Gregory W. Evans

Effects of intensive blood-pressure control in type 2 diabetes mellitus.

BACKGROUND There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. METHODS A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. RESULTS After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI, 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001). CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620.)

Arterial Wall Thickness Is Associated With Prevalent Cardiovascular Disease in Middle-Aged Adults: The Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND AND PURPOSE This study was done to assess the relationship between prevalent cardiovascular disease and arterial wall thickness in middle-aged US adults. METHODS The association of preexisting coronary heart disease, cerebrovascular disease, and peripheral vascular disease with carotid and popliteal intimal-medial thickness (IMT) (measured by B-mode ultrasound) was assessed in 13,870 black and white men and women, aged 45 to 64, during the Atherosclerosis Risk in Communities (ARIC) Study baseline examination (1987 through 1989). Prevalent disease was determined according to both participant self-report and measurements at the baseline examination (including electrocardiogram, fasting blood glucose, and medication use). RESULTS Across four race and gender strata, mean carotid far wall IMT was consistently greater in participants with prevalent clinical cardiovascular disease than in disease-free subjects. Similarly, the prevalence of cardiovascular disease was consistently greater in participants with progressively thicker IMT. The greatest differences in carotid IMT associated with prevalent disease were observed for reported symptomatic peripheral vascular disease (0.09 to 0.22 mm greater IMT in the four race-gender groups). CONCLUSIONS These data document the substantially greater arterial wall thickness observed in middle-aged adults with prevalent cardiovascular disease. Both carotid and popliteal arterial IMT were related to clinically manifest cardiovascular disease affecting distant vascular beds, such as the cerebral, peripheral, and coronary artery vascular beds.

Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. ARIC Investigators.

Background and Purpose B-mode ultrasound is a widely used technique for the clinical and epidemiological assessment of carotid atherosclerosis. This article provides a description of the distribution of carotid atherosclerosis in the general population. Methods Intimal-medial arterial wall thickness was measured by B-mode real-time ultrasound as an index of atherosclerotic involvement in the extracranial carotid arteries as part of the population-based Atherosclerosis Risk in Communities (ARIC) study. The distribution was described by race-sex strata, in which 759 to 4952 individuals were imaged depending on strata and location in the carotid system. Results Median wall thickness ranged between 0.5 and 1 mm at all ages; fewer than 5% of ARIC participants had values exceeding 2 mm. Individuals tended to have a larger wall thickness in the carotid bifurcation than in the common carotid artery. Internal carotid artery values were more variable, with higher proportions of both large and small wall thicknesses than in the common carotid. The proportion of individuals with a large wall thickness was greatest at the bifurcation and smallest at the common carotid artery. Men had uniformly larger wall thickness than women. Cross-sectional analysis suggests that age-related increases in wall thickness average approximately 0.015 mm/y in women and 0.018 mm/y in men in the carotid bifurcation, 0.010 mm/y for women and 0.014 mm/y for men in the internal carotid artery, and 0.010 mm/y in both sexes in the common carotid artery. Conclusions Estimates provided for wall thickness percentiles can serve as “nomograms” by age, race, and sex.

Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis:: the Atherosclerosis Risk in Communities (ARIC) Study

The resting ankle-brachial index (ABI) is a non-invasive method to assess the patency of the lower extremity arterial system and to screen for the presence of peripheral occlusive arterial disease. To determine how the ABI is associated with clinical coronary heart disease (CHD), stroke, preclinical carotid plaque and far wall intimal-medial thickness (IMT) of the carotid and popliteal arteries, we conducted analyses in 15 106 middle-aged adults from the baseline examination (1987-1989) of the Atherosclerosis Risk in Communities (ARIC) Study. The prevalence of clinical CHD, stroke/transient ischemic attack (TIA) and preclinical carotid plaque increased with decreasing ABI levels, particularly at those of < 0.90. Individuals with ABI < 0.90 were twice as likely to have prevalent CHD as those with ABI > 0.90 (age-adjusted odds ratio (OR) ranging from 2.2 (95% CI: 1.0-5.1) in African-American men to 3.3 (95% CI: 2.1-5.0) in white men). Men with ABI < 0.90 were more than four times as likely to have stroke/TIA as those with ABI > 0.90 (age-adjusted OR: 4.2 (95% CI: 1.8-9.5) in African-American men and 4.9 (95% CI: 2.6-9.0) in white men). In women the association was weaker and not statistically significant. Among those free of clinical cardiovascular disease, individuals with ABI < or = 0.90 had statistically significantly higher prevalence of preclinical carotid plaque compared to those with ABI > 0.90 (age-adjusted ORs ranging from 1.5 (95% CI: 1.0-1.9) in white women to 2.6 (95% CI: 1.0-6.6) in african-american men). The ABI was also inversely associated with far wall IMT of the carotid arteries (in both men and women) and the popliteal arteries (in men only). The associations of ABI with clinical CHD, stroke, preclinical carotid plaque and IMT of the carotid and popliteal arteries were attenuated and often not statistically significant after further adjustment for LDL cholesterol, cigarette smoking, hypertension and diabetes. These data demonstrate that low ABI levels, particularly those of < 0.90, are indicative of generalized atherosclerosis.

Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial

BACKGROUND Patients with mixed dyslipidaemia have raised triglycerides, low high-density lipoprotein (HDL) cholesterol, and high low-density lipoprotein (LDL) cholesterol. Augmentation of HDL cholesterol by inhibition of the cholesteryl ester transfer protein (CETP) could benefit these patients. We aimed to investigate the effect of the CETP inhibitor, torcetrapib, on carotid atherosclerosis progression in patients with mixed dyslipidaemia. METHODS We did a randomised double-blind trial at 64 centres in North America and Europe. 752 eligible participants completed an atorvastatin-only run-in period for dose titration, after which they all continued to receive atorvastatin at the titrated dose. 377 of these patients were randomly assigned to receive 60 mg of torcetrapib per day and 375 to placebo. We made carotid ultrasound images at baseline and at 6-month intervals for 24 months. The primary endpoint was the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Analysis was restricted to 683 patients who had at least one dose of treatment and had at least one follow-up carotid intima-media measurement; they were analysed as randomised. Mean follow-up for these patients was 22 (SD 4.8) months. This trial is registered with ClinicalTrials.gov, number NCT00134238. FINDINGS The change in maximum carotid intima-media thickness was 0.025 (SD 0.005) mm per year in patients given torcetrapib with atorvastatin and 0.030 (0.005) mm per year in those given atorvastatin alone (difference -0.005 mm per year, 95% CI -0.018 to 0.008, p=0.46). Patients in the combined-treatment group had a 63.4% relative increase in HDL cholesterol (p<0.0001) and an 17.7% relative decrease in LDL cholesterol (p<0.0001), compared with controls. Systolic blood pressure increased by 6.6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatin-only group (difference 5.4 mm Hg, 95% CI 4.3-6.4, p<0.0001). INTERPRETATION Although torcetrapib substantially raised HDL cholesterol and lowered LDL cholesterol, it also increased systolic blood pressure, and did not affect the yearly rate of change in the maximum intima-media thickness of 12 carotid segments. Torcetrapib showed no clinical benefit in this or other studies, and will not be developed further.

Common Carotid Intima-Media Thickness Measurements in Cardiovascular Risk Prediction: A Meta-analysis

CONTEXT The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. OBJECTIVE To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. DATA SOURCES Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. STUDY SELECTION Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. DATA EXTRACTION Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. RESULTS We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. CONCLUSION The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Carotid Intima-Media Thickness Measurements in Intervention Studies Design Options, Progression Rates, and Sample Size Considerations: A Point of View

Background— Carotid intima-media thickness (CIMT) measurements are currently widely used in randomized controlled trials (RCTs) to study the efficacy of interventions. In designing a RCT with CIMT as a primary outcome, several ultrasound options may be considered. We discuss the various options and provide a pooled estimate of CIMT progression. In addition, we quantify the effect of these choices on the sample size for a RCT. Summary of Comment— To estimate the average CIMT progression rate, we performed a pooled analysis using CIMT progression rates of control groups from published RCTs. The pros and cons of the following ultrasound options are discussed: which arterial segments may be studied; whether near and far wall CIMT measurements should be performed; whether a single image (1 angle of interrogation) or multiple images (more angles of interrogation) should be used; whether a manual or an automated edge detection reading system should be used; and whether images should be read in a random fashion or in batches. The pooled analysis showed an annual rate of change in mean common CIMT of 0.0147 mm (95% CI, 0.0122 to 0.0173) and in mean maximum CIMT of 0.0176 mm (95% CI, 0.0149 to 0.0203). Conclusions— Given the current evidence together with our experience with recently developed ultrasound protocols, we favor the use of mean maximum CIMT rather than mean common CIMT as the primary outcome measure in RCTs designed to evaluate the efficacy of pharmacological and nonpharmacological interventions in carotid artery atherosclerosis.

