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Background Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia. Objectives This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype. Methods Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers). Results Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908). Conclusions Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.

Background The effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline. Methods We did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (Findings We included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and 4788 (1·3%) 85 years and older. The hazard ratios for the risk of major cardiovascular events per 5 mm Hg reduction in systolic blood pressure for each age group were 0·82 (95% CI 0·76–0·88) in individuals younger than 55 years, 0·91 (0·88–0·95) in those aged 55–64 years, 0·91 (0·88–0·95) in those aged 65–74 years, 0·91 (0·87–0·96) in those aged 75–84 years, and 0·99 (0·87–1·12) in those aged 85 years and older (adjusted pinteraction=0·050). Similar patterns of proportional risk reductions were observed for a 3 mm Hg reduction in diastolic blood pressure. Absolute risk reductions for major cardiovascular events varied by age and were larger in older groups (adjusted pinteraction=0·024). We did not find evidence for any clinically meaningful heterogeneity of relative treatment effects across different baseline blood pressure categories in any age group. Interpretation Pharmacological blood pressure reduction is effective into old age, with no evidence that relative risk reductions for prevention of major cardiovascular events vary by systolic or diastolic blood pressure levels at randomisation, down to less than 120/70 mm Hg. Pharmacological blood pressure reduction should, therefore, be considered an important treatment option regardless of age, with the removal of age-related blood-pressure thresholds from international guidelines. Funding British Heart Foundation, National Institute of Health Research Oxford Biomedical Research Centre, Oxford Martin School.

Background The effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure. Methods We did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were excluded. Data from 51 studies published between 1972 and 2013 were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We pooled the data to investigate the stratified effects of blood pressure-lowering treatment in participants with and without prevalent cardiovascular disease (ie, any reports of stroke, myocardial infarction, or ischaemic heart disease before randomisation), overall and across seven systolic blood pressure categories (ranging from

Objective The purpose of this study was to examine the relationship between dynapenia and metabolic risk factors in obese and nonobese older adults. Methods A total of 1453 men and women (age ≥70 years) from the Lifestyle Interventions and Independence for Elders (LIFE) Study were categorized as (1) nondynapenic/nonobese (NDYN-NO), (2) dynapenic/nonobese (DYN-NO), (3) nondynapenic/obese (NDYN-O), or (4) dynapenic/obese (DYN-O), based on muscle strength (Foundation for the National Institute of Health criteria) and body mass index. Dependent variables were blood lipids, fasting glucose, blood pressure, presence of at least 3 metabolic syndrome (MetS) criteria, and other chronic conditions. Results A significantly higher likelihood of having abdominal obesity criteria in NDYN-NO compared with DYN-NO groups (55.6 vs 45.1%, P ≤ .01) was observed. Waist circumference also was significantly higher in obese groups (DYN-O = 114.0 ± 12.9 and NDYN-O = 111.2 ± 13.1) than in nonobese (NDYN-NO = 93.1 ± 10.7 and DYN-NO = 92.2 ± 11.2, P ≤ .01); and higher in NDYN-O compared with DYN-O ( P = .008). Additionally, NDYN-O demonstrated higher diastolic blood pressure compared with DYN-O (70.9 ± 10.1 vs 67.7 ± 9.7, P ≤ .001). No significant differences were found across dynapenia and obesity status for all other metabolic components ( P > .05). The odds of having MetS or its individual components were similar in obese and nonobese, combined or not with dynapenia (nonsignificant odds ratio [95% confidence interval]). Conclusion Nonobese dynapenic older adults had fewer metabolic disease risk factors than nonobese and nondynapenic older adults. Moreover, among obese older adults, dynapenia was associated with lower risk of meeting MetS criteria for waist circumference and diastolic blood pressure. Additionally, the presence of dynapenia did not increase cardiometabolic disease risk in either obese or nonobese older adults.

High levels of fibroblast growth factor 23 are associated with accelerated progression of CKD. Whether high fibroblast growth factor 23 levels also predict incident CKD is uncertain.A prospective case-cohort study was conducted within the Action to Control Cardiovascular Risk in Diabetes Trial. The analytic sample consisted of a random subcohort of 590 patients with type 2 diabetes without prevalent CKD at baseline, 124 of whom developed incident CKD during follow-up, and 520 additional patients with incident CKD outside the random subcohort. The association between serum intact fibroblast growth factor 23 and incident CKD, defined as the new onset of eGFR60 ml/min per 1.73 m(2) that represented a ≥25% decrease from baseline in an individual with eGFR≥60 ml/min per 1.73 m(2) and no microalbuminuria (30 mg/g creatinine) at baseline, was tested.The mean baseline eGFR in the random subcohort was 90.9±22.7 ml/min per 1.73 m(2). During a median follow-up of 4.7 years, there was a total of 644 patients with incident CKD. The median baseline fibroblast growth factor 23 level was modestly higher among patients with incident CKD versus controls (43.5, interquartile range=34.7-55.1 versus 39.8, interquartile range=31.9-49.5 pg/ml; P0.001). Higher baseline fibroblast growth factor 23 levels were associated with higher risk of incident CKD in unadjusted and demographics-adjusted models, but the effect was attenuated after additional adjustment for clinical risk factors and baseline eGFR (hazard ratio per SD of natural log fibroblast growth factor 23, 1.09; 95% confidence interval, 0.94 to 1.27), which was the strongest predictor of incident CKD. Consistent with the results of primary analyses, baseline fibroblast growth factor 23 was not associated with eGFR slope.Higher fibroblast growth factor 23 levels are not independently associated with higher risk of incident CKD in patients with type 2 diabetes.

