Patrick D Lyden

Cedars-Sinai Medical Center, Los Angeles, CA, United States

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Publications (239)1374.08 Total impact

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    ABSTRACT: Protease activated receptors (PARs) populate neurons and astrocytes in the brain. The serine protease thrombin, which activates PAR-1 during the first hours after stroke, appears to be associated with the cytotoxicity. Thrombin antagonists and PAR-1 inhibitors have been correlated with reduced cell death and behavioral protection after stroke, but no data yet supports a mechanistic link between PAR-1 action and benefit. We sought to establish the essential role of PAR-1 in mediating ischemic damage. Using a short hairpin mRNA packaged with green fluorescent protein in a lentivirus vector, we knocked downPAR-1 in the medial caudate nucleus prior to rat middle cerebral artery occlusion (MCAo) and in rat neurons prior to oxygen-glucose deprivation. We also compared aged PAR-1 knockout mice with aged PAR-3, PAR-4 mice and young wild-type mice in a standard MCAo model. Silencing PAR-1 significantly reduced neurological deficits, reduced endothelial barrier leakage, and decreased neuronal degeneration in vivo during MCAo. PAR-1 knock-down in the ischemic medial caudate allowed cells to survive the ischemic injury; infected cells were negative for TUNEL and c-Fos injury markers. Primary cultured neurons infected with PAR-1 shRNA showed increased neuroprotection during hypoxic/aglycemic conditions with or without added thrombin. The aged PAR-1 knockout mice showed decreased infarction and vascular disruption compared to aged controls or young wild types. We demonstrated an essential role for PAR-1 during ischemia. Silencing or removing PAR-1 significantly protected neurons and astrocytes. Further development of agents that act at PAR-1or its downstream pathways could yield powerful stroke therapy.
    Neuroscience 09/2014; · 3.12 Impact Factor
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    ABSTRACT: Background Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase. Methods We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3–6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality. Findings Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35–2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05–1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95–1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01–7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11–10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98–12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99–1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3–6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h. Interpretation Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits. Funding UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.
    Lancet. 08/2014;
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    ABSTRACT: Interventional Management of Stroke (IMS) III is a randomized, parallel arm trial comparing the approach of intravenous tissue plasminogen activator followed by endovascular treatment with intravenous tissue plasminogen activator alone in patients with acute ischemic stroke presenting <3 hours of symptom onset. The trial intended to enroll 900 subjects to ensure adequate statistical power to detect an absolute 10% difference in the percentage of subjects with good outcome, defined as modified Rankin Scale score of 0 to 2 at 3 months. In April 2012, after 656 subjects were randomized, further enrollment was terminated by the National Institute of Neurological Disorders and Stroke based on the prespecified criterion for futility using conditional power <20%. Conditional power was defined as the likelihood of finding statistical significance at the end of the study, given the accumulated data to date and with the assumption that a minimum hypothesized difference of 10% truly exists between the 2 groups. The evolution of study data leading to futility determination is described, including the interaction between the unblinded study statisticians and the Data and Safety Monitoring Board in the complex deliberation of analysis results. The futility boundary was crossed at the trial's fourth interim analysis. At this point, based on the conditional power criteria, the Data and Safety Monitoring Board recommended termination of the trial. Even in spite of prespecified interim analysis boundaries, interim looks at data pose challenges in interpretation and decision making, underscoring the importance of objective stopping criteria. Unique identifier: NCT00359424.
