Howard, George

Background and Purpose— 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. Methods— The ability to discriminate between stent operators who can successfully meet the published guideline of <3% combined rate of stroke and death is calculated under the binomial distribution, based on a small consecutive case series (n=24 patients). Results— A criterion of ≤2 stroke or death events among the 24 patients (<8% event rate) was required of operators. Setting such a high criterion, however, ensures an inability to exclude operators who cannot meet the criteria. In fact, if a good operator is defined as having a 2% event rate and a poor operator as a 6% event rate, even a series of 240 patients would (on average) still exclude 5.4% of the good operators and include 4.6% of the poor operators. Conclusions— The low periprocedural event rates in the trial suggest success in separating skillful operators from less skillful. However, it seems unlikely that statistical assessment of event rates in the lead-in contributed to successful selection, but rather successful selection was more likely because of peer review of subjective and other factors including patient volume and technical approaches. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00004732.

Background 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. Purpose 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. Methods 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. Results 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. Limitations 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. Conclusions 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.

Background— Stroke occurs more commonly after carotid artery stenting than after carotid endarterectomy. Details regarding stroke type, severity, and characteristics have not been reported previously. We describe the strokes that have occurred in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Methods and Results— CREST is a randomized, open-allocation, controlled trial with blinded end-point adjudication. Stroke was a component of the primary composite outcome. Patients who received their assigned treatment within 30 days of randomization were 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 were reported. A periprocedural stroke occurred among 81 of the 2502 patients randomized and among 69 of the 2272 in the present 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 7 hemorrhages, which occurred 3 to 21 days after the procedure, and 5 were fatal. Major stroke occurred in 13 (0.6%) of the 2272 patients. The estimated 4-year mortality after stroke was 21.1% compared with 11.6% for those without stroke. The adjusted risk of death at 4 years was higher after periprocedural stroke (hazard ratio, 2.78; 95% confidence interval, 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 nearly 3-fold increased future mortality. The delayed timing of major and hemorrhagic stroke after revascularization suggests that these strokes may be preventable. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00004732.

OBJECTIVE Stroke symptoms among individuals reporting no physician diagnosis of stroke are associated with an increased risk of future stroke. Few studies have assessed whether individuals with diabetes or prediabetes, but no physician diagnosis of stroke, have an increased prevalence of stroke symptoms. RESEARCH DESIGN AND METHODS This study included 25,696 individuals aged ≥45 years from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who reported no history of stroke or transient ischemic attack at baseline (2003–2007). Glucose measurements, medication use, and self-reported physician diagnosis were used to categorize participants into diabetes, prediabetes, or normal glycemia groups. The presence of six stroke symptoms was assessed using a validated questionnaire. RESULTS The prevalence of any stroke symptom was higher among participants with diabetes (22.7%) compared with those with prediabetes (15.6%) or normal glycemia (14.9%). In multivariable models, diabetes was associated with any stroke symptom (prevalence odds ratio [POR] 1.28 [95% CI 1.18–1.39]) and two or more stroke symptoms (1.26 [1.12–1.43]) compared with normal glycemia. In analyses of individual stroke symptoms, diabetes was associated with numbness (1.15 [1.03–1.29]), vision loss (1.52 [1.31–1.76]), half-vision loss (1.54 [1.30–1.84]), and lost ability to understand people (1.34 [1.12–1.61]) after multivariable adjustment. No association was present between prediabetes and stroke symptoms. CONCLUSIONS In this population-based study, almost one in four individuals with diabetes reported stroke symptoms, which suggests that screening for stroke symptoms in diabetes may be warranted.

Background and Purpose— We compared the associations of self-reported atrial fibrillation (AF) and ECG-detected AF with incident stroke in the Risk of Stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods— In this analysis, 27 109 participants aged 45 years or older without previous stroke were included. Stroke cases were identified and adjudicated during an average of 4.4 years of follow-up. Cox proportional hazards analysis was used to calculate hazard ratios (HR) of self-reported AF, ECG-detected AF, and AF detected by either method with incident stroke. We also examined the predictive ability of the Framingham Stroke Risk Score (FSRS) when the component AF was defined by different methods. Results— After adjustment for components of the FSRS, self-reported AF, ECG-detected AF, and AF by either method were predictive of incident stroke (HR, 1.41; 95% CI, 1.05–1.88; HR, 1.90; 95% CI, 1.10–3.27; HR, 1.53; 95% CI, 1.16–2.01, respectively). When self-report, ECG, or either method, separately, were considered as the method of AF ascertainment in the FSRS, the HR per 1% increase in the FSRS were identical across AF ascertainment methods (HR, 1.04; 95% CI, 1.03–1.04; HR, 1.04; 95% CI, 1.04–1.05; HR, 1.04; 95% CI, 1.03–1.04; respectively). Conclusions— Self-reported AF is a strong predictor of stroke that can be used interchangeably or in combination with ECG-detected AF in stroke risk prediction models.