Background Data are sparse regarding the value of physical activity ( PA ) surveillance among older adults—particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. Methods and Results Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home‐based activity data were collected by hip‐worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [ SD ] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84–0.96; P =0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65–0.89 [ P =0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow‐up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85–0.96 [ P =0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63–0.90 [ P =0.002]) were significantly associated with lower cardiovascular event rates. Conclusions Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01072500.

OBJECTIVE To determine the occurrence of extremely low HDL cholesterol (HDL-C) among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial and to examine the relationship of this finding with treatment with fenofibrate and thiazolidinedione (TZD). RESEARCH DESIGN AND METHODS The ACCORD Lipid Trial was a randomized, double-blind, placebo-controlled study conducted in patients with type 2 diabetes at 77 clinical centers across the U.S. and Canada in a 5,518-patient subset of the larger 10,251 ACCORD Glycemia Trial. Patients were enrolled from 11 January 2001 to 29 October 2005 and followed until the end of study visits between 1 March and 30 June 2009. Follow-up in the ACCORD Lipid Trial was 4–8 years (mean 4.7 years). Patients were treated with blinded fenofibrate or placebo on a background of simvastatin therapy. The main outcome measures for these descriptive, post hoc analyses was the occurrence of extremely low HDL-C (defined as RESULTS Among ACCORD Lipid Trial participants, the occurrence of extremely low HDL-C ever during study follow-up was 106% higher among those randomized to fenofibrate (10.1% fenofibrate vs. 4.9% placebo, P < 0.001). The occurrence of low HDL-C was associated with concurrent treatment with fenofibrate and TZD (7.0% for both vs. 2.2% for neither at 48 months postrandomization). CONCLUSIONS Idiosyncratic and marked reduction in HDL-C can occur in some patients treated with both fenofibrate and TZD. Practitioners should recognize this important potential idiosyncratic reaction and take appropriate corrective action.

OBJECTIVE We explore the effect of randomized treatment, comparing intensive to standard glucose-lowering strategies on major cardiovascular outcomes, death, and severe adverse events in older versus younger participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes (n = 10,251) with a mean age of 62 years, a median duration of diabetes of 10 years, and a median A1C of 8.1% (65 mmol/mol) were randomized to treatment strategies targeting either A1C RESULTS Older and younger ACCORD participants achieved similar intensive-arm A1C levels and between-arm A1C differences. Within the older subgroup, similar hazards of the cardiovascular primary outcome and total mortality were observed in the two arms. While there was no intervention effect on cardiovascular mortality in the older subgroup, there was an increased risk in the intensive arm for the younger subgroup (older hazard ratio [HR] = 0.97; younger HR = 1.71; P = 0.03). Regardless of intervention arm, the older subgroup experienced higher annualized rates of severe hypoglycemia (4.45% intensive and 1.36% standard) than the younger subgroup (2.45% intensive and 0.80% standard). CONCLUSIONS Intensive glucose lowering increased the risk of cardiovascular disease and total mortality in younger participants, whereas it had a neutral effect in older participants. The intensive to standard relative risk of severe hypoglycemia was similar in both age subgroups, with higher absolute rates in older participants within both treatment arms.

To evaluate the extent of variability in functional responses in participants in the Lifestyle Interventions and Independence for Elders (LIFE) study and to identify the relative contributions of intervention adherence, physical activity, and demographic and health characteristics to this variability.Secondary analysis.Multicenter institutions.A volunteer sample (N=1635) of sedentary men and women aged 70 to 89 years who were able to walk 400m but had physical limitations, defined as a Short Physical Performance Battery (SPPB) score of ≤9.Moderate-intensity physical activity (n=818) consisting of aerobic, resistance, and flexibility exercises performed both center-based (2times/wk) and home-based (3-4times/wk) sessions or health education program (n=817) consisting of weekly to monthly workshops covering relevant health information.Physical function (gait speed over 400m) and lower extremity function (SPPB score) assessed at baseline and 6, 12, and 24 months.Greater baseline physical function (gait speed, SPPB score) was negatively associated with change in gait speed (regression coefficient β=-.185; P.001) and change in SPPB score (β=-.365; P.001), whereas higher number of steps per day measured by accelerometry was positively associated with change in gait speed (β=.035; P.001) and change in SPPB score (β=.525; P.001). Other baseline factors associated with positive change in gait speed and/or SPPB score include younger age (P.001), lower body mass index (P.001), and higher self-reported physical activity (P=.002).Several demographic and physical activity-related factors were associated with the extent of change in functional outcomes in participants in the LIFE study. These factors should be considered when designing interventions for improving physical function in older adults with limited mobility.

