroke; however, they should not discourage further efforts to identify effective strategies to protect the ischaemic brain, especially because of preclinical literature showing convincing proof-of-principle for the possibility of this outcome. FUNDING:National Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation.

HomeStrokeVol. 43, No. 6Introspection Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBIntrospectionAn Analysis of the Citation Impact of Stroke Myron D. Ginsberg, MD Myron D. GinsbergMyron D. Ginsberg From the Department of Neurology, University of Miami Miller School of Medicine, Miami, FL. Originally published5 Apr 2012https://doi.org/10.1161/STROKEAHA.111.640235Stroke. 2012;43:1695–1699Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 IntroductionOne indicator of the influence of a scientific journal is the extent to which its articles are cited by others. A widely applied measure in this regard is so-called journal impact factor, an index devised by Eugene Garfield1 to quantify the extent to which the articles of that journal are cited in other peer-reviewed publications. The impact factor is typically computed as the quotient A/B, where A is the total number of times that articles published in a journal in 2 consecutive years (eg, 2008 and 2009) were cited in articles published during the following year (eg, 2010), and B is the total number of "citable items" published by that journal in those 2 years (see "impact factor" on Wikipedia http://en.wikipedia.org/wiki/Impact_factor [accessed July 21, 2011]). As quoted by Lo and Fisher in their recent editorial,2 the 2009 impact factor for Stroke was 7.041, compared to 8.172, 9.317, and 18.126 for the journals Neurology, Annals of Neurology, and Lancet Neurology, respectively. An obvious shortcoming of the impact factor, so-computed, is that it represents merely a numeric average that does not shed light on the extent to which the individual articles of a journal contribute to its overall citation impact. Thus, the intent of the present contribution is to provide an expanded analysis of the citation impact of articles and reviews published in Stroke in the years 2008 and 2009.Materials and MethodsThe present analysis utilized the Scopus database (SciVerse, Elsevier3), a large online abstract and citation database of the world's peer-reviewed literature in the world that provides citation data current as of the date-of-search. All "articles+reviews" published in the journal Stroke during the calendar years 2008 and 2009 were accessed, and their citation numbers as of the date of search (August 29, 2011) were tabulated. Note that whereas this search strategy excludes editorials and letters, it does not exclude reviews; it accesses citation numbers up to the date of search (rather than only during the subsequent calendar year, as is the case in the traditional impact factor computation). To gain a deeper understanding of citation trends for Stroke, each of the individual articles and reviews comprising the most cited and least cited quintiles (Table 1, n=234 each) was categorized and subcategorized according to the thematic rubrics presented in Table 2 by utilizing information contained in its abstract or, if needed, in its Methods section. In addition, the country of origin of each contribution was tabulated; articles originating from multiple countries were attributed to the country of the first author. The χ2 analysis was used for overall comparisons, and the Fisher exact test was used for individual categories.Table 1. Citations for Articles and Reviews (N=1168) Published in Stroke in 2008 and 2009First (Least Cited) QuintileSecond QuintileThird QuintileFourth QuintileFifth (Most Cited) QuintileOverallNo. of citations604145024253859864116 979Mean citations per article2.66.210.416.636.914.5SD citations per article1.41.01.52.325.116.6SD indicates standard deviation.Table 2. Thematic Categorization of the Most Cited and Least Cited QuintilesCategorySubcategoryNo. of Articles, Most Cited QuintileNo. of Articles, Least Cited QuintileCategory SumSubcategory SumCategory SumSubcategory SumCLINICALTotal=187Total=203Multicenter randomized controlled trial*Primary report27992Secondary analysis167Meta-analysis20Other types of multicenter studies†Primary report291631Secondary or other analysis112Meta-analysis20Smaller randomized controlled trial‡Primary report10472Treatment comparison65Other types of smaller trials§75Descriptive articles¶Primarily clinical‖1022214162‖‖Primarily MRI and neuroimaging**1525Primarily laboratory-based††1115Database or population analysis‡‡3126Device, modeling, simulation, other69Literature review§§174Major guidelines articles80Conference recommendations20Brief review and/or opinion pieces¶¶238BASICTotal=47Total=31Animal studies3428In vitro studies43Methodology, computational modeling40Review article40Conference recommendations10Total234234MRI indicates magnetic resonance imaging.