Effects of niacin on the incidence of new onset diabetes and cardiovascular events in patients with normoglycaemia and impaired fasting glucose.

BACKGROUND: This post hoc analysis from the Coronary Drug Project (CDP) evaluated the effects of niacin vs. placebo on the incidence of new onset type 2 diabetes mellitus (T2DM) and cardiovascular event rates in patients with normal and impaired fasting glucose (IFG). METHODS: The CDP was a randomised, placebo-controlled clinical trial of lipid-modifying agents in men with previous myocardial infarction. Normoglycaemia and IFG were defined as fasting plasma glucose (FPG) < 5.6 mmol/l and FPG ≥ 5.6 but < 7.0 mmol/l, respectively. New onset T2DM was defined by ≥ 1 of the following: clinical diagnosis of T2DM, use of an antihyperglycaemic therapy, or two FPG values ≥ 7.0 mmol/l. RESULTS: The incidence of new onset T2DM was higher in patients with IFG (16.5%) compared with those with normoglycaemia (5.4%), and was slightly higher with niacin vs. placebo in both normoglycaemic (6.8% vs. 4.9%; p = 0.07) and IFG (19.8% vs. 15.2%; p = 0.05) patients. Consistent with previous analyses, the cardiovascular benefit of niacin was independent of baseline glycaemic status (normal, IFG, T2DM) and change in fasting glucose level from baseline to year 1. CONCLUSION: Despite a modest increase in risk of new onset T2DM with long-term niacin therapy, there is a potential cardiovascular benefit of niacin.

Lessons from the post coronary artery bypass graft study in evaluating and controlling technical variability in angiographic trials. Post CABG Investigators.

Although many investigators have evaluated the technical variability of quantitative angiographic techniques used to study atherosclerosis regression in native coronary arteries, few have studied the variability inherent in repeated studies of atherosclerotic saphenous vein grafts. This study describes 2 studies performed during the course of the Post Coronary Artery Bypass Graft (CABG) Clinical Trial that were designed to assess the reproducibility of: (1) repeated angiographic views within a short time period; and (2) reproducibility of the total process of quantitative analysis of saphenous vein graft angiograms. Statistical methods are described that provide a more meaningful assessment of the impact of measurement variability in the analytic process versus the variability related to changes induced by pharmacologic interventions. One such method, the increase in standard deviation (SD) among patients (ISDP), showed that repeated angiographic views increased the variability of calculation of lesion minimal diameter by 1.5%, whereas the ISDP for repetition of the entire process of quantitative angiographic readings increased variability 6.4%. These data from the Post CABG trial reveal that technical variability is small and has negligible impact on the conclusions of the study.

An application of the Zucker-Wittes modified ratio estimate statistic in the Post Coronary Artery Bypass Graft (CABG) clinical trial.

In the Post Coronary Artery Bypass Graft (POST CABG) clinical trial, the primary outcome is substantial worsening (i.e., narrowing of the lumen diameter) of the vein grafts upon comparison of the baseline and follow-up angiograms. The patients had one to five non-occluded vein grafts at entry, so there may be from one to five primary outcome responses per patient. A modified ratio estimate (MRE) statistic, as described previously by Zucker and Wittes, may be used to analyze data of this kind. In the present paper we propose a more powerful MRE statistic when the event rates and/ or intraclass correlations vary according to number of grafts per patient. We also adapt this statistic to the factorial treatment design of the POST CABG clinical trial.

The Hypertension Prevention Trial: assessment of the quality of blood pressure measurements.

Blood pressure variability is an important consideration in hypertension trials for determining required sample size and consequently making accurate outcome statements. The Hypertension Prevention Trial was a randomized controlled trial carried out in 1983-1986 in four US clinics on men and women with high normal diastolic blood pressure. This trial provided an opportunity to assess conditions affecting blood pressure measurement variability. Trained blood pressure observers measured systolic and diastolic blood pressures twice, 30 seconds apart, using a random-zero sphygmomanometer. The quality of blood pressure measurements was assessed by computing the variability of the two readings per participant-visit for each blood pressure observer at each study clinic. Other sources of variability investigated included observer digit preference, time of day, and ambient temperature. On the basis of data from this population, it is estimated that the standard deviation of blood pressure values can be reduced by 5% by taking two measurements per participant-visit. An additional reduction of variability can be effected by having the duplicate blood pressure measurements made by different blood pressure observers. In special instances where the range of blood pressure values is very restricted, use of the random-zero sphygmomanometer can increase or decrease the among-participant variability in blood pressure values, depending upon where the distribution of blood pressure values is centered.

