Intensive glucose control and macrovascular outcomes in type 2 diabetes.

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.

Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) Project.

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 approximately 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.

Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators.

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.

Effects of lovastatin and warfarin on early carotid atherosclerosis: sex-specific analyses. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group.

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 x 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.

Effect of propranolol in patients with myocardial infarction and ventricular arrhythmia.

The Beta-Blocker Heart Attack Trial was a placebo-controlled, randomized, double-blind clinical trial of the long-term administration of propranolol hydrochloride to patients who had had at least one myocardial infarction. Among 3,837 patients followed up for an average of 25 months, 3,290 (85.7%) had 24 hour ambulatory electrocardiograms performed at the baseline examination. Four classifications of arrhythmia were examined. One of these, the presence of complex ventricular arrhythmias (at least 10 ventricular premature beats/h, or at least one pair or run of ventricular premature beats or multiform ventricular premature beats) was the subgroup of major interest. Regardless of the classification, the presence of arrhythmia identifies a group of patients with a higher risk of total mortality, coronary heart disease mortality, sudden cardiac death and instantaneous cardiac death. The a priori subgroup hypothesis that sudden death would be preferentially reduced by propranolol in patients with complex ventricular arrhythmias was not supported. The relative benefit of propranolol in reducing sudden death for this subgroup was 28 versus 16% for the subgroup without ventricular arrhythmia (relative risk of 0.72 versus 0.84, a nonsignificant relative difference of 14%). There were similar findings for two of the three other classifications of arrhythmia and for the other response variables. Although propranolol does not appear to be of special relative benefit in patients with ventricular arrhythmia, the presence of the arrhythmia does identify a high-risk group. The mechanism by which propranolol reduces mortality is still unclear, but is probably not solely an antiarrhythmic one.

Reductase inhibitor monotherapy and stroke prevention.

BACKGROUND: Epidemiologic evidence and meta-analyses of data from early clinical trials suggest that lowering the levels of cholesterol does not reduce the events of stroke. These analyses have not included more recent clinical trials using reductase inhibitors. OBJECTIVE: To conduct a meta-analysis of the effect of reducing cholesterol levels on stroke in all reported clinical trials of primary (n = 4) and secondary (n = 8) prevention of coronary heart disease that used reductase inhibitor monotherapy and provided information on incident stroke. RESULTS: Analysis of combined data from primary and secondary prevention trials showed a highly statistically significant reduction of stroke associated with the use of reductase inhibitor monotherapy (27% reduction in stroke; P = .001). Analysis of secondary prevention trials alone disclosed a similar statistically significant effect (32% reduction in stroke; P = .001). A smaller nonsignificant reduction in stroke was noted in the primary prevention trials (15% reduction in stroke; P = .48). CONCLUSIONS: Reductase inhibitors now in use for lowering cholesterol levels are more potent and have fewer side effects than the cholesterol-lowering agents previously available. They appear to reduce stroke, most notably in patients with prevalent coronary artery disease, which may be partly due to the effects of lowering the levels of cholesterol on the progression and plaque stability of extracranial carotid atherosclerosis or the marked reduction of incident coronary heart disease associated with treatment.

Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM.

OBJECTIVE: ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism. The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension. Prospectively defined cardiovascular events were assessed as secondary outcomes. RESEARCH DESIGN AND METHODS: Inclusion criteria included a diagnosis of NIDDM and hypertension (systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg). Exclusion criteria included a history of coronary heart disease or stroke, serum creatinine > 1.5 mg/dl, albuminuria > 40 micrograms/min, and use of lipid-lowering drugs, aspirin, or antihypertensive agents other than beta-blockers or diuretics. A total of 380 hypertensive diabetics were randomly assigned to open-label fosinopril (20 mg/day) or amlodipine (10 mg/day) and followed for up to 3.5 years. If blood pressure was not controlled, the other study drug was added. RESULTS: Both treatments were effective in lowering blood pressure. At the end of follow-up, between the two groups there was no significant difference in total serum cholesterol, HDL cholesterol, HbA1c, fasting serum glucose, or plasma insulin. The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infarction, stroke, or hospitalized angina than those receiving amlodipine (14/189 vs. 27/191; hazards ratio = 0.49, 95% CI = 0.26-0.95). CONCLUSIONS: Fosinopril and amlodipine had similar effects on biochemical measures, but the patients randomized to fosinopril had a significantly lower risk of major vascular events, compared with the patients randomized to amlodipine.