*"Multicenter randomized controlled trial": multicenter trials that are prospectively designed, randomized, blinded, and placebo-controlled.†"Other types of multicenter studies": multicenter observational studies that do not conform to the definition of *, eg, are not prospectively designed and/or not placebo-controlled (eg, case-control, cohort design, and others) and/or not blinded.‡"Smaller randomized controlled trial": smaller typically nonmulticenter trials that conform to the design requirements listed in *.§"Other types of smaller trial": smaller typically nonmulticenter observational studies that do not conform to the definition of *, eg, are not prospectively designed and/or not placebo-controlled (e.g., case-control, cohort design, and others) and/or not blinded.¶Descriptive articles are distinguished from articles designated as "trials" in that the primary intent of the former is to describe the characteristics of a single designated group (using continuous or categorical variables) and only subsequently to explore relationships among these observations. By contrast, the explicit primary (a priori) intent of a "trial" is to compare the characteristics of ≥2 groups.‖"Primarily clinical": descriptions of clinical series (variously prospective, retrospective, cross-sectional, chart-review-based, and others; variously combined with neuroimaging, genetic analysis, or other laboratory variables).**"Primarily MRI and neuroimaging": may also include clinical or genetic analyses.††"Primarily laboratory-based": variously emphasizing clinical chemistry; physiological variables; protein, mRNA, or cell analysis; pathological findings and others.‡‡"Database or population analysis": typically based on clinical or epidemiological databases and registries, often involving several hundreds or thousands of subjects.§§"Literature review": thorough topic reviews with many references.¶¶"Brief review and/or opinion pieces": typically brief (1–2 pages) and usually lacking an abstract.‖‖Eight of these are reports of only 1 or 2 cases.A citation analysis also was performed of cerebrovascular articles published in selected major general neurology journals in 2008 and 2009 to allow comparisons with recently published data.2ResultsA total of 1168 "articles + reviews" were published in Stroke during 2008 and 2009, and these articles had been cited in other publications a total of 16 979 times as of the date of search. Figure 1 presents a citation histogram for these 1168 papers, and Table 1 shows the citation data by quintiles. As expected, the distribution shown in Figure 1 departs markedly from a normal (ie, Gaussian) distribution. Thus, whereas the mean value of citations per article is 14.5, the median value is 10; that is, one-half of the articles published in Stroke in 2008 and 2009 were cited ≤10 times over the ensuing 20 months, and 25% of articles received ≤5 citations. Twenty-four articles and reviews were never cited in other publications in the ensuing 20 months, and another 79 articles were cited only once or twice.Download figureDownload PowerPointFigure 1. The bar graph is a histogram showing citation numbers for articles and reviews published in Stroke in 2008 and 2009 (left axis). The curved line shows the cumulative percentage of total citations for these articles and reviews (right axis).At the other extreme, 35 articles (or 3%) were cited >50 times, and 7 articles (or 0.6%) received >100 citations. It is instructive to consider the subjects of the most highly cited articles: article 1 (244 citations) was a report of the final results of the Multi MERCI mechanical thrombectomy trial;4 article 2 (189 citations) was an update to the American Heart Association (AHA)/American Stroke Association (ASA) recommendations for stroke prevention in patients with stroke and transient ischemic attack;5 article 3 (170 citations) was a Guidelines article on the management of aneurysmal subarachnoid hemorrhage;6 article 4 (138 citations) was the AHA Special Writing Group report on the management of stroke in infants and children;7 article 5 (111 citations) was the report of a pivotal clinical trial of the Penumbra revascularization device;8 article 6 (104 citations) was an AHA/ASA scientific advisory concerning the use of intravenous tissue plasminogen activator within an expanded time window;9 and article 7 (102 citations) was an AHA/ASA scientific statement on the definition