OBJECTIVE Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C RESULTS Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6–9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%. CONCLUSIONS These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.

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.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.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%) (P0.001).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.)

Most patients with type 2 diabetes mellitus develop cardiovascular disease (CVD), with substantial loss of life expectancy. Nonfatal CVD contributes greatly to excess healthcare costs and decreased quality of life in patients with diabetes. The current epidemic of obesity has raised expectations that CVD associated with type 2 diabetes will become an even greater public health challenge. Despite the importance of this health problem, there is a lack of definitive data on the effects of the intensive control of glycemia and other CVD risk factors on CVD event rates in patients with type 2 diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized, multicenter, double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type 2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors. ACCORD is testing the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality. All participants are in the glycemia trial, which is testing the hypothesis that a therapeutic strategy that targets a glycosylated hemoglobin (HbA1c) level of6.0% will reduce the rate of CVD events more than a strategy that targets an HbA1c level of 7.0%-7.9%. The lipid trial includes 5,518 of the participants, who receive either fenofibrate or placebo in a double-masked fashion to test the hypothesis of whether, in the context of good glycemic control, a therapeutic strategy that uses a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) to lower low-density lipoprotein cholesterol will reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo. The blood pressure trial includes the remaining 4,733 participants and tests the hypothesis that a therapeutic strategy that targets a systolic blood pressure of120 mm Hg in the context of good glycemic control will reduce the rate of CVD events compared with a strategy that targets a systolic blood pressure of140 mm Hg. The primary outcome measure for all 3 research questions is the first occurrence of a major CVD event, specifically nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Upon the expected completion of participant follow-up in 2009, the ACCORD trial should document for the first time the benefits and risks of intensive glucose control, intensive blood pressure control, and the combination of fibrate and statin drugs in managing blood lipids in high-risk patients with type 2 diabetes.

Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates 2-4 times higher than patients without diabetes but with similar demographic characteristics. The prevalence of diabetes is increasing in the United States and, thus, the prevention of CVD in patients with diabetes poses an urgent public health challenge. The objective of this report is to review the current knowledge base for the prevention of CVD in patients with diabetes, with particular emphasis on the control of glycemia, lipids, and blood pressure. Epidemiologic analyses suggest that each 1% increase in glycosylated hemoglobin increases the risk for CVD by approximately 18%; however, evidence from the randomized trials that have examined whether glucose lowering reduces this risk is conflicting. Randomized trials have shown that lowering low-density lipoprotein cholesterol reduces CVD event rates by 17%-43% in patients with diabetes. Limited data support a role for lowering triglycerides and increasing high-density lipoprotein cholesterol in the prevention of CVD. Evidence from clinical trials shows that reducing systolic blood pressure to140 mm Hg results in 30%-60% reductions in CVD events; however, epidemiologic evidence suggests that lowering to optimal systolic blood pressure levels (120 mm Hg) may be additionally beneficial. Important questions regarding prevention of CVD in patients with diabetes remain unresolved, including the benefits of near-normal glycemic control, comprehensive therapy for diabetes-related dyslipidemia, and optimal blood pressure control. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial will test hypotheses to address these unanswered questions.

Abstract— Left ventricular hypertrophy (LVH), a marker of cardiac end-organ damage, is a common complication of hypertension. Regression of LVH is achievable by sustained lowering of systolic blood pressure (BP). However, it is unknown whether a strategy aimed at lowering BP beyond that recommended would lower the risk of LVH. We examined the effect of intensive (systolic BPP =0.91) and the mean Cornell index (1456 versus 1470 µV; P =0.45) were similar in the intensive (n=2154) and standard (n=2177) BP-lowering arms, respectively. However, after median follow-up of 4.4 years, intensive, compared with standard, BP lowering was associated with a 39% lower risk of LVH (odds ratio [95% confidence interval], 0.61[0.43, 0.88]; P =0.008) and a significantly lower adjusted mean Cornell index (1352 versus 1447 µV; P Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000620

The Prospective Pravastatin Pooling (PPP) Project was a prospectively defined collaboration of three randomized, placebo-controlled, long-term, monotherapy (40 mg/d) trials of the lipid-lowering agent pravastatin. A pooled database of 19,768 participants with a mean of 5.2 years of follow-up was created, providing the investigators with over 100,000 patient-years of experience to address questions on total and cause-specific mortality, coronary incidence, stroke, and safety. One trial (West of Scotland Coronary Prevention Study) was primary prevention and two (Cholesterol and Recurrent Events and Long-term Intervention with Pravastatin in Ischemic Disease) were secondary prevention. Pravastatin was shown to safely reduce all-cause mortality, fatal and nonfatal coronary events, and stroke events in patients with a broad range of patient characteristics.

Importance Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. Objective To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. Design, Setting, and Participants Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL ( Interventions Passive follow-up of study participants previously treated with fenofibrate or masked placebo. Main Outcomes and Measures Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. Results The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n = 1445; 31%), nonwhite individuals (n = 1094; 21%), and those with preexisting cardiovascular events (n = 1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P = .25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P = .32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95). Conclusions and Relevance Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. Trial Registration clinicaltrials.gov Identifier:NCT00000620.