    Stroke 04/2014; · 6.16 Impact Factor
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    ABSTRACT: We showed previously robust neuroprotection with the thrombin inhibitor argatroban and now sought additional support for its neuroprotective potential. We used behavioral and histological end points; rigorously blinded the study groups; extended the treatment window to 3 hours after ischemia onset; and used 2 separate models. First, 2-hour filament middle cerebral artery occlusion in 64 male Sprague-Dawley rats was followed by learning and memory testing and quantitative histomorphometry. Randomly assigned treatment was 0.45 mg argatroban, saline, or 0.4 U thrombin. Second, we used the quantal bioassay (n=272) after 2-hour middle cerebral artery occlusion to detect the longest time delay after which therapy failed. Argatroban powerfully and significantly reversed learning and memory deficits because of focal ischemia compared with saline or thrombin (P<0.03; ANOVA). Argatroban was significantly (P<0.05; t test with Bonferroni) protective when given immediately or after 1, 2, 3, but not 4 hours delay. We obtained supportive evidence for argatroban protection of the neurovascular unit using behavioral and histological measurements at realistic therapeutic time windows.
    Stroke 01/2014; · 6.16 Impact Factor
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    ABSTRACT: Background and Purpose. Activated Protein C (APC) stimulates multiple cytoprotective pathways via the protease activated receptor-1 (PAR-1) and promotes anticoagulation. 3K3A-APC was designed for preserved activity at PAR-1 with reduced anticoagulation. This Phase 1 trial characterized pharmacokinetics and anticoagulation effects of 3K3A-APC. Methods. Subjects (n=64) were randomly assigned to receive 3K3A-APC (n=4) at 6, 30, 90, 180, 360, 540 or 720 µg/kg or placebo (n=6) and were observed for 24 hr. After safety review additional subjects received drug every 12 hr for 5 doses (n=6 per group) at 90, 180, 360, or 540 µg/kg or placebo (n=8) and were observed for 24 hr. Results. All subjects returned for safety assessments at 72 hours and 15 days. We found few adverse events in all groups. Systolic blood pressure increased in both active and placebo groups. Moderately severe headache, nausea and vomiting were reported in one of two subjects treated with 720 µg/kg so 540 µg/kg was considered the highest tolerated dose. Mean plasma concentrations increased in proportion to dose. Clearance ranged from 11,693 ± 807 to 18,701 ± 4,797 mL/hr, volume of distribution ranged from 4,873±828 to 6,971 ± 1,169 mL, and elimination half-life ranged from 0.211 ± 0.097 to 0.294 ± 0.054 hours. Elevations in aPTT were minimal. Conclusions. 3K3A-APC was well tolerated at multiple doses as high as 540 µg/kg. These results should be confirmed in stroke patients with relevant co-morbidities.
    Current pharmaceutical design 12/2013; · 4.41 Impact Factor
  • Marian C Brady, Ali M, Lyden P
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    ABSTRACT: Background Aphasia and dysarthria have major implications for activities of daily living and social participation following stroke. Few studies describe recovery in the acute stroke setting. We described the evolution of aphasia and dysarthria by three-months poststroke. Methods We conducted a retrospective analysis of pooled clinical trial data from the Virtual International Stroke Trials Archive. We defined aphasia and dysarthria at baseline as a score of ≥1 on the Best Language (Item 9) and Dysarthria (Item 10) domains of the National Institutes of Health Stroke Scale, respectively. We described recovery from these impairments by three-months. Covariate adjusted analyses described the associations between aphasia, dysarthria, and functional outcome using the modified Rankin Scale at three-months following stroke. ResultsAt baseline, 4039/8904 (45·4%) people presented with aphasia and 6192 (69·5%) with dysarthria; 2639 (29·6%) had both impairments. By three–months, aphasia and dysarthria had resolved in 1292/7219 (17·9%) and 2892/7219 (40·1%) survivors, respectively, but persisted in 1713/7219 (23·7%) and 1940/7219 (27%), respectively. Age and severity of initial stroke were associated with poor recovery, whereas thrombolysis was associated with improved recovery. Aphasia at baseline [P = 0·049, odds ratio = 0·89, 95% confidence interval (0·79,1·00)] and persistent aphasia at three-months [P < 0·0001, odds ratio = 0·31, 95% confidence interval (0·27, 0·35)] were each associated with poorer modified Rankin Scale scores at three-months. Conclusion Aphasia or dysarthria persisted in at least a quarter of people in our dataset at three-months following stroke. The association between persistent aphasia at three-months and poor modified Rankin Scale renders this impairment a major therapeutic target for recovery and restitution.
