Association of knee pain and different definitions of knee osteoarthritis with health-related quality of life: a population-based cohort study in southern Sweden.

BACKGROUND: While the impact of knee pain and knee osteoarthritis (OA) on health-related quality of life (HRQoL) has been investigated in the literature, there is a lack of knowledge on the impact of different definitions of OA on HRQoL. The main aim of this study was to measure and compare the impact of knee OA and its different definitions on HRQoL in the general population. METHODS: A random sample of 1300 participants from Malmö, Sweden with pain in one or both knees in the past 12 months with duration ≥4 weeks and 650 participants without were invited to clinical and radiographic knee examination. A total of 1527 individuals with a mean (SD) age 69.4 (7.2) participated and responded to both generic (EQ-5D-3L) and disease-specific (the Knee injury and Osteoarthritis Outcome Score) questionnaires. Knee pain was defined as pain during the last month during most of the days. Knee OA was defined radiographically (equivalent to Kellgren and Lawrence grade ≥2) and clinically according to the American College of Rheumatology (ACR) criteria. RESULTS: Of participants with either knee pain or knee OA or both, 7 % reported no problem for the EQ-5D-3L attributes. The corresponding proportion among references (neither knee pain nor OA) was 42 %. The participants with knee pain and OA had all HRQoL measures lower compared to those with knee pain but no OA. The ACR clinical definition of knee OA was associated with lower HRQoL than the definition based on radiographic knee OA (adjusted difference -0.08 in UK EQ-5D-3L index score). CONCLUSIONS: Applying different definitions of knee OA result in different levels of HRQoL and this is mainly explained by the knee pain experience. These differences may lead to discrepant conclusions from cost-utility analyses.

Health-related quality of life of ticagrelor versus clopidogrel in patients with acute coronary syndromes-results from the PLATO trial.

OBJECTIVES: The purpose of this study was to compare the effects of ticagrelor versus clopidogrel on health-related quality of life in the PLATelet inhibition and patient Outcomes (PLATO) trial. BACKGROUND: The PLATO trial showed that ticagrelor was superior to clopidogrel for the prevention of cardiovascular death, myocardial infarction, or stroke in a broad population of patients with acute coronary syndromes. METHODS: HRQOL in the PLATO study was measured at hospital discharge, 6-month visit, and end of treatment (anticipated at 12 months) by using the EuroQol five-dimensional (EQ-5D) questionnaire. All patients who had an EQ-5D questionnaire assessment at discharge from the index hospitalization (n = 15,212) were included in the study. Patients who died prior to the end-of-treatment visit were assigned an EQ-5D questionnaire value of 0. RESULTS: The EQ-5D questionnaire value at discharge among 7631 patients assigned to ticagrelor was 0.847 and among 7581 patients assigned to clopidogrel was 0.846 (P = 0.71). At 12 months, the mean EQ-5D questionnaire value was 0.840 for ticagrelor and 0.832 for clopidogrel (P = 0.046). Excluding patients who died resulted in mean EQ-5D questionnaire values of 0.864 among ticagrelor patients and 0.863 among clopidogrel patients (P = 0.69). CONCLUSIONS: In patients hospitalized with acute coronary syndromes with or without ST-segment elevation, treatment with ticagrelor was associated with a lower mortality but otherwise no difference in quality of life relative to treatment with clopidogrel. The improved survival and reduction in cardiovascular events with ticagrelor are therefore obtained with no loss in quality of life.

The effects of inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma.

