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Asthma control cost-utility randomized trial evaluation (ACCURATE): the goals of asthma treatment
© Honkoop et al; licensee BioMed Central Ltd. 2011
Received: 16 September 2011
Accepted: 24 November 2011
Published: 24 November 2011
Despite the availability of effective therapies, asthma remains a source of significant morbidity and use of health care resources. The central research question of the ACCURATE trial is whether maximal doses of (combination) therapy should be used for long periods in an attempt to achieve complete control of all features of asthma. An additional question is whether patients and society value the potential incremental benefit, if any, sufficiently to concur with such a treatment approach. We assessed patient preferences and cost-effectiveness of three treatment strategies aimed at achieving different levels of clinical control:
1. sufficiently controlled asthma
2. strictly controlled asthma
3. strictly controlled asthma based on exhaled nitric oxide as an additional disease marker
720 Patients with mild to moderate persistent asthma from general practices with a practice nurse, age 18-50 yr, daily treatment with inhaled corticosteroids (more then 3 months usage of inhaled corticosteroids in the previous year), will be identified via patient registries of general practices in the Leiden, Nijmegen, and Amsterdam areas in The Netherlands. The design is a 12-month cluster-randomised parallel trial with 40 general practices in each of the three arms. The patients will visit the general practice at baseline, 3, 6, 9, and 12 months. At each planned and unplanned visit to the general practice treatment will be adjusted with support of an internet-based asthma monitoring system supervised by a central coordinating specialist nurse. Patient preferences and utilities will be assessed by questionnaire and interview. Data on asthma control, treatment step, adherence to treatment, utilities and costs will be obtained every 3 months and at each unplanned visit. Differences in societal costs (medication, other (health) care and productivity) will be compared to differences in the number of limited activity days and in quality adjusted life years (Dutch EQ5D, SF6D, e-TTO, VAS). This is the first study to assess patient preferences and cost-effectiveness of asthma treatment strategies driven by different target levels of asthma control.
Netherlands Trial Register (NTR): NTR1756
Despite the availability of effective therapies, asthma remains a source of significant morbidity and use of health care resources [1, 2]. The societal costs of asthma are considerable. Asthma negatively affects work productivity as well as labour force participation. Furthermore, a survey showed that in the Netherlands 30% of asthmatics needed urgent care in the past year, which was on average 8% more than in other European countries . Under a system designed for acute rather than chronic care, patients are not adequately taught to care for their own illness. Sixty-two percent of patients visit their pulmonary specialists or general practitioners only if they have an acute health problem. Only 15% of Dutch asthmatics had a doctor-written action plan for their asthma . In addition, there is a major discrepancy between patients' perceived control of asthma and symptom severity . National and international guidelines define the goal of treatment as to achieve and maintain clinical asthma control [5, 6]. Daily treatment with inhaled corticosteroids is recommended on a long-term basis as first-line therapy to keep asthma under clinical control in patients with persistent asthma. Short-term bronchodilators are used on an as-needed basis to reverse bronchoconstriction and relieve symptoms. The 2006 updated international guidelines  introduced a management approach based on asthma control. According to the Global Initiative for Asthma (GINA) guidelines the levels of asthma control are defined as follows:
1) Partly controlled asthma is defined as the presence of any of the following: daytime symptoms ≥ twice per week, limitations of activities, nocturnal symptoms, need for reliever treatment, reduced lung function and exacerbations (further referred as sufficiently controlled).
2) Controlled asthma is defined as daytime symptoms that are present ≤ twice per week or the absence of limitations of activities, nocturnal symptoms, need for reliever treatment, reduced lung function and exacerbations (further referred as strictly controlled).
3) Uncontrolled asthma is defined as ≥ 3 features of partly controlled or the presence of an exacerbation.
The level of asthma control can be assessed using composite measures such as the validated Asthma Control Questionnaire (ACQ) . Each patient should be assessed to establish the current treatment regimen, adherence to the current regimen, and the level of asthma control. If asthma is uncontrolled on the current treatment regimen, treatment should be stepped up until control is achieved. If asthma is partly controlled, the guidelines recommend that a step-up in treatment should be considered.