    International Journal of Stroke 12/2013; · 2.75 Impact Factor
  • Patrick D Lyden
    Therapeutic hypothermia and temperature management. 12/2013; 3(4):171-2.
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    ABSTRACT: Therapeutic hypothermia improves neurological outcome after out-of-hospital cardiac arrest or neonatal hypoxic-ischemic injury. Although supported by preclinical evidence, therapeutic hypothermia for acute stroke remains under study. In the Intravascular Cooling in the Treatment of Stroke (ICTuS) trial, awake stroke patients were successfully cooled using an endovascular cooling catheter and a novel antishivering regimen. In the ICTuS-L study, the combination of endovascular hypothermia and thrombolysis proved feasible; while hypothermia was associated with no increased risk of bleeding complications, there was an increased association with pneumonia. Despite efforts to expedite, cooling began on average six-hours after stroke onset. We designed a novel Phase 2/3 trial to further test the safety of combined thrombolysis and endovascular hypothermia and to determine if the combination shows superiority compared with thrombolysis alone. ICTuS 2 (n = 400) will assess four hypotheses, and if milestones are met, ICTuS 3 (n = 1200) will begin as a seamless continuation for a total sample of 1600 patients. The ICTuS 2 milestones include (1) target temperature reached within six-hours of symptom onset; (2) no increased risk of pneumonia; (3) no increase in signs/symptoms of fluid overload due to chilled saline infusions; and (4) sufficient recruitment to complete the trial on time. The ICTuS 2/3 protocol contains novel features - based on the previous ICTuS and ICTuS-L trials - designed to achieve these milestones. Innovations include scrupulous pneumonia surveillance, intravenous chilled saline immediately after randomization to induce rapid cooling, and a requirement for catheter placement within two-hours of thrombolysis. An Investigational Device Exemption has been obtained and an initial group of sites initiated.
    International Journal of Stroke 11/2013; · 2.75 Impact Factor
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    ABSTRACT: 3K3A-activated protein C (APC) protects young, healthy male rodents after ischemic stroke. 3K3A-APC is currently under development as a neuroprotectant for acute ischemic stroke in humans. Stroke Therapy Academic Industry Roundtable recommends that after initial studies in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions. Here, we studied the effects of delayed 3KA-APC therapy alone and with tissue-type plasminogen activator (tPA) in aged female mice and spontaneously hypertensive rats. We used Stroke Therapy Academic Industry Roundtable recommendations for ensuring good scientific inquiry. Murine recombinant 3K3A-APC (0.2 mg/kg) alone or with recombinant tPA (10 mg/kg) was given intravenously 4 hours after transient middle cerebral artery occlusion in aged female mice and rats and after embolic stroke in spontaneously hypertensive rat. 3K3A-APC was additionally administered within 3 to 7 days after stroke. The neuropathological analysis and neurological scores, foot-fault, forelimb asymmetry, and adhesive removal tests were performed within 7 and 28 days of stroke. In all models, tPA alone had no effects on the infarct volume or behavior. 3K3A-APC alone or with tPA reduced the infarct volume 7 days after the middle cerebral artery occlusion in aged female mice and embolic stroke in spontaneously hypertensive rat by 62% to 66% and 50% to 53%, respectively, significantly improved (P<0.05) behavior, and eliminated tPA-induced intracerebral microhemorrhages. In aged female mice, 3K3A-APC was protective within 4 weeks of stroke. 3K3A-APC protects from ischemic stroke and extends the therapeutic window of tPA in aged female mice and in spontaneously hypertensive rat with a comorbid condition.
    Stroke 10/2013; · 6.16 Impact Factor
  • Therapeutic hypothermia and temperature management. 09/2013; 3(3):114-9.
