Association between comorbidity and clinical characteristics of MS.

BACKGROUND: Comorbidity may be associated with the clinical phenotype of disease and may affect prognostication and treatment decisions. Using the North American Research Committee on Multiple Sclerosis Registry, we described comorbidities present at onset and diagnosis of multiple sclerosis (MS) and examined whether comorbidities present at onset were associated with clinical course or age of MS symptom onset. METHODS: In 2006, 8983 participants reported their physical and mental comorbidities; smoking status; height; and past and present weight. We compared clinical course at onset and age of symptom onset by comorbidity status. RESULTS: At MS onset, a substantial proportion of participants had physical (24%) or mental (8.4%) comorbidities. The mean (SD) age of MS onset was 31.2 (9.0) years. Vascular, autoimmune, cancer, visual, and musculoskeletal comorbidities were associated with a later age of symptom onset. Among men and women, the odds of a relapsing course at onset were increased if mental comorbidities (OR 1.48; 1.08-2.01) were present at symptom onset. In women, gastrointestinal comorbidities (OR 1.78; 1.25-2.52) and obesity (OR 2.08 1.53-2.82) at MS onset were also associated with a relapsing course at onset. CONCLUSIONS: Comorbidity is frequently present at onset of MS and is associated with differences in clinical characteristics.

Boosting enrollment in neurology trials with Local Identification and Outreach Networks (LIONs).

OBJECTIVE: Our purpose was to develop a geographically localized, multi-institution strategy for improving enrolment in a trial of secondary stroke prevention. METHODS: We invited 11 Connecticut hospitals to participate in a project named the Local Identification and Outreach Network (LION). Each hospital provided the names of patients with stroke or TIA, identified from electronic admission or discharge logs, to researchers at a central coordinating center. After obtaining permission from personal physicians, researchers contacted each patient to describe the study, screen for eligibility, and set up a home visit for consent. Researchers traveled throughout the state to enroll and follow participants. Outside the LION, investigators identified trial participants using conventional recruitment strategies. We compared recruitment success for the LION and other sites using data from January 1, 2005, through June 30, 2007. RESULTS: The average monthly randomization rate from the LION was 4.0 participants, compared with 0.46 at 104 other Insulin Resistance Intervention after Stroke (IRIS) sites. The LION randomized on average 1.52/1,000 beds/month, compared with 0.76/1,000 beds/month at other IRIS sites (p = 0.03). The average cost to randomize and follow one participant was $8,697 for the LION, compared with $7,198 for other sites. CONCLUSION: A geographically based network of institutions, served by a central coordinating center, randomized substantially more patients per month compared with sites outside of the network. The high enrollment rate was a result of surveillance at multiple institutions and greater productivity at each institution. Although the cost per patient was higher for the network, compared with nonnetwork sites, cost savings could result from more rapid completion of research.

Impaired insulin sensitivity among nondiabetic patients with a recent TIA or ischemic stroke.

OBJECTIVES: To determine the prevalence of impaired insulin sensitivity among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. METHODS: Eligible subjects were nondiabetic men and women over age 45 years who were hospitalized with a TIA or ischemic stroke. To measure insulin sensitivity, subjects underwent an oral glucose tolerance test between 2 and 6 months after their event. Impaired insulin sensitivity was defined by a value of < or =2.5 on the Composite Insulin Sensitivity Index derived from insulin and glucose values during the test. RESULTS: Between July 2000 and June 2001, we identified 177 eligible patients, among whom 105 declined to participate and 72 enrolled. The median age of participants was 71 years and 46 (64%) were men. The baseline event was stroke for 57 subjects (79%). A history of myocardial infarction (MI) was reported by 14 subjects (19%), and 16 (22%) were obese (body mass index > 30). Fasting glucose was normal (<110 mg/dL) for 58 (80%) participants and impaired (110 to 125 mg/dL) for 14 (20%). Among 72 participants, the median insulin sensitivity index value was 2.6 (range 0.9 to 10.2). The prevalence of impaired insulin sensitivity was 36 of 72 (50%, 95% CI 38% to 62%). Impaired insulin sensitivity was more prevalent among younger patients and patients with obesity, lacunar stroke etiology, and disability (Rankin grade >1). CONCLUSION: Impaired insulin sensitivity is highly prevalent among nondiabetic patients with a recent TIA or nondisabling ischemic stroke. This finding has important therapeutic implications if treatment to improve insulin sensitivity is shown to reduce risk for subsequent stroke and heart disease.

