Thomas G Brott

University of Washington Seattle, Seattle, Washington, United States

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Publications (243)1770.61 Total impact

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    ABSTRACT: The Carotid Revascularization Endarterectomy versus Stenting Trial was completed with a low stroke and death rate. A lead-in series of patients receiving carotid artery stenting was used to select the physician-operators for the study, where performance was evaluated by complication rates and by peer review of cases. Herein, we assess the potential contribution of statistical evaluation of complication rates.
    09/2014;
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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: The accuracy of stroke diagnosis in administrative claims for a contemporary population of Medicare enrollees has not been studied. We assessed the validity of diagnostic coding algorithms for identifying stroke in the Medicare population by linking data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study to Medicare claims.
    Circulation Cardiovascular Quality and Outcomes 06/2014; · 5.66 Impact Factor
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    ABSTRACT: After ischemic or hemorrhagic stroke, neurons in the penumbra surrounding regions of irreversible injury are vulnerable to delayed but progressive damage as a result of ischemia and hemin-induced neurotoxicity. There is no effective treatment to rescue such dying neurons. Mesenchymal stem cells (MSCs) hold promise for rescue of these damaged neurons. In this study, we evaluated the efficacy and mechanism of MSC-induced neuro-regeneration and immune modulation.
    Cytotherapy 06/2014; · 3.06 Impact Factor
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    ABSTRACT: Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years' funding ($21 112 866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2500 randomized participants at 40 sites.AimsHerein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials.Methods Projections of the original grant's fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant's fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated.ResultsUsing a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2500 targeted sample size, 138 (5·5%) were randomized during the first five years and 1387 (55·5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13 845) of the projected per-patient costs ($152 992) of the fixed model.Conclusions Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity.
    International Journal of Stroke 04/2014; · 2.75 Impact Factor
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    ABSTRACT: Objective Patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) had duplex ultrasound (DU) scans prior to treatment and during follow-up to document the severity of carotid disease and the anatomic outcome of carotid endarterectomy (CEA) or carotid artery stenting (CAS). An ultrasound core laboratory (UCL) reviewed DU data from the clinical sites. This analysis was done to determine the agreement between site-reported and UCL-verified DU velocity measurements. Methods Clinical site DU worksheets, B-mode images, and Doppler velocity waveforms for the treated carotid arteries were reviewed at the UCL. The highest internal carotid artery peak systolic velocity (PSV) and associated Doppler angle were verified. If the angle was misaligned by >3 degrees, it was remeasured at the UCL and the PSV was recalculated. Agreement for PSV was defined as site-reported PSV within ±5% of UCL-verified PSV. Transcription errors were corrected by the UCL but were not considered as disagreements. Follow-up analysis was limited to patients who received the assigned treatment. Results The UCL reviewed 1702 prior-to-treatment and 1743 12-month follow-up DU scans (873 CEA, 870 CAS) from 111 clinical sites. Site-reported and UCL-verified PSV agreed in 1124 (66%) of the prior-to-treatment scans and 1200 (69%) of the follow-up scans. In those cases with a disagreement, Doppler angle accounted for disagreement in 339 (59%) of the prior-to-treatment scans and 277 (51%) of the follow-up scans. Based on a threshold PSV for ≥70% stenosis of ≥230 cm/s on the prior-to-treatment scans and ≥300 cm/s on the follow-up scans, UCL review resulted in reclassification of stenosis severity in 75 (4.4%) of the prior-to-treatment scans and 13 (0.75%) of the follow-up scans. There is evidence that the proportion of reclassification at follow-up was greater for CAS (10 scans; 1.2%) than for CEA (three scans; 0.34%) (P = .057). Conclusions There was a high rate of agreement between site-reported and UCL-verified DU results in CREST, and UCL review was associated with a low rate of stenosis reclassification. However, angle alignment errors were quite common and prompted recalculation of velocity in 20% of prior-to-treatment scans and 18% of follow-up scans. The use of a UCL provides a uniform process for DU interpretation and can identify sources of error and suggest technical improvements for future studies.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 01/2014; 57(5):49S–50S. · 3.52 Impact Factor
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    ABSTRACT: Censoring that is dependent on covariates associated with survival can arise in randomized trials due to changes in recruitment and eligibility criteria to minimize withdrawals, potentially leading to biased treatment effect estimates. Imputation approaches have been proposed to address censoring in survival analysis; while these approaches may provide unbiased estimates of treatment effects, imputation of a large number of outcomes may over- or underestimate the associated variance based on the imputation pool selected. We propose an improved method, risk-stratified imputation, as an alternative to address withdrawal related to the risk of events in the context of time-to-event analyses. Our algorithm performs imputation from a pool of replacement subjects with similar values of both treatment and covariate(s) of interest, that is, from a risk-stratified sample. This stratification prior to imputation addresses the requirement of time-to-event analysis that censored observations are representative of all other observations in the risk group with similar exposure variables. We compared our risk-stratified imputation to case deletion and bootstrap imputation in a simulated dataset in which the covariate of interest (study withdrawal) was related to treatment. A motivating example from a recent clinical trial is also presented to demonstrate the utility of our method. In our simulations, risk-stratified imputation gives estimates of treatment effect comparable to bootstrap and auxiliary variable imputation while avoiding inaccuracies of the latter two in estimating the associated variance. Similar results were obtained in analysis of clinical trial data. Risk-stratified imputation has little advantage over other imputation methods when covariates of interest are not related to treatment. Risk-stratified imputation is intended for categorical covariates and may be sensitive to the width of the matching window if continuous covariates are used. The use of the risk-stratified imputation should facilitate the analysis of many clinical trials, in which one group has a higher withdrawal rate that is related to treatment.