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    Stroke 07/2013; · 6.16 Impact Factor
  • International Journal of Stroke 06/2013; 8:278-283. · 2.75 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: The objective of this pooled analysis was to determine the level of agreement between central read and each of 2 groups (spoke radiologists and hub vascular neurologists) in interpreting head computed tomography (CT) scans of stroke patients presenting to telestroke network hospitals. METHODS: The Stroke Team Remote Evaluation Using a Digital Observation Camera (STRokE DOC and STRokE DOC-AZ TIME) trials were prospective, randomized, and outcome blinded comparing telemedicine and teleradiology with telephone-only consultations. In each trial, the CT scans of the subjects were interpreted by the hub vascular neurologist in the telemedicine arm and by the spoke radiologist in the telephone arm. We obtained a central read for each CT using adjudicating committees blinded to treatment arm and outcome. The data were pooled and the results reported for the entire population. Kappa statistics and exact agreement rates were used to assess interobserver agreement for radiographic contraindication to recombinant tissue plasminogen activator (rt-PA), presence of hemorrhage, tumor, hyperdense artery, acute stroke, prior stroke, and early ischemic changes. RESULTS: Among 261 analyzed cases, the agreement with central read for the presence of radiological rt-PA contraindication was excellent for hub vascular neurologist (96.2%, κ = .81, 95% CI .64-.97), spoke radiologist report (94.7%, κ = .64, 95% CI .39-.88), and overall (95.4%, κ = .74, 95% CI .59-.88). For rt-PA-treated patients (N = 65), overall agreement was 98.5%, and vascular neurologist agreement with central read was 100%. CONCLUSIONS: Both vascular neurologists and reports from spoke radiologists had excellent reliability in identifying radiologic rt-PA contraindications. These pooled findings demonstrate that telestroke evaluation of head CT scans for acute rt-PA assessments is reliable.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 05/2013;
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    ABSTRACT: BACKGROUND: Aphasia affects up to a third of the stroke population and is associated with poor social participation and quality of life. Yet people with aphasia may be excluded from some types of stroke research due to challenges in informing, consenting, and conducting follow-up in this population. AIMS AND/OR HYPOTHESIS: We described the representation of those with aphasia in acute stroke clinical research, the level of inclusion across international trial sites, and whether there have been improvements in the inclusion of this population in recent clinical trials. METHODS: We conducted a retrospective analysis of clinical trial data from the Virtual International Stroke Trials Archive (VISTA), defining aphasia using the Best Language (item 9) domain of the National Institutes of Health Stroke Scale. We used proportional odds modeling, adjusting for age, gender, ethnicity, stroke severity, medical history, hemisphere affected by stroke, and trial eligibility criteria, to examine the associations between year, location of enrollment, inclusion, and attrition of those with aphasia. RESULTS: Data were available for 8904 patients from 10 trials; no trials listed aphasia as an exclusion criterion. At baseline, aphasia was present in 4039 (45·4%); severe/global aphasia was present in 2688 (30·2%). We observed no geographic or longitudinal disparity in the attrition of these patients at three-months. Centers in the Philippines recruited fewer people [P = 0·05, odds ratio = 0·5, 95% confidence interval (0·2, 1·0)], while centers in Central and South America included more people with severe/global aphasia [P = 0·0004, odds ratio = 2·4, 95% confidence interval (1·3, 4·3)], when compared with centers in the USA and Canada. CONCLUSIONS: Acute stroke trials have demonstrated the feasibility of including people with aphasia in stroke research; we observed geographic variations that were not entirely explained by case mix or trial eligibility criteria. Similar levels of inclusion should be sought in nonemergency stroke trials to improve the applicability of research findings to this population.