BACKGROUND: Previous studies have suggested a reduced benefit from therapy with inhaled corticosteroids (ICSs) in asthmatic patients who smoke. The objective of this post hoc study was to study the effects of low-dose inhaled budesonide on lung function in smokers and nonsmokers with mild persistent asthma. METHODS: Adult patients (age, >or= 18 years) in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, a 3-year, randomized, placebo-controlled, double-blind study, were stratified according to their smoking habits. The effects on lung function of therapy with budesonide vs placebo were compared in 492 asthmatic patients who smoked habitually and 2,432 nonsmokers. RESULTS: When treated with placebo, newly diagnosed asthmatic patients who smoke had a greater 3-year decline in post-bronchodilator therapy FEV(1), the change being -263.9 mL (SE, 21.8), when compared with nonsmokers on placebo, which was -180.8 mL (SE, 10.6), the mean difference being -83.1 mL (p < 0.001). Budesonide treatment was associated with a statistically significant 3-year increase in post-bronchodilator therapy FEV(1) in both groups. The effect of budesonide vs placebo was 71.5 mL (p = 0.011) in smokers and 46.5 mL (p = 0.001) in nonsmokers. The corresponding effect in pre-bronchodilator therapy FEV(1) was 118.1 mL (p = 0.002) in smokers and 72.9 mL (p < 0.001) in nonsmokers. CONCLUSIONS: Asthmatic patients who smoke, and are not treated with ICSs, have a greater decline in lung function than asthmatic patients who do not smoke. The benefits of therapy with inhaled budesonide on preventing lung function decline are similar in smokers and nonsmokers with mild persistent asthma.

Severe exacerbations and decline in lung function in asthma.

RATIONALE: To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline in patients with asthma. OBJECTIVES: To determine whether severe asthma exacerbations are associated with a persistent decline in lung function. METHODS: The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5-66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function. MEASUREMENTS AND MAIN RESULTS: There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator FEV(1) % predicted from baseline to the end of the study, in patients who did or did not experience a severe exacerbation was -6.44% and -2.43%, respectively (P < 0.001). A significant difference was seen in both children and in adults, but not in adolescents. In the budesonide group, the change in the post-bronchodilator FEV(1) % predicted in patients who did or did not experience a severe exacerbation was -2.48% and -1.72%, respectively (P = 0.57). The difference in magnitude of reduction afforded by budesonide, in patients who experienced at least one severe asthma-related event compared with those who did not, was statistically significant (P = 0.042). CONCLUSIONS: Severe asthma exacerbations are associated with a more rapid decline in lung function. Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline.

The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma.

BACKGROUND: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study enrolled 7241 patients aged 5 to 66 years with recent-onset, mild persistent asthma to assess early intervention with the inhaled corticosteroid budesonide on long-term asthma control. OBJECTIVE: The open-label phase of the START study was included to determine the effect on lung function and asthma control of adding budesonide to the reference group patients who had not initially received inhaled corticosteroids. METHODS: Patients were randomized to double-blind treatment with budesonide, 200 mug (those aged < 11 years) or 400 mug once daily, or placebo plus the usual asthma therapy for 3 years, after which all patients received 2 years of open-label treatment with budesonide once daily. RESULTS: During the full 5-year study period, postbronchodilator FEV(1) percent predicted decreased, irrespective of randomized treatment during the double-blind phase, by an average of 2.22% (SE, 0.15%). However, patients with inhaled budesonide in the double-blind phase had a significantly lower risk (odds ratio, 0.61; P < .001) of a severe asthma-related event during the full 5-year study period than those in the reference group. Moreover, patients in the reference group used more additional asthma medications during both the open-label and double-blind phases. CONCLUSIONS: In mild persistent asthma early intervention with inhaled budesonide was associated with improved asthma control and less additional asthma medication use.

Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma.

