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Meloxicam (Mobic((R))) was introduced in the UK in 1996 as a nonsteroidal anti-inflammatory drug (NSAID). To help evaluate the postmarketing experience with meloxicam in the UK, we used the General Practitioners Research Database (GPRD) to characterize the baseline risk of an upper gastrointestinal (GI) event among new users of meloxicam, ibuprofen, diclofenac, naproxen and indomethacin. We selected for analysis a random sample of 5000 meloxicam users, and 5000 users of each of the comparator NSAIDS except indomethacin, for which we selected 2500 subjects. Comparators were matched to meloxicam subjects on age and sex. We examined for each subject history of certain GI diagnoses and recent use of anti-inflammatory drugs and acid-suppressing drugs. We found that patients receiving meloxicam were at least twice as likely as patients receiving other NSAIDs to have a recent history of GI diagnoses or treatment. We conclude that in the UK meloxicam was used more often than other popular NSAIDs among patients who were at increased baseline risk of GI events. The occurrence of GI events among users of meloxicam, even at a relatively high frequency, therefore, would be expected based solely on this increased baseline risk. Copyright (c) 2000 John Wiley & Sons, Ltd.

There is widespread interest in assessing the clinical importance of a study result. This goal is impeded, however, by a lack of clarity about the biological interpretability of epidemiological effect measures, such as the relative risk. A relative risk is often interpreted merely as a measure of some vague statistical association, without a view toward a biological effect as an object of measurement. Not infrequently, if it is not statistically significant, the relative risk estimate is ignored completely. A key to biological interpretation is appreciating the theoretical framework stipulating that outcome rates derived from 2 comparison groups actually represent measures of different effects in the same population. For instance, by using a placebo group to estimate the number of background cases that occurred in the treatment group, an estimate of the number of excess cases that occurred as a result of treatment can be made. This kind of biological entity can be derived from a relative risk, and can be more easily evaluated as to its clinical importance than a statistical association or a statement about statistical significance. Interpretation then becomes a more directed task, with a focus on the validity of certain ancillary hypotheses upon which biological interpretability rests.

Background: We evaluated whether the risk of stroke depends on aspirin dose in patients with a previous transient ischemic attack or stroke., Methods: We conducted a metaregression analysis of stroke by using published randomized, placebo-controlled trials. We analyzed studies of patients who had recently had a transient ischemic attack or stroke (ie, secondary prevention). We abstracted data on the treatment regimen and stroke. To evaluate the dose-response relationship, we conducted a metaregression analysis of study-specific risk ratios by means of weighted linear regression., Results: Eleven randomized, placebo-controlled trials contributed a total of 5228 patients randomized to aspirin only and 4401 patients randomized to placebo only. The slope of the dose-response curve was virtually flat across a wide range of aspirin doses from 50 to 1500 mg/d (P = .49 for test of slope not =0). Summarizing across studies, aspirin decreases the risk of stroke by about 15% (risk ratio, 0.85;95% confidence interval, 0.77-0.94)., Conclusions: Aspirin reduces the risk of stroke by approximately 15%, and this effect is uniform across aspirin doses from 50 to 1500 mg/d. The lowest effective aspirin dose has not yet been identified, but it could be lower than 50 mg/d.

We used automated health insurance claims records of a New England insurer to assess the relation between salmeterol and severe nonfatal asthma. We identified 61,712 members who received a beta-agonist from January 1, 1993 to August 31, 1995, including 2, 708 recipients of salmeterol. Compared with recipients of other beta-agonists, future salmeterol recipients had higher rates of asthma hospitalization and dispensings of asthma medications during the year before they received salmeterol. We selected as a comparison group 3,825 recipients of sustained-release theophylline. We defined a baseline period as the year before the start of the follow-up period, and we characterized patients according to age, sex, calendar period, presence of baseline hospitalizations for asthma, presence of chronic obstructive pulmonary disease (COPD), and baseline dispensings of asthma medications. After adjusting for baseline factors, incidence rates of severe asthma in the salmeterol group were not elevated for emergency care (rate ratio estimate [RR] = 0.69, 95% confidence intervals [CI] = 0.42, 1.11), hospitalization (RR = 1.09, 95% CI = 0.60, 1.98), or intensive care unit (ICU) stays (RR = 0.81, 95% CI = 0.25, 2.62). We conclude that salmeterol was prescribed preferentially to high-risk patients and, after adjusting for baseline risk, salmeterol recipients did not have a greater risk than theophylline recipients of severe nonfatal asthma.

