Reagan H. Bradford

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin

This randomized, double-blind, multicenter, diet-and-placebo-controlled study was designed to clarify the dose-response relationship of lovastatin therapy to lipid-modifying efficacy and drug-related adverse events. Exclusion criteria were minimized so that study patients were representative of the majority of patients with moderate hypercholesterolemia seen in medical practice. After 6 weeks on the American Heart Association Step 1 Diet, a total of 8,245 patients were randomly assigned to 48 weeks of treatment with diet and placebo or lovastatin at dosages of 20 or 40 mg once a day or 20 or 40 mg twice a day. All adverse events were monitored, with particular attention to evaluation of liver and muscle. Liver transaminase elevations suggestive of possible hepatotoxicity, defined as successive elevations in either aspartate transaminase or alanine aminotransferase greater than 3 times the upper limit of normal, occurred in equal numbers of placebo and lovastatin 20 mg/day treated patients (0.1%). The frequencies were higher in lovastatin 40 mg/day and 80 mg/day patient groups (0.9 and 1.5%, respectively). No patient was diagnosed as having clinically symptomatic hepatic dysfunction. Creatinine kinase (CK) elevations above the upper limit of normal occurred frequently in placebo- (29%), as well as lovastatin-treated patients (29-35%), and muscle symptoms were reported with similar frequency in all groups (7-9%). The combination of muscle symptoms with marked CK elevations (greater than 10 times the upper limit of normal) was seen in only five patients: one in a 40 mg/day dose group and four in the 80 mg/day dose group. No patient developed rhabdomyolysis. The incidence of clinical and laboratory adverse events requiring discontinuation was 6% for the placebo group and from 7% (20 mg/day) to 9% (80 mg/day) for lovastatin treatment groups. No new types of adverse experiences related to lovastatin treatment were reported. Lovastatin, as an adjunct to diet for the reduction of elevated LDL cholesterol, was generally very well tolerated.

The diagnosis of diabetic retinopathy. Ophthalmoscopy versus fundus photography.

PURPOSE To compare fundus photography with ophthalmoscopy in the detection of diabetic retinopathy. METHODS Ophthalmoscopy and fundus photographs with a nonmydriatic camera, both performed through dilated pupils, were compared to diagnose retinopathy in a cohort of 410 Oklahoma Indians with noninsulin-dependent diabetes mellitus. A total of 795 eyes were examined using both methods. The mean age of participants was 60.3 years, with a mean duration of diabetes of 17.3 years. RESULTS An overall agreement of 86.3% with a kappa statistic kappa of 0.74 was found between ophthalmoscopy and fundus photography with a nonmydriatic camera. For the diagnosis of proliferative diabetic retinopathy, kappa = 0.84 with an agreement of 98.1%. With a total of 61 cases of proliferative retinopathy diagnosed by either method in our study, ophthalmoscopy alone detected 88.5% and fundus photography, 78.7%. When compared on a lesion-by-lesion basis, agreement between the two diagnostic methods was highest for nonproliferative retinopathy, as well as fibrous proliferation. CONCLUSION The fundus photography with a nonmydriatic camera, performed with mydriasis, is comparable to ophthalmoscopy for the detection of retinopathy. It may prove to be a suitable, cost-effective method for routine screening in diabetes clinics, provided ophthalmologic referral is ensured for those with a diagnosis of any form of retinopathy, questionable retinopathy, nondiabetic retinopathy, those with poor quality photographs, as well as those with acute changes in visual acuity.

Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia

In the multicenter, double-blind EXCEL (Expanded Clinical Evaluation of Lovastatin) study the efficacy of lovastatin in modifying plasma lipids and lipoproteins in 8,245 participants with moderate primary hypercholesterolemia was evaluated. Patients were randomly assigned to 48 weeks of treatment with diet and placebo or diet and lovastatin 20 or 40 mg once a day, or 20 or 40 mg twice a day. At all of these dosages, lovastatin produced substantial dose-dependent reductions in low-density-lipoprotein (LDL)-cholesterol levels, averaging 24% (20 mg/day) to 40% (80 mg/day). The magnitude of the effect of this lipoprotein was further reflected by the percentage of patients who achieved National Cholesterol Education Program (NCEP) goals. In the absence of coronary artery disease (CAD) or two other CAD risk factors, the LDL-cholesterol goal of 4.14 mmol/L (160 mg/dL) was attained by 22% of patients in the placebo group and between 81% (20 mg/day) and 96% (80 mg/day) of those treated with lovastatin. For those with CAD or at least two other CAD risk factors, the LDL-cholesterol goal of 3.36 mmol/L (130 mg/dL) was attained by 4% of placebo patients and between 38% (20 mg/day) and 83% (80 mg/day) of those treated with lovastatin. Lovastatin also increased high-density-lipoprotein cholesterol (7-10%) and decreased triglycerides (10-19%) in a dose-dependent manner. Thus, when used as an adjunct to a prudent diet, lovastatin produces favorable changes in the entire lipoprotein profile and is a highly effective agent for managing patients with primary hypercholesterolemia.

Expanded clinical evaluation of lovastatin (EXCEL) study : design and patient characteristics of a double-blind, placebo-controlled study in patients with moderate hypercholesterolemia

The randomized, double-blind, placebo-controlled trial described in this report was undertaken to clarify the dose-response relation of lovastatin therapy to lipid-modifying efficacy (lipid/lipoprotein modification) and drug-related adverse events in a population with moderately elevated fasting plasma total cholesterol (240 to 300 mg/dl) and low-density lipoprotein cholesterol (greater than or equal to 160 mg/dl). Men or women (postmenopausal or surgically sterile), aged 18 to 70 years, were entered into the trial with minimal exclusion criteria. After 4 to 6 weeks of an American Heart Association phase I diet or a more stringent diet, 8,245 patients from 362 sites were randomized to 1 of 5 parallel diet and drug treatment groups: placebo (n = 1,663) or lovastatin, 20 mg (n = 1,642) and 40 mg (n = 1,645) with the evening meal, and 20 mg (n = 1,646) or 40 mg twice daily (n = 1,649). The regimen of diet and lovastatin (or placebo) was followed for 48 weeks. The 5 treatment groups were similar at baseline. The total cohort had the following characteristics: 59% were men (mean age 56 years); 92% were white; 59% had completed at least 1 year of education beyond high school; 57% had a history of cardiovascular and associated disease; 40% had a history of hypertension; and 29% had coronary artery disease. Health habits were similar among groups, with 18% of patients reporting cigarette smoking, 14% reporting that they consume greater than 1 alcoholic beverage daily and 67% reporting no strenous exercise. Mean lipid/lipoprotein levels were also similar among groups, with the following average levels: total cholesterol (258 mg/dl), low-density lipoprotein cholesterol (180 mg/dl), high-density lipoprotein cholesterol (45 mg/dl) and triglycerides (median = 155 mg/dl). The large size of this trial, its placebo-controlled, double-blind design and the similarity of treatment groups at baseline should allow clear documentation of the long-term effects of lovastatin treatment and generalization of the results to a substantial portion of patients who may be candidates for lipid-modifying therapy.