STUDY OBJECTIVES: Asthmatic patients lose lung function faster than normal subjects. The effectiveness of early intervention with inhaled corticosteroids on this decline in lung function is not established in recent-onset disease. DESIGN: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma study was a randomized, double-blind study in 7,165 patients (5 to 66 years old), with persistent asthma for < 2 years to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events and the decline in lung function. Patients received budesonide (200 mug qd for children < 11 years old and 400 mug qd for others) or placebo for 3 years in addition to usual asthma medications. RESULTS: Treatment with budesonide significantly improved prebronchodilator and postbronchodilator FEV(1) percentage of predicted and reduced the mean declines from baseline for postbronchodilator FEV(1) at 1 year and 3 years: - 0.62% and - 1.79% for budesonide and - 2.11% and - 2.68% for placebo, respectively (p < 0.001). The decline was more marked for male patients, active smokers, and patients > 18 years old, and the smallest treatment effects were in adolescents. CONCLUSIONS: Long-term, once-daily treatment with low-dose budesonide improved both prebronchodilator and postbronchodilator FEV(1) in patients with recent-onset, persistent asthma, and reduced the loss of lung function over time.

Early intervention of recent onset mild persistent asthma in children aged under 11 yrs: the Steroid Treatment As Regular Therapy in early asthma (START) trial.

Inhaled corticosteroids are known to be effective in persistent asthma, but their long-term effect in mild persistent disease of recent onset, which is particularly relevant in children, requires clarification. The objective of this study was to determine the long-term efficacy of regular inhaled low-dose budesonide in children aged <11 yrs with mild persistent asthma with onset within 2 yrs of enrollment. Children aged 5-10 yrs formed part of the population of the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study, and they were randomized in a double-blind manner to treatment with once daily budesonide 200 microg or placebo via Turbuhaler in addition to usual clinical care and other asthma medication. The double-blind treatment phase continued for 3 yrs. Of the 1974 children, 1000 in the budesonide group and 974 in the placebo group, were analyzed for efficacy. Addition of once-daily budesonide to usual care was associated with a significant increase in the time to first severe asthma-related event (SARE) and significantly reduced risk of SARE over 3 yrs. The hazard ratio relative to usual care (placebo) was 0.60 (95% confidence interval: 0.40-0.90; p = 0.012), with a relative risk reduction of 40%. Children receiving budesonide also needed significantly less intervention with other inhaled corticosteroids (12.3% vs. 22.5% over 3 yrs; p < 0.01), with trends towards decreased usage of oral/systemic corticosteroids and inhaled short-acting beta2-agonists. Budesonide treatment also had a significant beneficial effect on lung function relative to placebo. In conclusion, early intervention adding once-daily budesonide to usual care in children with mild, persistent asthma of recent onset reduces the long-term risk and frequency of SAREs and improves lung function compared with usual care alone.

Cost-effectiveness of early intervention with once-daily budesonide in children with mild persistent asthma: results from the START study.

The inhaled Steroid Treatment As Regular Therapy in early asthma (START) study has shown that early intervention with inhaled budesonide in mild persistent asthma improves clinical outcomes in both adults and children. The aim of this study was to estimate the incremental cost-effectiveness of early treatment with budesonide Turbuhaler in children aged 5-10 yr who participated in START. Direct and indirect costs associated with asthma were determined for 1974 children participating in the double-blind, 3-year part of the study. Randomization was to placebo or to budesonide 200 microg once daily in each case in addition to usual asthma care. Cost-effectiveness ratios were calculated from the healthcare payer's and societal perspectives (using US prices). The addition of once-daily budesonide therapy to usual asthma care was associated with 16 additional symptom-free days (SFDs) per child over the 3-yr period (p < 0.001), with a substantial reduction (50%) in the mean number of days spent in hospital, and with reduced frequency of emergency room visits and missed school and caregiver work days. From the healthcare payer's perspective (direct costs), the increase in mean direct cost over 3 yr with budesonide was 169 dollars, which translated into an incremental cost of early intervention with budesonide in children of 10.50 dollars (95% CI 1.20-33.30 dollars) per SFD gained. From the societal perspective, there was a cost reduction over 3 yr of 192 dollars with budesonide relative to placebo. From a societal perspective, budesonide was therefore dominant. In conclusion, early intervention with once-daily budesonide added to usual asthma care in children with mild persistent asthma is cost-saving from a societal perspective and is acceptably cost-effective when viewed from a healthcare payer perspective.