Objective: To assess the effect on FEV1 and clinical outcomes of adding ipratropium bromide to salbutamol in the treatment of acute asthma., Methods: We conducted a pooled analysis of three randomized double-blinded clinical trials conducted in the United States, Canada, and New Zealand. The studies enrolled 1,064 patients aged 18 to 55 years who presented at the emergency department with acute asthma. Patients were randomized to treatment with a combination of nebulized 2.5 mg salbutamol plus 0.5 mg ipratropium bromide, or 2.5 mg salbutamol alone. Medications were administered at baseline and, in the US study, at 45 min. FEV1 was measured at baseline, 45 min, and 90 min. Patients were followed up for 48 h after hospital discharge for occurrence of asthma exacerbation and hospitalization., Results: Treatment groups were comparable at baseline. Of the 1,064 patients randomized, 1,015 patients (95%) remained in the study for measurement at 45 min, and 961 patients (90%) completed the final measurement at 90 min. Comparison of overall improvement in FEV1 at 45 min indicated a better response for patients receiving combination therapy (mean difference=43 mL, 95% confidence interval [CI]=-20, 107). The distribution of change in FEV1 was skewed by a small number of patients with extreme values (38 of 1,064=3.6%) that may have been due to unreliable lung function testing. Removing these outliers produced a larger and more precise estimate of effect (mean difference=55 mL, 95% CI=2,107). Because the distribution was skewed, we performed nonparametric analyses that showed evidence of a beneficial effect of combination therapy. The difference between median values at 45 min is 40 mL (Wilcoxon p value=0.03). In addition, 4.9% (95% CI=-1%, 11%) more patients in the combination group achieved at least 20% of their potential improvement, as measured by the difference between their baseline FEV1 and their predicted FEV1. Patients receiving combination therapy had lower risk for each of three clinical outcomes: the need for additional treatment (relative risk [RR]=0.92, 95% CI=0.84, 1.0), risk of asthma exacerbation (RR=0.84, 95% CI=0.67, 1.04), and risk of hospitalization (RR=0.80, 95% CI=0.61, 1.06)., Conclusion: Adding ipratropium bromide to salbutamol in the treatment of acute asthma produces a small improvement in lung function, and reduces the risk of the need for additional treatment, subsequent asthma exacerbations, and hospitalizations. These apparent benefits of adding ipratropium bromide were independent of the amount of beta-agonist that had been used earlier in the attack, and possibly related to a recent upper respiratory tract infection. Confirmatory studies are needed, especially for clinical outcomes.

To estimate the frequency of adverse effects associated with the use of the transdermal nicotine patch, we abstracted and analysed data from 47 reports of 35 clinical trials. The meta-analysis presented here represents a synthesis of data from 41 groups of nicotine patch recipients totalling 5501 patients, and 33 groups of placebo recipients totalling 3752 patients. Smoking abstinence was the primary outcome in 32 of the trials, and relief of colitis symptoms was the primary outcome in 2 of the trials; 1 study of contact sensitisation was included in the skin irritation analysis. The patch was clearly effective as an aid to smoking abstinence. Despite the large number of patients in the analysis, few adverse cardiovascular outcomes (myocardial infarction, stroke, tachycardia, arrhythmia, angina) were reported, and no excess of these outcomes was detected among patients assigned to nicotine-patch use. The incidences of several minor adverse effects were clearly elevated among the nicotine-patch groups, especially sleep disturbances, nausea or vomiting, localised skin irritation and respiratory symptoms, but the background rates and risk ratios varied considerably across studies. The incidence of nausea or vomiting appeared to be lowest when the patch dose was tapered. The results of this meta-analysis indicate that very large studies would be needed to assess the effect of the patch, if any, on serious, rare outcomes. These results also suggest that the rate of minor adverse effects might be lowered by modifying patch-use protocols.

Objective: To describe the frequency and costs of medical services for patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in a managed care setting., Methods: Individual utilization records of medical and pharmacy services for OA and RA patients were obtained from a group-model health maintenance organization (HMO). Estimates were made for costs of drugs and medical services for arthritis from July 1, 1993 to June 30, 1994 using Medicare reimbursement schedules and average wholesale drug prices. Calculated rates for each population were expressed as counts of events or as dollars per person-year., Results: The average individual cost rate of arthritis-related care for 365 RA patients was $2,162 per year, and the total cost of RA care to the HMO was $703,053. Prescription medications accounted for 62% ($436,440) of the total cost of RA care, while ambulatory care accounted for 21% ($150,938), and hospital visits accounted for 16% ($115,674). With regard to 10,101 OA patients, the average individual cost rate was $543 per year, and total cost to the HMO was $4,728,425. Hospital care accounted for 46% ($2,170,890) of the total cost of OA care, medications accounted for 32% ($1,509,637), and ambulatory care accounted for 22% ($1,047,898)., Conclusion: RA care, in the setting of this study, was characterized by intensive treatment, especially frequent use of medications that were delivered to most patients. Although the cost of RA care per patient was high, cost to the managed care provider was relatively low, owing to the rarity of RA. OA care tended to be infrequent, and the largest component of cost was hospital care for a small proportion of patients (5%). Owing to the greater prevalence of OA, care of OA was nearly 7 times more costly to the managed care provider than was care of RA.