Background and Purpose— Warfarin reduces stroke risk by approximately 60% in patients with atrial fibrillation (AF). Differences in awareness and treatment of AF may contribute to racial and geographic disparities in stroke mortality. The objective was to examine predictors of awareness of the diagnosis of AF and treatment with warfarin. Methods— RE asons for G eographic a nd R acial D ifferences in S troke (REGARDS) is a national, population-based, longitudinal study of 30 239 blacks and whites ≥45 years old with oversampling from blacks and the southeastern stroke belt states. Participants were enrolled January 2003 to October 2007. Data were collected using telephone interview, in-home evaluation, and self-administered questionnaires. The main variable of awareness of AF was defined by a positive answer to “Has a doctor or other health professional ever told you that you had atrial fibrillation?” and whether there was evidence of treatment on the basis of an in-home medications inventory. Results— From baseline electrocardiograms, 432 individuals (88 black and 344 white) had AF. Of these, 88% (360 of 409) had at least 1 additional CHADS 2 stroke risk factor and 60% (258 of 432) were aware of their AF. The odds of blacks being aware of their AF were one third that of whites (OR=0.32; 95% CI: 0.20 to 0.52). Among those aware, the odds of blacks being treated with warfarin were only one fourth as great as whites (OR=0.28; 0.13 to 0.60). Conclusion— Blacks were less likely than whites to be aware of having AF or to be treated with warfarin. Potential reasons for the racial disparity in warfarin treatment warrant further investigation.

Rationale Carotid endarterectomy (CEA) and medical therapy were shown superior to medical therapy alone for symptomatic (ge;50%) and asymptomatic (≥60%) stenosis. Carotid angioplasty stenting (CAS) offers a less invasive alternative. Establishing safety, efficacy, and durability of CAS requires rigorous comparison with CEA in symptomatic and asymptomatic patients. Aims The objective is to compare the efficacy of CAS versus CEA in patients with symptomatic (≥50%) or asymptomatic (≥60%) extracranial carotid stenosis. Design The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) is a prospective, randomized, parallel, two-arm, multi-center trial with blinded endpoint adjudication. Primary endpoints are analyzed using standard time-to-event statistical modeling with adjustment for major baseline covariates. Primary analysis is on an intent-to-treat basis. Study Outcomes The primary outcome is the occurrence of any stroke, myocardial infarction, or death during a 30-day peri-procedural period, and ipsilateral stroke during follow-up of up to four years. Secondary outcomes include restenosis and health-related quality of life.

Background and Purpose— Previous studies of multiple-day dosing with the defibrinogenating agent, ancrod, in acute ischemic stroke yielded conflicting results but suggested that a brief dosing regimen might improve efficacy and safety. The Ancrod Stroke Program was designed to test this concept in subjects beginning ancrod or placebo within 6 hours of the onset of acute ischemic stroke. Methods— Five hundred subjects with acute ischemic stroke who could begin receiving study material within 6 hours of symptom onset were infused intravenously with either ancrod (0.167 IU/kg per hour) or placebo over 2 or 3 hours. The primary efficacy outcome was a dichotomized, modified Rankin score at 90 days with less stringent cut-points for higher prestroke modified Rankin score and pretreatment NIHSS total score (“responder analysis”). Safety variables included mortality, major bleeding, and intracranial hemorrhage. Results— Although the desired changes in fibrinogen level were seen in >90% of ancrod subjects, interim analysis for futility led to the study being halted for lack of efficacy. Positive responder status in the interim dataset was seen in 39.6% of ancrod subjects and 37.2% of placebo subjects ( P =0.47). Ninety-day mortality did not differ between the 2 groups (ancrod, 15.6%; placebo, 14.1%; P =0.32), and the incidence of symptomatic intracranial hemorrhage within the first 72 hours, although not significantly different in ancrod compared to placebo subjects ( P =0.19), was approximately twice as high (3.9% vs 2.0%; P =0.19). Conclusion— These results demonstrate that intravenous ancrod starting within 6 hours after symptom onset in a broad selection of subjects with ischemic stroke did not improve their outcome and revealed a trend to increased bleeding despite successful efforts to achieve rapid initial defibrinogenation and avoid prolonged hypofibrinogenemia.

Background and Purpose— Stroke symptoms in the absence of recognized stroke are common, but potential associated dysfunctions have not been described. Methods— We assessed quality-of-life measures using the Physical and Mental Component Summary scores of the Short Form 12 (PCS-12 and MCS-12) in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Differences in mean PCS-12 and MCS-12 scores were assessed among participant groups symptoms-free (n=16 090); history of stroke symptoms but free of stroke/transient ischemic attack (n=3404); history of stroke (n=1491); and history of transient ischemic attack (n=818). Results— Participants with symptoms (but no diagnosis) had average PCS-12 scores 5.5 (95% CI: 5.2 to 5.9) points lower than those without symptoms, a difference similar to transient ischemic attack (6.0; 95% CI: 5.3 to 6.7) and over one half the effect of stroke (8.4; 95% CI: 8.0 to 9.0). MCS-12 scores were 2.7 (95% CI: 2.4 to 3.0) points lower for those with symptoms, −0.5 for transient ischemic attack (95% CI: 0.0 to −1.1), and −1.6 for stroke (95% CI: −1.2 to −2.0). Differences in demographic and vascular risk factors, health behaviors, physiological measures, and indices of socioeconomic status did not fully explain these differences. Those reporting history of weakness or numbness had larger current decrements in physical functioning, and those reporting history of inability to express themselves or understand language had larger current decrements in mental functioning. Conclusions— Individuals with clinically consistent symptoms but no stroke diagnosis have a lower quality of life than those without symptoms. The difference in physical functioning is substantial with a smaller decline in mental functioning. Apart from so-called “silent stroke,” there appear to be many individuals with possibly symptomatic cerebrovascular disease—either stroke or transient ischemic attack—who are not being diagnosed. Furthermore, these symptomatic but undiagnosed strokes may not be benign.