Efficacy and Tolerability of Lovastatin in 3390 Women with Moderate Hypercholesterolemia

The risk for coronary heart disease death for younger adults is 3 to 10 times greater in men than in women, but this differential diminishes with advancing age [1]. Among women older than 50 years, 53% of deaths are due to heart disease and stroke [2]. Annually, more women than men die of either coronary heart disease or stroke [2]. Once diagnosed with coronary heart disease, women often have a worse prognosis than men. Women have a higher mortality rate after symptomatic myocardial infarction [3]. Women undergoing coronary bypass grafting have less complete revascularization, reduced patency rate, less relief of symptoms, and a higher mortality rate than do men [4, 5]. Percutaneous transluminal angioplasty also appears to have a lower initial success rate and higher procedure-associated mortality rate among women [6]. The prevention of coronary heart disease in women, as well as in men, is increasingly recognized as being of great public health importance. In this report, we evaluated the efficacy and tolerability of lovastatin in women who participated in the Expanded Clinical Evaluation of Lovastatin (EXCEL) study [7]. Patients in the EXCEL study had moderately elevated baseline levels of plasma total and low-density lipoprotein (LDL) cholesterol, typical of those seen in the usual clinical practice. The study design provided for large treatment groups so that the incidence of abnormal laboratory safety tests and clinical adverse events (particularly involving liver and muscle) could be reliably determined among treatment groups even at low frequency. Although an analysis based on gender was not an a priori objective of the EXCEL study design, the large sample size provided an opportunity to investigate the effect of lovastatin in women, to assess the effect of concomitant administration of estrogen-replacement therapy on the efficacy of lovastatin, and to detect any clinically important gender differences in efficacy and tolerability. Methods The design of this study and the methods used have been described previously [7]. In summary, the EXCEL study evaluated the efficacy and tolerability of lovastatin using a diet- and placebo-controlled, randomized, double-blind design. The protocol excluded premenopausal women unless surgically sterilized; however, data classifying women as surgically sterilized or postmenopausal were not collected. After a minimum of 4 weeks on an American Heart Association Step I diet, 8245 patients (3390 women) with moderate primary hypercholesterolemia (total cholesterol, 6.21 to 7.76 mmol/L [240 to 300 mg/dL]; LDL cholesterol 4.14 mmol/L (160 mg/dL); and triglycerides < 3.95 mmol/L [350 mg/dL]) from 362 clinical centers were instructed to continue diet and were randomly assigned to 48 weeks of treatment with one of the following five regimens: placebo, or 20 or 40 mg lovastatin once daily, or 20 or 40 mg twice daily. The study was approved by institutional review boards and participants gave written informed consent. Laboratory tests were performed by SmithKline Beecham Laboratories (Clinical Trials Division, Van Nuys, California). Efficacy Analyses Total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using standard enzymatic techniques [7]. The LDL cholesterol was calculated using the Friedewald approximation [8]. Response to treatment was calculated by the formula percent change equals ([baseline level minus treatment level] divided by baseline level) 100. A patients baseline level was the mean of two measurements in 91% to 92% of patients in each treatment group. The treatment values represented the mean of up to four measurements taken every 12 weeks during treatment. In calculations of LDL cholesterol response, data from 606 to 650 (92.5% [lovastatin, 20 mg once daily] to 93.5% [lovastatin, 20 mg twice daily]) women and 897 to 941 (94.3% [lovastatin, 20 mg twice daily] to 95.3% [lovastatin, 20 mg once daily]) men in each treatment group were available for both baseline and treatment period measurements. For total LDL and HDL cholesterol, two-sided t-tests were used to assess differences in mean percentage change between placebo and each lovastatin treatment group. The Wilcoxon rank sum test was used for testing differences in triglyceride levels. A less extensive approach, using linear statistical models, was used to assess the effects of concomitant use of estrogen. The covariates included in this modeling were baseline effects of age and lipid/lipoprotein levels. Safety Analyses Elevations in serum alanine aminotransferase and aspartate aminotransferase and muscle symptoms (complaints of pain, tenderness, or weakness) with increased levels of serum creatine kinase represent clinical and laboratory abnormalities associated with lovastatin therapy. Analyses presented here examine gender differences in both the incidence of elevations greater than the upper limit of normal and