Use of Ephedra-containing products and risk for hemorrhagic stroke.

This case-control study examined the association between Ephedra use and risk for hemorrhagic stroke. For use of Ephedra at any dose during the 3 days before the stroke, the adjusted OR was 1.00 (95% CI 0.32 to 3.11). For daily doses of < or =32 mg/day, the OR was 0.13 (95% CI 0.01 to 1.54), and for >32 mg/day, the OR was 3.59 (95% CI 0.70 to 18.35). Ephedra is not associated with increased risk for hemorrhagic stroke, except possibly at higher doses.

Insulin resistance and risk for stroke.

BACKGROUND AND PURPOSE: Resistance to insulin-mediated glucose uptake by peripheral tissues is a cardinal defect in type 2 diabetes mellitus. Insulin resistance is also common among nondiabetic individuals, and may be an important risk factor for stroke in both populations. The authors review the definition, epidemiology, and treatment of insulin resistance. METHODS: The authors searched Medline (1977-2001) and reviewed bibliographies to identify pertinent English-language publications. RESULTS: Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. The principal pathophysiologic defect is impaired intracellular signaling in muscle tissue leading to defective glycogen synthesis. Insulin resistance is associated with numerous metabolic, hematologic, and cellular events that promote atherosclerosis and coagulation. The association between insulin resistance and risk for stroke has been examined in four case-control studies and five prospective observational cohort studies. Six of the nine studies are methodologically sound and provide evidence that insulin resistance is associated with risk for stroke. CONCLUSION: Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.

A clinical trial of estrogen-replacement therapy after ischemic stroke.

BACKGROUND: Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of estradiol-17beta per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. RESULTS: During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Estrogen therapy did not reduce the risk of death alone (relative risk, 1.2; 95 percent confidence interval, 0.8 to 1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk, 2.9; 95 percent confidence interval, 0.9 to 9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits. CONCLUSIONS: Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.

A nested case-control study of the effectiveness of screening for prostate cancer: research design.

Although prostate-specific antigen (PSA) and digital rectal examination (DRE) are commonly used to screen for prostate cancer, available data do not confirm that either test improves survival. This report describes the methodological aspects of a nested case-control study addressing the question of whether PSA screening, with or without DRE, is effective in increasing survival. Potential sources of bias are discussed, as well as corresponding strategies used to avoid them. Results are expected in the year 2002.

A quality-of-life instrument for young hemorrhagic stroke patients.

BACKGROUND AND PURPOSE: Hemorrhagic stroke has a high initial mortality rate. While survivors often recover motor function, many experience significant changes in their quality of life (QOL). Available outcome measures assess neurological impairment, disability, or handicap, yet often inadequately characterize the full impact of a stroke on patients' lives. In this study, we develop and validate a QOL instrument specific for young patients with hemorrhagic strokes. METHODS: Methodological guidelines for instrument development were initially established. Based on the content of 40 open-ended patient interviews, a 54-item instrument (HSQuale) was developed. The reliability (test-retest and internal consistency) and validity (content and construct) of HSQuale were assessed in another 71 patients (18 to 49 years of age, 63% women, 77% white), at 1 year after their hemorrhagic stroke. Comparisons were made between HSQuale and other commonly used outcome measures. RESULTS: HSQuale demonstrated reproducibility (test-retest kappa, 0.40 to 0.96) and internal consistency (Cronbach alpha >/=0.80 for 5 of 7 domains). HSQuale scores had broad frequency distributions (

Social support as a buffer to the psychological impact of stressful life events in women with breast cancer.