Covariate adjustment of treatment effects in clinical trials.

It has been previously shown that the magnitude of adjustment of a treatment effect Z value for a baseline covariate depends on both the degree of disparity of the covariate between the treatment groups and the degree of correlation between the covariate and the outcome variable. In this article, the magnitude of adjustment is further explored and tabulated for a variety of situations. Theoretically, the magnitude of adjustment may be great, for example, from Z = 3.0 unadjusted to 13.1 adjusted, or Z = 2.0 unadjusted to -1.6 adjusted. However, in more practically realistic situations the magnitude of adjustment will generally fall in the range of 1 to 2 standard error units, when the Z value for disparity of the covariate between the treatment groups is as great as +/- 3. If there is perfect comparability of treatment groups with respect to baseline covariate, there may still be a sizable difference between adjusted and unadjusted Z value for treatment effect, with adjusted almost always greater in absolute value than unadjusted Z value.

Coronary drug project: experience with niacin. Coronary Drug Project Research Group.

Niacin was one of the treatments compared in the Coronary Drug Project, a placebo-controlled, multicenter trial of lipid-lowering drugs in the secondary prevention of coronary heart disease. A total of 1119 men, aged 30-64 at entry, were randomized to niacin and 2789 to placebo by the end of recruitment in March 1969. Although side-effects interfered with adherence to the niacin regimen, it was the most effective agent in achieving cholesterol-lowering (10% overall); other agents in the trial were clofibrate, dextrothyroxine, and conjugated equine estrogens. At the scheduled conclusion of the trial in February 1975, the niacin-treated group exhibited a statistically significantly lower incidence of definite, non-fatal myocardial infarction (MI) than the placebo group. There was a trend toward improvement in the life-table mortality curve, but this was not statistically significant. In 1981 an extended follow-up was carried out concerning vital status for the 6008 men who were still alive at the end of treatment and active follow-up in the trial in 1975 (827 in the niacin group and 2008 in placebo groups). Vital status was determined for 99.1% of these men after a mean of 9 years from conclusion of the trial. In the group previously randomized to niacin, there were 69 (11%) fewer deaths than were expected on the basis of mortality in the placebo group. This difference was significant (z = -3.52; P = 0.0004). The data also suggested that patients with a higher baseline cholesterol experienced greater benefit from niacin therapy, as did those with the best response to the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality assurance and monitoring in the Hypertension Prevention Trial. Hypertension Prevention Trial Research Group.

The Hypertension Prevention Trial (HPT), was a randomized, controlled, multicenter (four clinics, four resource centers) trial designed to test the feasibility of achieving and sustaining dietary changes in the intake of calories, sodium, and potassium and to assess the effect of those changes on blood pressure in a normotensive population. The trial involved 841 men and women (plus a test cohort of 78) who, at the first baseline (BL) examination were in the age range of 25-49 years and had diastolic blood pressure (DBP) greater than or equal to 76 but less than 100 mm Hg (average of two readings), and at the examination prior to randomization (BL 2) had DBP greater than or equal to 78 but less than 90 mm Hg (also averaged). Participants were randomly assigned to a control treatment group (no dietary counseling) or to one of four dietary treatment groups involving counseling designed to reduce calorie intake, reduce sodium intake, reduce sodium and calorie intake, and reduce sodium and increase potassium intake. This chapter describes HPT procedures for training and certifying clinic staff, for data entry checks and data audits of its distributed data entry system, and for inspecting clinical equipment. Replicate analyses were performed regularly by the two arms of the Data Coordinating Center. The Food Coding Center and the Central Laboratory were evaluated by both internal and external monitoring techniques. The performance monitoring report, prepared semiannually for the governing committees of the HPT, reported on the effectiveness of quality assurance procedures and served to alert staff to developing problems.

An overview of six clinical trials of aspirin in coronary heart disease.

Data from six randomized, placebo-controlled clinical trials of aspirin, involving a total of 10,703 post-myocardial infarction patients, have been compared and combined. An apparent heterogeneity of findings among the six trials with respect to all-cause mortality is noted (P = 0.08). The reasons for this heterogeneity are explored. Two common methods of combining the results of several trials--the logrank and the log odds ratio methods--yield two-sided P-values of 0.112 and 0.110, respectively, for the aspirin-placebo effect on all-cause mortality. Alternative statistical methods of combining the results of the six trials give two-sided P-values ranging from 0.017 to 0.487.

