Pierre Ernst

The use of β-agonists and the risk of death and near death from asthma

Abstract Background. Morbidity and mortality from asthma appear to be increasing, and it has been suggested that medications used to treat asthma are contributing to this trend. We investigated a possible association between death or near death from asthma and the regular use of β2-agonist bronchodilators. Methods. Using linked health insurance data bases from Saskatchewan, Canada, we conducted a matched case–control study of subjects drawn from a cohort of 12,301 patients for whom asthma medications had been prescribed between 1978 and 1987. We matched 129 case patients who had fatal or near-fatal asthma with 655 controls (who had received medications for asthma but had not had fatal or near-fatal events) with respect to region of residence, age, receipt of social assistance, and previous hospitalization for asthma. Results. The use of β-agonists administered by a metered-dose inhaler was associated with an increased risk of death from asthma (odds ratio, 2.6 per canister per month; 95 percent confidence...

Low-dose inhaled corticosteroids and the prevention of death from asthma.

BACKGROUND Although inhaled corticosteroids are effective for the treatment of asthma, it is uncertain whether their use can prevent death from asthma. METHODS We used the Saskatchewan Health data bases to form a population-based cohort of all subjects from 5 through 44 years of age who were using antiasthma drugs during the period from 1975 through 1991. We followed subjects until the end of 1997, their 55th birthday, death, emigration, or termination of health insurance coverage; whichever came first. We conducted a nested case-control study in which subjects who died of asthma were matched with controls within the cohort according to the length of follow-up at the time of death of the case patient (the index date), the date of study entry, and the severity of asthma. We calculated rate ratios after adjustment for the subjects age and sex; the number of prescriptions of theophylline, nebulized and oral beta-adrenergic agonists, and oral corticosteroids in the year before the index date; the number of canisters of inhaled beta-adrenergic agonists used in the year before the index date; and the number of hospitalizations for asthma in the two years before the index date. RESULTS The cohort consisted of 30,569 subjects. Of the 562 deaths, 77 were classified as due to asthma. We matched the 66 subjects who died of asthma for whom there were complete data with 2681 controls. Fifty-three percent of the case patients and 46 percent of the control patients had used inhaled corticosteroids in the previous year, most commonly low-dose beclomethasone. The mean number of canisters was 1.18 for the patients who died and 1.57 for the controls. On the basis of a continuous dose-response analysis, we calculated that the rate of death from asthma decreased by 21 percent with each additional canister of inhaled corticosteroids used in the previous year (adjusted rate ratio, 0.79; 95 percent confidence interval, 0.65 to 0.97). The rate of death from asthma during the first three months after discontinuation of inhaled corticosteroids was higher than the rate among patients who continued to use the drugs. CONCLUSIONS The regular use of low-dose inhaled corticosteroids is associated with a decreased risk of death from asthma.

Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality

Background The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown. Methods The authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990–2005, using the healthcare databases from the province of Quebec, Canada. Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified. The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity. Results The cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively. The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to <4 months from the 9th to the 10th. The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first. Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months. Conclusions The course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation. Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality.

Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma

Background: Inhaled corticosteroids are effective at preventing asthma morbidity and mortality. Most studies, however, have focused on short term effects, raising uncertainty about their effectiveness in the long term. Methods: The Saskatchewan Health databases were used to form two population based cohorts of asthma patients aged 5–44 between 1975 and 1991. The first cohort included all subjects from the start of asthma treatment, while the second included subjects hospitalised for asthma from the date of discharge. Subjects were followed up, starting 1 year after cohort entry and continuing until 1997, 54 years of age, or death. The outcome was the first asthma hospital admission and readmission, respectively, to occur during follow up. A nested case-control design was used by which all cases were matched on calendar time and several markers of asthma severity to all available controls within the cohort. Results: The full cohort included 30 569 asthmatic subjects of which 3894 were admitted to hospital for asthma and 1886 were readmitted. The overall rate of asthma hospitalisation was 42.4 per 1000 asthma patients per year. Regular use of inhaled corticosteroids was associated with reductions of 31% in the rate of hospital admissions for asthma (95% confidence interval (CI) 17 to 43) and 39% in the rate of readmission (95% CI 25 to 50). The rate reduction found during the first 4 years of follow up was sustained over the longer term. Regular use of inhaled corticosteroids can potentially prevent between five hospital admissions and 27 readmissions per 1000 asthma patients per year. Conclusion: Regular use of low dose inhaled corticosteroids prevents a large proportion of hospital admissions with asthma, both early and later on in the course of the disease.

Inhaled corticosteroids in COPD and the risk of serious pneumonia.

Background Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use. Methods We formed a new-user cohort of patients with COPD treated during 1990–2005. Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia. A nested case–control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity. Results The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year). Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75). The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17). The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26). Conclusions ICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials.