Background —Stroke is a leading cause of death and disability. Although clinical trials of the early lipid-lowering therapies did not demonstrate a reduction in the rates of stroke, data from recently completed statin trials strongly suggest benefit. Methods and Results —The effect of pravastatin 40 mg/d on stroke events was investigated in a prospectively defined pooled analysis of 3 large, placebo-controlled, randomized trials that included 19 768 patients with 102 559 person-years of follow-up. In all, 598 participants had a stroke during ≈5 years of follow-up. The 2 secondary prevention trials (CARE [Cholesterol And Recurrent Events] and LIPID [Long-term Intervention with Pravastatin in Ischemic Disease]) individually demonstrated reductions in nonfatal and total stroke rates. When the 13 173 patients from CARE and LIPID were combined, there was a 22% reduction in total strokes (95% CI 7% to 35%, P =0.01) and a 25% reduction in nonfatal stroke (95% CI 10% to 38%). The beneficial effect of pravastatin on total stroke was observed across a wide range of patient characteristics. WOSCOPS (West of Scotland Coronary Prevention Study, a primary prevention trial in hypercholesterolemic men) exhibited a similar, although smaller, trend for a reduction in total stroke. Among the CARE/LIPID participants, pravastatin was associated with a 23% reduction in nonhemorrhagic strokes (95% CI 6% to 37%), but there was no statistical treatment group difference in hemorrhagic or unknown type. Conclusions —Pravastatin reduced the risk of stroke over a wide range of lipid values among patients with documented coronary disease. This effect was due to a reduction in nonfatal nonhemorrhagic strokes.

Background —The results of angiographic studies have suggested that calcium channel–blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both. Methods and Results —The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter: 0.084 versus 0.095 mm, respectively ( P =0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis: the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0.0126-mm decrease in the amlodipine group ( P =0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization. Conclusions —Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization.

OBJECTIVE Investigators from the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) previously reported that the isradipine group had a higher incidence of cardiovascular disease (CVD) events than the diuretic group. The ultimate objective of the analyses presented here was to assess how indices of glycemia (specifically, serum glucose, serum insulin, and HbAlc)might have influenced the effects of the two agents on blood pressure control and CVD events. RESEARCH DESIGN AND METHODS Inclusion criteria included men and women ≥40 years of age with ultrasonographically confirmed carotid atherosclerosis and a diastolic blood pressure of >90 mmHg. Although insulin-dependent diabetic patients were excluded, the three glycemia indices had wide enough ranges to include patients who may be classified as prediabetic. A total of 883 patients were randomized either to the dihydropyridine calcium antagonist (CA) isradipine (2.5–5 mg twice a day) or to the diuretic hydrochlorothiazide (12.5–25 mg twice a day) and followed in double-blind fashion for 3 years. RESULTS Both treatment groups had achieved comparable control of diastolic blood pressure, and there were no statistically significant differences in any of the glycemia indices, either at baseline or during follow-up. However, the excess isradipine events were noted to be clustered among those patients with elevated baseline levels of HbA1c who also experienced greater blood pressure reductions during follow-up. CONCLUSIONS The increased cardiovascular risk associated with dihydropyridine CAs in prediabetic patients may be an explanation for the overall CA debate.

Patients with managed care are less likely to see dermatologists for skin problems than are patients with traditional insurance. Through 1992, increase in the demand for treatment of skin problems reduced the effect of managed care on dermatologists. We assessed the continued impact of managed care on visits to dermatologists. Skin disease visits from the National Ambulatory Medical Care Survey were analyzed for the years 1990-1994. We found that demand for treatment of skin problems did not rise between 1992 and 1994, but demand for dermatologists services within the managed care sector more than doubled. In 1994 patients with HMO/prepaid insurance with skin disease were just as likely to see a dermatologist as were patients with commercial insurance. Mean visit duration for skin problems was 19% longer for nondermatologists than for dermatologists (p0.001). We conclude that dermatologists are more efficient at treating skin disease than nondermatologists and that utilization of dermatologists within managed care is increasing.

Background: The provision of ambulatory dermatologic procedural care is not well characterized. Objective: Our purpose was to determine the frequency that different cutaneous procedures are performed by different physician specialties and the diagnoses corresponding to these procedures. Methods: Outpatient dermatologic procedures recorded in the 1993 and 1994 National Ambulatory Medical Care Survey were analyzed. To define dermatologic procedures and diagnoses, the International Classification of Diseases diagnosis and procedure codes were identified that related to the skin and subcutaneous tissues. Sampling weights were applied to achieve the nationally representative estimates. Results: During 1993 and 1994, an estimated 37 million dermatologic procedures were performed. Most were performed by dermatologists (69%) and by family and general practice physicians (15%). A single procedure, "Other local excision or destruction of lesion or tissue of skin and subcutaneous tissue," constituted 65% of all of the dermatologic procedures. UV light treatments, ambulatory microscopic examination of skin specimens, and acne surgical procedures were performed almost exclusively by dermatologists. Most skin biopsies (82%) and excision/destruction procedures (71%) were performed by dermatologists. Actinic keratoses and viral warts accounted for 25% of all cutaneous dermatologic diagnoses treated. Conclusion: Dermatologists have far more experience performing skin biopsies and excision/destruction procedures than other physicians. Cost containment efforts that deny coverage for treatment of actinic keratoses and viral warts would affect a significant portion of cutaneous procedures. (J Am Acad Dermatol 1997;37:719-24.)