and evaluation of transient ischemic attack.10 Together, these 7 articles (or 0.6% of the total) accounted for over 6% of the total citations of Stroke articles published in 2008 and 2009.Table 2 presents in detail the categories and subcategories used to classify each of 234 articles or reviews comprising the most cited and least cited quintiles published in Stroke during 2008 and 2009 (Table 1). Figure 2 provides a graphic comparison of the major thematic categories. The complete data set used in this analysis is contained in the online-only Data Supplement. Overall, clinical themes accounted for 80% and 87% of articles in the most cited and least cited quintiles, respectively; basic science themes comprised the remaining 20% and 13%. The clinical/basic proportion did not differ significantly between these quintiles (P=not significant, Fisher test). Of the clinical articles, the most cited quintile contained a much higher proportion of multicenter clinical trial reports than the least cited quintile (30% versus 6%; P<0.0001, Fisher test; Table 2, Figure 2), as well as a significantly greater proportion of detailed literature reviews (9% versus 2%; P=0.003, Fisher test) and major Guidelines articles (4% versus 0%; P=0.003). By contrast, the least cited quintile contained much higher proportions of brief clinical review and/or opinion pieces (most cited quintile, 1%; least cited quintile, 19%; P<0.0001, Fisher test), as well as a higher proportion of primarily descriptive analyses (most cited quintile, 55%; least cited quintile, 69%; P=0.003). A common characteristic of the 9 multicenter randomized clinical trials falling into the least cited quintile was that these studies were either entirely negative (6 studies) and/or they reported secondary analyses of trials with primary outcomes that had been reported elsewhere (3 studies).Download figureDownload PowerPointFigure 2. Comparison of the major themes of the most cited vs least cited quintiles of articles and reviews published in Stroke during 2008 and 2009. The χ2 analysis revealed a highly significant overall difference between the 2 quintile groups (χ2=104.8; 10 degrees of freedom; P<0.001).Another manner of viewing these results is to consider the pool of 468 articles comprising the highest cited quintile plus lowest cited quintile and to analyze manner in which various article types are distributed between these respective groups. Of the 36 multicenter trial reports appearing in these 2 groups, 75% were within the highest cited quintile and 25% were in the lowest cited quintile. Similarly, a disproportionate number of "other types of multicenter studies" (91%) were in the highest cited quintile, and only 9% were in the lowest cited group. A similar trend was seen for major guidelines articles (100% versus 0%). By contrast, "brief review and/or opinion pieces" were overwhelmingly distributed within the lowest cited quintile (95%) as compared to the highest cited quintile (5%).Countries of origin are shown in Table 3. The majority of articles originated in North America or Europe. Comparison of the most cited and least cited quintiles failed to reveal any important intergroup differences in this respect (χ2=9.8; 5 degrees of freedom; P=not significant).Table 3. Countries of OriginContinentCountryMost Cited QuintileLeast Cited QuintileAsiaTotal=23Total=33China610Israel01Japan1215Korea22Singapore13Taiwan11Thailand10Turkey01AustraliaTotal=7Total=13Australia712New Zealand01EuropeTotal=84Total=86Austria10Czech Republic01Denmark33Finland32France89Germany2115Hungary03Italy54Netherlands1015Norway33Poland11Portugal10Spain74Sweden54Switzerland32United Kingdom1320North AmericaTotal=120Total=98Canada1513United States10585South AmericaTotal=0Total=2Brazil01Chile01Other02In their recent editorial, Lo and Fisher2 compared the citations accorded the 25 most highly cited articles in Stroke over the past 10 years with the most highly cited cerebrovascular articles in 3 leading general neurology journals during that period. The present analysis adopted a similar but broader strategy using the same search terms ("stroke OR cerebral ischemia OR cerebral hemorrhage [topic]"; date of search: July 20, 2011).2 The results are shown in Figure 3, which compares all citations of 2008 to 2009 articles in Stroke with citations of 2008 to 2009 cerebrovascular articles in Neurology, Annals of Neurology, and Lancet Neurology. There is considerable distributional overlap between Stroke and Neurology; the curve for cerebrovascular articles in Annals of Neurology is largely similar but with a greater proportion of highly cited articles, while cerebrovascular articles in Lancet Neurology