Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer.

We conducted a 2-year, randomized, double-blind, placebo-controlled toxicity trial of therapy with tamoxifen (10 mg twice a day) in 140 postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes. These women had been treated with surgery with or without radiotherapy. At a 3-month evaluation, tamoxifen-treated women showed a significant decrease in fasting plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which persisted at 6- and 12-month evaluations. During the first 12 months, plasma triglyceride levels increased; small but significant decreases in high-density lipoprotein cholesterol (HDL) were observed in tamoxifen-treated women, but ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably. While data relating lipid/lipoprotein profiles and cardiovascular disease are limited in women, current evidence suggests that total cholesterol and possibly low-density lipoprotein cholesterol are risk factors. We conclude that during the first 12 months of treatment, tamoxifen exerts a favorable effect on the lipid profile in postmenopausal women with early stage breast cancer.

Wisconsin Epidemiologic Study of Diabetic Retinopathy. XII. Relationship of C-peptide and diabetic retinopathy.

The relationship between plasma C-peptide and the frequency and severity of diabetic retinopathy was examined in a population-based study in Wisconsin in 1984-1986. Individuals with younger- (n = 835) and older- (n = 940) onset diabetes were included. C-peptide was measured by radioimmunoassay with Heding's M1230 antiserum. Retinopathy was determined from stereoscopic fundus photographs. The highest frequencies and most severe retinopathy were found in insulin-using individuals with undetectable or low plasma C-peptide (less than 0.3 nM), whereas the lowest frequencies of retinopathy were found in older-onset overweight individuals not using insulin. In older-onset individuals using insulin, having no detectable C-peptide was significantly associated with the presence of proliferative retinopathy. Otherwise, within each group (younger onset using insulin, older onset using insulin, and older onset not using insulin), after controlling for other characteristics associated with retinopathy, there was no relationship between higher levels of C-peptide and lower frequency of or less severe retinopathy.

Proteinuria in diabetes.

In a population-based study in southern Wisconsin, 1370 diabetic persons diagnosed after 29 years of age were examined using standard protocols to determine the prevalence of proteinuria and associated risk variables. Proteinuria (greater than or equal to 0.30 g/L) was present in 18.0% of persons taking insulin and 12.2% of the persons not taking insulin. Proliferative retinopathy and proteinuria were associated with each other. Proteinuria was also associated with increasing duration of diabetes, high systolic blood pressure, use of digoxin, and being male, but not with a history of cigarette smoking or metabolic control as measured by glycosylated hemoglobin.

Relation of ocular and systemic factors to survival in diabetes.

The relationship of survival to systemic and ocular factors in diabetic persons was studied using data collected as part of the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Six years after the baseline examination, 9.5% of 996 insulin-taking people who were younger than age 30 years when their diabetes was diagnosed (younger onset) had died. Of 1370 people whose diabetes was diagnosed after age 30 years (older onset), 35.3% had died. After adjusting for age and sex, longer duration of diabetes, presence of proteinuria, a history of cardiovascular disease, higher blood pressure, diuretic use, a history of smoking, poorer visual acuity, and more severe retinopathy were significantly associated with decreased survival in both groups. Glaucoma was associated with decreased survival in the younger onset group and cataract in the older onset group. These findings suggest that some ocular complications are important risk indicators for death. Their presence in diabetic patients suggests the need for frequent examinations to detect systemic complications and to intervene to minimize their effect.

Is blood pressure a predictor of the incidence or progression of diabetic retinopathy?