    Clinical Trials 07/2013; · 2.20 Impact Factor
  • James F Meschia, Kevin M Barrett, Thomas G Brott
    Mayo Clinic Proceedings 05/2013; · 5.79 Impact Factor
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    ABSTRACT: OBJECTIVE: There are few data regarding the effect of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial results on the management of intracranial atherosclerotic disease (ICAD). We sought to understand the impact of the SAMMPRIS trial on current ICAD clinical practices and future trial design. METHODS: During the ICAD symposium at the 2012 International Stroke Conference, electronic data were collected regarding attendees' clinical management of ICAD and opinions on the feasibility of future trials post-SAMMPRIS. RESULTS: 217 attendees from different specialties, including neurologists (57%), neurointerventionalists (9%) and neurosurgeons (5%), participated in the session. The majority of respondents (77%) indicated that the results of SAMMPRIS have impacted their consideration for intracranial stenting. Post-SAMMPRIS, 84% selected 'SAMMPRIS-style' medical management for the treatment of ICAD. For patients with ICAD who failed aggressive medical therapy, 82% would consider an alternative approach to continuing medical therapy (30% considered clinical trial enrollment, 28% suggested angioplasty and stenting and 24% angioplasty). The majority of participants (85%) were willing to randomize patients with symptomatic ICAD in future trials. For the next ICAD trial, 29% indicated that angioplasty alone should be compared with aggressive medical therapy. CONCLUSIONS: Our polling results suggest that the SAMMPRIS trial has had an impact on the current treatment of ICAD. Treatment of patients who failed medical therapy varied widely from aggressive medical therapy to balloon angioplasty, stenting or enrollment in future clinical trials. The willingness to continue clinical trials and randomize patients supports the need for future ICAD studies.
    Journal of neurointerventional surgery 04/2013; · 1.38 Impact Factor
  • Joseph L Blackshear, Thomas G Brott
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    ABSTRACT: The majority of carotid revascularization procedures performed at present are in asymptomatic patients. Since such procedures convey no immediate benefit, but rather protect from future hazard, optimization of procedural safety is mandatory. The authors focus their discussion on the methodologies that assess periprocedural myocardial damage and brain injury, as used in past clinical trials, from the fields of perioperative medicine and neurovascular imaging, and discuss methodologies to reduce both events in carotid revascularization.
    Expert Review of Cardiovascular Therapy 04/2013; 11(4):469-84.
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    ABSTRACT: BACKGROUND AND PURPOSE: Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). METHODS: This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. RESULTS: IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). CONCLUSIONS: This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences.
    Stroke 01/2013; · 6.16 Impact Factor
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    ABSTRACT: Mutations within the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CADASIL mutations appear to be restricted to the first twenty-four exons, resulting in the gain or loss of a cysteine amino acid. The role of other exonic NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in ischemic stroke remains unresolved. All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American affected sibling pair study and 95 healthy Caucasian control subjects. Variants identified by sequencing in the SWISS probands were then tested for association with ischemic stroke using US Caucasian controls collected at the Mayo Clinic (n=654), and further assessed in a Caucasian (n=802) and African American (n=298) patient-control series collected through the Ischemic Stroke Genetics Study (ISGS). Sequencing of the 269 SWISS probands identified one (0.4%) with small vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the 19 common NOTCH3 variants identified, the only variant significantly associated with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403; Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50, P=0.0022) where presence of the minor allele was protective against ischemic stroke. Although only significant prior to adjustment for multiple testing, p.T101T (rs3815188; Exon 3) was associated with an increased risk of small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in Caucasians. No significant associations were observed in the small African American series. Cysteine-affecting NOTCH3 mutations are rare in patients with typical ischemic stroke, however our observation that common NOTCH3 variants may be associated with risk of ischemic stroke warrants further study.
    PLoS ONE 01/2013; 8(9):e75035. · 3.53 Impact Factor
  • Catheterization and Cardiovascular Interventions 01/2013; 81(1):E76-E123. · 2.51 Impact Factor