BACKGROUND: Three theoretical models by which social support may influence the impact of stressful life events on cancer patients' psychological state were tested: 1) the additive model, in which social support and stressful life events each directly influence cancer patients' adjustment, irrespective of the magnitude of the other; 2) the buffering hypothesis, in which stressful events occurring in the presence of social support should produce less distress than if they occur in its absence; and 3) both additive and buffering models. METHODS: One hundred seventy-nine patients who had Stage II breast cancer (median age, 56 yrs; 68% disease free), treated a mean of 6.8 years since entry to Cancer and Leukemia Group B (CALGB) 8541, were interviewed by telephone concerning their psychosocial adjustment. The following measures were used: Medical Outcome Study Social Support Survey (MOS-SSS), Life Experience Survey (LES) a measure of stressful life events within the past 12 months, European Organization for Research on the Treatment of Cancer (EORTC QLQ-C30) a measure of quality of life, Mental Health Inventory (MHI), and the Systems of Belief Inventory (SBI) a measure of spiritual and religious involvement. RESULTS: Hierarchical regression analyses revealed that less than excellent levels of social support (P < 0.01), greater negative impact of LES fateful life events (e.g., death of family member) (P < 0.05), personal illness or injury (P < 0.05), and all other negative life events in the past year (< 4; P < 0.01) were significant predictors of greater MHI psychological distress, in addition to being divorced or separated (P < 0.001), and more recently treated for cancer on CALGB 8541 (P < 0.05). The interaction of LES scores with MOS-SSS or SBI social support, used to test the buffering hypothesis, did not significantly improve the prediction of MHI psychological distress. CONCLUSIONS: The results supported the additive model, with both stressful life events and social support independently and significantly affecting patients' emotional state. However, the level of social support needed to be very high to reduce the likelihood of severe psychological distress.

Phenylpropanolamine and the risk of hemorrhagic stroke.

BACKGROUND: Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study. METHODS: Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient. RESULTS: There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants. CONCLUSIONS: The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Randomized, controlled trials, observational studies, and the hierarchy of research designs.

BACKGROUND: In the hierarchy of research designs, the results of randomized, controlled trials are considered to be evidence of the highest grade, whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects. We used published meta-analyses to identify randomized clinical trials and observational studies that examined the same clinical topics. We then compared the results of the original reports according to the type of research design. METHODS: A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of randomized, controlled trials and meta-analyses of either cohort or case-control studies that assessed the same intervention. For each of five topics, summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual randomized, controlled trials and the individual observational studies. RESULTS: For the five clinical topics and 99 reports evaluated, the average results of the observational studies were remarkably similar to those of the randomized, controlled trials. For example, analysis of 13 randomized, controlled trials of the effectiveness of bacille Calmette-Guérin vaccine in preventing active tuberculosis yielded a relative risk of 0.49 (95 percent confidence interval, 0.34 to 0.70) among vaccinated patients, as compared with an odds ratio of 0.50 (95 percent confidence interval, 0.39 to 0.65) from 10 case-control studies. In addition, the range of the point estimates for the effect of vaccination was wider for the randomized, controlled trials (0.20 to 1.56) than for the observational studies (0.17 to 0.84). CONCLUSIONS: The results of well-designed observational studies (with either a cohort or a case-control design) do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topic.

Correlates and impact on outcomes of worsening renal function in patients > or =65 years of age with heart failure.

1.5 mg/dl. Based on the number of these factors, a patient's risk for developing worsening renal function ranged between 16% (< or =1 factor) and 53% (> or =5 factors). After adjusting for confounding effects, worsening renal function was associated with a significantly longer length of stay by 2.3 days, higher in-hospital cost by $1,758, and an increased risk of in-hospital mortality (odds ratio 2.72; 95% confidence interval 1.62 to 4.58). In conclusion, worsening renal function, an event that frequently occurs in elderly patients hospitalized with heart failure, confers a substantial burden to patients and the healthcare system and can be predicted by 6 admission characteristics.

Placebos, active control groups, and the unpredictability paradox.

Randomized controlled trials often rely on placebo control groups to estimate treatment differences. Recently, the high frequency of negative trials and ethical concerns surrounding the use of placebos have brought the use of placebo control groups under increased scrutiny. Although many psychiatric researchers argue that placebo control groups should be replaced with active control groups, we argue that preferential use of active control groups will not reduce the number of negative trials. Rather, we suggest that some of the variation and contradiction in randomized controlled trial results arises from the clinical heterogeneity of patient characteristics, disease severity, comorbidity, and cotherapies. Further characterization of patient heterogeneity, through improved disease taxonomies, severity indices, and classification of comorbid diseases, will serve to reduce clinical heterogeneity among patients and reduce the number of negative trials produced by wide variation in treatment and control response rates.