To evaluate the hypothesis that fenoterol or all inhaled beta-agonists caused an epidemic of asthma mortality in New Zealand from the late 1970s to the mid-1980s, we examined trends from 1970 to 1992 in per capita sales of inhaled fenoterol, inhaled beta-agonists, and asthma mortality in New Zealand and nine other countries that marketed fenoterol. During the last two decades, there has been a large and widespread increase in sales of inhaled beta-agonists, including fenoterol. Asthma mortality in most countries, however, has been relatively stable. Only New Zealand experienced an epidemic of asthma mortality. In addition, sales rates of fenoterol similar in magnitude to those in New Zealand near the peak of the epidemic also occurred in Belgium, Austria, and Germany, while asthma mortality in these countries remained low. Also, sales rates of all beta-agonists in Australia were similar to those in New Zealand, but no epidemic of asthma mortality occurred in Australia. Therefore, the difference between asthma mortality rates in New Zealand and other countries is not explained by differences in per capita sales of fenoterol or all beta-agonists. Within New Zealand, the beginning and end of the epidemic correlated with a rise and fall in sales of all beta-agonists, including fenoterol. From 1980 to 1989, however, sales of fenoterol and all beta-agonists doubled in New Zealand while asthma mortality declined by 40%. International data on medication sales and asthma mortality, therefore, do not point to a relation between asthma mortality and beta-agonists in general nor fenoterol in particular.

Objectives: To measure the association between asthma drugs and death or ICU admission due to asthma (severe life-threatening attack of asthma [SLTA]), and to assess the possibility that these associations may not be causal but due to the prescription of these drugs to patients with more severe disease (confounding)., Design: Retrospective cohort study of 655 asthmatics who attended an emergency department in 1986 to 1987 followed till death or May 1989., Methods: Outcome events were death or ICU admission due to asthma (SLTA). All hospital attendances were identified and patients classified at each according to drug exposure and a wide variety of measures of asthma severity. Incidence rates were computed as total outcome events divided by person-time contributed for each subject classified according to drug use and asthma severity. Rate ratio (RR) estimates for severe asthma outcomes associated with use as compared to nonuse of asthma drugs were calculated. Severity markers were identified and used to adjust the crude RR estimates., Results: One hundred five SLTAs (15 deaths, 90 ICU admissions) occurred in 66 patients. Like inhaled fenoterol, oral beta-agonists, theophylline, cromolyn, inhaled steroids, and oral steroids were all associated with an increased risk of SLTA. When adjusted progressively for measures of severity, these increased risks became insignificant except for cromolyn., Conclusion: Unadjusted RR estimates for severe asthma events comparing exposure to a particular drug with nonuse are overestimates due to confounding. Control with two severity markers (hospital admission in the last year, use of oral corticosteroid at the time of previous admission) removes some confounding but control for additional severity markers not available in previous studies reduces the effect estimates further. These results suggest that the problem of confounding is substantial in nonrandomized epidemiologic studies of asthma drugs. Previous studies reporting RR estimates are likely to be confounded.

In order to characterise asthma management in a managed care setting, we identified 10,301 patients who were diagnosed with asthma between 1 January 1988 and 31 December 1991 at a group model health maintenance organisation in central Massachusetts, US. We obtained for these patients automated utilisation files containing data on medications, hospitalisations, emergency room visits, office visits, and estimated costs of these services. The medication dispensed to the greatest proportion of patients was beta 2 agonists either by inhalation (56%) or orally (21%). Theophylline was dispensed to 23% of the patients. Maintenance therapy was inhaled anti-inflammatory medication was uncommon, as inhaled corticosteroids (17%) and sodium cromoglycate (cromolyn sodium) [8%] were dispensed to fewer patients than other asthma medications. Among patients who had been hospitalised in the previous year, 36% were presently receiving inhaled corticosteroids, and among patients who used at least one beta 2 agonist metered-dose inhaler per month, 49% were presently receiving inhaled corticosteroids. Economic analyses showed that only 8% of the patients had either a hospital admission or an emergency room visit, but hospital costs among these patients accounted for 25% of the total costs of asthma care. In addition, the top 10% most expensive patients accounted for 42% of the total cost of asthma care. We conclude that a substantial proportion of patients at increased risk of a severe attack, by virtue of having a recent hospitalisation, do not receive maintenance anti-inflammatory therapy, and that hospitalisations among a relatively small proportion of asthma patients contribute significantly to the cost of asthma care.