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are more efficacious than older lipid-lowering agents and there-fore may be more effective in reducing the incidence of coronary events. The objective of this prespecified analysis was to examine in coronary patients the effect of the lipid-lowering agent pravastatin on 3-year rates of coronary event incidence, all-cause mortality, and nonfatal myocardial infarction (M1), and to determine whether any observed benefit was also evident in patients 265 years of age. The design of this analysis was to pool the data from 2 concurrent 3-year placebo-controlled clinical trials of pravastatin monotherapy in coronary patients (Pravastatin Limitation of Atherosclerosis in the Coronary Arteries [PLAC I] and the Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries [PLAC II]). This pooled database included 559 coronary patients with moderately elevated levels of low density lipoprotein cholesterol (between the 60th and 90th percentiles for age and gender in the United States). Over the 3 years of follow-up, use of pravastatin was associated with a 55% reduction in coronary incidence (p = 0.014). Pravastatin was also associated with a 67% reduction in nonfatal M1 (p = 0.006). Eleven placebo patients died over the 3 years of follow-up compared with 7 in the pravastatin groups (a 40% reduction). Among older patients (age ≥65 years), pravastatin therapy was associated with a 79% reduction in coronary event incidence (95% confidence interval [CI] 33–100%) and with a 86% reduction in nonfatal myocardial infarction (CI, 35–100%). These results provide strong evidence that pravastatin prevents recurrent clinical events in coronary patients, including those ≥65 years of age.

The Asymptomatic Carotid Artery Progression Study (ACAPS) compared the usefulness of lovastatin alone or in combination with warfarin in the prevention of 3-year progression of mean maximum intimal-me

A b s t r ac t Background Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events. Methods We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial. Results Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P = 0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups. Conclusions As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.)

The Pravastatin, Lipids, and Atherosclerosis in the Carotids trial (PLAC-II) was initiated in 1987 and is the first double-masked randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable. The trial will compare a lipid-lowering agent (pravastatin, a hydroxymethylglutaryl CoA reductase inhibitor) with placebo for ability to retard the rate of progression of extracranial carotid atherosclerosis over 3 years. Inclusion criteria consisted of prevalent coronary artery disease, moderately elevated low-density lipoprotein (LDL) cholesterol (between the 60th and 90th percentiles), and the presence of at least one extracranial carotid artery atherosclerotic plaque that had an intimal-medial thickness (IMT) ⩾ 1.3 mm as visualized by B-mode ultrasound. Of approximately 650 patients who qualified on the basis of coronary disease and elevated LDL cholesterol, 55% were excluded because of B-mode criteria. One hundred and fifty-one males and females 50–75 years of age were recruited. Random allocation produced placebo-treated and test-treated groups that were similar for baseline historical data, physical findings, laboratory tests, lipid values, and B-mode characteristics. Baseline concentrations of plasma total cholesterol, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol were 234, 166, and 41 mg/dl, respectively. Baseline plasma concentration of triglyceride was 170 mg/dl. Despite selection of participants whose arteries, overall, were suitable for the trial, individual segments in some participants could not be visualized. Ninety-seven percent of the individual carotid artery segments were visualized in the common carotid, 88% in the bifurcation, and 63% in the internal carotid artery. Far walls were slightly more often visualized than near walls, and nonvisualization was most common for the near wall of the internal carotid. Nonvisualized segments were comparable between both treatment groups. The distribution of arterial walls with qualifying plaque of ⩾1.3 mm IMT was similar for the two groups, and the two groups were also comparable for the primary outcome determinant, mean maximum IMT (mean of maximum of all visualizable sites, 1.32 mm for each treatment group). There are special problems related to recruitment and evaluation of patients for a clinical trial such as this, but the atherosclerosis outcome measurement markedly enhances power and compensates for difficulty in recruitment.

AIMS/HYPOTHESIS: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. METHODS: A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. RESULTS: A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). CONCLUSIONS/INTERPRETATION: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.

