Change in cholesterol awareness and action. Results from national physician and public surveys.

The National Heart, Lung, and Blood Institute, Bethesda, Md, sponsored national telephone surveys of practicing physicians and the adult public in 1983, 1986, and 1990 to assess attitudes and practices regarding high serum cholesterol levels. Each time, approximately 1600 physicians and 4000 adults were interviewed. Trends show continuing change in medical practice and public health behavior relating to serum cholesterol. In 1990, physicians reported treating serum cholesterol at considerably lower levels than in 1986 and 1983. The median range of serum cholesterol at which diet therapy was initiated was 5.17 to 5.66 mmol/L (200 to 219 mg/dL) in 1990, down from 6.21 to 6.70 mmol/L (240 to 259 mg/dL) in 1986 and 6.72 to 7.21 mmol/L (260 to 279 mg/dL) in 1983. The median ranges for initiating drug therapy were 6.21 to 6.70 mmol/L (240 to 259 mg/dL) in 1990, 7.76 to 8.25 mmol/L (300 to 319 mg/dL) in 1986, and 8.79 to 9.28 mmol/L (340 to 359 mg/dL) in 1983. The number of adults who reported having had their cholesterol level checked rose from 35% to 46% to 65% in 1983, 1986, and 1990, respectively. Between 1983 and 1990, the number of adults reporting a physician diagnosis of high serum cholesterol increased from 7% to 16%; the number reporting a prescribed cholesterol-lowering diet increased from 3% to 9%. Reports of self-initiated diet efforts reached a high of 19% in 1986 and decreased to 15% in 1990 compared with 1% in earlier years. In 1990, over 90% of physicians reported awareness and use of the recommendations from the Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, and the public reported marked increases in awareness of dietary methods to lower serum cholesterol. These changes suggest educational gains; the data also suggest areas for continued cholesterol educational initiatives.

Morphometric analysis of the composition of coronary arterial plaques in isolated unstable angina pectoris with pain at rest.

Coronary artery plaque morphology was studied in 354 five-mm segments of the 4 major (left main, left anterior descending, left circumflex and right) epicardial coronary arteries in 10 patients with isolated unstable angina pectoris with pain at rest. The 4 major coronary arteries were sectioned at 5-mm intervals and a drawing of each of the resulting 354 Movat-stained histologic sections was analyzed using a computerized morphometry system. The major component of plaque was a combination of dense acellular and cellular fibrous tissue with much smaller portions of plaque being composed of pultaceous debris, calcium, foam cells with and without inflammatory infiltrates and inflammatory infiltrates without foam cells. There were no differences in plaque composition among any of the 4 major epicardial coronary arteries. Plaque composition varied as a function of the degree of luminal narrowing. Linear increases were observed in the mean percent of dense fibrous tissue (from 5 to 50%), calcific deposits (from 1 to 10%), pultaceous debris (from 0 to 10%) and inflammatory infiltrates without significant numbers of foam cells (from 0 to 5%), and a linear decrease was observed in the mean percent of cellular fibrous tissue (from 94 to 22%) in sections narrowed up to 25% to more than 95% in cross-sectional area. Multiluminal channels were seen in all 10 patients (28 [19%] of the 146 sections narrowed greater than 75% in cross-sectional area and in 36 [10%] of all 354 segments); occlusive thrombi in no patient; nonocclusive thrombi in 2 patients (1 section each of 2 arteries); plaque rupture in 2 patients (4 segments from 2 arteries); and plaque hemorrhages in 6 patients (11 sections from 10 arteries).

Risk of infective endocarditis in mitral valve prolapse with and without precordial systolic murmurs.

The risk of infective endocarditis (IE) associated with a systolic murmur in patients with mitral valve prolapse (MVP) was investigated in a case-control study. The case group comprised all patients with MVP (n = 19) from a series of 136 consecutive adult admissions for IE. Three matched control subjects were chosen for each case from a series of 144 MVP patients without IE. Seventeen of the 19 cases (89%) had documented evidence of systolic murmurs existing before the IE episode; systolic murmurs were documented in 25 of the 57 control subjects (47%). The data indicate a significant increase in the risk of IE in MVP patients with a systolic murmur (p less than 0.01). The absolute probability of IE developing in a patient with MVP and a murmur was estimated to be approximately 1 in 1,400 per year; this was 35 times greater than the probability in a patient with MVP without a murmur. The results suggest that by restricting prophylaxis to MVP patients with a systolic murmur, cover would be provided for almost 90% of those with MVP in whom IE would be likely to develop.