    International Journal of Stroke 03/2013; · 2.75 Impact Factor
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    ABSTRACT: BACKGROUND: Admitting facility may significantly affect outcome for spontaneous subarachnoid hemorrhage patients. We assessed outcomes of patients admitted directly to a comprehensive stroke center with those initially admitted to a general hospital and subsequently transferred. The comprehensive stroke center included a neurocritical care ICU, cerebrovascular neurosurgeons and endovascular specialists. METHODS: We identified 107 consecutive spontaneous subarachnoid hemorrhage cases. Of these cases, 31 (29%) patients were admitted directly and 76 (71%) were transferred from general hospitals. Univariate and multivariate analyses evaluated differences in mortality, complications, discharge disposition, and in-hospital length of stay. RESULTS: Differences in baseline parameters (age, gender, admission Glasgow Coma Scale, Fisher grade, admission Hunt and Hess grade) were not statistically significant between direct-admit and transfer patients at our institution. Transferred patients developed vasospasm more frequently (58% vs. 32%; P < 0·05) and had a longer delay time to surgery (3·9-days vs. 2·4-days: P < 0·05). Multivariate analysis showed that the likelihood of vasospasm was significantly higher for transfer patients (OR 3·46, CI: 1·2-10·3, P = 0·03). In addition, longer in-hospital stays and higher odds of non-routine discharge were observed in transferred patients (P < 0·01). No differences in outcome could be identified for surgical vs. endovascular treatment rates between direct-admit and transfer patients. An association, but no causative link, can be made between the effect of transfer and the outcomes of SAH patients due to the retrospective nature of our study. CONCLUSIONS: Spontaneous subarachnoid hemorrhage patients admitted directly to our comprehensive stroke center showed less complications compared to those transferred from general hospitals. This improvement was independent of time to treatment. Additional research in multiple centers using prospective analysis should be conducted to confirm that preferential direct transport to a comprehensive stroke center would likely yield considerable improvements in public health.
    International Journal of Stroke 03/2013; · 2.75 Impact Factor
  • Therapeutic hypothermia and temperature management. 03/2013; 3(1):3-6.
  • Patrick Lyden, Karin Ernstrom, Rema Raman
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    ABSTRACT: Therapeutic hypothermia is a promising neuroprotective therapy with multiple mechanisms of action. Previously, we demonstrated the feasibility of thrombolysis combined with endovascular hypothermia and an antishivering regimen, but pneumonia occurred more often in cooled patients. We sought to identify whether any factors could be identified that increased pneumonia risk. We examined 26 patients who underwent endovascular hypothermia. Pneumonia was assessed and scored as present by the treating physician without prespecified definitions or surveillance protocols. Using logistic regression, we examined the risk of pneumonia; the effects of age, weight, body mass index (BMI), body surface area, respiration rate, heart rate, blood pressure, baseline National Institutes of Health Stroke Scale (NIHSS), gender, shivering, and area under the curve below 34°C; and total meperidine dose, individually and in a multivariable model. Pneumonia was reported by site investigators in 13 subjects (50%). In univariate analyses, BMI and baseline NIHSS emerged as the baseline variables that were independently associated with risk of pneumonia. Multivariable logistic regression analysis identified baseline NIHSS as marginally associated with risk of pneumonia, after adjustment for BMI (OR: 1.19, 95% CI: 0.98, 1.43; p=0.0740). In a group of hypothermia patients suffering a 50% reported incidence of pneumonia, we found no variables that explained risk other than baseline NIHSS. Future trials should include rigorous definitions of pneumonia and prespecified surveillance methods to minimize case ascertainment bias. Measures to prevent pneumonia are needed in all patients treated with hypothermia.
    Therapeutic hypothermia and temperature management. 03/2013; 3(1):24-27.
