Neil R. Powe

Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus

Context The relationship between glycosylated hemoglobin and cardiovascular disease in diabetic persons is less clear than its relationship with microvascular disease. Contribution This meta-analysis of 13 observational studies estimates that, for every 1-percentage point increase in glycosylated hemoglobin, the relative risk for any cardiovascular disease event is 1.18 for patients with type 2 diabetes mellitus and 1.15 for patients with type 1 diabetes mellitus. Cautions Although this analysis suggests that improvements in glycosylated hemoglobin level might translate into reductions in cardiovascular events, confirmation from randomized trials is necessary. The Editors Persons with diabetes mellitus are at an increased risk for cardiovascular disease; they have more than a 2-fold increased risk for cardiovascular death compared with persons without diabetes (1-3). Cardiovascular death accounts for more than 75% of all deaths among persons with diabetes mellitus (3, 4). Because this excess risk is only partially explained by traditional risk factors, such as obesity, dyslipidemia, and hypertension, diabetes is often considered an independent risk factor for cardiovascular disease. A strong body of evidence links chronic hyperglycemia to microvascular complications, such as retinopathy, neuropathy, and nephropathy, in persons with diabetes (5-10). In randomized clinical trials, improving glycemic control substantially reduces the incidence of microvascular disease in persons with diabetes (5, 6, 11). However, few randomized trials have specifically been designed to examine the influence of glycemic control on macrovascular complications, such as coronary heart disease, stroke, and peripheral arterial disease. Results from clinical trials that collected information on cardiovascular outcomes have been equivocal. In interpreting recent clinical trial data in a position statement, the American Diabetes Association stated that the role of hyperglycemia in cardiovascular complications is still unclear (12). Fasting blood glucose levels in diabetic and nondiabetic persons have been linked to an excess risk for cardiovascular disease (13-15); this link suggests an association between glycemic control and cardiovascular risk. A meta-regression analysis that combined data from more than 95 000 persons without diagnosed diabetes found a graded relationship between fasting and postprandial blood glucose levels and subsequent risk for a cardiovascular event (15). An important clinical question is whether improving long-term glycemic control in persons with diabetes reduces the risk for cardiovascular disease events. Glycosylated hemoglobin reflects long-term glycemic control and is a more accurate and stable measure than fasting blood glucose levels (16). It tracks well over time in persons with diabetes and has less measurement error than fasting blood glucose (17-20). Glycosylated hemoglobin is at the center of the clinical management of hyperglycemia in persons with diabetes. However, clinical guidelines for glycosylated hemoglobin levels are based on cut-points relevant for the prevention of microvascular complications (21). The relationship between glycosylated hemoglobin and cardiovascular disease, the most deadly complication of diabetes mellitus, has not been adequately characterized. We performed a systematic review to characterize the risk relation between long-term glycemic control, as measured by glycosylated hemoglobin, and cardiovascular end points (peripheral arterial disease, coronary heart disease, and cerebrovascular disease) in persons with type 1 and type 2 diabetes mellitus. Methods Study Design We systematically reviewed prospective cohort studies of glycosylated hemoglobin and cardiovascular disease in persons with diabetes mellitus. This study was part of a larger project commissioned by the Agency for Healthcare Research and Quality, which was conducted by the Johns Hopkins Evidenced-based Practice Center (22). Study Selection We searched the MEDLINE database for articles published in English from 1966 to July 2003 by using Medical Subject Heading terms and text words related to cardiovascular disease (coronary heart disease, peripheral arterial disease, or cerebrovascular disease), diabetes mellitus, glycemic control, and glycosylated hemoglobin (the Appendix contains the full text of the search string). We reviewed all abstracts obtained from our search for relevance. We manually reviewed bibliographies and review articles for additional citations and obtained the full text of all potentially relevant articles. We also queried experts to identify any additional studies. Our prespecified inclusion criteria were as follows: 1) prospective cohort studies that examined the cardiovascular outcomes of interest (peripheral arterial disease, coronary heart disease, and stroke) and 2) studies that reported a measure of glycosylated hemoglobin and that were conducted in samples that included persons with type 1 or type 2 diabetes. Persons described as having insulin-dependent diabetes mellitus or younger- or juvenile-onset diabetes were classified as having type 1 diabetes. Individuals described as having noninsulin-dependent diabetes mellitus or older-onset diabetes were classified as having type 2 diabetes. We excluded studies if they 1) had no original data, 2) did not address persons with diabetes, 3) involved nonprospective studies (for example, cross-sectional and retrospective casecontrol studies), 4) had less than 1 year of follow-up, 5) assessed the effect of glycemic control on cardiovascular outcomes after admission to a hospital or after surgery, and 6) involved only patients receiving dialysis or transplants. We excluded 1 additional study (23) in which the outcome was self-reported and the authors did not use standard definitions for classifying cardiovascular outcomes. When several, sequentially published studies were performed in the same sample, the publication with the longest follow-up was selected for inclusion in our analysis. For multiple studies of the same sample with equivalent follow-up, the most recent publication was selected. Data Abstraction Two investigators independently reviewed each article that met the selection criteria and abstracted the data by using standardized data abstraction forms. Discrepancies were resolved by consensus. Data abstracted were age, percentage of male and female study participants, sample size, outcome or outcomes, duration of follow-up, method of measuring glycosylated hemoglobin, main results, statistical methods, number of study participants included in the final analysis, and variables included in the adjusted model or models. For each prospective cohort study that met our inclusion criteria, we abstracted adjusted effect estimates (odds ratios, relative risks, or relative hazards) for the association between cardiovascular risk (based on incident events during follow-up) and baseline or updated mean glycosylated hemoglobin values. Standard errors for the estimates were abstracted or derived by using data reported in the manuscript. The cardiovascular disease end points, defined a priori, were fatal and nonfatal coronary heart disease (myocardial infarction, angina, and ischemic heart disease); cerebrovascular disease (fatal and nonfatal stroke); peripheral arterial disease (lower-extremity peripheral arterial disease, amputation, and claudication); and a combined cardiovascular disease outcome that included studies of coronary heart disease and stroke (but not peripheral arterial disease). We conducted separate analyses for each cardiovascular end point and for samples of persons with type 1 and type 2 diabetes. Studies using a combined outcome that included both coronary heart disease and stroke (24-26) were excluded from the pooled effect estimates for stroke alone and coronary heart disease alone but were included in the combined coronary heart disease and stroke subgroup. Statistical Analysis We conducted separate meta-analyses of the prospective cohort studies for study samples of persons with type 1 and type 2 diabetes and for the different cardiovascular outcomes. Most studies reported glycosylated hemoglobin as percentage hemoglobin A1c or its equivalent, although some studies (27-32) measured hemoglobin A1 and 1 study (33) measured total glycosylated hemoglobin. Although the American Diabetes Association advises that all measurements of glycosylated hemoglobin be reported as percentage hemoglobin A1c or its equivalent (16), there are direct linear relationships between glycosylated hemoglobin subfractions (34); therefore, we did not consider the measured subfraction to be an important source of heterogeneity across studies. For 4 studies (27, 30-32) that reported relative risk estimates for participants in the highest tertile of glycosylated hemoglobin compared with participants in the 2 lowest tertiles, we assumed a normal distribution for glycosylated hemoglobin values and used the reported mean and SD to estimate the 33rd and 83rd percentiles of glycosylated hemoglobin (corresponding to the midpoints of the 2 lowest and the highest tertiles, respectively). Then, we divided the log relative risk by the difference of these 2 values to estimate the effect of a 1-unit change in glycosylated hemoglobin (35). For the study (36) that reported a dichotomous relative risk estimate (it compared glycosylated hemoglobin above and below the median), we used the same method to estimate the effect of a 1-unit change in glycosylated hemoglobin but calculated the 25th and 75th percentiles and divided the log relative risk by the difference of these 2 values. One study (29) did not report relative risks or odds ratios but reported the mean and SD of glycosylated hemoglobin in persons with and without cardiovascular disease events. In this case, we estimated the odds ratio and its 95% CI on the basis of a linear discriminant function model. This m