Rationale and design of the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (HIT) for secondary prevention of coronary artery disease in men with low high-density lipoprotein cholesterol and desirable low-density lipoprotein cholesterol.

Although a large body of epidemiologic evidence suggests that low levels of high-density lipoprotein (HDL) cholesterol are strongly associated with an increased risk of coronary artery disease (CAD), no large-scale clinical trials focusing on this association have been reported. This report describes the rationale and design of the Department of Veterans Affairs HDL Intervention Trial (HIT), a multicenter, randomized, controlled clinical trial designed to determine whether lipid therapy reduces the combined incidence of CAD death and nonfatal myocardial infarction in men with established CAD who have low levels of HDL cholesterol with "desirable" levels of low-density lipoprotein (LDL) cholesterol. Twenty-five hundred men with CAD and HDL cholesterol < or = 40 mg/dl, LDL cholesterol < or = 140 mg/dl, and triglycerides < or = 300 mg/dl are being recruited at 20 Department of Veterans Affairs medical centers, randomized to either gemfibrozil or placebo, and followed in a double-blind manner for an average of 6 years. In this population, gemfibrozil is expected to increase HDL cholesterol by 10 to 15%, have a negligible effect on LDL cholesterol, and lower triglycerides by 30 to 40%. Because an estimated 20 to 30% of patients with CAD have a low HDL cholesterol as their primary lipid abnormality, the results of this trial are expected to have far-reaching clinical implications.

Use of a highly purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient alpha 1-antitrypsin phenotypes.

Diagnosis of the hereditary disorder alpha 1-antitrypsin (alpha 1AT) deficiency is critically dependent on quantification of serum levels of alpha 1AT, a 52-kDa antiprotease that serves to protect the lung from destruction by neutrophil elastase. Although the measurement of serum alpha 1AT levels is not difficult, there is no international standard for alpha 1AT, and investigators in the field recognize that widely used commercially available standards vary by as much as 50 percent. To establish accurate ranges for the common normal and deficient alpha 1AT phenotypes, the present study uses a purified alpha 1AT standard to quantify the alpha 1AT serum levels of 443 individuals with common normal and deficient alpha 1AT phenotypes, including MM, ZZ, SS, MZ, MS, and SZ. Based on the observed values, a statistical model was developed to generate predicted frequency distributions of alpha 1AT serum levels for each of these phenotypes. Based on these studies, the ranges (5th to 95th percentile) for alpha 1AT serum levels of the common phenotypes are: MM, 20 to 53 mumol/L; SS, 20 to 48 mumol/L; ZZ, 3.4 to 7.0 mumol/L; MZ, 15 to 42 mumol/L; MS, 18 to 52 mumol/L; and SZ, 10 to 23 mumol/L. This alpha 1AT standard and these ranges are being used for the National alpha 1-Antitrypsin Deficiency Registry organized under the auspices of the National Heart, Lung, and Blood Institute.

Cisplatin in the treatment of metastatic breast carcinoma: A prospective randomized trial of two dosage schedules.

Thirty-seven patients with metastatic breast carcinoma were treated in randomized study with cisplatin 60 mg/m2 or 120 mg/m2 I.V. q3 weeks. Most patients were heavily pretreated, having received an average of four prior cytotoxic agents. Partial responses were seen in 4/19 patients initially receiving cisplatin 120 mg/m2 and 0/18 receiving 60mg/m2. One of the five patients responded when crossed over from cisplatin 60mg/m2 to cisplatin 120 mg/m2. Average duration of response was 3 months and responses were seen in soft tissue and lung metastases. Toxicity in the form of nausea, vomiting, and inanition significantly limited the use of cisplatin in this patient population. We conclude that cisplatin is active in breast carcinoma and that a cisplatin at 120 mg/m2 may be more effective than at 60 mg/m2. However the study stopped short of statistical significance due to the toxicities of nausea, vomiting, and inanition.

The estimation of false negatives in medical screening.

