Longer Study Period Research Articles

Gastrointestinal Cancer and the Long-term Use of Pravastatin in the Elderly

To the Editor: We have no doubts about the benefit of pravastatin on cardiovascular morbidity and mortality among subjects aged 70 to 82 years as reported in the PROSPER study (1). However, we are uneasy about the safety of pravastatin as reflected by the significantly higher incidence of cancer (8.5%) in patients treated with pravastatin compared with those on placebo (6.8%) (p /0.02). Although any p-value cannot totally exclude a random error effect, we do not agree with the authors, who argue that this is most likely a chance finding. The results of the LIPID trial on pravastatin already showed that older persons had a significantly higher overall incidence of cancer compared with younger persons (pB/0.001) (2). This difference was also thought to be a chance finding. We are not convinced by the authors’ arguments referring to their metaanalysis and some large-scale trials, because the subjects in most of these trials are much younger and therefore less susceptible to cancer (3 /5) and because the follow-up period tends to be relatively short. The authors claim that the high incidence of cancers in the pravastatin group was not confined to any particular site. However, compared to the placebo group, the incidence of gastrointestinal cancer was higher in the pravastatin group (relative risk /1.46; 95% CI /1.00 /2.13). We compared the incidence of gastrointestinal cancers over the 4-year study period and found that during the first year there was a similar incidence in the placebo group (558 per 100 000 persons) compared to the treatment group (528 per 100 000 persons) (p /0.88). During the complete study period the incidence of gastrointestinal cancers remained around that level in the placebo group (see Fig. 1). From the second year on, the incidence in the treatment group increased, resulting in a relative risk of 2.74 for the fourth year (Table 1). A similar picture was found for all cancers starting from the third year. In a linear regression analysis, the year explained 90% of the variance of the yearly relative risks for both gastrointestinal and all cancers (p /0.05). If pravastatin has a carcinogenic effect, it is to be expected that no differences in cancer incidence could be observed during the first year of the study but only after a longer period. By including the cancer figures for the first year the magnitude and the significance of any later differences could be masked, and for this reason we recalculated the significance between the placebo and the treatment groups over the last 3 years. We found 29 gastrointestinal cancers in the placebo group and 50 in the pravastatin group. The differences are significant when calculated for either the placebo group (n / 2 913) compared with the treatment group (n /2 891) (p /0.016) or when calculated per person-year in the placebo group (6 155 person-years) compared with the treatment group (6 102 personyears) (p /0.016). We are aware of the fact that our levels of significance are fairly low. However, we believe that higher significance levels could be obtained over a longer study period and with more subjects. Before a definite conclusion about the safety of pravastatin in the elderly can be drawn, more long-term observations are needed.

Salmeterol Powder Provides Significantly Better Benefit than Montelukast in Asthmatic Patients Receiving Concommitant Inhaled Corticosteroid Therapy