The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a randomized, double-blind, active-control trial to compare the effectiveness of two treatment regimens for the control of hypertension in reducing the rate of progression of early extracranial carotid artery atherosclerosis in hypertensive patients. The two double-blind treatment regimens are 2.5 or 5 mg isradipine twice daily and 12.5 mg or 25 mg hydrochlorothiazide twice daily. Patients whose blood pressure is not controlled with either of these regimens will receive, in addition to the highest tolerated dose of the blinded drug, 2.5 to 10 mg open-label enalapril twice daily. The MIDAS study has enrolled 883 patients to treatment with either isradipine or hydrochlorothiazide. Inclusion criteria included men and women over the age of 40 years, the presence of an atherosclerotic lesion in the extracranial carotid artery demonstrated on B-mode ultrasound scanning (maximum thickness between 1.3 and 3.5 mm), an average sitting diastolic blood pressure between 90 and 115 mm Hg, and low-density lipoprotein levels between 130 and 189 mg/dL. An assessment of each patient's blood pressure and any side effects is made every three months; a B-mode ultrasound examination of the carotid arteries was performed at baseline and every six months thereafter; an electrocardiogram was carried out at baseline and once a year thereafter; and a brief quality-of-life assessment was made at baseline and every year thereafter.

In the Beta Blocker Heart Attack Trial (BHAT), 3837 patients were randomized to propranolol (180-240 mg/day) or placebo 5-21 days after a documented myocardial infarction and were followed in a double blind manner for a mean period of 25 months. Twelve lead electrocardiograms were routinely obtained at the time of randomization (baseline electrocardiogram) and at 12 and 24 months of follow-up. There was a positive correlation between baseline QTc interval prolongation (but not QT prolongation) and mortality and sudden death that was independent of treatment group. The data for non-sudden death and non-fatal reinfarction exhibit similar trends. We conclude that: (1) QTc prolongation identifies a high risk subset of post myocardial infarction patients. (2) The relative benefit of propranolol is similar in patients with normal and prolonged QTc.

Background — Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data. Methods and Results — The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3× the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo. Conclusions — This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.

Background —Few clinical trials have documented the efficacy of preventive treatment in asymptomatic women. Methods and Results —Lovastatin and minidose warfarin were evaluated in a factorially designed, placebo-controlled, randomized trial. The primary outcome was 3-year change in the mean maximum intimal-medial thickness of the carotid arteries as measured by B-mode ultrasonography. Participants (n=919) were randomized to 1 of 4 treatment groups: lovastatin alone, warfarin alone, lovastatin+warfarin combination, or a double-placebo group. Eligible participants were asymptomatic for cardiovascular disease, with evidence of early carotid atherosclerosis and moderately elevated LDL cholesterol level. Almost half (n=445) of the participants were women. To avoid confounding, 117 women taking estrogen were excluded from analysis. Both sexes experienced reductions in disease progression with lovastatin; there was no evidence of an overall sex×treatment interaction ( P =0.72). When estimates of the sex-specific results were examined post hoc, women experienced disease regression to the greatest extent with the lovastatin+warfarin combination ( P =0.02), although the women on lovastatin alone also had a reduction in progression ( P =0.09). Men experienced the greatest reduction with lovastatin alone ( P =0.02), although there is a suggestion that warfarin may also reduce progression to some extent. Conclusions —Lovastatin is beneficial in reducing disease progression in women and men. Warfarin has no effect in women, although it may reduce progression in men. In men, warfarin does not add to the benefit of lovastatin and has no advantage over lovastatin alone.

In the July 2004 issue of Diabetes Care, Brown et al. (1) conclude by stating, “our results strongly suggest that the recommended [HbA1c] threshold for [treatment] action should be 7.0% or lower” and “an even stronger signal would be provided by a treatment threshold of 6.0%, which has proved widely …

A select group of screened applicants initially disqualified from a four-center, primary prevention drug lipid-lowering trial because of borderline elevated serum low-density lipoprotein cholesterol (LDL-C) levels, as defined in National Cholesterol Education Program-Adult Treatment Panel I (NCEP-ATP I) guidelines, participated in a dietary intervention protocol that was incorporated into the screening phase of the trial. Seventy-seven screened applicants for the Asymptomatic Carotid Artery Progression Study entered the dietary program, which was overseen by an experienced registered dietitian at the central operations sites who collaborated with local staff at clinical sites during program implementation. NCEP-ATP I fat-modified step I diet specifications served as the basis for the intervention. The program, consisting of five sessions conducted over an 8-week period, primarily used written and audiovisual educational materials in combination with behavioral approaches. Of the original 77 participants, 36 responded to the intervention by achieving their LDL-C goal. Twenty-nine were nonresponders and 12 were dropouts. Responders achieved an average 11.7% drop in total cholesterol at the end of the 8-week program. Mean LDL-C decline paralleled total cholesterol change. High-density lipoprotein cholesterol also decreased significantly. These results were sustained for 24 of the responders attending the final screening visit approximately a month later, when another fasting blood lipid measurement was made. Participants who dropped out were more likely to be smokers. Pre- and postintervention nutrition data assessed by semiquantitative food frequency questionnaire for 20 screenees randomized into the study indicated significant reductions in total fat, saturated fat, polyunsaturated fat, and dietary cholesterol, all known to influence blood lipid levels. Similar programs may prove useful to other drug lipid-lowering trials to maximize recruitment efforts.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have proven to be more effective in reducing levels of low density lipoprotein (LDL) cholesterol and to be better tolerated than other lipid-lowering compounds. Most of the trials evaluating the effects of these new agents on progression of atherosclerosis have not included individuals asymptomatic for cardiovascular disease and who have LDL cholesterol levels at or below the limits established by the National Cholesterol Education Program for initiating treatment. The Asymptomatic Carotid Artery Progression Study (ACAPS) tested the effect of the HMG-CoA reductase inhibitor, lovastatin, on early-stage carotid atherosclerosis (as detected by B-mode ultrasonography) in 919 asymptomatic men and women, 40-79 years of age, who had LDL cholesterol levels between the 60th and 90th percentiles. Participants randomized into this double-blind, placebo-controlled, factorially designed study received lovastatin (20-40 mg/day) or lovastatin-placebo and warfarin (1 mg/day), or warfarin-placebo over a 3-year period. The progression of the mean maximum intimal-medial thickness (IMT) over 12 walls of both carotid arteries represented the primary outcome. Lovastatin treatment was associated with a reduction in progression of mean maximum IMT (p0.001). Levels of LDL cholesterol were reduced by 28% (43.5 mg/dl [11.25 mmol/liter]) in the lovastatin group within 6 months (p0.0001) and remained stable throughout the follow-up period, whereas these levels remained essentially unchanged in the lovastatin-placebo group. The difference in incidence of major cardiovascular events for patients in the lovastatin-placebo group was significant: 5 versus 14, respectively (p0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