Isradipine in prediabetic hypertensive subjects.

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 HbA1c) 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 > or = 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.

Biologic determinants of propranolol disposition: results from 1308 patients in the Beta-Blocker Heart Attack Trial.

Our objective was to identify biologic determinants of propranolol serum levels in 1308 patients after myocardial infarction (MI). Patients had had their MI within the previous month. A steady-state propranolol dosage of 40 mg every 8 hours produced a mean trough concentration of 42 ng/ml with extremely great (fiftyfold) interindividual variability. Univariate and multivariate analyses suggested that this variability was the result of many biologic factors. Serum levels were higher in women, in older patients, and in patients receiving concomitant therapy with other antiarrhythmic drugs. Serum levels were also higher in patients with elevated serum creatinine and lactate dehydrogenase levels. Serum levels were lower in black patients than in white patients. Also, serum levels in smokers were lower than those in nonsmokers, but only markedly so in the outpatient setting (6 months after the MI). The influence of sex and race on drug disposition has not previously been reported for beta-blocking drugs. Although a genetic deficiency in the oxidative metabolism of propranolol has been indicated, the frequency distribution of serum propranolol levels did not demonstrate a bimodal distribution for genetically distinct populations.

HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data.

Although associations of cholesterol and coronary heart disease (CHD) are well accepted, the association between cholesterol and stroke has been a subject of some confusion. Epidemiologic evidence suggests no association between plasma concentrations of cholesterol and stroke, and earlier clinical trials were also negative. Two early meta-analyses of clinical trials designed to evaluate the effects of cholesterol lowering on CHD concluded that cholesterol lowering had no effect. More recently newer, more potent and better tolerated agents (HMG-CoA reductase inhibitors, reductase inhibitors) have become available and have been tested for their efficacy in reducing cholesterol and CHD in both primary prevention and secondary prevention trials. Meta-analyses of these trials, in contrast to the earlier trials, reveal a powerful statistically significant effect to reduce stroke as well as CHD in secondary prevention (30%); the direction of the effect is the same in trials of primary prevention or trials that randomized patients with and without CHD (mixed primary and secondary prevention trials) where the risk reductions for stroke, although not reaching statistical significance are 11 and 30%, respectively. An important difference in the newer analysis is the availability of several trials of secondary prevention in which low density lipoprotein cholesterol was lowered 25-30% and in which CHD event reduction was similarly reduced by 30%. Mechanisms for stroke reduction likely involve retardation of plaque progression in the intracranial and extracranial carotid arteries, plaque stabilization, and, in addition, stroke may be reduced partly as a consequence of CHD reduction.

Multicenter isradipine diuretic atherosclerosis study (MIDAS). Design features. The Midas Research Group.

The Multicenter Isradipine Diuretic Atherosclerosis Study is a randomized, double-blind, clinical trial designed to compare the effectiveness of isradipine against hydrochlorothiazide in retarding the rate of progression of atherosclerotic lesions in the carotid arteries of hypertensive subjects. Eight hundred hypertensive men and women, 40 years of age or older, with minor plaques, are being recruited at eight clinical centers in the United States and will be followed for three years. Quantification of the atherosclerotic lesions at baseline and semiannually is done using B-mode ultrasonography. The background of the trial and its design features are discussed.

Propranolol-induced lipid changes and their prognostic significance after a myocardial infarction: the Beta-Blocker Heart Attack Trial experience.

Beta blockers represent the only documented effective long-term prophylactic treatment for patients after myocardial infarction (MI). Concern continues to be expressed about the lipid-altering effects of their long-term use, especially beta blockers without intrinsic sympathomimetic activity such as propranolol. Data collected for the Beta-Blocker Heart Attack Trial, the largest long-term clinical trial of beta-blocker use in patients after MI, have been analyzed to address the following questions. To what extent does propranolol alter lipid levels at least 6 months after MI and initiation of therapy? How predictive of subsequent coronary events and mortality are lipid levels 6 months after MI? Is there any evidence that altered lipid levels attenuate any of the beneficial effect of propranolol on coronary morbidity and mortality? By the 6-month post-MI visit, propranolol was shown to raise serum triglyceride levels by about 17% (approximately equal to 35 mg/dl) and lower serum high density lipoprotein (HDL) cholesterol by about 6% (approximately equal to 3 mg/dl). There was no effect on total cholesterol or low density lipoprotein cholesterol. In other analyses, no lipid measured 6 months after the MI was strongly predictive of subsequent coronary events or mortality. For example, every 1-mg-lower HDL value was associated with only a 0.7% relative increase in the mortality rate. Theoretically, the estimated relative increase on all-cause mortality associated with propranolol-induced HDL reduction is about 2%. In multivariate analyses adjusting for changes in HDL and serum triglyceride, propranolol-induced beneficial reductions in mortality and morbidity remained on the order of 20%, 10 times the estimated hazard.