Strictly controlled asthma can be achieved in the majority of patients with uncontrolled asthma by a treatment strategy with (high dose) inhaled corticosteroids alone or with combination therapy of an inhaled corticosteroid and a long-acting bronchodilator . Symptoms and lung function will improve and the number of awakenings and severe exacerbation rate will reduce . However, this is in marked contrast with the levels of control observed in community studies, where patients tend to be partly controlled . Current guidelines show some ambiguity whether treatment target should be controlled or partly controlled . Another question is not only whether maximal doses of (combination) therapy should be used for long periods in an attempt to achieve complete control of all features of asthma, but also whether patients would value the potential incremental benefit sufficiently to concur with such a treatment approach . In addition, there is only limited data available on the cost-effectiveness of treatment strategies aimed at different levels of asthma control [11, 12].
Recently, the fraction of exhaled nitric oxide (FeNO) has been introduced as a non-invasive marker of airway inflammation in asthma. The role of FeNO in titrating anti-inflammatory treatment to the most effective dose of inhaled corticosteroids in asthma is still controversial . Addition of FeNO as an indicator of control of asthma has led to higher  as well as lower  doses of inhaled corticosteroids without a difference in symptomatic asthma control. Adjustments to medication dose based on FeNO measurements seem to reduce the number of exacerbations, but recent studies had insufficient power to reach statistical significance when adjusting for multiple exacerbations within patients . Therefore, it is not yet determined whether FeNO measurements may indicate whether a step-up in treatment is effective or a step-down can be achieved without loss of asthma control and thereby contribute to the efficiency of asthma care.
Therefore, we aim to investigate whether a treatment strategy aimed at strict asthma control is more (cost-)effective as compared to a treatment strategy aimed at achieving sufficiently controlled asthma. In addition we postulate that a treatment strategy aimed at strict asthma control is more (cost-)effective when the treatment step is additionally guided by measurements of exhaled nitric oxide (FeNO) as compared to a treatment strategy aimed at achieving strictly controlled asthma or sufficiently controlled asthma without the addition of FeNO.
An internet application will be used to assist the physician/nurse practitioner/physician assistant in adjusting the treatment step according to the 3 treatment algorithms. In the Self-Management of Asthma Supported by Hospitals, Information and communication technology, Nurses and General practitioners (SMASHING) -project we have already used an internet application for monitoring Forced Expiratory Volume in 1 second (FEV1) and asthma control questionnaire (ACQ) . Furthermore, in this project we have set-up electronic versions http://www.netquestionnaires.nl of the majority of questionnaires. In the OPPAS-project (UMCN) we have already explored the distribution of levels of asthma control in general practice patients with asthma .
1 SUFF-strategy: achieving sufficiently controlled asthma based on conventional asthma control measures
2 STRICT-strategy: achieving strictly controlled asthma based on conventional asthma control measures
3 FeNO-strategy: achieving strictly controlled asthma based on conventional asthma control measures and an indirect marker of airways inflammation (FeNO).
General practices will be randomly assigned to the 3 groups using a computer generated permuted block scheme, ensuring concealment of allocation. Treatment assignment will be stratified according to characteristics of general practices (solo/duo/etc practice, rural/urban). The patients will visit the general practice for an introduction visit and control visits at baseline, 3, 6, 9, and 12 months. In case of asthma exacerbations patients pay an additional visit to the general practice or chest physician.
Levels of Asthma Control
Strictly Controlled (All of the following)
Sufficiently Controlled (Any measure present in any week)
None (twice or less/week)
More than twice/week
Three or more features of sufficiently controlled asthma present in any week
Limitations of activities
Need for reliever/rescue treatment
None (twice or less/week)
More than twice/week
Lung function (FEV1)
< 80% predicted
1st moderate exacerbation
≥ 2 moderate exacerbation† or severe exacerbation
Management approach based on control (GINA guidelines)
As needed rapid-acting ß2-agonist
As needed rapid-acting ß2-agonist
Add one or more
Add one or both
Low-dose ICS plus long-acting ß2-agonist
Medium- or high dose ICS plus long-acting ß2-agonist
Oral corticosteroid (lowest dose)
Medium- or high dose ICS
Low-dose ICS plus Leukotriene modifier†
Treatment strategy algorithms
Levels of asthma control
- 3 mo: no change
step-up: treatment choice
step-up: treatment choice
- > 3 mo: step-down
step-up: treatment choice
- Low FeNO level
- 3 mo: no change/change within current step to LABA
- > 3 mo: step-down ICS
- Intermediate FeNO level
step-up: treatment choice
step-up: treatment choice
- High FeNO level
step-up/change within current step to ICS
step-up: 1 × ICS
step-up: 2 × ICS*
720 Patients with mild to moderate persistent asthma (prevalent cases) will be recruited from general practices via patient registries in three regions in The Netherlands:
-Leiden University Medical Center (LUMC) general practice network LEON (240 patients, 40 general practices)
-Radboud University Nijmegen Medical Centre general practice network (240 patients, 40 general practices)
-Amsterdam Medical Center (AMC) general practice network (240 patients, 40 general practices)
Only general practices with a practice nurse (or nurse practitioner/or physician assistant, further referred to as 'practice nurse') will participate (70% of general practices in the Netherlands currently have a employed such a professional ). Based on previous research experience in patients with asthma in general practice (SMASHING-project CME number P05.136), we estimate a response rate of 40% with an inclusion of 6 patients per 'standard' practice (i.e. practice with 2,300 patients) and 40 'standard' general practices per treatment strategy.