We randomized 151 coronary patients to placebo or pravastatin and treated them for 3 years. B-mode ultrasound quantification of carotid artery intimal-medial thickness (IMT) was obtained at baseline and sequentially during this period. The primary outcome was the change in the mean of the maximal IMT measurements across time. Effects on individual carotid artery segments (common, bifurcation, and internal carotid) and on clinical events were also investigated. Plasma concentrations of total cholesterol were lower with active treatment than with placebo (4.80 vs 6.07 mmol/L [186 vs 235 mg/dl], respectively) as were concentrations of low-density lipoprotein cholesterol (3.11 vs 4.30 mmol/L [120 vs 167 mg/dl], respectively). Plasma concentrations of high-density lipoprotein2 cholesterol were higher with active treatment (0.16 vs 0.14 mmol/L [6.1 vs 5.5 mg/dl], respectively). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 to 0.059 mm/year) and a statistically significant 35% reduction in IMT progression in the common carotid. Active treatment was also associated with a reduction in fatal and nonfatal coronary events [corrected] (p = 0.09) and of any fatal event plus nonfatal myocardial infarction (p = 0.04).

BACKGROUND HMG CoA reductase inhibitors (or statins), a new class of lipid-lowering compounds, have raised expectations for more widespread use than that of the older lipid-lowering drugs. Not only are they more effective in lowering LDL cholesterol, but they are better tolerated as well. No data exist concerning the effect of statins on early carotid atherosclerosis and clinical events in men and women who have moderately elevated LDL cholesterol levels but are free of symptomatic cardiovascular disease. METHODS AND RESULTS Lovastatin (20 to 40 mg/d) or its placebo was evaluated in a double-blind, randomized clinical trial with factorial design along with warfarin (1 mg/d) or its placebo. This report is limited to the lovastatin component of the trial. Daily aspirin (81 mg/d) was recommended for everyone. Enrollment included 919 asymptomatic men and women, 40 to 79 years old, with early carotid atherosclerosis as defined by B-mode ultrasonography and LDL cholesterol between the 60th and 90th percentiles. The 3-year change in mean maximum intimal-medial thickness (IMT) in 12 walls of the carotid arteries was the primary outcome; change in single maximum IMT and incidence of major cardiovascular events were secondary outcomes. LDL cholesterol fell 28%, from 156.6 mg/dL at baseline to 113.1 mg/dL at 6 months (P < .0001), in the lovastatin groups and was largely unchanged in the lovastatin-placebo groups. Among participants not on warfarin, regression of the mean maximum IMT was seen after 12 months in the lovastatin group compared with the placebo group; the 3-year difference was statistically significant (P = .001). A larger favorable effect of lovastatin was observed for the change in single maximum IMT but was not statistically significant (P = .12). Five lovastatin-treated participants suffered major cardiovascular events--coronary heart disease mortality, nonfatal myocardial infarction, or stroke--versus 14 in the lovastatin-placebo groups (P = .04). One lovastatin-treated participant died, compared with eight on lovastatin-placebo (P = .02). CONCLUSIONS In men and women with moderately elevated LDL cholesterol, lovastatin reverses progression of IMT in the carotid arteries and appears to reduce the risk of major cardiovascular events and mortality. Results from ongoing large-scale clinical trials may further establish the clinical benefit of statins.