Effectiveness of the Leukotriene Receptor Antagonist Zafirlukast for Mild-to-Moderate Asthma: A Randomized, Double-Blind, Placebo-Controlled Trial

In 1990, the total cost of asthma in the United States was estimated to be more than

Canadian Asthma Consensus Conference Summary of Recommendations

6 billion per year, of which some

Adult Asthma Consensus Guidelines Update 2003

1.1 billion, or almost 20%, was spent on drug therapy [1]. Moreover, the overall cost of drugs for the treatment of asthma is expected to increase substantially as a result of a greater emphasis on expensive anti-inflammatory agents, such as inhaled corticosteroids and cromolyn [2-4], and the introduction of new drugs, such as long-acting -agonists. It is hoped, however, that the higher initial costs will be offset by the reduction in morbidity and absence from work that may result from the use of these newer, more effective medications. The effect of a new drug on relevant and costly outcomes now needs to be shown during the introduction of that drug. As of 1992, no studies of the economic effectiveness of either existing or new drugs for the treatment of asthma had been done [5]. Recently, studies assessing the effect of inhaled corticosteroids in patients with asthma and chronic obstructive pulmonary disease have shown that the higher initial costs of these drugs may be offset by the savings generated by reduced use of health care [6, 7]. Leukotriene receptor antagonists, a new generation of asthma medications, are being developed because they interfere with the action of leukotrienes. Leukotrienes are implicated in bronchoconstriction and the formation of airway edema, which result from the inflammatory process in patients with asthma. Several leukotriene receptor antagonists are currently at different stages of development and testing [8]. Zafirlukast (ICI-204, 219, or ACCOLATE [Zeneca Pharmaceuticals, Wilmington, Delaware]) is one such compound; it acts through selective leukotriene receptor antagonism. It has been shown to block both early and late asthmatic responses to inhaled allergens [9]. In phase II dose-ranging studies, it was found to decrease the use of concurrent asthma medication, improve FEV1 and the morning peak expiratory flow rate, and decrease the incidence of asthma symptoms [10]. The effect of zafirlukast on clinical and economic outcomes has yet to be examined. We studied the clinical and economic effectiveness of zafirlukast among patients with mild-to-moderate asthma who were receiving only -agonists as needed (the need was frequent) and who therefore might have obtained benefit from additional regular medication. We focus particularly on clinical effectiveness outcomes (such as symptoms, limitation of activity, and sleep disturbance) and economic effectiveness outcomes (such as health care use, the need for other medications, and absence from work or school). Methods The data for this effectiveness study originated from a large, randomized, double-blind, multicenter trial designed to assess the efficacy of zafirlukast in 762 patients with mild-to-moderate asthma who were followed for 13 weeks [11]. Of the 63 centers participating in that trial, 28 agreed to collect the additional outcome data needed for our study. Of the 335 patients from those 28 centers, 150 agreed to participate; these 150 patients are the subject of our analysis. Clinical Protocol The trial from which this study arose was designed to compare zafirlukast plus as-needed -agonist therapy with placebo plus as-needed -agonist therapy in patients with mild-to-moderate asthma who needed additional treatment but would not have been unduly put at risk if such treatment were to be delayed for 3 months. After an initial 1-week observation period (visits 1 and 2) and a 7- to 14-day placebo run-in period (visit 3), the patients were randomly assigned in a 2 to 1 ratio to receive either zafirlukast and -agonists (albuterol from a metered-dose inhaler, 100 g per inhalation) or placebo and -agonists. Patients were then followed every 2 weeks for visits 4 and 5 and every 3 weeks thereafter (visits 6 through 8), for a total of 13 weeks. The initial 1-week period was devoted to observation, screening, eligibility testing, and instruction about questionnaires and the general structure of the trial. The run-in period, during which both groups received placebo, was used to assess final eligibility criteria and compliance with study procedures. After randomization, patients received zafirlukast, 20 mg, or placebo orally in a double-blind manner twice daily. With the exception of -agonists, no concurrent medications for asthma were permitted. Patients were eligible for the study if they were 12 years of age or older, had not smoked cigarettes in the previous 6 months, had a smoking history of less than 10 pack-years, and had an FEV1 at least 55% of the predicted value. They had to 1) have a 15% or greater improvement in FEV1 after inhalation of a bronchodilator within the previous 6 months or 2) show bronchial hyperresponsiveness (a decrease in FEV1 20% at an inhaled concentration 8.0 mg/mL of histamine or methacholine). Patients also had to be symptomatic (defined as a 7-day asthma symptom score 8) during the run-in period. The asthma symptom score was the sum over 7 days of an overall assessment of asthma symptoms, which were rated daily by the patient as 0 = none, 1 = mild (no interference with activities), 2 = moderate (interference with some activities), or 3 = severe (interference with many activities). The occurrence of more than one visit to an emergency department, one hospitalization for asthma, or the worsening of asthma necessitating therapy with agents other than -agonists resulted in the termination of follow-up for treatment failure. Follow-up was also terminated for severe adverse reactions, development of concurrent severe disease unrelated to asthma, voluntary withdrawal, and noncompliance with study procedures. Information on pulmonary function, daytime symptoms (classified as none, mild, moderate, or severe), nighttime awakenings, symptoms on arising, the occurrence and duration of adverse events, the use of other medications (type and duration), and the use of -agonist inhalers (number of puffs per day) was collected daily using patient report forms. Physical and physiologic data were obtained at each visit. Outcomes Subprotocol We obtained data through an extended patient report form, which was given to each participant for the purpose of collecting daily information on major clinical and economic effectiveness outcomes, such as activity limitation due to asthma; absence from work or school due to asthma; and additional clinic visits, hospital visits, and contacts with health care personnel outside of the scheduled protocol structure. All procedures done and medications given outside of the trial structure were also described on the form. Data on quality of life were obtained but are not presented here; they will be combined with data from an ongoing study of patient preferences in a separate quality-of-life and costutility analysis. Clinical and Economic Effectiveness Outcomes Days without symptoms, days without limitation of activity, days without use of -agonists, days without sleep disturbance, and days without episodes of asthma were selected as measures of clinical effectiveness because they were simple and clinically relevant. We obtained information on the daily occurrence of asthma symptoms, asthma-related limitation of activity, use of -agonists, and sleep disturbance due to asthma directly from the daily patient report forms to compute the number of days per month that were free of each outcome. A composite outcome variable, episode-free days, was defined as the number of days without an asthma attack (severe symptoms), without the use of -agonists, without sleep disturbance due to asthma, and without an adverse event [12]. The economic effectiveness outcomes included the use of health services and resources as well as the extent of absenteeism. Only the health services that varied between arms of the trial were considered; thus, the protocol-driven resources incurred by each patient (which were theoretically equal between the arms of the trial) were ignored. These resources were the frequency of unscheduled health care visits and contacts, the total number of -agonist inhalers used, and the number of prescriptions for all nonasthma medications consumed. Absenteeism was quantified as the number of days of absence from work or school due to asthma. Statistical Analysis Measures were computed across patient-days. Patient-days for which data were missing during follow-up were not directly included in the calculations, but estimates derived from nonmissing data were extrapolated to the totality of all follow-up days for a given patient. This was done by imputing the average for the days that were not missing data to the days that were missing data. For all outcome variables, the individual approach to data analysis was used, with the patient as the unit of analysis. For the clinical effectiveness outcomes, for which the patient either had or did not have a clinical event reported daily, the measure was based on the proportion of relevant days (for example, days without symptoms) of all of the patients follow-up days of treatment. These were standardized into mean days per month by multiplying by 30. For these clinical effectiveness measures, multiple linear regression was used to estimate the mean differences between the two groups and to assess the statistical significance of those differences [13]. These estimates were adjusted for baseline differences and for baseline values of the effectiveness measures to increase precision. In addition, a generalized linear regression model with a logarithmic link was used for these outcomes to estimate the percentage change for each mean outcome [14]. For the economic effectiveness outcomes, which were based on infrequent events, a Poisson regression model with a logarithmic link and with variances adjusted for between-subject overdispersion by the deviance was used to estimate the percentage change in the outcome rate between groups [14]. To im

Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases

The Asthma Committee of the Canadian Thoracic Society invited a group of Canadian physicians with a particular interest in asthma to meet in Montebello, Quebec, March 9-12, 1995 to arrive at a consensus statement on the optimal approach to the management of asthma in the pediatric and adult ambulatory care settings. The societies and associations represented are listed in the appendix with the names of the contributors to this document. The objectives of the Montebello conference were: 1. To review the current ambulatory care management of asthma in Canada; 2. To develop guidelines with the participation of family physicians and specialists; 3. To develop guidelines which are evidence-based; 4. In creating evidence-based guidelines to focus attention on aspects of asthma management that are currently not supported by randomized controlled trials; 5. To develop strategies that allow for the implementation of rational guidelines at a local level. Recommendations were based on a critical review of the scientific literature by small groups prior to the meeting and are categorized according to the strength of the scientific evidence supporting each recommendation (Table 1).

Inhaled Corticosteroids and the Risks of Diabetes Onset and Progression

BACKGROUND Several sets of Canadian guidelines for the diagnosis and management of asthma have been published over the past 15 years. Since the last revision of the 1999 Canadian Asthma Consensus Report, important new studies have highlighted the need to incorporate new information into the asthma guidelines. OBJECTIVES To review the literature on adult asthma management published between January 2000 and June 2003; to evaluate the influence of the new evidence on the recommendations made in the 1999 Canadian Asthma Consensus Guidelines and its 2001 update; and to report new recommendations on adult asthma management. METHODS Three specific topics for which new evidence affected the previous recommendations were selected for review: initial treatment of asthma, add-on therapies in the treatment of asthma and asthma education. The resultant reviews were discussed in June 2003 at a meeting under the auspices of the Canadian Thoracic Society, and recommendations for adult asthma management were reviewed. RESULTS The present report emphasises the importance of the early introduction of inhaled corticosteroids in symptomatic patients with mild asthma; stresses the benefit of adding additional therapy, preferably long-acting beta2-agonists, to patients incompletely controlled on low doses of inhaled corticosteroids; and documents the essential role of asthma education. CONCLUSION The present report generally supports many of the previous recommendations published in the 1999 Canadian Asthma Consensus Report and provides higher levels of evidence for a number of those recommendations.