Ankle-Arm Index as a Predictor of Cardiovascular Disease and Mortality in the Cardiovascular Health Study

Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.

The importance of surgeon experience for clinical and economic outcomes from thyroidectomy.

OBJECTIVE To determine whether individual surgeon experience is associated with improved short-term clinical and economic outcomes for patients with benign and malignant thyroid disease who underwent thyroid procedures in Maryland between 1991 and 1996. SUMMARY BACKGROUND DATA There is a prevailing belief that surgeon experience affects patient outcomes in endocrine surgery, but there is a paucity of objective evidence outside of clinical series published by experienced surgeons that supports this view. METHODS A cross-sectional analysis of all patients who underwent thyroidectomy in Maryland between 1991 and 1996 was conducted using a computerized statewide hospital discharge data base. Surgeons were categorized by volume of thyroidectomies over the 6-year study period: A (1 to 9 cases), B (10 to 29 cases), C (30 to 100 cases), and D (>100 cases). Multivariate regression was used to assess the relation between surgeon caseload and in-hospital complications, length of stay, and total hospital charges, adjusting for case mix and hospital volume. RESULTS The highest-volume surgeons (group D) performed the greatest proportion of total thyroidectomies among the 5860 discharges, and they were more likely to operate on patients with cancer. After adjusting for case mix and hospital volume, highest-volume surgeons had the shortest length of stay (1.4 days vs. 1.7 days for groups B and C and 1.9 days for group A) and the lowest complication rate (5.1 % vs. 6.1% for groups B and C and 8.6% for group A). Length of stay and complications were more determined by surgeon experience than hospital volume, which had no consistent association with outcomes. CONCLUSIONS Individual surgeon experience is significantly associated with complication rates and length of stay for thyroidectomy.