Cost-effectiveness analysis of early intervention with budesonide in mild persistent asthma.

BACKGROUND: The Inhaled Steroid as Regular Therapy in Early Asthma (START) study reported that early intervention with budesonide in mild persistent asthma reduces severe asthmatic events and improves symptom outcomes and lung function in adults and children. OBJECTIVE: We sought to estimate the incremental cost-effectiveness of early intervention with budesonide, as observed within the START study. METHODS: START was a randomized, 3-year controlled trial of budesonide in early onset mild asthma among 7165 subjects ages 5 to 66 years. Three age groups (5-10, 11-17, and >or=18 years) were studied separately and overall. Differences in the probability of emergency treatments, symptom-free days (SFDs), and costs of health care were determined. Incremental cost-effectiveness ratios were estimated from the health care payer and societal perspectives. RESULTS: Compared with usual therapy, patients receiving budesonide experienced an average of 14.1 (SE, 1.3) more SFDs per year (P <.001), fewer hospital days (69%, P <.001), and fewer emergency department visits (67%, P <.05). From the health care payer perspective, the net cost of early use of budesonide was an additional US dollars 0.42 (SE, dollars 0.04) per day, and the resultant cost-effectiveness ratio was US dollars 11.30 (95% CI, US dollars 8.60-US dollars 14.90) per SFD gained. From the societal perspective, the cost offsets of lower absence from school or work reduced the net cost of early budesonide to US dollars 0.14 (SE, US dollars 0.07) per day and decreased the cost-effectiveness ratio to US dollars 3.70 (95% CI, US dollars 0.10-US dollars 8.00). Early intervention was more effective and cost saving in the youngest age group. CONCLUSION: Long-term treatment with budesonide appears to be cost-effective in patients with mild persistent asthma of recent onset.

Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial.

BACKGROUND: Although inhaled glucocorticosteroids are recommended for persistent asthma, their long-term effect on recent onset, mild, persistent asthma has yet to be established. METHODS: We did a randomised, double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids. Patients aged 5-66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications. The daily budesonide dose was 400 microg, or 200 microg for children younger than 11 years. The primary outcome was time to first severe asthma-related event, and analysis was by intention to treat. FINDINGS: 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation; hazard ratio 0.56 (95% CI 0.45-0.71, p<0.0001). Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo. Compared with placebo, budesonide increased postbronchodilator forced expiratory volume in 1 s (FEV1) from baseline by 1.48% (p<0.0001) after 1 year and by 0.88% (p=0.0005) after 3 years (expressed as percent of the predicted value). The corresponding increase in prebronchodilator FEV1 was 2.24% after 1 year and 1.71% after 3 years (p<0.0001 at both timepoints). The effect of treatment on all outcome variables was independent of the baseline lung function (prebronchodilator or postbronchodilator) or baseline medication. In children younger than 11 years, 3-year growth was reduced in the budesonide group by 1.34 cm. The reduction was greatest in the first year of treatment (0.58 cm) than years 2 and 3 (0.43 cm and 0.33 cm, respectively). INTERPRETATION: Long-term, once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset.

Coping with missing data in clinical trials: a model-based approach applied to asthma trials.

In most clinical trials, some patients do not complete their intended follow-up according to protocol, for a variety of reasons, and are often described as having 'dropped out' before the conclusion of the trial. Their subsequent measurements are missing, and this makes the analysis of the trial's repeated measures data more difficult. In this paper we briefly review the reasons for patient drop-out, and their implications for some commonly used methods of analysis. We then propose a class of models for modelling both the response to treatment and the drop-out process. Such models are readily fitted in a Bayesian framework using non-informative priors with the software BUGS. The results from such models are then compared with the results of standard methods for dealing with missing data in clinical trials, such as last observation carried forward. We further propose the use of a time transformation to linearize an asymptotic pattern of repeated measures over time and therefore simplify the modelling. All these ideas are illustrated using data from a five-arm asthma clinical trial.