Measurements of intimal-medial thickness (IMT) of the carotid artery by B-mode ultrasonography are widely used as markers of atherosclerosis. This report describes empirical features of these measurements to characterize their distribution within arterial wall segments, to explore their potential as study outcome measures, and to examine their links with traditional risk factors for cardiovascular disease. Sequential transverse measurements of IMT in the carotid arteries were made in 899 participants from the Asymptomatic Carotid Artery Progression Study (ACAPS) at baseline. Data from 17 intrasegment sites in each of 12 arterial wall segments were used to describe patterns of thickness and visualization and to characterize cross-sectional area, severity, and roughness/irregularity by the intrasegment averages, maxima, and SDs of IMT, respectively. Serial correlations of IMT measurements indicated localized and diffuse features of disease. The spatial distribution of IMT had two dominant features: overall mass and mass relative to roughness. The validity of these features was demonstrated by their correlation to known risk factors for carotid atherosclerosis: body mass index, age, high-density lipoprotein cholesterol, systolic blood pressure, smoking, and sex. Both the mean and maxima of intrasegment measurements appear to be good candidates for use in clinical studies. B-mode ultrasonography has validity for the description of IMT roughness and shape. Both of these features are linked to cardiovascular risk factors, which supports the multifaceted nature of atherosclerosis.

The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a double-blind, randomized, controlled clinical trial comparing the effects of isradipine and hydrochlorothiazide on the progression or regression of early carotid atherosclerosis in 883 hypertensive patients. Assessment of the outcome is by B-mode ultrasonographic measurement of early lesions (as reflected by intimal-medial wall thickening) at baseline and semiannually over 36 months. At baseline, the participants' mean age was 58.5 years. The study population was 78.6% male and 72.4% white. The average resting systolic and diastolic blood pressures were 149.8 and 96.5 mm Hg, respectively. Mean total serum cholesterol and low-density lipoprotein (LDL)-cholesterol levels were 216.2 mg/dL and 146.6 mg/dL, respectively. Risk factors for coronary artery disease were balanced at baseline between the two study groups. The mean maximum intimal-medial thickness at baseline (measured in the near and far walls of three segments for both carotid arteries) was 1.17 +/- 0.20 mm; the mean intimal-medial thickness of the single thickest lesion was 2.11 +/- 0.51 mm. Cross-sectional analyses show that intimal-medial thickness correlates independently with male gender, age, number of cigarettes smoked per day, levels of LDL cholesterol, systolic blood pressure, and white blood cell count. The MIDAS endpoint results will be available in 1993.

Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Design Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A1C) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A1C

Hypertension is a major risk factor for coronary heart disease (CHD) and is the primary risk factor for stroke. Drug trials lowering blood pressure by pharmacological means have demonstrated impressive reduction in both fatal and nonfatal stroke (33 to 50%) that are virtually identical to the predicted stroke reduction, considering the observed diastolic blood pressure change (5 to 6mm Hg). On the other hand, reduction of CHD risk has been less impressive in these same trials. Although statistically significant, the reduction in CHD risk is roughly one-half (14%) of that predicted (25%) when results from these drug trials are analysed in aggregate. Most trials have used moderate to high dosages of thiazide diuretics or beta-blockers as therapies. Several factors may account for the disappointing results in CHD risk reduction. These drugs may induce metabolic disturbances in lipids, increased glucose tolerance, insulin resistance, or cause inadequate regression of left ventricular hypertrophy, thus attenuating the predicted reduction in CHD risk associated with pharmacological blood pressure lowering. Isradipine is a new dihydropyridine calcium antagonist that is highly effective in lowering blood pressure. Isradipine also has antiatherogenic properties in animal models of atherosclerosis. The effect of isradipine on atherosclerosis in humans is unknown. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) is a 3-year double-blind, randomised trial in over 800 men and women with hypertension, aged 40 years or older. The primary aim of MIDAS is to compare the efficacy of isradipine 2.5 to 5.0mg twice daily vs hydrochlorothiazide 12.5 to 25mg twice daily in retarding the progression of extracranial carotid atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Background In randomized trials of secondary prevention, pravastatin sodium and aspirin reduce risks of cardiovascular disease. Pravastatin has a predominantly delayed antiatherogenic effect, and aspirin has an immediate antiplatelet effect, raising the possibility of additive clinical benefits. Methods In 5 randomized trials of secondary prevention with pravastatin (40 mg/d), comprising 73 900 patient-years of observation, aspirin use was also prescribed in varying frequencies, and data were available on a large number of confounding variables. We tested whether pravastatin and aspirin have additive benefits in the 2 large trials (Long-term Intervention With Pravastatin in Ischaemic Disease trial and the Cholesterol and Recurrent Events trial) that were designed to test clinical benefits. We also performed meta-analyses of these 2 trials and 3 smaller angiographic trials that collected clinical end points. In all analyses, multivariate models were used to adjust for a large number of cardiovascular disease risk factors. Results Individual trials and all meta-analyses demonstrated similar additive benefits of pravastatin and aspirin on cardiovascular disease. In meta-analysis, the relative risk reductions for fatal or nonfatal myocardial infarction were 31% for pravastatin plus aspirin vs aspirin alone and 26% for pravastatin plus aspirin vs pravastatin alone. For ischemic stroke, the corresponding relative risk reductions were 29% and 31%. For the composite end point of coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or ischemic stroke, the relative risk reductions were 24% and 13%. All relative risk reductions were statistically significant. Conclusion More widespread and appropriate combined use of statins and aspirin in secondary prevention of cardiovascular disease will avoid large numbers of premature deaths.