Vitamin D–Binding Protein and Vitamin D Status of Black Americans and White Americans

BACKGROUND Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D-binding protein has not been considered in the assessment of vitamin D deficiency. METHODS In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D-binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D-binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants. RESULTS Mean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D-binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D-binding protein, 168±3 μg per milliliter vs. 337±5 μg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D-binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P=0.71) and within quintiles of parathyroid hormone concentration. CONCLUSIONS Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.).

Cultural competence: A systematic review of health care provider educational interventions

Objective:We sought to synthesize the findings of studies evaluating interventions to improve the cultural competence of health professionals. Design:This was a systematic literature review and analysis. Methods:We performed electronic and hand searches from 1980 through June 2003 to identify studies that evaluated interventions designed to improve the cultural competence of health professionals. We abstracted and synthesized data from studies that had both a before- and an after-intervention evaluation or had a control group for comparison and graded the strength of the evidence as excellent, good, fair, or poor using predetermined criteria. Main Outcome Measures:We sought evidence of the effectiveness and costs of cultural competence training of health professionals. Results:Thirty-four studies were included in our review. There is excellent evidence that cultural competence training improves the knowledge of health professionals (17 of 19 studies demonstrated a beneficial effect), and good evidence that cultural competence training improves the attitudes and skills of health professionals (21 of 25 studies evaluating attitudes demonstrated a beneficial effect and 14 of 14 studies evaluating skills demonstrated a beneficial effect). There is good evidence that cultural competence training impacts patient satisfaction (3 of 3 studies demonstrated a beneficial effect), poor evidence that cultural competence training impacts patient adherence (although the one study designed to do this demonstrated a beneficial effect), and no studies that have evaluated patient health status outcomes. There is poor evidence to determine the costs of cultural competence training (5 studies included incomplete estimates of costs). Conclusions:Cultural competence training shows promise as a strategy for improving the knowledge, attitudes, and skills of health professionals. However, evidence that it improves patient adherence to therapy, health outcomes, and equity of services across racial and ethnic groups is lacking. Future research should focus on these outcomes and should determine which teaching methods and content are most effective.

Race and Trust in the Health Care System

Objective. A legacy of racial discrimination in medical research and the health care system has been linked to a low level of trust in medical research and medical care among African Americans. While racial differences in trust in physicians have been demonstrated, little is known about racial variation in trust of health insurance plans and hospitals. For the present study, the authors analyzed responses to a cross-sectional telephone survey to assess the independent relationship of self-reported race (non-Hispanic black or non-Hispanic white) with trust in physicians, hospitals, and health insurance plans. Methods. Respondents ages 18–75 years were asked to rate their level of trust in physicians, health insurance plans, and hospitals. Items from the Medical Mistrust Index were used to assess fear and suspicion of hospitals. Results. Responses were analyzed for 49 (42%) non-Hispanic black and 69 (58%) non-Hispanic white respondents (N=118; 94% of total survey population). A majority of respondents trusted physicians (71%) and hospitals (70%), but fewer trusted their health insurance plans (28%). After adjustment for potential confounders, non-Hispanic black respondents were less likely to trust their physicians than non-Hispanic white respondents (adjusted absolute difference 37%; p=0.01) and more likely to trust their health insurance plans (adjusted absolute difference 28%; p=0.04). The difference in trust of hospitals (adjusted absolute difference 13%) was not statistically significant. Non-Hispanic black respondents were more likely than non-Hispanic white respondents to be concerned about personal privacy and the potential for harmful experimentation in hospitals. Conclusions. Patterns of trust in components of our health care system differ by race. Differences in trust may reflect divergent cultural experiences of blacks and whites as well as differences in expectations for care. Improved understanding of these factors is needed if efforts to enhance patient access to and satisfaction with care are to be effective.