In a medical screening program for early detection of disease, one or more screening modes are administered to an apparently healthy population. Knowledge of the true disease status for all screened individuals would allow estimation of the false negative and false positive rates for each mode of detection and for the program as a whole. This paper develops capture-recapture methods applicable to programs as a whole. This paper develops capture-recapture methods applicable to programs when follow-up of individuals negative on screening is not performed or is incomplete. The methods require at least two independent modes of detection. Data from a breast cancer screening program illustrate the procedure. The results of four screening examinations at approximately one-year intervals and the long-term follow-up of all screened individuals support the usefulness of these methods in the evaluation of a screening program.

Rank tests for survival analysis: a comparison by analogy with games.

Several commonly used two-sample linear rank tests for censored data have been shown to be closely linked in mathematical structure. This pedagogical paper elucidates the relationships among the tests by introducing a videogame played between a boys' team and a girls' team with different rules of payment by the consecutive losers considered. Depending on the rule of payment, the total amount of money the girls win as a team becomes the Wilcoxon statistic, the Savage statistic, or their generalizations under censoring.

Recruitment in NHLBI population-based studies and randomized clinical trials: data analysis and survey results.

Data on screening and recruitment from current and previous NHLBI population-based studies (PBSs) and randomized clinical trials (RCTs) were examined. In only two of the studies examined was the projected recruitment completed within the planned recruitment period. The shape of the graph of the relation between enrollment of participants and time varies by study. A single summary statistic for measuring the efficiency of recruitment in RCTs and PBSs is proposed and applied to the examined studies. In addition to providing summary data on recruitment for several studies, this article reports the survey results of a questionnaire sent to the coordinating centers of currently and previously funded National Heart, Lung, and Blood Institute and Veteran's Administration studies. The purpose was to ascertain the desirability of recommending that a generic core of information be collected on recruitment and screening in future studies. Most respondents believed that comparing data collected uniformly and prospectively might be helpful in designing further studies. The variables most respondents believed to be potentially useful are described.

Combination chemotherapy in metastatic malignant melanoma: a randomized study of three DTIC-containing combination.

The activity of three DTIC-containing combinations was compared in a prospective randomized study. Of 101 patients randomized to receive one of the three regimens, 95 received adequate trials. Response rates were as follows: DTIC + cyclophosphamide 7/29 (24%); DTIC + vinblastine 6/34 (18%); DTIC + procarbazine 4/32 (13%). None of these response rates is significantly superior to any of the others. When the activity of the combination is analyzed by sex, DTIC + cyclophosphamide appears more active in females than the other regimens, but the difference is not statistically significant. Response to treatment is associated with significant prolongation of life; the median survival among responders was 11 months, while those who progressed lived a median of 4 months from the start of therapy. Toxicity of all regimens appeared to be about the same; therapy with DTIC + procarbazine was associated with significantly more nausea and vomiting. This study has failed to demonstrate clearly that any of three combinations is superior to any of the others.

Birth order, family size and school failure.

The effect of birth order on educational outcome in the Netherlands is reported for two major social classes, manual and non-manual. The rates of school failure (those who attended schools for the mentally retarded and who failed lower school) were studied in a population of some 200,000 young adult Dutch males born between 1944 and 1946 and whose families of origin had from one to six children. The data used were the records of the Dutch military pre-induction examination. Rates of school failure rose both with increased birth order and with increased family-size, with the exception of one-child families. School failure rates for the first, middle-and last-born were examined for the two social classes, with family size controlled. In general, school-failure rates were significantly related to birth-order position. For each family size and in both social classes, the last-born were at greater risk of school failure than were the first-born.

Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death.