(all of the following criteria)
- age 18-50 yr
- doctor's diagnosis of asthma
- patients who need inhaled corticosteroids as controller medication (step 2-4 GINA guidelines)
- inhaled corticosteroids ≥ 3 months in the previous year
- written informed consent
- no exacerbation of asthma within 1 month before entry
- daily or alternate day oral corticosteroid therapy for at least 1 month before entering into the study
- inability to understand written and oral Dutch instructions
- active diseases likely to interfere with the purpose of the study, such as end-stage disease or inability to visit the general practitioner
Methods of measurements
Assessment of level of asthma control:
driving treatment step
Quality of life
beliefs about medicines
health care + other costs
Assessment of level of asthma control
asthma control questionnaire (ACQ-score) 
lung function level (FEV1)
FeNO (only in the FeNO-strategy)
presence of exacerbations, now or in previous weeks
Asthma control questions
Asthma control will be assessed every 3 months with the Asthma Control Questionnaire (ACQ), which consists of 6 items with a 7-point scale (0 = totally controlled, 6 = severely uncontrolled) . In addition, the ACQ will be completed monthly at home. The ACQ contains questions on respiratory symptoms over the previous week. The patients will be asked whether these symptoms were representative for the last 4 weeks. If not, the ACQ will be assessed from the most representative of the last 4 weeks. The optimal cut-point for "strictly controlled" asthma is defined as a mean ACQ score ≤ 0.75 and a score of ≥1.50 confirms "uncontrolled" asthma . We regard control to be sufficient if 0.75 < mean ACQ < 1.50.
Lung function measurements
Spirometry will be performed in the general practices according to national  and international guidelines . For the baseline visit patients will be instructed to refrain from bronchodilator use for a specified number of hours before the scheduled spirometry test. Reversibility of airways obstruction will be measured 20 min after administering 4 single puffs of 100 μg salbutamol per metered dose-inhaler connected to a spacer (Volumatic®). The response will be expressed as ml and percentage change in predicted value of FEV1.
Exhaled nitric oxide
Fraction of exhaled Nitric Oxide (FeNO) will be measured in the general practices according to international guidelines  with the NIOX-MINO (Aerocrine, Solna, Sweden) . At baseline and at the last visit all patients will perform FeNO measurement, whereas at 3, 6, and 9 months FeNO only will be assessed in the FeNO Group. FeNO will be measured before spirometric manoeuvres, at an exhaled rate of 50 ml/sec maintained for 10 seconds. Patients are not allowed to smoke at least one hour before the measurements. Results are expressed as the NO concentration in ppb (equivalent to nanolitres/litre) based on the first approved measurement. FeNO levels will be categorized into low when FeNO ≤ 25 ppb (absence of inflammation), intermediate 25 ppb < FeNO < 50 ppb and high FeNO ≥ 50 ppb (presence of airway inflammation) . Results will be adjusted for smoking (yes/no), gender and height .
Patients will be instructed to pay an additional visit to their general practice if they experience worsening of asthma symptoms. In line with the national  and GINA guidelines  exacerbations of asthma are defined as acute or subacute episodes of progressively worsening shortness of breath, cough, wheezing, and chest tightness, or some combination of these symptoms  and will be treated by the general practitioner . FeNO will be performed only in the FeNO strategy. Additional questionnaires and lung function will be performed at home (Table 4).