International Comparison of the Relationship of Chronic Kidney Disease Prevalence and ESRD Risk

ESRD incidence is much lower in Europe compared with the United States. This study investigated whether this reflects a difference in the prevalence of earlier stages of chronic kidney disease (CKD) or other mechanisms. CKD prevalence in Norway was estimated from the population-based Health Survey of Nord-Trondelag County (HUNT II), which included 65,181 adults in 1995 through 1997 (participation rate 70.4%). Data were analyzed using the same methods as two US National Health and Nutrition Examination Surveys in 1988 through 1994 (n = 15,488) and 1999 through 2000 (n = 4101). The primary analysis used gender-specific cutoffs in estimating persistent albuminuria for CKD stages 1 and 2. ESRD rates and other relevant data were extracted from national registries. Total CKD prevalence in Norway was 10.2% (SE 0.5): CKD stage 1 (GFR >90 ml/min per 1.73 m2 and albuminuria), 2.7% (SE 0.3); stage 2 (GFR 60 to 89 ml/min per 1.73 m2 and albuminuria), 3.2% (SE 0.4); stage 3 (GFR 30 to 59 ml/min per 1.73 m2), 4.2% (SE 0.1); and stage 4 (GFR 15 to 29 ml/min per 1.73 m2), 0.2% (SE 0.01). This closely approximates reported US CKD prevalence (11.0% in 1988 through 1994 and 11.7% in 1999 through 2000). The relative risk for progression from CKD stages 3 or 4 to ESRD in US white patients compared with Norwegian patients was 2.5. This was only modestly modified by adjustment for age, gender, and diabetes. Age and GFR at start of dialysis were similar, hypertension and cardiovascular mortality in the populations were comparable, but US white patients were referred later to a nephrologist and had higher prevalence of obesity and diabetes. In conclusion, CKD prevalence in Norway was similar to that in the United States, suggesting that lower progression to ESRD rather than a smaller pool of individuals at risk accounts for the lower incidence of ESRD in Norway.

MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39–0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.

Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study.

Although atherosclerotic cardiovascular disease (ASCVD) risk in end-stage renal disease (ESRD) is 5 to 30 times that of the general population, few data exist comparing ASCVD risk factors among new dialysis patients to the general population. This cross-sectional study of 1041 dialysis patients describes the prevalence of ASCVD risk factors at the beginning of ESRD compared with estimates of ASCVD risk factors in the adult US population derived from the Third National Health and Nutrition Examination (NHANES III). CHOICE Study participants had a high prevalence of diabetes (54%), hypertension (96%), left ventricular hypertrophy by electrocardiogram (EKG) criteria (22%), low physical activity (80%), hypertriglyceridemia (36%), and low HDL cholesterol (33%). CHOICE participants were more likely to be older, black, and male than NHANES III participants. After adjustment for age, race, gender, and ASCVD (defined as myocardial infarction, revascularization procedure, stroke, carotid endarterectomy, and amputation in CHOICE; and as myocardial infarction and stroke in NHANES III), the prevalence of diabetes, hypertension, left ventricular hypertrophy by EKG, low physical activity, low HDL cholesterol, and hypertriglyceridemia were still more common in CHOICE participants. Smoking, obesity, hypercholesterolemia, and high LDL cholesterol, however, were less common in CHOICE than NHANES III participants. The projected 5-yr ASCVD risk based on the Framingham Risk Equation among those older than 40 yr without ASCVD was higher in CHOICE Study participants (13%) than in the NHANES III participants (6%). In summary, many ASCVD risk factors are more prevalent in ESRD than in the general population and may explain some, but probably not all, of the increased ASCVD risk in ESRD.

Barriers to Recruiting Underrepresented Populations to Cancer Clinical Trials : A Systematic Review

Racial and ethnic minorities, older adults, rural residents, and individuals of low socioeconomic status are underrepresented among participants in cancer‐related trials. The authors conducted a systematic review to determine the barriers to participation of underrepresented populations in cancer‐related trials. Their search included English‐language publications that reported original data on the recruitment of underrepresented groups to cancer treatment or prevention trials between 1966 and December 2005 in multiple electronic databases. They also hand‐searched titles in 34 journals from January 2003 to December 2005 and they examined reference lists for eligible articles. Titles and abstracts were reviewed to identify relevant studies. Data on barriers to participation were synthesized both qualitatively and based on statistically significant associations with trial enrollment. Of 5257 studies that were cited, 65 studies were eligible for inclusion in the current analysis, including 46 studies on recruitment into cancer therapeutic trials, 15 studies on recruitment into prevention trials, and 4 studies on recruitment into both prevention and treatment trials. Numerous factors were reported as barriers to participation in cancer‐related trials. However, only 20 of the studies reported statistically significant associations between hypothesized barriers and enrollment. The available evidence had limitations in quality regarding representativeness, justification of study methods, the reliability and validity of data‐collection methods, potential for bias, and data analysis. The results indicated that underrepresented populations face numerous barriers to participation in cancer‐related trials. The current systematic review highlighting the literature on recruitment of underrepresented populations to cancer trials and may be used as the evidence base toward developing an agenda for etiologic and intervention research to reduce the disparities in participation in cancer‐related trials. Cancer 2008.