are, overall, much more highly cited than those of the other 3 journals. Admittedly, the numbers of articles from the general neurology journals on which these curves are based are very small in comparison with Stroke (Figure 3).Download figureDownload PowerPointFigure 3. Citation numbers for articles and reviews published in 2008 and 2009. The data for Stroke are for all "articles+reviews," whereas the data for the other 3 journals are based on articles on cerebrovascular topics.DiscussionIt is evident from this analysis that individual articles in Stroke contribute in a markedly uneven manner to its overall citation impact. The most highly cited articles in Stroke are AHA/ASA management guidelines articles, major scientific advisories, and reports of multicenter randomized clinical trials. In contrast to the most cited articles, the least cited group contains a much higher proportion of brief review and/or opinion pieces, as well as more nontrial-based descriptive clinical reports.The results of this analysis thus indicate that the citation impact of the journal Stroke would be predictably enhanced if it could attract a greater proportion of publications reporting major randomized clinical trial results. This is admittedly difficult to achieve, however, given the strong competition of first-rank general clinical journals (eg, New England Journal of Medicine, JAMA, Lancet) for these reports. The AHA/ASA Guidelines articles, major scientific advisories, and detailed well-referenced literature reviews also tend to be highly cited. By contrast, brief review and/or opinion pieces (typically 1–2 pages and lacking an abstract), despite their possible appeal to the general readership, tend to have a very low citation impact. Nontrial-based reports of a purely descriptive nature, whether emphasizing primarily clinical, neuroimaging, or other laboratory measures, tend to be highly represented among the most cited as well as the least cited Stroke articles. For these articles, it becomes critical for the reviewers of Stroke to be able to discern the potential impact of an article in deciding on acceptance or rejection. Regarding editorial policy, it might be considered whether Stroke would be better-served by decreasing its total number of published articles by rejecting an additional percentage of those predicted to have very low impact while increasing the page length devoted to important articles and topics judged likely to become highly cited.Lo and Fisher call attention to the enormous number of electronic "views" (ie, online accesses) of the content of Stroke (>5 million in 2010).2 This impressive fact underscores that the "impact" of Stroke must be gauged in terms beyond those reflected in citation statistics. In this regard, it would be of great interest for the Stroke editors to analyze the full-article online views in greater detail and, if possible, to develop article-by-article "view" statistics comparable with the citation statistics presented here. The results of such an analysis might further guide future editorial policies regarding journal content and emphasis.DisclosuresNone.FootnotesThe online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.640235/-/DC1.Correspondence to Myron D. Ginsberg, MD, Department of Neurology (D4-5), University of Miami Miller School of Medicine, PO Box 016960, Miami, FL 33101. E-mail [email protected]miami.eduReferences1. Garfield E. The history and meaning of the journal impact factor. JAMA. 2006; 295:90–93.CrossrefMedlineGoogle Scholar2. Lo EH, Fisher M. Stroke: impact beyond the impact factor?Stroke. 2011; 42:1803–1804.LinkGoogle Scholar3. Scopus database. SciVerse Scopus. 2011Elsevier B.V.Available at: http://www.scopus.com/home.url. Accessed August 29, 2011.Google Scholar4. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS , et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke. 2008; 39:1205–1212.LinkGoogle Scholar5. Adams RJ, Albers G, Alberts MJ, Benavente O, Furie K, Goldstein LB , et al. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2008; 39:1647–1652.LinkGoogle Scholar6. Bederson JB, Connolly ES, Batjer HH, Dacey RG, Dion JE, Diringer MN , et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009; 40:994–1025.LinkGoogle Scholar7. Roach ES, Golomb MR, Adams R, Biller J, Daniels S, Deveber G , et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke. 2008; 39:2644–2691.LinkGoogle Scholar8. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009; 40:2761–2768.LinkGoogle Scholar9. Del Zoppo GJ, Saver JL, Jauch EC, Adams HP, American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009; 40:2945–2948.LinkGoogle Scholar10. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E , et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke. 2009; 40:2276–2293.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Wang M, Jiao S, Zhang J, Zhang X and Zhu N Identification High Influential Articles by Considering the Topic Characteristics of Articles, IEEE Access, 10.1109/ACCESS.2020.3001190, 8, (107887-107899) Krauskopf E (2018) A bibiliometric analysis of the Journal of Infection and Public Health: 2008–2016, Journal of Infection and Public Health, 10.1016/j.jiph.2017.12.011, 11:2, (224-229), Online publication date: 1-Mar-2018. Tahamtan I, Safipour Afshar A and Ahamdzadeh K (2016) Factors affecting number of citations: a comprehensive review of the literature, Scientometrics, 10.1007/s11192-016-1889-2, 107:3, (1195-1225), Online publication date: 1-Jun-2016. Stevens M, Park K, Tian G, Kim K and Ewing R (2019) Why Do Some Articles in Planning Journals Get Cited More than Others?, Journal of Planning Education and Research, 10.1177/0739456X19827083, (0739456X1982708) June 2012Vol 43, Issue 6 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.111.640235PMID: 22492521 Manuscript receivedSeptember 30, 2011Manuscript acceptedDecember 22, 2011Originally publishedApril 5, 2012 Keywordsimpact factorcitationsscience journalspublication policybiomedical journalsPDF download Advertisement SubjectsCerebrovascular Disease/StrokeEthics and Policy

Albumin (ALB), the plasma's most abundant protein, is a multifunctional molecule with potent antioxidant and intravascular actions. Albumin is in widespread clinical use to provide circulatory support in the settings of shock, burns, and surgery. More recently, we have shown that albumin when administered in high doses acts as a powerful neuroprotective agent in acute ischemic stroke and brain injury. In experimental studies of focal cerebral ischemia conducted in physiologically monitored rats, animals treated with ALB (typically 25% solution in doses of 1.25 g/kg and above) showed improved neurological score, substantial reductions of infarct volume, and markedly reduced brain swelling compared to saline placebo-treated rats, with a therapeutic window of 4-5 h. In mechanistic studies, ALB improved local blood flow in the ischemic penumbra; antagonized postischemic microvascular thrombosis; improved perfusion distal to microvascular thrombi; and facilitated delivery of fatty acids to the postischemic brain. In a two-center dose-escalation human pilot clinical trial, ALB was generally well tolerated; the chief adverse event was mild-to-moderate pulmonary edema in 13% of subjects, which could be readily managed. A major phase III multicenter clinical efficacy trial-the ALIAS (Albumin in Acute Stroke) Trial-is now underway in the U.S., Canada, and Israel, employing ALB at the 2 g/kg dose shown in experimental studies to be neuroprotective.

Background and Purpose— The Albumin in Acute Stroke (ALIAS) Part 2 Trial is directly testing whether 2 g/kg of 25% human albumin (ALB) administered intravenously within 5 hours of ischemic stroke onset results in improved clinical outcome. Recruitment into Part 1 of the ALIAS Trial was halted for safety reasons. ALIAS Part 2 is a new, reformulated trial with more-stringent exclusion criteria. Our aim was to explore the efficacy of ALB in the ALIAS Part 1 data and to assess the statistical assumptions underlying the ALIAS Part 2 Trial. Methods— ALIAS is a multicenter, blinded, randomized controlled trial. Data on 434 subjects, comprising the ALIAS Part 1 subjects, were analyzed. We examined both the thrombolysis and nonthrombolysis cohorts combined and separately in a “target population” by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients >83 years of age, those with elevated baseline troponin values, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale score of 0 to 1 and/or a National Institutes of Health Stroke Scale score of 0 to 1 at 90 days after randomization. Results— In the combined thrombolysis plus nonthrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared with 36.0% in the saline group (absolute effect size=8.7%; 95% CI, −2.2% to 19.5%). Among thrombolyzed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared with 36.6% in the saline group (absolute effect size=10.1%; 95% CI, −2.0% to 20.0%). Conclusions— Preliminary results from the ALIAS Part 1 suggest a trend toward a favorable primary outcome in subjects treated with ALB and support the validity of the statistical assumptions that underlie the ALIAS Part 2 Trial. The ALIAS Part 2 Trial will confirm or refute these results. Clinical Trial Registration— URL: http://www.clinicaltrials.gov/ALIAS . Unique identifier: NCT00235495.