The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI Phase I) trial.

In Phase I of the NHLBI trial of Thrombolysis in Myocardial Infarction (TIMI), 290 patients admitted within 7 hr after onset of acute infarction were randomly assigned to intravenous treatment with either streptokinase (SK) or recombinant tissue-type plasminogen activator (rt-PA). Left ventricular function was measured from contrast ventriculograms in 145 patients with both pretreatment and predischarge studies analyzable. Regional wall motion in the infarct site was measured by the centerline method and expressed in units of standard deviations (SDs) from the mean motion in 52 normal subjects. Patients treated with rt-PA (n = 77) achieved a significantly higher reperfusion rate after 90 min of treatment. Perfusion of the infarct-related artery improved from visual grade 0 or 1 (total occlusion or penetration without perfusion) to grade 2 or 3 (partial or full reperfusion) in 62% receiving rt-PA vs 31% receiving SK (n = 68) (p less than .001). However, the ejection fraction did not change significantly from before treatment to before discharge in either treatment group (+0.7 +/- 6.7% vs +1.0 +/- 8.3%, respectively). A small but significant increase in regional wall motion was observed in each of the two groups (+0.4 +/- 0.8 vs +0.3 +/- 0.8 SD/chord, respectively; each p less than .001 compared with baseline). This was countered by declines in the hyperkinesis of the noninfarct region (-0.3 +/- 1.0 SD/chord [p = .01] compared with baseline and -0.2 +/- 1.0 SD/chord [p = .23], respectively). Analysis of the combined groups revealed that the ejection fraction increased only in patients who achieved reperfusion by 90 min after onset of therapy or who had subtotal occlusions initially. There was greater recovery of left ventricular function in patients who achieved reperfusion earlier vs later than 4 hr after symptom onset and in patients with vs without some collateral circulation to the infarct-related artery.

External monitoring of a data coordinating center: experience of the National Cooperative Gallstone Study.

A Biostatistical Monitoring Committee was established to review periodically the procedures and performance of the data coordinating center of the National Cooperative Gallstone Study. The functions of this committee, the types of data coordinating center activities reviewed, the manner in which monitoring of these activities was carried out, and an assessment of the value of this committee to the study are discussed in this article.

Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.

The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.

Factors influencing the development of visual loss in advanced diabetic retinopathy. Diabetic Retinopathy Study (DRS) Report No. 10.

Natural history data from the Diabetic Retinopathy Study were examined by multivariate methods to determine which baseline characteristics could predict the occurrence of severe visual loss (SVL) in eyes originally assigned to no treatment. The presence and extent of new blood vessels on the optic disc (NVD) had the strongest association with SVL. Several other ocular characteristics also were strongly associated with visual outcome. In the absence of NVD at baseline, the degree of intraretinal hemorrhages and microaneurysms (HMA) had the strongest association with development of SVL. Macular edema was a factor in determining visual loss to 20/200 but not SVL (less than 5/200). Among systemic characteristics, urinary protein was the best predictor of visual outcome, but none were as good as the major ocular variables.

Timing, mechanism and clinical setting of witnessed deaths in postmyocardial infarction patients.

The temporal distribution and mechanism of death were studied in a large multicenter secondary prevention trial (Aspirin Myocardial Infarction Study) in which acute witnessed death represented 72% (270 of 376) of the deaths due to arteriosclerotic heart disease. Instantaneous deaths represented 28.9% (78 of 270) of the acute witnessed deaths; 45.2% (122 of 270) occurred in the first hour after the onset of symptoms and were defined as sudden deaths. In the subsequent 23 hours, an additional 113 deaths (41.8%) occurred and were defined as intermediate deaths; 29 late deaths (10.7%) occurred after 24 hours. Cardiac arrhythmia was the mechanism of death in 83% (194 of 235) of deaths within 24 hours. Univariate analysis of baseline clinical and electrocardiographic characteristics indicates that a history of congestive heart failure, cardiomegaly, angina pectoris, multiple myocardial infarctions and therapy with digitalis and nitroglycerin were more common in those who died than in survivors, regardless of the timing of death.