We studied at necropsy atherosclerotic plaque composition in the four major (right, left main, left anterior descending, and left circumflex) epicardial coronary arteries in 15 patients who died of consequences of an acute myocardial infarction (AMI) and in 12 patients with sudden coronary death (SCD) without AMI. The coronary epicardial arteries were sectioned at 5-mm intervals, and a Movat-stained section of each segment of artery was prepared and analyzed using a computerized morphometry system. Within the AMI group and within the SCD group, there were no differences in plaque composition among any of the four major epicardial coronary arteries. Within both groups, plaque morphology varied as a function of cross-sectional-area narrowing of the segments. In both groups, the amount of dense relatively acellular fibrous tissue, calcified tissue, and pultaceous debris (amorphous debris containing cholesterol clefts, presumably rich in extracellular lipid) increased in a linear fashion with increasing degrees of cross-sectional-area narrowing of the segments, and the amount of cellular fibrous tissue decreased linearly. In the AMI group, the percentage of plaque consisting of pultaceous debris and of cellular fibrous tissue separated significantly narrowed (greater than 75% cross-sectional area) segments from less narrowed (less than 75%) segments. A comparison of the AMI group to the SCD group showed significant differences. The percentage of plaque consisting of pultaceous debris (16% in the AMI group and 7% in the SCD group), of cellular fibrous tissue (11% vs. 18%), and of heavily calcified tissue (8% vs. 16%) were significantly different in the severely narrowed segments in the AMI and SCD groups. When all arteries containing thrombi were deleted from the analysis, there were no significant changes in the results. Occlusive coronary thrombi were present in 13 of the 15 AMI patients and in one of the 12 SCD patients. Thus, the frequency of coronary thrombi and plaque composition differ in patients with AMI and in those with SCD without AMI.

Internal pilot studies II: comparison of various procedures.

The two-stage design involves sample size recalculation using an interim variance estimate. Stein proposed the design in 1945; biostatisticians recently have shown renewed interest in it. Wittes and Brittain proposed a modification aimed at greater efficiency; Gould and Shih proposed a similar procedure, but with a different interim variance estimate based on blinded data. We compare the power of Stein's original test, an idealized version of the Wittes-Brittain test, and a theoretical optimal test which can be approximated in practice. We also compare two procedures that control the conditional type I error rate given the actual final sample size: Gould and Shih's procedure and a newly proposed 'second segment' procedure. The comparison among the first three procedures indicates that the Stein test is, unexpectedly, the test of choice under the original design alternative, whereas the approximate-optimal and Wittes-Brittain procedures appear to have superior power for detecting smaller treatment differences. As between the latter two procedures, the second segment procedure is more powerful when many observations are likely to be taken after the interim resizing, whereas otherwise the Gould-Shih procedure is superior.

Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema.

In patients with alpha 1-antitrypsin deficiency, the development of emphysema is believed to be caused by the unchecked action of proteases on lung tissue. We evaluated the feasibility, safety, and biochemical efficacy of intermittent infusions of alpha 1-antitrypsin in the treatment of patients with alpha 1-antitrypsin deficiency. Twenty-one patients were given 60 mg of active plasma-derived alpha 1-antitrypsin per kilogram of body weight, once a week for up to six months. After a steady state had been reached, the group had trough serum levels of alpha 1-antitrypsin of 126 +/- 1 mg per deciliter as compared with 30 +/- 1 mg per deciliter before treatment, and serum anti-neutrophil elastase capacities of 13.3 +/- 0.1 microM as compared with 5.4 +/- 0.1 microM. The alpha 1-antitrypsin level in the epithelial-lining fluid of the lungs was 0.46 +/- 0.16 microM before treatment, and the anti-neutrophil elastase capacity was 0.81 +/- 0.13 microM. Six days after infusion, alpha 1-antitrypsin levels (1.89 +/- 0.17 microM) and anti-neutrophil elastase capacities (1.65 +/- 0.13 microM) in the lining fluid were significantly increased (P less than 0.0001). Because of the chronicity of the disorder and the lack of sensitive measures of lung destruction, the clinical efficacy of this therapy could not be studied rigorously. No changes in lung function were observed in our patients over six months of treatment. The only important adverse reactions to the 507 infusions were four episodes of self-limited fever. This study demonstrates that infusions of alpha 1-antitrypsin derived from plasma are safe and can reverse the biochemical abnormalities in serum and lung fluid that characterize this disorder. Together with lifetime avoidance of cigarette smoking, replacement therapy with alpha 1-antitrypsin may be a logical approach to long-term medical treatment.

Change in physician perspective on cholesterol and heart disease. Results from two national surveys.

