Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Trial).

Controlled clinical trials have demonstrated the efficacy of reducing the blood levels of low-density lipoprotein cholesterol in reducing the incidence of coronary artery disease in hypercholesterolemic middle-aged men. However, a similar reversibility of the risk of coronary artery disease has not been demonstrated for high-density lipoprotein cholesterol elevation and triglyceride reduction. Therefore, the effect of administering 400 mg of bezafibrate retard daily versus placebo (double blind) to patients with myocardial infarction preceding randomization by 6 months to 5 years, or a clinically manifest anginal syndrome documented by objective evidence of dynamic myocardial ischemia, or both, is being investigated. Three thousand subjects (aged 45 to 74 years) are being enrolled from 19 cardiac departments in Israel, with total serum cholesterol between 180 and 250 mg/dl, high-density lipoprotein cholesterol < or = 45 mg/dl and triglycerides < or = 300 mg/dl. In addition, low-density lipoprotein cholesterol concentrations are required to be < or = 180 mg/dl (< or = 160 mg/dl for patients aged < 50 years). Patients needing lipid-modifying therapy, exhibiting > or = 1 prespecified exclusion criterion or not giving informed consent, or a combination, are not randomized. The primary end points for evaluating efficacy are the incidence of fatal and nonfatal myocardial infarction, and sudden death. The hypothesized effect of bezafibrate administration under the aforementioned protocol is to reduce an estimated cumulative end point event incidence of > or = 15% by 20 to 25% over an average follow-up period of 6.25 years, through early 1998, when the last patient recruited will have completed 5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Multivariate analysis of the twenty-year follow-up of the Donolo-Tel Aviv Prospective Coronary Artery Disease Study and the usefulness of high density lipoprotein cholesterol percentage.

The aim of this study was to assess the role of high density lipoprotein (HDL)-cholesterol percentage and its relation to other variables assumed to be coronary risk factors. The 20-year follow-up involved 2,633 presumably healthy subjects, 1,308 men and 1,325 women, aged 25 to 69 years at the beginning of the study in 1964. Variables determined at entry examination included total cholesterol, HDL cholesterol, systolic and diastolic blood pressures, body mass index and cigarette smoking. During the 20-year period there were 242 fatal and nonfatal definite coronary events in men, and 108 in women. All variables differed in varying degrees between subjects who did and did not have a definite coronary event. Three multiple logistic regression models revealed that among these variables the most important was HDL-cholesterol percentage, which significantly improved the regression, even after total cholesterol was included with all other risk factors. With the first model, goodness-of-fit tests indicated that predicted values fit the observed values well, even after the first step, if HDL-cholesterol percentage is entered. The second and third models significantly fit the predicted values only after entering the HDL-cholesterol percentages. This means that although all the other variables, including total cholesterol, differed significantly between the affected and nonaffected groups, they were insufficient predictors alone. The results reveal that HDL-cholesterol percentage had the highest predictive value for risk of future coronary disease; it significantly improved the predictive capability of the logistic regression model, even after adjustment for all other mentioned variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipo- and apolipoproteins in a population survey subset in MONICA-Israel.

Lipo- and apolipoproteins in a population survey subset in MONICA-Israel. A group of 169 healthy men and women selected at random from the population survey of the MONICA-Israel Project were screened for baseline values of serum lipoproteins and apolipoprotein A-I and B concentrations. The apolipoprotein measurements were obtained using a recently developed immunoturbidimetric assay. The study population was subdivided into age groups of 25-44 years and 45-64 years. It was found that women aged 45-64 years had significantly higher levels of apolipoprotein A-I, apolipoprotein B, total cholesterol (TC), LDL cholesterol (LDL-c) and a lower ratio of HDL-cholesterol (HDL-c) to TC (HDL-c%) than did their younger counterparts. These parameters did not differ significantly between younger and older men. The results suggest that the HDL of women over the age of 45 years contains relatively less cholesterol and more protein than the HDL of younger women. Further studies will show to what degree apolipoprotein concentrations, and their relation to lipoproteins will sharpen the assessment of coronary risk.

The efficacy of isosorbide-5-mononitrate on effort-induced electrocardiographic ischemic changes in patients with angina pectoris.