Purpose of the Study. To compare inhaled salmeterol powder to oral montelukast in patients with persistent asthma who are not well-controlled on inhaled corticosteroids (ICS).Study Population. Male and nonlactating, nonpregnant females ≥15 years of age with the diagnosis of asthma for at least 6 months were recruited from 71 private and university clinics in the United States and Puerto Rico. The group included 948 subjects (61% female, 85% Caucasian). All subjects were symptomatic with their asthma for at least 6 weeks before screening and at a constant dose of ICS for 30 days before screening. Baseline forced expiratory volume in 1 second (FEV1) was 50% to 80% and all subjects had at least 12% improvement in FEV1 postbronchodilator.Methods. Two multicenter, randomized, double-blind, parallel-group clinical trials were conducted comparing 50 μg bid of salmeterol by dry powder inhaler (n = 476) versus 10 mg po daily of montelukast (n = 472). All subjects underwent baseline history and physical, and pulmonary function tests including FEV1 reversibility. After a 7- to 14-day run-in period to assess symptoms, diary card completion, and patient proficiency with inhaler use, patients whose FEV1 remained within 50% to 80% of normal were eligible for enrollment. Subjects also had to meet at least 1 of the following criteria during the 7 days before randomization: use of an average of ≥4 puffs per day of albuterol, a symptom score of ≥2 on ≥3 days, and/or ≥3 nights of nocturnal asthma symptoms. The subjects remained on their current ICS dose throughout the study and rescue albuterol, but no other asthma medications were allowed other than study drug. Subjects were asked to record am and pm peak flows (PEF), nocturnal awakenings, albuterol use, asthma symptoms, and daily study drug use. Symptoms were rated using a 5-point scale and were targeted to affects on activity level. Subjects returned for assessments at 1, 4, 8, and 12 weeks of treatment. The subjects completed a satisfaction survey at the end of the 12-week study.Results. A total of 476 subjects received inhaled salmeterol and 472 received montelukast. The treatment groups had similar demographics and disease characteristics at baseline, with 61% women, >80% Caucasian, >70% with asthma ≥10 years, mean baseline FEV1 68% of predicted, and mean baseline PEF of 370 l/m. Morning PEF in the salmeterol treated group increased more significantly (mean = 35 l/m) than the montelukast treated group (mean = 21.7 l/m). The bronchodilator properties of salmeterol were superior than montelukast over all treatment weeks. Patients in the salmeterol group had a significantly greater increase in symptom-free days than the montelukast group (24% vs 16%; P < .001). Symptom scores for all parameters except wheezing were significantly improved in the salmeterol group vs the montelukast group. Subjects in the salmeterol group used significantly less rescue albuterol than the montelukast group. Regarding patient satisfaction with the drug, the salmeterol group had greater satisfaction other than in how long the medication worked, where there was no difference in scores. The number of asthma exacerbations and the number of adverse events was similar in both groups, with 13 in each group withdrawing from the study because of adverse events.Conclusion. The addition of salmeterol in moderate to severe persistent adult asthmatics poorly controlled on ICS was superior to the addition of montelukast in improvement in PEF and overall symptom control.Reviewer’s Comments. The addition of inhaled salmeterol in subjects who were not adequately controlled on ICS showed significantly greater improvement in lung function and control of symptoms (other than wheezing) compared with oral montelukast. Other groups have compared salmeterol as an additive agent versus doubling the ICS dose and versus another leukotriene modifier, but not all in that study were on baseline ICS. Future studies are needed to determine if these findings will hold true over longer study periods and whether either long-acting β-agonists or leukotriene modifiers have a bearing on the natural history of asthma. In addition, similar studies in children are needed to see if the same patterns of response occur in all age groups.

The acute effects of exercise on bone turnover.

Exercise is known to have long-term benefits on bone mass, but little is known about the short-term effects of exercise on bone turnover. The purpose of this study was to investigate whether acute effects of exercise on bone remodelling could be detected by measuring blood and urinary markers of bone turnover. We measured biochemical markers of bone turnover in ten healthy, young men before and up to 32 hours after 30 minutes of brisk treadmill walking. Blood samples were taken before, immediately after and at 0.5, 1, 8, 24 and 32 hours after the exercise. These were assayed for osteocalcin and bone specific alkaline phosphatase. Twenty-four hour urine samples were taken over three days (day before, day of and day after exercise) and measured for pyridinoline and deoxypyridinoline crosslinks. Crosslink excretion was standardised for total body bone mineral content (TBBMC) and urinary creatinine. Total body bone mineral density (and content) and body composition were measured by dual energy X-ray absorptiometry. No changes in the levels of either osteocalcin or alkaline phosphatase were seen at any time point following the exercise. Both urinary crosslinks exhibited an increase in levels on the day of the exercise and a further significant increase the day after (pyridinoline 38.7%, p = 0.05; deoxypyridinoline 42.3%, p = 0.025; median, corrected for TBBMC). There were significant negative correlations between the crosslinks, osteocalcin and body fat percentage. In conclusion, the exercise appears to have stimulated bone resorption within 32 hours of moderate exercise, but there was no measurable effect on bone formation after 32 hours. A longer study period may be necessary to detect changes in bone formation.