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    ABSTRACT: OBJECTIVE: Outcomes in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) did not differ between carotid artery stenting (CAS) and carotid endarterectomy (CEA) for the composite primary end point of stroke, myocardial infarction (MI), or death during the periprocedural period or ipsilateral stroke within 4 years. Rigorous credentialing and training of interventionists, including vascular surgeons, were required for the randomization phase of CREST. Because the lead-in phase of CREST had suggested higher perioperative risks after CAS performed by vascular surgeons, the purpose of this analysis was to examine differences in outcomes after randomization between CAS and CEA performed by vascular surgeons. METHODS: CREST is a prospective randomized controlled trial with blinded end point adjudication. Vascular surgeons performed 237 (21%) of the CAS procedures and 765 (65%) of the CEA procedures among 2320 patients who received their assigned treatment. Proportional hazards analyses were used to estimate the relative efficacy of CAS vs CEA for the composite primary end point and also for stroke and death. RESULTS: Among 2502 randomized patients, 1321 (53%) were symptomatic and 1181 (47%) were asymptomatic. For procedures performed exclusively by vascular surgeons, the primary end point did not differ between CAS and CEA at 4-year follow-up (6.2% vs 5.6%, respectively; hazard ratio [HR], 1.30; 95% confidence interval [CI], 0.70-2.41; P = .41) In this subgroup, the periprocedural stroke and death rates were higher after CAS than CEA for symptomatic patients (6.1% vs 1.3%; P = .01). Asymptomatic patients also had slightly higher stroke and death rates after CAS (2.6% vs 1.1%; P = .20), although this difference did not reach statistical significance. Conversely, cranial nerve injuries (0.0% vs 5.0%; P < .001) were less frequent after CAS than CEA. The MI rates were slightly lower after CAS (1.3% vs 2.6%; P = .24). In performing CAS, vascular surgeons had outcomes for the periprocedural primary end point comparable to the outcomes of all interventionists (HR, 0.99; 95% CI, 0.50-2.00) after adjusting for age, sex, and symptomatic status. Vascular surgeons also had similar results after CEA for the periprocedural primary end point compared with other surgeons (HR, 0.73; 95% CI, 0.42-1.27). CONCLUSIONS: When performed by surgeons, CAS and CEA have similar net outcomes, although the periprocedural risks vary (lower stroke with CEA and lower MI with CAS). These data suggest that appropriately trained vascular surgeons may safely offer both CEA and CAS for the prevention of stroke. The remarkably low stroke and death rates after CEA performed by vascular surgeons in CREST, particularly among symptomatic patients, represent the best outcomes ever reported after carotid interventions from a randomized controlled trial. ClinicalTrials.gov identifier: NCT0000473.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 12/2012; · 3.52 Impact Factor
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    ABSTRACT: BACKGROUND: Stroke occurs more commonly after carotid artery stenting than carotid endarterectomy. Details regarding stroke type, severity, and characteristics have not been previously reported. We describe the strokes occurring in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). METHODS AND RESULTS: CREST is a randomized, open-allocation, controlled trial with blinded endpoint adjudication. Stroke was a component of the primary composite outcome. Patients who received their assigned treatment within 30 days of randomization are included. Stroke was adjudicated by a panel of board-certified vascular neurologists with secondary central review of clinically-obtained brain images. Stroke type, laterality, timing, and outcome are reported. A periprocedural stroke occurred among 81 of the 2502 patients randomized and among 69 of the 2272 in this analysis. Strokes were predominantly minor (81%, n=56), ischemic (90%, n=62), in the anterior circulation (94%, n=65), and ipsilateral to the treated artery (88%, n=61). There were seven hemorrhages, occurring 3-21 days post-procedure, and five were fatal. Major stroke occurred in 13 (0·6%) of the 2272 patients. The estimated four-year mortality after stroke was 21·1% compared to 11·6% for those without stroke. The adjusted risk of death at four years was higher after periprocedural stroke (HR = 2·78, CI(95) 1·63-4·76). CONCLUSIONS: Stroke, particularly severe stroke, was uncommon after carotid intervention in CREST, but stroke was associated with significant morbidity and was independently associated with a near threefold increased future mortality. The delayed timing of major and hemorrhagic stroke after revascularization suggests that these strokes may be preventable. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov. Identifier: NCT00004732.
    Circulation 11/2012; · 15.20 Impact Factor
  • Brajesh K Lal, Thomas G Brott
    The Lancet Neurology 11/2012; · 23.92 Impact Factor
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    ABSTRACT: Objectives The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. Background A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. Methods and results Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, the Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. Conclusions This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
    European Heart Journal 10/2012; 33(19):2403-18. · 14.10 Impact Factor
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    ABSTRACT: The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 10/2012; 42(5):S45-60. · 2.40 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10(-4); discovery and replication combined OR = 1.21, P = 4.7 × 10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.
    Nature Genetics 09/2012; 44(10):1147-1151. · 35.21 Impact Factor
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    ABSTRACT: Carotid endarterectomy (CEA) has been shown to prevent stroke in patients with severe carotid stenosis. Carotid artery stenting (CAS) has emerged as a less invasive alternative technique. Data regarding comparative effectiveness of CAS and CEA are now available and merit review. Four large randomized controlled trials (RCTs) comparing CAS and CEA have shown a higher rate of stroke in symptomatic patients. The largest and most recent trial reported a lower occurrence of myocardial infarction (MI) following CAS and showed overall comparability of CAS to CEA for both symptomatic and asymptomatic patients. Despite methodological differences, these RCTs are consistent in finding an interaction of patient age with outcomes. In younger patients, CAS appears equivalent or superior to CEA if considering the sum of death, stroke, and MI. In elderly patients, CEA appears to have a lower complication rate. For asymptomatic patients, reduction in event rates with current medical therapy may render previous trial results invalid. CAS is an alternative to CEA in patients requiring carotid intervention. Comparison of both CAS and CEA with contemporary medical management will also be required before recommendations can be made regarding the optimal treatment of patients with asymptomatic carotid stenoses.
    Current opinion in cardiology 08/2012; 27(6):565-71. · 2.66 Impact Factor