The relationship between blood pressure and the 4-year incidence and progression of diabetic retinopathy was examined in a population-based study in Wisconsin. Younger- (n = 891) and older-onset (n = 987) persons participating in baseline and follow-up examinations were included. Blood pressure was measured using the Hypertension Detection and Follow-up Program protocol. Retinopathy was determined from stereoscopic fundus photographs. In the younger-onset group, comparing the highest with the lowest quartile of systolic blood pressure, the relative risk for developing any diabetic retinopathy was 1.8 and for diastolic blood pressure it was 1.2; for progression of diabetic retinopathy, it was 1.1 and 1.3 for systolic and diastolic blood pressure, respectively. After controlling for other risk variables, systolic blood pressure remained a significant predictor of the incidence of diabetic retinopathy; diastolic blood pressure was of borderline significance in predicting progression in the younger-onset group. Blood pressure was not related to incidence or progression of retinopathy either in the older-onset group using insulin or the older-onset group not using insulin.

Retinopathy in young-onset diabetic patients.

The relative importance of duration of diabetes before and after 13 yr of age as a risk factor for retinopathy was investigated using data from 200 persons who were younger than 26 yr of age. These persons were identified in a population-based study of diabetic retinopathy in southern Wisconsin in 1980-1982. Retinopathy was found in 9% of persons who were younger than 13 yr and in 34% of persons who were 13 yr or older and had been diagnosed at or after 13 yr. Presence of retinopathy was more strongly associated with the duration of diabetes after 13 yr of age than before it.

The clinical features of submassive and massive pulmonary emboli.

Clinical findings in 167 patients with angiographically established pulmonary emboli were analyzed in detail. The clinical symptoms and physical findings in this group were compared with the findings in 160 patients (diagnosis established by angiography) from an earlier similar study. The observations from this, the largest known group of patients with documented pulmonary emboli that has been studied and reported on, revealed that many of the "classic signs and symptoms" occurred infrequently. Most patients in this study had prognostic value. The data from this study demonstrate that no clinical findings are specific for the diagnosis of pulmonary emboli, but the absence of isolated frequently occurring signs and symptoms should mitigate against the presence of pulmonary emboli.

Factors associated with visual outcome after photocoagulation for diabetic retinopathy. Diabetic Retinopathy Study Report #13.

Six risk factors for severe visual loss despite panretinal (scatter) photocoagulation were identified by analyzing data collected during the first 5 years after randomization in the Diabetic Retinopathy Study. Proportional hazards regression revealed NVD (neovascularization on/around the optic disc) to be the most important risk factor. The risk of severe visual loss rose with increasing NVD, hemorrhages/microaneurysms, retinal elevation, proteinuria, and hyperglycemia and fell with increasing "treatment density." These results are similar to previous DRS findings on untreated eyes. The importance of "treatment density" as an independent predictor of visual outcome is a new finding and lends support to the common clinical practice of repeating photocoagulation if initial treatment does not reduce or stabilize retinal neovascularization.

History and physical examination in acute pulmonary embolism in patients without preexisting cardiac or pulmonary disease.

The history and physical examination were assessed in 215 patients with acute pulmonary embolism uncomplicated by preexisting cardiac or pulmonary disease. The patients had been included in the Urokinase Pulmonary Embolism Trial or the Urokinase-Streptokinase Embolism Trial. Presenting syndromes were (1) circulatory collapse with shock (10 percent) or syncope (9 percent); (2) pulmonary infarction with hemoptysis (25 percent) or pleuritic pain and no hemoptysis (41 percent); (3) uncomplicated embolism characterized by dyspnea (12 percent) or nonpleuritic pain usually with tachypnea (3 percent) or deep venous thrombosis with tachypnea (0.5 percent). The most frequent symptoms were dyspnea (84 percent), pleuritic pain (74 percent), apprehension (63 percent) and cough (50 percent). Hemoptysis occurred in only 28 percent. Dyspnea, hemoptysis or pleuritic pain occurred separately or in combination in 94 percent. All three occurred in only 22 percent. The most frequent signs were tachypnea (respiration ate 20/min or more) (85 percent), tachycardia (heart rate 100 beats/min or more) (58 percent), accentuated pulmonary component of the second heart sound (57 percent) and rales (56 percent). Signs of deep venous thrombosis were present in only 41 percent and a pleural friction rub was present in only 18 percent. Either dyspnea or tachypnea occurred in 96 percent. Dyspnea, tachypnea or deep venous thrombosis occurred in 99 percent. As a group, the identified clinical manifestations, although nonspecific, are strongly suggestive of acute pulmonary embolism. Conversely, acute pulmonary embolism was rarely identified in the absence of dyspnea, tachypnea or deep venous thrombosis.