Blood pressure exceeding national guidelines among women after stroke.

BACKGROUND AND PURPOSE: After a transient ischemic attack or stroke, the risk for recurrence may be reduced by treatment of hypertension. The purpose of this study was to determine how commonly blood pressure exceeds national guidelines among patients who have had one of these events. METHODS: Subjects were 644 women participating in a randomized trial of estrogen for secondary stroke prevention. We measured blood pressure 1 month after the stroke or TIA while patients were under the care of their personal physicians. Among 536 patients, a second measure was made at an average of 2.9 years after the first. RESULTS: The mean age of participants was 71 years, and 73% reported a history of hypertension. At baseline, only 44% (280/644) of the women had blood pressure values within national guidelines (<140/90 mm Hg). With separate guidelines used for diabetics (<130/85 mm Hg) and nondiabetics (<140/90 mm Hg), the proportions of women within the guidelines were 27% and 44%, respectively. Overall, 39% of patients were within the diabetes-adjusted guidelines. Among patients whose blood pressure exceeded 140/90 mm Hg at first examination, 55% were still in excess at follow-up. Features associated with severe hypertension at first examination (>160/100 mm Hg) were history of hypertension, education less than college, and higher cognitive functioning. CONCLUSIONS: Blood pressure values in excess of national guidelines are common after stroke and TIA, especially among diabetic patients. Efforts to lower blood pressure control may enhance secondary prevention.

The stroke prognosis instrument II (SPI-II) : A clinical prediction instrument for patients with transient ischemia and nondisabling ischemic stroke.

BACKGROUND AND PURPOSE: In 1991 we developed the Stroke Prognosis Instrument (SPI-I) to stratify patients with transient ischemic attack or ischemic stroke by prognosis for stroke or death in 2 years. In this article we validate and improve SPI-I (creating SPI-II). METHODS: To validate SPI-I, we applied it to 4 test cohorts and calculated pooled outcome rates. To create SPI-II, we incorporated new predictive variables identified in 1 of the test cohorts and validated it in the other 3 cohorts. RESULTS: For SPI-I, pooled rates (all 4 test cohorts) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 24%, respectively (P<0.01, log-rank test). SPI-II was created by adding congestive heart failure and prior stroke to SPI-I. Each patient's risk group was determined by the total score for 7 factors: congestive heart failure (3 points); diabetes (3 points); prior stroke (3 points); age >70 years (2 points); stroke for the index event (not transient ischemic attack) (2 points); hypertension (1 point); and coronary artery disease (1 point). Risk groups I, II, and III comprised patients with 0 to 3, 4 to 7, and 8 to 15 points, respectively. For SPI-I, pooled rates (3 cohorts excluding the SPI-II development cohort) of stroke or death within 2 years in risk groups I, II, and III were 9%, 17%, and 23%, respectively. For SPI-II, pooled rates were 10%, 19%, and 31%, respectively. In receiver operator characteristic analysis, the area under the curve was 0.59 (95% CI, 0.57 to 0.60) for SPI-I and 0.63 (95% CI, 0.62 to 0.65) for SPI-II, confirming the better performance of the latter. CONCLUSIONS: Compared with SPI-I, SPI-II achieves greater discrimination in outcome rates among risk groups. SPI-II is ready for use in research design and may have a role in patient counseling.

Predictors of readmission among elderly survivors of admission with heart failure.

BACKGROUND: Readmission rates for patients discharged with heart failure approach 50% within 6 months. Identifying factors to predict risk of readmission in these patients could help clinicians focus resource-intensive disease management efforts on the high-risk patients. METHODS: The study sample included patients 65 years of age or older with a principal discharge diagnosis of heart failure who were admitted to 18 Connecticut hospitals in 1994 and 1995. We obtained patient and clinical data from medical record review. We determined outcomes within 6 months after discharge, including all-cause readmission, heart failure-related readmission, and death, from the Medicare administrative database. We evaluated 2176 patients, including 1129 in the derivation cohort and 1047 in the validation cohort. RESULTS: Of 32 patient and clinical factors examined, 4 were found to be significantly associated with readmission in a multivariate model. They were prior admission within 1 year, prior heart failure, diabetes, and creatinine level >2.5 mg/dL at discharge. The event rates according to number of risk predictors were similar in the derivation and the validation sets for all outcomes. In the validation cohort, rates for all-cause readmission and combined readmission or death were 26% and 31% in patients with no risk predictors, 48% and 54% in patients with 1 or 2 risk predictors, and 59% and 65% in patients with 3 or all risk predictors. CONCLUSIONS: Few patient and clinical factors predict readmission within 6 months after discharge in elderly patients with heart failure. Although we were unable to identify a group of patients at very low risk, a group of high-risk patients were identified for whom resource-intensive interventions designed to improve outcomes may be justified.

