Maureen Rutten-van Mölken

Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (bronchitis randomized on NAC cost-utility study, BRONCUS) : a randomised placebo- controlled trial

BACKGROUND Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes. METHODS In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat. FINDINGS The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation. INTERPRETATION N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.

Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD

BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD. METHODS In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year. RESULTS A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group. CONCLUSIONS These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

Cost effectiveness of physiotherapy, manual therapy, and general practitioner care for neck pain: economic evaluation alongside a randomised controlled trial

Abstract Objective: To evaluate the cost effectiveness of physiotherapy, manual therapy, and care by a general practitioner for patients with neck pain. Design: Economic evaluation alongside a randomised controlled trial. Setting: Primary care. Participants: 183 patients with neck pain for at least two weeks recruited by 42 general practitioners and randomly allocated to manual therapy (n=60, spinal mobilisation), physiotherapy (n=59, mainly exercise), or general practitioner care (n=64, counselling, education, and drugs). Main outcome measures: Clinical outcomes were perceived recovery, intensity of pain, functional disability, and quality of life. Direct and indirect costs were measured by means of cost diaries that were kept by patients for one year. Differences in mean costs between groups, cost effectiveness, and cost utility ratios were evaluated by applying non-parametric bootstrapping techniques. Results: The manual therapy group showed a faster improvement than the physiotherapy group and the general practitioner care group up to 26 weeks, but differences were negligible by follow up at 52 weeks. The total costs of manual therapy (€447; £273;

Real-life compliance and persistence among users of subcutaneous and sublingual allergen immunotherapy

402) were around one third of the costs of physiotherapy (€1297) and general practitioner care (€1379). These differences were significant: P<0.01 for manual therapy versus physiotherapy and manual therapy versus general practitioner care and P=0.55 for general practitioner care versus physiotherapy. The cost effectiveness ratios and the cost utility ratios showed that manual therapy was less costly and more effective than physiotherapy or general practitioner care. Conclusions: Manual therapy (spinal mobilisation) is more effective and less costly for treating neck pain than physiotherapy or care by a general practitioner. What is already known on this topic The cost of treating neck pain is considerable Many conservative interventions are available, such as prescription drugs, yet their cost effectiveness has not been evaluated No randomised trials of conservative treatment for neck pain have so far included an economic evaluation What this study adds Manual therapy is more effective and less costly than physiotherapy or care by a general practitioner for treating neck pain Patients undergoing manual therapy recovered more quickly than those undergoing the other interventions

Chronic low-back pain: what does cognitive coping skills training add to operant behavioral treatment? Results of a randomized clinical trial.

BACKGROUND Subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are safe and effective treatments of allergic rhinitis, but high levels of compliance and persistence are crucial to achieving the desired clinical effects. OBJECTIVE Our objective was to assess levels and predictors of compliance and persistence among grass pollen, tree pollen, and house dust mite immunotherapy users in real life and to estimate the costs of premature discontinuation. METHODS We performed a retrospective analysis of a community pharmacy database from The Netherlands containing data from 6486 patients starting immunotherapy for 1 or more of the allergens of interest between 1994 and 2009. Two thousand seven hundred ninety-six patients received SCIT, and 3690 received SLIT. Time to treatment discontinuation was analyzed and included Cox proportional hazard models with time-dependent covariates, where appropriate. RESULTS Overall, only 18% of users reached the minimally required duration of treatment of 3 years (SCIT, 23%; SLIT, 7%). Median durations for SCIT and SLIT users were 1.7 and 0.6 years, respectively (P < .001). Other independent predictors of premature discontinuation were prescriber, with patients of general practitioners demonstrating longer persistence than those of allergologists and other medical specialists; single-allergen immunotherapy, lower socioeconomic status; and younger age. Of the persistent patients, 56% were never late in picking up their medication from the pharmacy. Direct medication costs per nonpersistent patient discontinuing in the third year of treatment were €3800, an amount that was largely misspent. CONCLUSION Real-life persistence is better in SCIT users than in SLIT users, although it is low overall. There is an urgent need for further identification of potential barriers and measures that will enhance persistence and compliance.

Long-term effectiveness and cost-effectiveness of smoking cessation interventions in patients with COPD

This study examined the supplemental value of a cognitive coping skills training when added to an operant-behavioral treatment for chronic low-back pain patients. The complete treatment package (OPCO) was compared with an operant program + group discussion (OPDI) and a waiting-list control (WLC). After the WL period, the WLC patients received a less protocolized operant program usually provided in Dutch rehabilitation centers (OPUS). Regression analyses showed that, compared with WLC, both OPCO and OPDI led to less negative affect, higher activity tolerance, less pain behavior, and higher pain coping and pain control. At posttreatment, OPCO led to better pain coping and pain control than OPDI. Calculation of improvement rates revealed that OPCO and OPDI had significantly more improved patients than OPUS on all the dependent variables. The discussion includes findings regarding treatment credibility, compliance, and contamination bias.