the mean levels of change from baseline to the end of treatment. Survival analysis methods specific for analyzing incidence have been described previously [9]. For serum transaminases, 95% confidence intervals for mean differences between women and men that did not overlap zero were considered statistically significant. The Cochran-Mantel-Haenszel test [10], after stratification by treatment group, was used to assess gender differences in muscle symptoms and in the incidence of elevated serum transaminases and creatine kinase. The Fisher exact test was used to evaluate treatment differences between placebo and lovastatin groups; this test was done separately for women and men. The proportion of patients having a clinical adverse experience (any change in health status) that investigators rated blindly (without knowledge of treatment group assignment) as being possibly, probably, or definitely drug related was examined by gender and by estrogen use with lovastatin. These were categorized into serious drug-related adverse experiences (resulted in death; required or prolonged hospitalization; were cancers; or caused permanent disability), nonserious adverse experiences, and adverse experiences requiring discontinuation of therapy. The Cochran-Mantel-Haenszel test [10] was used to test for gender differences after stratification by treatment group. Results Characteristics of Women at Baseline Of the total 8245 patients, 3390 (41%) were women (Table 1). The number of women randomized to each treatment group ranged from 655 to 695. The average age was 58.4 years, 89.8% were white, 18.3% reported that they currently smoked cigarettes, and 42.1% were hypertensive. The mean baseline total cholesterol level was 6.74 mmol/L (261 mg/dL), and the mean LDL cholesterol level was 4.60 mmol/L (178 mg/dL). Although gender differences were not evident in most baseline characteristics, the mean age of women was 4.5 years older. They were less likely to have a history of coronary heart disease (16.3% versus 37.3%), less likely to consume alcohol (43% versus 65%) and particularly seven or more drinks per week (5% versus 19%), had higher mean HDL cholesterol levels (1.32 mmol/L [51 mg/dL] versus 1.05 mmol/L [41 mg/dL]), and lower median triglyceride levels (1.65 mmol/L [147 mg/dL] versus 1.94 mmol/L [173 mg/dL]). Table 1. Baseline Characteristics of Randomized Women* Lipid and Lipoprotein Response Lovastatin produced dose-dependent (20 to 80 mg/d) reductions of 24.4% to 40.4% in LDL cholesterol and 9.4% to 17.9% in triglycerides, and increases of 6.7% to 8.6% in HDL cholesterol (Table 2). Lovastatin treatment groups differed (P < 0.001) from placebo in the mean percentage changes from baseline for all lipid and lipoprotein parameters. Overall, these results were similar to those found in men. Table 2. Change from Baseline in Plasma Lipid/Lipoprotein Levels of Women* To assess the achievement of National Cholesterol Education Program (NCEP) [11] LDL cholesterol goals after 48 weeks of lovastatin treatment, patients were categorized into two groups: a lower-risk group without coronary heart disease and with fewer than two coronary heart disease risk factors, and a high-risk group with coronary heart disease or at least two coronary heart disease risk factors, or both. In the lower-risk women, the NCEP LDL cholesterol goal of less than 4.14 mmol/L (160 mg/dL) was reached by 26% given placebo and from 82% to 95% treated with lovastatin (20 to 80 mg/d) (Figure 1). In high-risk women, the NCEP LDL cholesterol goal of less than 3.36 mmol/L (130 mg/dL) was reached by 4% given placebo and from 40% to 87% treated with lovastatin (20 to 80 mg/d). Similar results were observed in men. Figure 1. Percentage of women achieving National Cholesterol Education Program target levels for low-density cholesterol at week 48. In both women and men, lovastatin-associated elevations in HDL cholesterol were dose dependent, and the percentage increases were larger when baseline levels of HDL cholesterol were low. When baseline HDL cholesterol levels were less than 0.91 mmol/L (35 mg/dL), lovastatin (20 to 80 mg/d) increased the placebo-corrected mean HDL cholesterol level in women by 1.6% to 11.5%. When baseline HDL cholesterol levels were 0.91 mmol/L or higher, the corresponding placebo-corrected increases were 4.7% to 5.9%. Fewer women than men (5% to 8%, versus 25% to 30%) had HDL cholesterol levels less than 0.91 mmol/L. Safety Analyses Successive elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal were found in one woman (0.2%) given placebo; two (0.4%) given 20 mg/d; three (0.5%) given 40 mg every evening; five (1.0%) given 20 mg twice daily, and eight (1.6%) given 80 mg/d. No statistically significant gender differences in incidence were observed. Mean alanine aminotransferase levels, however, showed less increase with lovastatin treatment in women (up to 0.05 kat/L [26.3%] at 80 mg/d) than in men (0.06 to 0.11 kat/L [19.6% to 30.1%] at