  • Patrick D Lyden
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    ABSTRACT: BACKGROUND: Despite the increasing use of thrombolytic therapy for acute ischemic stroke, hemorrhagic transformation remains a significant complication. Transformation appears to occur more frequently with age, diabetes, and hypertension, but clinical data are mixed. In addition to risk factors, matrix metalloproteinase expression mediates hemorrhage. We sought to test the effects of age, hypertension, and matrix metalloproteinases during recombinant tissue plasminogen activator (rt-PA) treatment in a standard model of filament occlusion of the middle cerebral artery. METHODS: We compared young and aged rats who were genetically predisposed to hypertension to similar and dissimilar strains to separate the effect of hypertension and age. RESULTS: Hemorrhagic transformation occurred significantly more frequently in chronically hypertensive animals-23 of 53 (44%) compared to 2 of 23 (9%) normotensive, genetically similar rats (Chi-square; P < .001; Mantel-Haenszel common odds ratio estimate 12.33 [95% confidence interval 2.7-57.0]). Hemorrhage rates were comparable in aged and young chronically hypertensive animals. Induced acute hypertension during reperfusion did not appear to alter rates of transformation. In hypertensive (n = 26) compared to genetically similar normotensive (n = 12) animals, rt-PA treatment increased mortality to 35% from 0% (Chi-square; P < .05), while hemorrhage occurred in 50% of the rt-PA-treated hypertensive subjects compared to 8% of the normotensive animals (Chi-square; P < .05). Two different inhibitors of matrix metalloproteinases significantly reduced mortality but not hemorrhage rates. CONCLUSIONS: Our data suggest for the first time an effect of chronic hypertension separate from age on the risk of hemorrhagic transformation. In addition, inhibitors of matrix metalloproteinases may protect the neurovascular unit directly, even without reducing hemorrhage risk. These findings will require additional research.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 02/2013;
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    ABSTRACT: BACKGROUND AND PURPOSE: Intravenous thrombolysis with alteplase is approved for acute ischemic stroke, but its use is limited by numerous contraindications and warnings arising from trial selection criteria or expert opinions. We examined outcomes from alteplase-treated versus untreated patients, registered in a trials archive, according to presence or absence of specified contraindications and warnings. METHODS: We analyzed 90-day modified Rankin Scale across the whole distribution of scores using the Cochran-Mantel-Haenszel test, with adjustment for age and baseline National Institutes of Health Stroke Score, followed by proportional odds logistic regression analysis to estimate the odds ratios for preferred outcome. RESULTS: We used data from 9613 ischemic stroke patients of whom 2755 were treated with thrombolysis. Adjusted odds ratios showed a broad trend of more favorable 3-month outcome associated with alteplase treatment versus no treatment in various subgroups of patients with contraindications and warnings; for example, 1.40 (95% confidence interval [CI], 1.14-1.70) in patients aged >80 (n=1805), 1.50 (95% CI, 1.03-2.18) in patients with combined history of prior stroke and diabetes mellitus (n=672), 1.42 (95% CI, 1.19-1.70) in patients on prior single antiplatelet agent (n=1626), 2.20 (95% CI, 1.12-4.32) in patients on oral anticoagulation, and International Normalized Ratio≤1.7 (n=157), 1.50 (95% CI, 1.15-1.97) in patients with baseline glucose >180 (n=879), and 1.57 (95% CI, 1.12-2.18) in patients with pretreatment National Institutes of Health Stroke Score >22 (n=620).Conclusions This comprehensive retrospective analysis of various contraindications and warnings provides reassurance about benefits and risks of intravenous alteplase treatment in common clinical situations.