Publication Stats

14k Citations
1,770.61 Total Impact Points

Institutions

  • 2005–2014
    • University of Washington Seattle
      • Department of Surgery
      Seattle, Washington, United States
    • Mayo Clinic
      Jacksonville, Florida, United States
  • 2000–2014
    • Mayo Foundation for Medical Education and Research
      • • Division of Cardiovascular Diseases
      • • Department of Neurology
      • • Division of Vascular Surgery
      • • Department of Pharmacology
      Rochester, Michigan, United States
    • University of Pittsburgh
      • Department of Neurology
      Pittsburgh, PA, United States
    • American Heart Association
      Dallas, Texas, United States
    • Emory University
      • Department of Neurology
      Atlanta, GA, United States
  • 2013
    • Medical College of Wisconsin
      • Department of Neurology
      Milwaukee, WI, United States
  • 2012
    • The University of Calgary
      • Hotchkiss Brain Institute
      Calgary, Alberta, Canada
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
  • 2011
    • Oregon Health and Science University
      • Stroke Center
      Portland, Oregon, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 2009–2011
    • University of Alabama at Birmingham
      • Department of Epidemiology
      Birmingham, AL, United States
    • University of Maryland Medical Center
      • Division of Vascular Surgery
      Baltimore, Maryland, United States
  • 2010
    • Rutgers New Jersey Medical School
      • Department of Surgery
      Newark, NJ, United States
    • University at Buffalo, The State University of New York
      • Department of Neurosurgery
      Buffalo, NY, United States
  • 2007–2009
    • National Institutes of Health
      • • Section on Mammalian Molecular Genetics
      • • Section on Molecular Genetics of Immunity
      Bethesda, MD, United States
    • Umeå University
      Umeå, Västerbotten, Sweden
  • 1990–2009
    • University of Cincinnati
      • • Department of Neurology
      • • Department of Emergency Medicine
      • • Department of Electrical and Computer Engineering and Computer Science
      Cincinnati, Ohio, United States
  • 2008
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
    • National Institute on Aging
      • Laboratory of Neurogenetics (LNG)
      Baltimore, Maryland, United States
  • 2003–2008
    • University of Virginia
      • • Department of Public Health Sciences
      • • Department of Neurology
      Charlottesville, VA, United States
    • University of Massachusetts Medical School
      • Department of Neurology
      Worcester, MA, United States
  • 2006
    • University of Groningen
      • Department of Surgery
      Groningen, Groningen, Netherlands
  • 1997–2001
    • University of California, San Diego
      • Department of Neurosciences
      San Diego, CA, United States
  • 1999
    • Universität Heidelberg
      • Neurological Clinic
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1994
    • Cornell University
      Ithaca, New York, United States
  • 1993–1994
    • University of Michigan
      • Department of Emergency Medicine
      Ann Arbor, MI, United States
  • 1992
    • Henry Ford Hospital
      • Department of Neurology
      Detroit, MI, United States