Effect of amlodipine on mode of death among patients with advanced heart failure in the PRAISE trial. Prospective Randomized Amlodipine Survival Evaluation.

Investigations of calcium antagonists in patients with advanced heart failure have raised concern over an increased risk of worsening heart failure and heart failure deaths. We assessed the effect of amlodipine on cause-specific mortality in such patients enrolled in a randomized, double-blind, placebo-controlled trial. In total, 1,153 patients in New York Heart Association class IIIb or IV heart failure were randomized to receive amlodipine or placebo, along with angiotensin-converting enzyme inhibitors, diuretics, and digitalis. Over a median 14.5 months of follow-up, 413 patients died. Cardiovascular deaths accounted for 89% of fatalities, 50% of which were sudden deaths and 45% of which were due to pump failure, with fewer attributed to myocardial infarction (3.3%) or other cardiovascular causes (1.6%). Amlodipine treatment resulted in a greater relative reduction in sudden deaths (21%) than in pump failure deaths (6.6%) overall. When patients were classified by etiology of heart failure (ischemic or nonischemic), cause-specific mortality did not differ significantly between treatment groups in the ischemic stratum. In the nonischemic stratum, however, sudden deaths and pump failure deaths were reduced by 38% and 45%, respectively, with amlodipine. Thus, when added to digitalis, diuretics, and angiotensin-converting enzyme inhibitors in patients with advanced heart failure, amlodipine appears to have no effect on cause-specific mortality in ischemic cardiomyopathy, but both pump failure and sudden deaths appear to be decreased in nonischemic heart failure patients treated with amlodipine.

Issues in the early termination of the aspirin component of the Physicians' Health Study. Data Monitoring Board of the Physicians' Health Study.

The Physicians' Health Study is a randomized, double-blind, placebo-controlled prevention trial of 22,071 US physicians, using a factorial design to evaluate the role of aspirin in the prevention of cardiovascular mortality and beta carotene in the reduction of cancer incidence. After approximately 5 years of follow-up, the aspirin component was terminated, 3 years ahead of schedule. Several factors were considered in the decision to terminate, including a cardiovascular mortality rate markedly lower than expected in both aspirin and placebo subjects, precluding the evaluation of the primary aspirin hypothesis, and a highly significant (P < .00001) and impressive (44%) reduction in the risk of first myocardial infarction in the aspirin group. Issues in the decision to terminate are described in this report.

The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years.

In a population-based study in southern Wisconsin, 996 insulin-taking, younger-onset diabetic persons were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 17% to 97.5% in persons with diabetes for less than five years and 15 or more years, respectively. Proliferative retinopathy varied from 1.2% to 67% in persons with diabetes for less than ten years and 35 or more years, respectively. For persons with diabetes of 10 years' duration or less, the Cox regression model relates the severity or retinopathy to longer duration, older age at examination, and higher levels of glycosylated hemoglobin. After ten years of diabetes, severity of retinopathy was related to longer duration, high levels of glycosylated hemoglobin, presence of proteinuria, higher diastolic BP, and male sex.

The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years.

In a population-based study in southern Wisconsin, 1,370 patients given diagnoses of diabetes at age 30 years or older were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 28.8% in persons who had diabetes for less than five years to 77.8% in persons who had diabetes for 15 or more years. The rate of proliferative diabetic retinopathy varied from 2.0% in persons who had diabetes for less than five years to 15.5% in persons who had diabetes for 15 or more years. By using the Cox regression model, the severity of retinopathy was found to be related to longer duration of diabetes, younger age at diagnosis, higher glycosylated hemoglobin levels, higher systolic BP, use of insulin, presence of proteinuria, and small body mass.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years.