The National Heart, Lung, and Blood Institute sponsored national telephone surveys of practicing physicians in 1983 (N = 1610) and 1986 (N = 1277) to assess attitudes and practices regarding elevated serum cholesterol levels. The 1983 survey was conducted just before the release of the results of the Lipid Research Clinics Coronary Primary Prevention Trial, which showed that a reduction in the blood cholesterol level reduced coronary heart disease. In 1986, 64% of physicians thought that reducing high blood cholesterol levels would have a large effect on heart disease, up considerably from 39% in 1983. Whereas in 1983, physicians attributed considerably less preventive value to reducing the cholesterol level than to reducing blood pressure or smoking, this disparity was substantially smaller in 1986. The median range of blood cholesterol at which diet therapy was initiated was 6.21 to 6.70 mmol/L (240 to 259 mg/dL) in 1986, down from 6.72 to 7.21 mmol/L (260 to 279 mg/dL) in 1983; the median for drug therapy was 7.76 to 8.25 mmol/L. (300 to 319 mg/dL) in 1986 and 8.79 to 9.28 mmol/L (340 to 359 mg/dL) in 1983. In 1986, 87% of physicians surveyed felt that medical evidence warranted the recommended treatment levels set forth in the 1984 National Institutes of Health Consensus Conference on Lowering Blood Cholesterol. These changes indicate that by 1986, physicians were more convinced of the benefit of lowering high blood cholesterol levels and were treating patients accordingly. The data also suggest areas for continued educational initiatives.

Change in public perspective on cholesterol and heart disease. Results from two national surveys.

The National Heart, Lung and Blood Institute, Bethesda, Md, and the Food and Drug Administration, Washington, DC, sponsored two national probability telephone surveys (N = 4000) of adults to assess attitudes and knowledge about heart disease risk from high blood cholesterol levels and the public's efforts to lower blood cholesterol levels. The first survey was conducted in 1983, before release of the results from the Lipid Research Clinics Coronary Primary Prevention Trial, which showed that a reduction in the blood cholesterol level reduced coronary heart disease; the second survey was conducted in 1986. The percentage of adults who believed that reducing high blood cholesterol levels would have a large effect on heart disease increased from 64% in 1983 to 72% in 1986, so that the importance attached to reducing high blood cholesterol levels approached that attributed to reducing smoking and high blood pressure. In 1983, 35% of adults reported that they had their cholesterol level checked vs 46% in 1986. In both years, diet changes were most frequently chosen (greater than 60%) as ways to control the blood cholesterol level; reducing dietary fat was believed to be as important as reducing dietary cholesterol. By 1986, 23% of adults reported that they made dietary changes specifically to lower their blood cholesterol level, up from 14% in 1983. These comparative data show gains in public awareness and action relating to high blood cholesterol level risk. The data can be used to develop education programs.

Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial.

CONTEXT: A low plasma level of high-density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD). A secondary prevention study, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), demonstrated that CHD events were significantly reduced during a median follow-up of 5.1 years by treating patients with the fibric acid derivative gemfibrozil when the predominant lipid abnormality was low HDL-C. OBJECTIVE: To determine if the reduction in major CHD events with gemfibrozil in VA-HIT could be attributed to changes in major plasma lipid levels. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial conducted from September 1991 to August 1998. SETTING: The Department of Veterans Affairs Cooperative Studies Program, in which 20 VA medical centers were participating sites. PARTICIPANTS: A total of 2531 men with a history of CHD who had low HDL-C levels (mean, 32 mg/dL [0.83 mmol/L] ) and low low-density lipoprotein cholesterol (LDL-C) levels (mean, 111 mg/dL [2.88 mmol/L]). INTERVENTION: Participants were randomly assigned to receive gemfibrozil, 1200 mg/d (n = 1264), or matching placebo (n = 1267). MAIN OUTCOME MEASURE: Relation of lipid levels at baseline and averaged during the first 18 months of gemfibrozil treatment with the combined incidence of nonfatal myocardial infarction and CHD death. RESULTS: Concentrations of HDL-C were inversely related to CHD events. Multivariable Cox proportional hazards analysis showed that CHD events were reduced by 11% with gemfibrozil for every 5-mg/dL (0.13-mmol/L) increase in HDL-C (P =.02). Events were reduced even further with gemfibrozil beyond that explained by increases in HDL-C values, particularly in the second through fourth quintiles of HDL-C values during treatment. During gemfibrozil treatment, only the increase in HDL-C significantly predicted a lower risk of CHD events; by multivariable analysis, neither triglyceride nor LDL-C levels at baseline or during the trial predicted CHD events. CONCLUSIONS: Concentrations of HDL-C achieved with gemfibrozil treatment predicted a significant reduction in CHD events in patients with low HDL-C levels. However, the change in HDL-C levels only partially explained the beneficial effect of gemfibrozil.