MAINZ CONGENITAL BIRTH DEFECT MONITORING SYSTEM

The two most important aims of tho Mainz Congenital Birth Defect Monitoring Syitem wore to find “incidence” rates and to took for etiological causes of congenital malformations. All babies born in Mainz underwent a standardized physical and sonographic examination. Anamnestic data of family history, enviromental factors, drug exposure etc. were collected. Using case controll studies we looked for special correlations between morphologic defects and anamnestic data as factors of risk. The relative risk was calculated as odds ratio. Results: In 1990 and 1991 we examinated 8430 newborns. 656 (7,8%) children had major and 2609 (31,1%) minor malformations. Systemic localisation of major defects: Skeletal 2,6%, urogenital, 1.8%, cardiovascular 1,3%, nervouo 0,6%, digostive 0,5%, chromanomal anomalies 0,3% and others 0,6%. Localisat ion of minor defects: Simian crease 3,9%, Darwinian tubercle 3,8%, facial haemangioma 3,2%, auricular tag 3,0%, haemangioma 2,7%, auricular pits 2,3% and others 12,2%. Increased relative risks (odds ratios) were found for following factors: Sibling (2,4*)/parent (1,4) with major malformation, alcohol abuse (2,3), medication (1,8*) during pregnancy, consanguinity (1,8), diabetes mellitus (mother; 1,7), placental insufficiency (1,4) etc. (“:statistically significant).Conclusions: The Mainz Congenital Birth Defect Monitoring System is able to find regional “incidence” rates and represent a further step in the search for new etiological factors. More patients and a longer study period is necessary for in depth evalution. Comparisons with other regional monitoring systems are required.

The Contribution of Epidemiology to Pharmacoeconomic Research

Epidemiologic principles provide important guidelines for the conduct of pharmacoeconomic research. Inclusion of economic outcomes in clinical trials often requires longer study periods, nontraditi...

The Vitamin C Content of Seven Cultivars of Potatoes Grown Across Canada

During the 1986 growing season, samples of seven potato cultivars from eight provinces in Canada were tested for vitamin C content. The seven cultivars were: Superior, Russett Burbank, Red Pontiac, Norchip, Shepody, Yukon Gold and Kennebec. The mean vitamin C for the cultivars ranged from 12.4–18.1mg/100g potato, fresh weight. Variations in vitamin C were highly significant with respect to cultivar and location (P<0.01). The cultivars, Yukon Gold and Shepody, contained the highest amounts of vitamin C. The present study was for one year. It is suggested that a much longer study period (3–5 year) is required to give a better estimate for nutrient data tables where use of a range of vitamin C, rather than a mean, may be more appropriate.

Concreteness, imagery and temporal factors in paired-associate learning

Ss learned a paired-associate list in which concrete, high imagery and abstract, low imagery nouns served as stimuli for nonsense syllable associates. The lengths of the study-recall intervals and intertrial intervals were varied. Performance improved over trials and was superior for concrete stimuli and longer study-recall intervals. A significant interaction indicated that abstract noun stimuli need longer study periods than concrete noun stimuli for discovery and utilization in learning.

The Effects of Coaching Subjects in the Recognition of Facial Expressions

Abstract A wide range of individual differences in the ability to identify facial expressions of emotion has been reported. As evidence that these inequalities are due in large part to differences of practice in reacting to expressive criteria, rather than to innate factors, F. H. Allport has offered the data from an experimental observation of the effects of training subjects of varying ability for fifteen minutes in the analysis of facial expressions. The gain in score made by his subjects on the facial expression test after the training period was roughly inversely proportional to their original standing; i.e., the less proficient persons gained the most and the more proficient gained the least. Repeating this procedure with larger groups of subjects, both with the same and longer study periods, the writer largely confirmed Allport's data. However, a control experiment, affording no opportunity for study, yielded similar data, except that on the average no gain in score resulted. The inverse relationsh...