Population-based epidemiologic data on the incidence and progression of diabetic retinopathy are important in medical counseling and rehabilitative services and for developing approaches to preventing diabetic retinopathy. We performed a population-based study in southern Wisconsin of insulin-taking diabetic persons diagnosed before 30 years of age. Of the 271 who had no retinopathy at the first visit, 160 (59%) developed it by the time they were reexamined four years later, and 75 (11%) of the 713 free of proliferative diabetic retinopathy developed it. Overall, worsening of retinopathy occurred in 41% of the population, whereas improvement occurred in only 7%. The incidence of proliferative retinopathy rose with increasing duration until 13 to 14 years of diabetes, thereafter remaining between 14% and 17%. These incidence data underscore the need for careful ophthalmologic follow-up of these people.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more.

The four-year incidence and progression of retinopathy were investigated in a population-based sample of people with diabetes diagnosed at 30 years of age or older. For insulin users, 73 (47%) of the 154 who did not have any retinopathy at the first visit developed it in the four-year interval, and 31 (7%) of the 418 free of proliferative retinopathy developed it. Worsening of retinopathy occurred in a total of 34% (142/418). For nonusers of insulin, corresponding rates were 34% (110/320) for incidence of any retinopathy, 2% (11/486) for developing proliferative retinopathy, and 25% (121/486) for worsening. These population-based data clearly indicate the risk of retinopathy worsening in a short interval (four years) in a large proportion of people with older-onset diabetes, a group previously thought to be relatively protected from retinopathy. Such patients who make up the largest proportion of diabetic patients in the United States need examination when diabetes is first diagnosed and regular follow-up.

An overview of group sequential methods in longitudinal clinical trials.

During the last decade, several papers have been published on group sequential methods in general and on sequential longitudinal clinical trials in particular. This paper gives an overview of the proposed methods, emphasizing longitudinal clinical trials. Furthermore, it tries to answer some practical questions that may arise during the conduct of interim analyses in longitudinal trials. Simulations have been carried out to obtain insight in these practical considerations.

A double blind study of the effects of zinc sulfate on taste and smell dysfunction.

A randomized, double blind crossover study of the effects of zinc sulfate and placebo was carried out in 106 patients with taste and smell dysfunction secondary to a variety of etiological factors. In the patient group prior to treatment, mean serum zinc concentration and leukocyte alkaline phosphatase activity were significantly lower than normal. Results indicate that zinc sulfate was effectively equivalent to placebo in the treatment of these disorders. Although these results demonstrate abnormalities of zinc metabolism in some patients with taste and smell dysfunction they fail to provide evidence for a single, therapeutic approach to the many disorders which are associated with abnormalities of taste and smell. However, the methods and procedures developed in this study demonstrate that taste and smell dysfunction can be studied in a quantitative, systematic manner.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy. A comparison of retinopathy in younger and older onset diabetic persons.

In a population-based survey of diabetic persons, retinopathy was detected by stereoscopic color fundus photography in 70% of persons under 30 years of age at diagnosis and taking insulin (Group YO), in 62% of persons 30 years of age or older at diagnosis and taking insulin (Group OO-I) and in 36% of persons 30 years of age or older at diagnosis not taking insulin (Group OO-N). The mean duration of known diabetes was 14.6 years in Group YO, 11.0 years in Group OO-I and 6.9 years in Group OO-N. After 20 years of diabetes, proliferative retinopathy was present in about 50% of Group YO, about 25% of Group OO-I and about 5% of Group OO-N. After 15 years of diabetes, macular edema was present in about 18% of Group YO, about 20% of Group OO-I and about 12% of Group OO-N. When present, macular edema tended to be associated with more hard exudate in Group OO-N.