    Stroke 02/2013; · 6.16 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Approved use of intravenous alteplase for ischemic stroke offers net benefit. Pooled randomized controlled trial analysis suggests additional patients could benefit but others be harmed with treatment initiated beyond 4·5 h after stroke onset. We proposed prognostic scoring methods to identify a strategy for patient selection. METHODS: We selected 500 patients treated by intravenous alteplase and 500 controls from Virtual International Stroke Trials Archive, matching modified Rankin score outcomes to those from pooled randomized controlled trial 4·5-6 h data. We ranked patients by prognostic score. We chose limits to optimize our sample for a net treatment benefit significant at P = 0·01 by Cochran-Mantel-Haenszel test and by ordinal regression. For validation, we had these applied to the pooled randomized controlled trial data for 4·5-6 h, testing for net benefit by Cochran-Mantel-Haenszel test, ordinal regression, and also by dichotomized outcomes: modified Rankin score 0-1, mortality and parenchymal hemorrhage type 2 bleeds. All analyses were adjusted for age and National Institutes of Health Stroke Scale. RESULTS: In the training dataset, limits of 56-95 on a prognostic score retained 714 patients in whom there was net benefit significant at P = 0·01. When applied to the 1120 patients in the pooled randomized controlled trial 4·5-6 h dataset, score limits of 56-95 retained 711 patients and gave odds ratio for improved modified Rankin score distribution of 1·13, 95% confidence interval 0·87-1·47, Cochran-Mantel-Haenszel P = 0·89. More patients achieved modified Rankin score 0-1 (odds ratio 1·44, 1·02-2·05, P = 0·04) but mortality and parenchymal hemorrhage type 2 bleeds were increased: odds ratio 1·56, 1·01-2·40, P = 0·04; odds ratio 15·6, 3·7-65·8, P = 0·0002, respectively. CONCLUSION: Selection of patients between 4·5 and 6 h based on simple clinical measures failed to deliver a population in whom the alteplase effect would be safe and effective.
    International Journal of Stroke 01/2013; · 2.75 Impact Factor

Publication Stats

7k Citations
1,374.08 Total Impact Points


  • 2009–2013
    • Cedars-Sinai Medical Center
      • Cedars Sinai Medical Center
      Los Angeles, CA, United States
    • Mahidol University
      • Faculty of Medicine Siriraj Hospital
      Bangkok, Bangkok, Thailand
    • University of Otago
      • Department of Medicine (Dunedin)
      Dunedin, Otago, New Zealand
  • 2012
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
    • University of New Mexico
      • Department of Neurology
      Albuquerque, NM, United States
    • University of California, Los Angeles
      • Department of Neurology
      Los Angeles, California, United States
    • Tel Aviv University
      Tell Afif, Tel Aviv, Israel
  • 1987–2012
    • University of California, San Diego
      • • Department of Neurosciences
      • • Division of Urology
      • • Department of Emergency Medicine
      San Diego, California, United States
  • 2008–2011
    • Hospital of the University of Pennsylvania
      • Department of Neurology
      Philadelphia, Pennsylvania, United States
    • University of Wisconsin, Madison
      • Department of Neurology
      Madison, MS, United States
  • 2002–2011
    • University of Glasgow
      • • Institute of Cardiovascular and Medical Sciences
      • • Division of Neuroscience
      Glasgow, Scotland, United Kingdom
  • 2010
    • Mount Sinai School of Medicine
      • Department of Neurology
      Manhattan, New York, United States
  • 2006–2009
    • National University (California)
      San Diego, California, United States
    • Psychiatric Centers at San Diego
      San Diego, California, United States
  • 1998–2008
    • Naval Medical Center San Diego
      • Department of Emergency Medicine
      San Diego, CA, United States
  • 1998–2007
    • Wayne State University
      • • Department of Physical Medicine and Rehabilitation
      • • Department of Pharmacy Practice
      Detroit, MI, United States
  • 1999–2006
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2004
    • Huntington Medical Research Institutes
      Pasadena, California, United States
  • 2003
    • Vanderbilt University
      • Department of Psychology
      Nashville, MI, United States
  • 2001
    • University of Texas Medical School
      • Department of Neurology
      Houston, Texas, United States
  • 2000
    • University of Pittsburgh
      • Stroke Institute
      Pittsburgh, PA, United States
    • University of Alberta
      Edmonton, Alberta, Canada
  • 1997
    • CSU Mentor
      Long Beach, California, United States
  • 1995
    • University of South Alabama
      • Department of Neurology
      Mobile, AL, United States
  • 1991
    • Oregon Health and Science University
      • Department of Neurology
      Portland, OR, United States