Efficacy and Costs of Nutritional Rehabilitation in Muscle-Wasted Patients With Chronic Obstructive Pulmonary Disease in a Community-Based Setting: A Prespecified Subgroup Analysis of the INTERCOM Trial

Background The aim of this study was to estimate the long-term (cost-) effectiveness of smoking cessation interventions for patients with chronic obstructive pulmonary disease (COPD). Methods A systematic review was performed of randomised controlled trials on smoking cessation interventions in patients with COPD reporting 12-month biochemical validated abstinence rates. The different interventions were grouped into four categories: usual care, minimal counselling, intensive counselling and intensive counselling + pharmacotherapy (‘pharmacotherapy’). For each category the average 12-month continuous abstinence rate and intervention costs were estimated. A dynamic population model for COPD was used to project the long-term (cost-) effectiveness (25 years) of 1-year implementation of the interventions for 50% of the patients with COPD who smoked compared with usual care. Uncertainty and one-way sensitivity analyses were performed for variations in the calculation of the abstinence rates, the type of projection, intervention costs and discount rates. Results Nine studies were selected. The average 12-month continuous abstinence rates were estimated to be 1.4% for usual care, 2.6% for minimal counselling, 6.0% for intensive counselling and 12.3% for pharmacotherapy. Compared with usual care, the costs per quality-adjusted life year (QALY) gained for minimal counselling, intensive counselling and pharmacotherapy were €16 900, €8200 and €2400, respectively. The results were most sensitive to variations in the estimation of the abstinence rates and discount rates. Conclusion Compared with usual care, intensive counselling and pharmacotherapy resulted in low costs per QALY gained with ratios comparable to results for smoking cessation in the general population. Compared with intensive counselling, pharmacotherapy was cost saving and dominated the other interventions.

Health economic assessment of behavioural rehabilitation in chronic low back pain: a randomised clinical trial

RATIONALE Limited data are available on effectiveness and costs of nutritional rehabilitation for patients with COPD in community care. METHODS In a 2-year RCT, 199 COPD patients (FEV(1)%pred. 60% [SD 16%]) and impaired exercise capacity were randomized to the interdisciplinary community-based COPD management program (INTERCOM) or usual care (UC). A prescheduled subgroup analysis was performed on 39 of 199 patients who were muscle wasted and received UC or nutritional therapy in combination with exercise training. Body composition, muscle strength, and exercise capacity were assessed at baseline and 4, 12, and 24 months. RESULTS Between group differences after 4 months in favor of the intervention group: fat free mass index (FFMI 0.9 kg/m(2) [SE = 0.2, P < .001]), body mass index (BMI 1.0 kg/m(2) [SE = 0.4, P = .009]), maximum inspiratory mouth pressure (Pimax 1.4 kPa [SE = 0.5, P = .011]), quadriceps average power (QAP 13.1 Watt [SE=5.8, P = .036]), 6-minute walking distance (6MWD 27 m, [SE = 11.5, P = .028]), cycle endurance time (CET 525 seconds [SE=195, P = .013]), and peak exercise capacity (Wmax 12 Watt [SE = 5, P = .036]). Between group difference over 24 months in favor of the intervention group: Pimax 1.7 kPa (SE = 0.53, P = .004), QAP 19 Watt (SE = 6, P = .005), 6MWD 57 (SE = 19, P = .006), and CET 485 seconds (SE = 159, P = .006). After 4 months total costs were Euro 1501 higher in the intervention group than in the UC group (P < .05), but not significantly different after 24 months. Hospital admission costs were significantly lower in the intervention group -euro 4724 (95% CI -7704, -1734). CONCLUSION This study in muscle-wasted COPD patients with moderate airflow obstruction shows a prolonged positive response to nutritional support integrated in a community-based rehabilitation program.

Modelling the 5-year cost effectiveness of tiotropium, salmeterol and ipratropium for the treatment of chronic obstructive pulmonary disease in Spain

The aim of this cost-effectiveness study was to compare a combined operant programme plus cognitive/relaxation programme with an operant programme plus attention-control and to compare both programmes with a waiting-list control group and with operant rehabilitation provided, as usual, by the same rehabilitation centre. One hundred and forty eight patients with chronic low back pain were randomly assigned to the different conditions. The economic endpoints were the costs of the programme and other health care utilisation, costs for the patient, and indirect costs associated with production losses due to low back pain. The effects were measured in terms of global assessment of change and utilities, using rating scale and standard gamble methods. The 3-year study determined that adding a cognitive component to an operant treatment did not lead to significant differences in costs and improvement in quality of life when compared with the operant treatment alone. Compared with the common individual rehabilitation therapy it can be concluded that the same effects can be reached at the same or lower costs with a shorter, more intense standardised group programme. The operant treatment alone is more effective than providing no treatment in the waiting-list control group.

Nutritional assessment and therapy in COPD: a European Respiratory Society statement

Our objective was to assess the 5-year cost effectiveness of bronchodilator therapy with tiotropium, salmeterol or ipratropium for chronic obstructive pulmonary disease (COPD) from the perspective of the Spanish National Health System (NHS). A probabilistic Markov model was designed wherein patients moved between moderate, severe or very severe COPD and had the risk of exacerbation and death. Probabilities were derived from clinical trials. Spanish healthcare utilisation, costs and utilities were estimated for each COPD and exacerbation state. Outcomes were exacerbations, exacerbation-free months, quality-adjusted life years (QALYs), and cost(-effectiveness). The mean (SE) 5-year number of exacerbations was 3.50 (0.14) for tiotropium, 4.16 (0.40) for salmeterol and 4.71 (0.54) for ipratropium. The mean (SE) number of QALYs was 3.15 (0.08), 3.02 (0.15) and 3.00 (0.20), respectively. Mean (SE) 5-year costs were €6,424 (€305) for tiotropium, €5,869 (€505) for salmeterol, and €5,181 (€682) for ipratropium (2005 values). Ipratropium and tiotropium formed the cost-effectiveness frontier, with tiotropium being preferred when willingness to pay (WTP) exceeded €639 per exacerbation-free month and €8,157 per QALY. In Spain, tiotropium demonstrated the highest expected net benefit for ratios of the willingness to pay per QALY, well within accepted limits.