The efficacy of isosorbide-5-mononitrate 40 mg twice a day was tested in 10 patients suffering from effort-induced angina pectoris. Patients were studied with ergometer testing 6 hours after drug administration on the first treatment day, and again 8 and 12 hours after medication at 3 weeks and 6 months of therapy. At comparable and maximal workloads the patients expressed significantly less ST segment depression on treatment than prior to treatment. No tolerance was observed. Isosorbide-5-mononitrate treatment was demonstrated to have a beneficial effect on exercise tolerance in patients suffering from stable angina in effort.

Relation of serum total cholesterol and high-density lipoprotein cholesterol percentage to the incidence of definite coronary events: twenty-year follow-up of the Donolo-Tel Aviv Prospective Coronary Artery Disease Study.

This 20-year follow-up report presents the incidence of definite coronary events and its relation to serum total cholesterol (TC) and alpha-lipoprotein cholesterol percentage (percentage of serum TC bound with alpha-lipoprotein), now usually called high-density lipoprotein cholesterol percentage (HDL-C%). The cohort consists of 1,454 men and 1,481 women, presumably healthy, aged 35 to 64 years at the time of entrance examination in 1964. During the follow-up period 123 men and 44 women died from coronary disease. Ninety-six men and 42 women had nonfatal myocardial infarctions. The incidence of definite coronary events increased from 6% in men with TC levels of less than 200 mg/dl to 25% in men with levels of more than 264 mg/dl. The corresponding figures in women were 3% and 10%. The incidence of definite coronary events was inversely correlated to HDL-C%. The incidence of definite coronary events in 225 men with HDL-C% of less than 14% was 28%, and in 669 men with HDL-C% of 21% or more, 7%. The corresponding figures in 234 women with HDL-C% of less than 17% was 14%, and in 853 women with HDL-C% of 23% or more, 2%. Two HDL-C% subsets were assessed: "low" and "high" subsets refer to HDL-C% of less than 21% and 21% or more, respectively, in men and less than 23% and 23% or more in women.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of short- and long-term treatment with transdermally and orally administered nitroglycerin (a double-blind crossover study).

The efficacy of a once daily transdermally applied nitroglycerin system and of sustained release nitroglycerin capsules was assessed by ergometer stress testing in 12 patients with stable angina pectoris in a double-blind crossover study. In the morning the patients received transdermally applied nitroglycerin (TDS) which delivered 5.0 mg nitroglycerin in 24 hours together with a placebo capsule, respectively 1 nitroglycerin (NTR) capsule of 2.5 mg together with a plaster placebo. In the evening the first treatment group received 2 placebo capsules, and the second group 1 NTR capsule and 1 placebo capsule. Each period lasted 14 days. The patients performed a pre-medication ergometer stress test and repeated the test on the first and 14th day of each treatment period, 1 and 24 hours after medication. At the end of the second period all patients continued in an open study with TDS once a day for a further three months. Minor degrees of ST-segment depression, and in fewer patients, were observed at comparable workloads in the treatment tests compared with the pre-medication tests. The improvement after TDS on the first and last day of each period, 1 and 24 hours after medication, was significant and more marked than with NTR. The latter did not reach significance. Furthermore, increase of work capacity and elevation of angina threshold was greater with TDS than with NTR. Similar results were found at the end of the open study after 3 months' treatment with TDS. No development of tolerance was observed.

Thromboxane, prostacyclin, beta-thromboglobin, and diabetes mellitus.

Plasma levels of beta-thromboglobin (beta-TH) and of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1-alpha, the stable metabolites of thromboxane A2 and prostacyclin, were determined by radioimmunoassay methods in eight patients with noninsulin-dependent diabetes before and after dietary treatment and after administration of the sulfonylurea drug glibenclamide. Blood examinations were performed when hyperglycemia was detected for the first time, four weeks after a dietary regimen was started, and four and eight weeks after glibenclamide treatment was begun. Drug treatment was instituted because, despite a suitable diet, patients' postprandial blood sugar was higher than 8 mmol/L (145 mg/dl). At the initial examination, elevated TXB2 and beta-TH levels indicating platelet hyperactivity and hyperglycemia were found. TXB2 and beta-TH levels decreased significantly after glibenclamide treatment was started, as did the blood glucose level. There was no change in 6-keto-PGF1-alpha. We interpret these results to indicate that diabetes is associated with hyperactivity of platelet aggregation and that control of blood glucose is important because a lower blood glucose level attenuates platelet hyperactivity. Whether the decrease in platelet hyperactivity is a direct result of the lowered blood sugar or reflects the influence of the drug treatment requires clarification.