We studied mortality among 8,878 employees who worked at any time from 1965 to 1988 at a synthetic fibers plant in North Carolina that used a finishing agent containing glycerol polyglycidyl ether. Some glycidyl ethers are mutagenic and tumorigenic in laboratory animals. The main route of exposure to workers was inhalation of the spray mist, although there was also skin contact. We identified 553 deaths in the cohort and the standardized mortality ratio (SMR) from all causes of death combined was 0.80. For most causes of death, mortality rates in the cohort were similar to mortality rates in the U.S. population. Among categories with at least five observed deaths, the largest effect estimate was for cancer of the central nervous system (SMR = 1.77), and the SMR for lung cancer was 0.94. The cancer categories of central nervous system (brain) and "other" lymphopoietic cancers (lymphoma and myeloma) showed weak associations with duration of employment. In case-control analyses in which we utilized work history data to compute effect estimates by duration of exposure, we found no increased risk of lung cancer or brain cancer among employees with more than 5 years of exposure. Effect estimates for lymphoma and myeloma tended to increase with duration of exposure, although there were only seven deaths in this category and the effect estimates were very imprecise. To date, this study has identified no clear carcinogenic effect of glycerol polyglycidyl ether, but plausible induction periods have not yet elapsed. The cohort should continue to be monitored to obtain more precise estimates after moderate or long induction times.

Objective: We tested the hypothesis that multiphasic, low-dose monophasic, and high-dose monophasic oral contraceptives share a common protective effect against functional ovarian cysts., Study Design: We conducted a cohort study using the automatic files of Maine Medicaid to assemble a population of 7462 women between the ages of 15 and 44 who were prescribed an oral contraceptive between Jan. 1, 1987, and Dec. 31, 1988. We included as cases 32 women with a principal diagnosis of a functional ovarian cyst confirmed by medical records as being greater than 20 mm in diameter., Results: At comparison with the absence of an oral contraceptive prescription, we observed decreasing rates of functional ovarian cysts among women prescribed multiphasic pills (rate ratio 0.91, 95% confidence interval 0.3000 to 2.31), low-dose monophasic pills with less than or equal to 35 micrograms estrogen (rate ratio 0.52, 95% confidence interval 0.17 to 1.33), and high-dose monophasic pills with greater than 35 micrograms estrogen (rate ratio 0.24, 95% confidence interval 0.01 to 1.34)., Conclusions: The protective effect of oral contraceptives against functional ovarian cysts reported previously for high-dose monophasic pills may be attenuated with newer pills of lower hormonal potency.

In the context of reported data on asthma mortality, we examine two types of covariate misclassification. The first type is non-differential misclassification, in which the proportion of subjects misclassified is invariant over exposure and disease status. Building on work by Cox and Elwood and by Blettner and Wahrendorf, we find that the range of admissible values for misclassification proportions is bounded by the observed data, and may not include any values that account for observed heterogeneity of effect estimates. The second type is differential misclassification, in which the classification error differs according to the disease or exposure classes to which study subjects belong. If the relation between exposure and the confounding variable or between the confounding variable and disease is strong, differential misclassification can produce large variations in the stratum-specific odds ratio estimates.

Tampon use has been identified as a major risk factor for toxic shock syndrome, although the etiologic role of tampons is not clearly understood. Two epidemiologic studies conducted to date have reported an association between tampon absorbency and risk of toxic shock syndrome. This finding is not corroborated by laboratory studies, however, which have suggested that absorbency may be a marker for other characteristics that create an environment conductive to the elaboration of toxic shock syndrome toxin 1. We used data from the previously reported Tri-state study to estimate simultaneously the effects of tampon oxygen content, absorbency and chemical composition. Although the data are sparse, oxygen content was more strongly associated with risk of toxic shock syndrome than either absorbency or chemical composition. The results suggest that it may be possible to develop a highly absorbent tampon that is not associated with a high risk of toxic shock syndrome.

To elucidate further the etiology of toxic shock syndrome, we assessed the effects of certain contraceptive methods and recent history of vaginal infection on the incidence of toxic shock syndrome, with confounding effects of other risk factors controlled. We found a strong but imprecise positive association between toxic shock syndrome and tubal ligation (rate ratio = 7.9, 90% confidence interval 1.4 to 42.7). We also observed a negative association with oral contraceptives (rate ratio = 0.49, 90% confidence interval 0.22 to 1.1) and a positive association with a recent history of vaginitis (rate ratio = 2.1, 90% confidence interval 1.2 to 3.9).