Background and Purpose—The Albumin in Acute Stroke (ALIAS) Part 2 Trial is directly testing whether 2 g/kg of 25% human albumin (ALB) administered intravenously within 5 hours of ischemic stroke onset results in improved clinical outcome. Recruitment into Part 1 of the ALIAS Trial was halted for safety reasons. ALIAS Part 2 is a new, reformulated trial with more-stringent exclusion criteria. Our aim was to explore the efficacy of ALB in the ALIAS Part 1 data and to assess the statistical assumptions underlying the ALIAS Part 2 Trial. Methods—ALIAS is a multicenter, blinded, randomized controlled trial. Data on 434 subjects, comprising the ALIAS Part 1 subjects, were analyzed. We examined both the thrombolysis and nonthrombolysis cohorts combined and separately in a “target population” by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients 83 years of age, those with elevated baseline troponin values, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale score of 0 to 1 and/or a National Institutes of Health Stroke Scale score of 0 to 1 at 90 days after randomization. Results—In the combined thrombolysis plus nonthrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared with 36.0% in the saline group (absolute effect size 8.7%; 95% CI, 2.2% to 19.5%). Among thrombolyzed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared with 36.6% in the saline group (absolute effect size 10.1%; 95% CI, 2.0% to 20.0%). Conclusions—Preliminary results from the ALIAS Part 1 suggest a trend toward a favorable primary outcome in subjects treated with ALB and support the validity of the statistical assumptions that underlie the ALIAS Part 2 Trial. The ALIAS Part 2 Trial will confirm or refute these results. Clinical Trial Registration—URL: http://www.clinicaltrials.gov/ALIAS. Unique identifier: NCT00235495. (Stroke. 2011;42:1621-1625.)

Background and Purpose— Enrollment in the Albumin in Acute Stroke (ALIAS) Trial was suspended in late 2007 due to a safety concern. We present the safety data of that Trial (“Part 1”) and the rationale for the design of Part 2. Methods— ALIAS Part 1 was designed to assess whether 25% albumin (ALB) started within 5 hours of stroke onset would confer neuroprotection in subjects with acute ischemic stroke and baseline National Institutes of Health Stroke Scale of ≥6. Exclusion criteria included recent or current congestive heart failure, myocardial infarction, or cardiac surgery. The study comprised 2 cohorts: subjects who received thrombolysis and those who did not, each with 1:1 randomization to ALB or placebo. The primary outcome was the National Institutes of Health Stroke Scale and modified Rankin Scales at 90 days. The intended sample size was 1800. Results— Four hundred thirty-four subjects were enrolled, and 424 were used in the safety analysis (ALB 207, saline 217). There were 36 deaths within the first 30 days in the ALB group and 21 in the saline group. In contrast, death rates after 30 days were similar by treatment. Large strokes were the predominant cause of early death in both groups. In subjects >83 years of age, 90-day death rates were 2.3-fold higher with ALB than with saline (95% CI, 1.04 to 5.12). Similarly, 90-day deaths in subjects receiving excessive fluids were 2.10-fold greater with ALB than with saline (CI, 1.10 to 3.98). Conclusions— The ALIAS Part 2 Trial, which started in early 2009, was modified as follows to enhance safety: upper age limit of 83 years; requirement for normal baseline serum troponin level; restriction of total intravenous fluids in the first 48 hours to ≤4200 mL; mandatory diuretic at 12 to 24 hours; and detailed site retraining. Because of insufficient nonthrombolysed subjects (22%) in Part 1, the 2-cohort design was eliminated. The Data Safety Monitoring Board has reviewed the safety data of Part 2 3 times and has approved continuation of the trial.

Background and Purpose—Enrollment in the Albumin in Acute Stroke (ALIAS) Trial was suspended in late 2007 due to a safety concern. We present the safety data of that Trial (“Part 1”) and the rationale for the design of Part 2.Methods—ALIAS Part 1 was designed to assess whether 25% albumin (ALB) started within 5 hours of stroke onset would confer neuroprotection in subjects with acute ischemic stroke and baseline National Institutes of Health Stroke Scale of ≥6. Exclusion criteria included recent or current congestive heart failure, myocardial infarction, or cardiac surgery. The study comprised 2 cohorts: subjects who received thrombolysis and those who did not, each with 1:1 randomization to ALB or placebo. The primary outcome was the National Institutes of Health Stroke Scale and modified Rankin Scales at 90 days. The intended sample size was 1800.Results—Four hundred thirty-four subjects were enrolled, and 424 were used in the safety analysis (ALB 207, saline 217). There were 36 deaths within the first 30 days in the ALB group and 21 in the saline group. In contrast, death rates after 30 days were similar by treatment. Large strokes were the predominant cause of early death in both groups. In subjects >83 years of age, 90-day death rates were 2.3-fold higher with ALB than with saline (95% CI, 1.04 to 5.12). Similarly, 90-day deaths in subjects receiving excessive fluids were 2.10-fold greater with ALB than with saline (CI, 1.10 to 3.98).Conclusions—The ALIAS Part 2 Trial, which started in early 2009, was modified as follows to enhance safety: upper age limit of 83 years; requirement for normal baseline serum troponin level; restriction of total intravenous fluids in the first 48 hours to ≤4200 mL; mandatory diuretic at 12 to 24 hours; and detailed site retraining. Because of insufficient nonthrombolysed subjects (22%) in Part 1, the 2-cohort design was eliminated. The Data Safety Monitoring Board has reviewed the safety data of Part 2 3 times and has approved continuation of the trial.