Efficacy and Tolerability of Lovastatin in 459 African-Americans With Hypercholesterolemia *

A paucity of substantive data from clinical drug trials is available specifically evaluating the effects of therapy for hypercholesterolemia in African-Americans, even though a substantial number are candidates for medical advice and intervention for high blood cholesterol. The efficacy and safety of lovastatin in 459 African-Americans with hypercholesterolemia were studied in the Expanded Clinical Evaluation of Lovastatin study, a multicenter, double-blind, diet- and placebo-controlled trial. This trial involved 8,245 patients who were randomly assigned, regardless of race, to receive placebo or lovastatin at doses of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Among African-Americans, lovastatin produced sustained, dose-related (p <0.001) decreases in low-density lipoprotein cholesterol (20% to 38%), total cholesterol (14% to 28%), and triglycerides (8% to 15%). From 75% to 96% of African-Americans treated with lovastatin achieved the National Cholesterol Education Program goal of low-density lipoprotien cholesterol <160 mg/di, and from 33% to 71% achieved the goal <130 mg/di. The safety profile of lovastotin in African-Americans was generally favorable. A relatively high incidence of creatine kinase levels greater than the upper limit of normal was observed in African-Americans during the study, i.e., 63% in the placebo group and similar levels in lovastatin treatment groups. Lovastatin is highly effective and generally well tolerated as therapy for primary hypercholesterolemia in African-Americans.

Double-blind comparison of bezafibrate versus placebo in male volunteers with hyperlipoproteinemia

The efficacy and safety of bezafibrate were evaluated in 83 patients with type IIa, IIb, or IV hyperlipoproteinemia. Following a 12- to 14-week placebo period on a coronary-prudent diet (Period 1), patients were assigned randomly to receive either bezafibrate 600 mg/day or placebo, plus diet in a double-blind, 12-week treatment period (Period 2). The return of lipid and lipoprotein levels toward baseline was evaluated in a subsequent 8-week period on placebo plus diet (Period 3). In patients with type IIa hyperlipoproteinemia, bezafibrate significantly lowered total (14.6%, P less than 0.001) and LDL-cholesterol (16.4%, P less than 0.001) and total (29.9%, P less than 0.001) and VLDL-triglyceride (44.0%, P less than 0.001) and significantly increased HDL cholesterol (9.5%, P less than 0.001). In patients with type IIb, bezafibrate had a qualitatively similar effect to that seen in type IIa on each of these lipoproteins, but the sample size was too small for statistical evaluation. In patients with type IV, bezafibrate lowered total (48.3%, P less than 0.01) and VLDL-triglyceride (57.7%, P less than 0.001) and VLDL-cholesterol (56.8%, P less than 0.001) and increased HDL-cholesterol (16.6%, P less than 0.05). All values returned toward baseline during Period 3. Only two bezafibrate patients experienced adverse events that were considered definitely treatment related; one was dropped from the study because of elevations in SGOT and SGPT, 1.5- and 4-times the upper limit of normal, respectively. For other laboratory parameters, trends upward or downward were small and of doubtful clinical significance. Bezafibrate appears to be effective and safe for modifying lipid and lipoprotein levels in patients with types IIa, IIb and IV hyperlipoproteinemia.