Hypertension, Blood Pressure, and Heart Rate Variability. The Atherosclerosis Risk in Communities (ARIC) Study

Abstract—Dysregulation of the autonomic nervous system has been implicated in the development of hypertension. Heart rate variability is a noninvasive tool to quantitatively estimate cardiac autonomic activity and has been used to document decreased cardiac autonomic activity in hypertension. The ability of decreased heart rate variability to predict incident hypertension has not been well studied, and there are no studies of whether hypertension leads to changes in heart rate variability. We investigated the temporal sequence linking hypertension, blood pressure, and heart rate variability in a population-based cohort of 11 061 individuals aged 45 to 54 years at baseline. Individuals with hypertension had decreased heart rate variability at baseline, and this association was present across the full blood pressure range. Among 7099 individuals without hypertension at baseline, low heart rate variability predicted greater risk of incident hypertension over 9 years of follow-up. The hazard ratio (95% confidence interval [CI]) for the lowest compared with the highest quartile of the standard deviation of normal-to-normal R-R intervals was 1.24 (95% CI, 1.10–1.40), for the root mean square of successive differences in normal-to-normal R-R intervals was 1.36 (95% CI, 1.21–1.54), and for R-R interval was 1.44 (95% CI, 1.27–1.63). Over 9 years, there was no measurable difference in the rate of change in heart rate variability among those with and without hypertension, although the differences in heart rate variability at follow-up were smaller than those at baseline. These findings thus support the thesis that the autonomic nervous system is involved in the development of hypertension, yet suggest that differences in the autonomic profile of hypertensives and normotensives do not increase with time.

Effects of Cardiac Autonomic Dysfunction on Mortality Risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial

OBJECTIVE Intensive therapy targeting normal blood glucose increased mortality compared with standard treatment in a randomized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease (CVD) events. We evaluated whether the presence of cardiac autonomic neuropathy (CAN) at baseline modified the effect of intensive compared with standard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants. RESEARCH DESIGN AND METHODS CAN was assessed by measures of heart rate variability (HRV) and QT index (QTI) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements (mean age 63.0 years, 40% women). Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy. Outcomes were all-cause and CVD mortality. Associations between CAN and mortality were evaluated by proportional hazards analysis, adjusting for treatment group allocation, CVD history, and multiple prespecified baseline covariates. RESULTS During a mean 3.5 years follow-up, there were 329 deaths from all causes. In fully adjusted analyses, participants with baseline CAN were 1.55–2.14 times as likely to die as participants without CAN, depending on the CAN definition used (P < 0.02 for all). The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline (Pinteraction > 0.7). CONCLUSIONS Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort, these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with standard glycemia treatment in the ACCORD cohort.

Serum Uric Acid Predicts Incident Hypertension in a Biethnic Cohort The Atherosclerosis Risk in Communities Study

Serum uric acid has been positively associated with incident hypertension, but previous studies have had limited ability to explore this relationship across sex and ethnic strata. We sought to evaluate this association in a biethnic cohort of middle-aged men and women. Participants in the Atherosclerosis Risk in Communities (ARIC) study who were free of hypertension at baseline (N=9104) were evaluated for hypertension at 3-year intervals over 4 examinations. Adjusted Cox proportional hazards models evaluated risk of incident hypertension or progression of blood category for each SD higher baseline serum uric acid. At baseline, the mean age was 53.3 years (range: 45 to 64 years), with a mean (SD) systolic blood pressure of 113.8 (12.2) mm Hg, mean diastolic blood pressure of 70.2 (8.6) mm Hg, and mean serum uric acid of 5.7 (1.4). Higher serum uric acid was associated with greater risk of hypertension in the overall cohort (hazard ratio for each SD of higher uric acid [95% CI]: 1.10 [1.04 to 1.15]) and in subgroup analyses (black men: 1.32 [1.14 to 1.54]; black women: 1.16 [1.03 to 1.31]; white men: 1.01 [0.94 to 1.09]; white women: 1.04 [0.96 to 1.11]), after adjustment for age, baseline blood pressure, body mass index, renal function, diabetes, and smoking. The pattern was similar when modeling blood pressure progression (overall: 1.10 [1.05 to 1.14]; black men: 1.26 [1.11 to 1.42]; black women: 1.18 [1.06 to 1.31]; white men: 1.05 [0.99 to 1.11]; white women: 1.05 [1.00 to 1.12]). In conclusion, serum uric acid was positively associated with incident hypertension over 9 years of follow-up, and this relationship was stronger in blacks than in whites. More research is warranted concerning the physiological and clinical consequences of hyperuricemia, especially in blacks.