Stratified randomization for clinical trials.

Trialists argue about the usefulness of stratified randomization. For investigators designing trials and readers who use them, the argument has created uncertainty regarding the importance of stratification. In this paper, we review stratified randomization to summarize its purpose, indications, accomplishments, and alternatives. In order to identify research papers, we performed a Medline search for 1966-1997. The search yielded 33 articles that included original research on stratification or included stratification as the major focus. Additional resources included textbooks. Stratified randomization prevents imbalance between treatment groups for known factors that influence prognosis or treatment responsiveness. As a result, stratification may prevent type I error and improve power for small trials (<400 patients), but only when the stratification factors have a large effect on prognosis. Stratification has an important effect on sample size for active control equivalence trials, but not for superiority trials. Theoretical benefits include facilitation of subgroup analysis and interim analysis. The maximum desirable number of strata is unknown, but experts argue for keeping it small. Stratified randomization is important only for small trials in which treatment outcome may be affected by known clinical factors that have a large effect on prognosis, large trials when interim analyses are planned with small numbers of patients, and trials designed to show the equivalence of two therapies. Once the decision to stratify is made, investigators need to chose factors carefully and account for them in the analysis.

The International Health Program: the fifteen-year experience with Yale University's Internal Medicine Residency Program.

The purpose of this study was to assess the impact of international health electives on physicians-in-training. A retrospective study was conducted using an anonymous, self-administered mailed survey to internal medicine residents who trained at Yale from 1982 to 1996 based on their experience with our International Health Program (IHP). The response rate was 61%, with 96 completed surveys in the participant group and 96 completed surveys in the nonparticipant group. Participants were more likely than nonparticipants to care for patients on public assistance (77 versus 49; P < 0.001) and immigrant patients (41 versus 23; P = 0.006). Among residents who changed their career plans, participants (22) were more likely than nonparticipants (14) to switch from subspecialty medicine to general medicine (P = 0.02). Participants were significantly more likely to have a positive view of health care delivery in developing countries. Compared with nonparticipants (64), IHP participants (74) believed that the physical examination is under-used by physicians from the United States as a diagnostic skill (P = 0.03). International health experiences appeared to have an important impact on the decisions and attitudes of residents.

Sex differences in mortality after myocardial infarction: evidence for a sex-age interaction.

BACKGROUND: Studies of sex differences in mortality after myocardial infarction (MI) have shown conflicting results. OBJECTIVES: To test the hypothesis that sex differences in mortality after MI vary according to patients' age, with younger women, but not older women, having a higher mortality compared with men. METHODS: We performed a retrospective cohort study of 1025 consecutive patients who met accepted criteria for MI in 1992 and 1993 in 15 Connecticut hospitals. Data for the study were abstracted from medical records. RESULTS: Women had a 40% higher hospital mortality rate than men. Simple age adjustment eliminated the sex difference in mortality rate (odds ratio, 0.99; 95% confidence interval, 0.66-1.48). However, when the sample was subdivided into 2 age groups, women younger than 75 years showed twice as high a mortality rate as men in the same age group, while among older patients no difference in mortality was found. In multivariate analyses the interaction of sex with age was highly significant, even after adjusting for comorbid conditions, clinical severity, process of care, and hospital characteristics. In the fully adjusted model, this interaction indicated that among patients younger than 75 years women had 49% higher odds of hospital death than men, while in the age group 75 years or older women had 46% lower odds of death compared with men. CONCLUSIONS: A higher mortality of women compared with men after MI is confined to the younger age groups. The sex-age interaction should be considered when examining sex differences in mortality after MI.