Prognostic significance of ventricular ectopic activity in survivors of acute myocardial infarction who receive propranolol.

Beta blockers are frequently prescribed for survivors of acute myocardial infarction (AMI). Although ventricular ectopic activity was found to be associated with mortality in several cohorts, there are no data on the relation of ventricular ectopic activity to mortality in patients with AMI who receive beta blockers. One thousand six hundred and fifty participants in the Beta-Blocker Heart Attack Trial who were randomized to receive propranolol (60 or 80 mg 3 times daily) had 24-hour ambulatory electrocardiography at baseline. By multivariate analysis considering 16 variables, ventricular ectopic activity was independently associated with sudden death (p = 0.02 to 0.001) and total mortality (p = 0.04 to 0.0001) for an average follow-up of 25 months. By univariate analysis, ventricular ectopic activity was associated with increased total mortality (odds ratios 2.13 to 3.54) and sudden death mortality (odds ratio 2.26 to 3.93). The association of ventricular ectopic activity with mortality was observed in both high- and low-risk patient subsets with odds ratios similar to the placebo group. Thus, treatment with propranolol does not alter the relation between ventricular ectopic activity and mortality.

Results of the primary outcome measure and clinical events from the Asymptomatic Carotid Artery Progression Study.

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 (p < 0.001). Levels of LDL cholesterol were reduced by 28% (43.5 mg/dl [11.25 mmol/liter]) in the lovastatin group within 6 months (p < 0.0001) 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 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II).

The Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries trial (PLAC-II) was initiated in 1987 and was the first double-blind, randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable. 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 maximum IMT measurements over time. Effects on individual carotid artery segments (common, bifurcation, internal carotid artery) and on clinical events were also investigated. During follow-up, plasma concentrations of total cholesterol were lower in pravastatin-treated patients compared with those of placebo-treated patients (4.81 vs 6.08 mmol/liter [186 vs 235 mg/dl]) as were concentrations of low density lipoprotein (LDL) cholesterol (3.10 vs 4.29 mmol/liter [120 vs 167 mg/dl]). Plasma concentrations of high density lipoprotein2 (HDL2) cholesterol were higher in pravastatin-treated patients than in placebo-treated patients (0.16 vs 0.14 mmol/liter [6.1 vs 5.5 mg/dl]). Active treatment resulted in a nonsignificant 12% reduction in progression of the mean-maximum IMT (from 0.068 mm/yr placebo to 0.059 mm/yr pravastatin) and a statistically significant 35% reduction in IMT progression in the common carotid (p = 0.03). Active treatment was also associated with a 60% reduction of nonfatal myocardial infarction plus death caused by coronary artery disease (p = 0.09), a 61% reduction of any fatal event plus any nonfatal myocardial infarction (p = 0.04), and an 80% reduction of fatal plus any nonfatal myocardial infarction (p = 0.03).

Reduction in coronary events during treatment with pravastatin. PLAC I and PLAC II Investigators. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries.

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, are more efficacious than older lipid-lowering agents and therefore 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 (MI), and to determine whether any observed benefit was also evident in patients > or = 65 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 MI (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 > or = 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%).(ABSTRACT TRUNCATED AT 250 WORDS)

Rationale, design, and baseline characteristics of the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT).

The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial is the first angiographic clinical trial to be designed to test whether an agent can slow or even reverse the progression of early coronary atherosclerosis in patients with documented disease. In addition, a subset of patients are undergoing carotid ultrasound examinations, providing a unique opportunity to assess and correlate disease progression in 2 arterial beds.

Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II)

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).

Prognostic value of prolonged ventricular repolarization following myocardial infarction: the BHAT experience. The BHAT Study Group.

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.

MIDAS, the Multicenter Isradipine/Diuretic Atherosclerosis Study. Design features and baseline data.

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.