An electronic safety reporting (ESR) module was developed and integrated into a home-grown web-based clinical trial management system (CTMS) to enhance the efficiency, completeness and consistency of reporting and reviewing serious adverse events, monitoring safety, and submitting safety reports to regulatory authorities for a large multicenter clinical trial. The architecture of this integrated module provided many advantages. First, the ESR module was developed based on a comprehensive procedure which incorporated both computer logic processing steps and human intervention steps in order to deal with the complex and unexpected situations where pre-programmed computer logic may fail. Second, safety and efficacy data were managed within the same relational database. Relevant data captured on efficacy case report forms, such as demographics, medical history, lab data and concomitant medications, were directly retrievable for MedWatch report composition without requiring redundant data entry. Finally, the ESR module shared the same generic user interfaces and data processing functions with other modules in the CTMS. These generic components include data editing, data retrieving, data reporting, dictionary-based automatic and interactive coding, event-driven and calendar-driven automatic email notifications, and user privilege management. This integrated ESR module was implemented in the Albumin in Acute Stroke (ALIAS) Trial-Part 1. A total of 397 serious adverse event reports were processed and 33 FDA MedWatch reports, 28 initial reports, and 5 follow-up reports were submitted to FDA and Health Canada using this system. Experiences and lessons learned from the development and implementation of this system are presented in this paper.

Wikipedia offers the following, quite apposite definition of translational research: “Translational research is a way of thinking about and conducting scientific research to make the results of research applicable to the population under study... In the field of medicine, for example, it is used to translate the findings in basic research more quickly and efficiently into medical practice and, thus, meaningful health outcomes ...” [1]. While the potential benefits of the translational approach are self-evident, and notwithstanding the frequent homage paid to the concept (for example, the founding of this journal), one cannot help being concerned by a variety of current structural impediments that, unless attended to and remedied, threaten to diminish future prospects for real success in translational stroke research. In his 2005 Thomas Willis Lecture [2], Vladimir Hachinski captures the essence of the translational challenge with characteristic eloquence: “Advances in stroke are occurring at an unprecedented pace, but often in disciplinary isolation and without optimal mechanisms for systematically translating, integrating and applying the findings. Knowledge accrues in pieces, but is understood in patterns [italics mine]. To optimize knowledge acquisition and application, infrastructures and systems need to be set up along with appealing incentives. The approach needs to be transdisciplinary, going beyond the bounds of any given discipline, reciprocally translational, and transactional, meaning that the interchanges have to yield previously agreed benefits to the parties (The Triple T Approach). A new breed of leaders needs to be developed and nurtured to catalyze the process.... Systematically integrating what we know and evaluating what we do could spur progress. Research is not only an activity but an attitude... No system can replace the individual initiative, creativity and insights that lead to the great discoveries, but progress is not made by breakthroughs alone. No one's work is so exalted that it cannot be improved, nor so humble that it has no value. We can all make a difference” [2]. What, then, are some remediable factors hindering translational stroke research? In my opinion, there are several:

Abundant preclinical studies have identified multiple mechanisms of ischemic brain injury and have provided proof of principle that strategies designed to counter these mechanisms can protect the ischemic brain. This review article emphasizes the translation of these strategies from the laboratory to clinical trials. It is a disappointing fact that many agents have been brought to clinical trial despite only modest or inconsistent preclinical evidence of neuroprotective efficacy. Preclinical investigations require rigorous attention to a variety of variables that may influence outcome. The widely touted STAIR criteria represent constructive guidelines for preclinical testing but, as experience has shown, do not increase the likelihood of translational success. Of the approximately 160 clinical trials of neuroprotection for ischemic stroke conducted as of late 2007, only approximately 40 represent larger-phase completed trials, and fully one half of the latter utilized a window to treatment of >6 hours, despite strong preclinical evidence that this delay exceeds the likely therapeutic window of efficacy in acute stroke. Other shortcomings of these trials include the use of agents lacking robust, consistent preclinical efficacy; inability to achieve adequate dosing in humans; and suboptimal clinical and statistical design features. Taken together, these factors identify areas of needed improvement for future trials.

Object. The authors have recently demonstrated that high-dose human albumin is markedly neuroprotective in experimental traumatic brain injury (TBI) and cerebral ischemia. The pathophysiology of TBI involves acute uncoupling of cerebral glucose utilization and blood flow. The intent of this study was to establish whether the use of human albumin therapy in a model of acute TBI would influence this phenomenon. Methods. Anesthetized, physiologically regulated rats received moderate (1.5-2 atm) fluid-percussion injury to the parietal lobe. Fifteen minutes after trauma or sham injury, rats in one group received human albumin (2.5 g/kg) administered intravenously and those in another group received 0.9% saline vehicle. At 60 minutes and 24 hours posttrauma, autoradiographic studies of local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu) were conducted, and the LCMRglu/LCBF ratio was determined. Sham-injured rats had normal levels of LCBF and LCMRglu, and no differences between vehicle- and albumin-treated rats were evident. Sixty minutes after TBI, LCBF was moderately reduced bilaterally in vehicle-treated rats, whereas in albumin-treated animals, the LCBF contralateral to the side of injury was generally normal. Despite acutely depressed LCBF, LCMRglu in vehicle-treated rats at 60 minutes was paradoxically normal bilaterally, and foci of elevated LCMRglu were noted in the ipsilateral hippocampus and thalamus. By contrast, in albumin-treated rats studied 60 minutes post TBI, reduced LCMRglu values were measured in the ipsilateral caudoputamen and parietal cortex, whereas LCMRglu in other ipsilateral and contralateral sites did not differ from that measured in sham-injured animals. The metabolism/blood flow ratio was normal in sham-injured rats, but became markedly elevated in vehicle-treated rats 60 minutes post-TBI ton average, by threefold ipsilaterally and 2.1-fold contralaterally). By contrast, the mean metabolism/blood flow ratio in albumin-treated animals was elevated by only 1.6-fold ipsilaterally and was normal contralaterally. Twenty-four hours after TBI, LCBF contralateral to the side of injury had generally returned to normal levels in the albumin-treated group. Conclusions. These results demonstrate that human albumin therapy benefits the posttraumatic brain by diminishing the pronounced metabolism > blood flow dissociation that would otherwise occur within the Ist hour after injury. Viewed together with our previous evidence of histological neuroprotection, these findings indicate that human albumin therapy may represent a desirable treatment modality for acute TBI.

Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safety-feasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 h therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. (C) 2007 Elsevier Ltd. All rights reserved.

Background and Purpose— Results of our recent pilot clinical trial suggest that the efficacy of thrombolytic therapy in acute ischemic stroke may be enhanced by the coadministration of high-dose albumin. Here, we explored the microvascular hemodynamic effects of this combined therapy in a laboratory model of cortical arteriolar thrombosis. Methods— We studied the cortical microcirculation of physiologically monitored rats in vivo by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran. We induced focal thrombosis in 30- to 50-μm cortical arterioles by laser irradiation and measured arteriolar flow velocity by repeated line-scanning. At 30 minutes post-thrombosis, we treated animals with the thrombolytic agent, reteplase, which was coadministered with either human albumin, 2 g/kg, or with saline control. Results— Baseline arteriolar flow velocity averaged 3.8±0.7 mm/s, was immediately reduced by thrombosis to 22% to 25% of control values, and remained unchanged before treatment. Subthrombolytic doses of reteplase combined with saline led to a median increase in flow velocity to 37% of control distal to the thrombus ( P =nonsignificant versus pretreatment). By contrast, reteplase combined with albumin therapy resulted in a prompt, highly significant increase of median flow velocity to 58% of control levels ( P =0.013 versus reteplase+saline), which remained significantly higher than the reteplase+saline group at multiple time-points over the subsequent hour. Conclusions— The beneficial effect of subthrombolytic doses of reteplase on microvascular hemodynamics distal to a cortical arteriolar thrombosis is markedly enhanced by the coadministration of high-dose albumin therapy; these results have important clinical implications for the management of patients with acute ischemic stroke.