After an exacerbation is resolved the patient visits the nurse practitioner who will assess the current level of asthma control. GINA is not clear about the incorporation of exacerbations in the assessment of asthma control (Table 4.3-1 from the GINA guidelines; 'personal communication'), but in the same GINA document exacerbations are also referred to as evidence of poor asthma control. Therefore, in the present study exacerbations are handled as follows. Questions will be asked on new respiratory symptoms, medication change and hospitalisation . The exacerbation will be classified according to severity as based on the presence of respiratory symptoms, prescribed medication and/or hospitalisation. A moderate exacerbation is defined as a (sub)acute deterioration in symptoms and/or lung function with increased rescue bronchodilator use (or ICS) which lasts 2 days or more, not severe enough warrant oral steroids (for 3 days or more) or hospitalisation. A severe exacerbation is defined as (sub)acute deterioration in asthma resulting in the need for oral steroids for 3 days or more or hospitalisation (as judged by the physician) . Subsequently, the level of control will be assessed as based on Table 1 and maintenance therapy will be assigned according to the treatment algorithm after exacerbation treatment is finished.
Assessment of cost-utilities and patient preferences Costs
- cost questionnaires: health care consumption; absenteeism and productivity loss (CostQ) 
- the Foundation for Accountability (FACCT) 
- the Brief Illness Perception Questionnaire (Brief IPQ) 
- the Beliefs about Medicines Questionnaire (BMQ) 
Quality of life, patient utilities
- patient utilities: the Asthma Symptom Utility Index (ASUI) . Patient utilities will additionally be assessed by the time-trade-off method by telephonic interview and a web-page (e-TTO) at each planned and unplanned period (exacerbation) 
- number of limited activity days by questionnaire
The analysis will be carried out on an intention to treat basis. The data set will consist of all included patients from randomised practices.
Data-analysis and presentation/synthesis
At baseline, data from all planned and unplanned contact will be collected according to the scheme in Table 4. The instruments include variables of:
- patient characteristics: age, sex, socioeconomic status, smoking status and smoking history
- medical outcomes: FEV1, FeNO, ACQ, current treatment step, asthma medication
- patient preferences: FACCT, IPQ, BMQ, MARS
- quality of life: AQLQ, SF-36
- patient utilities: ASUI, SF-6D and EQ-5D, QALYs, e-TTO, number of limited activity days
- costs: health care consumption; CostQ
The economic evaluation will compare differences in societal effects and costs to differences in the number of limited activity days (cost-effectiveness analysis, CEA) and quality adjusted life years (cost-utility analysis, CUA). The analysis will have a 12-months time horizon, without discounting. Group averages will be statistically compared using two-sided bootstrapping and net-benefit analysis will be used to relate costs to patient outcome. Sensitivity analyses will be performed on the perspective (societal versus health care) and the applied utility measure (Dutch EQ5D, SF6D, e-TTO, AQLQ-5D).
The primary end-point is the evaluation of the cost-effectiveness of treatment strategies by incremental net-benefit analysis . Net health benefit addresses cost-effectiveness ratios by assuming values for the willingness-to-pay per unit of effectiveness.
The cost analysis will include both medical (medication, visits, and hospitalizations) and non-medical costs (productivity losses, informal care). Purchased medication will be assessed from electronic patient records (with written patient permission), complemented with the patient's report on medication purchased elsewhere . Other costs will be estimated using quarterly cost questionnaires (CostQ) . Costs will be valued according to standard prices charges  including time and travel costs.
Analysis of effectiveness
The differences in levels and changes in utilities based on EQ-5D, SF-6D, VAS, e-TTO and the number of limited activity days will be compared between the treatment strategies using a random-effects analysis accounting for within-patient repeated measurements and clustering on general practice.
Patient outcome analysis
Utilities will be assessed every three months. In the base case analysis, quality-adjusted life years (QALYs) will be estimated using societal utilities obtained using the Dutch EQ5D tariff . As sensitivity analyses, QALYs will be estimated using the SF-6D and individual utilities obtained using the e-TTO and visual analogue scale (transformed using a power transformation).
Ethical approval was obtained from the Medical Ethics Committee of the Leiden University Medical Center (ABR no: 24488).
The aim of the ACCURATE trial is to compare the cost-effectiveness and patient preferences of three asthma treatment strategies: 1) sufficiently controlled strategy, aiming to achieve sufficiently controlled asthma based on conventional asthma control measures (ACQ and lung function); 2) strictly controlled strategy, aiming to achieve controlled asthma also based on asthma conventional control measures; and 3) FeNO-strategy, aimed at achieving strictly controlled asthma based on conventional asthma control measures plus an indirect marker of airways inflammation. For this purpose we will implement an internet-based programme, to be used by care providers in general practices.
To our knowledge, this is the first study to assess patient preferences and cost-effectiveness of asthma treatment strategies aimed at different levels of control on asthma. Notably, the current study is fully investigator driven, granted by governmental funding rather than pharmaceutical funding. Current guidelines advise clinicians to ensure that asthma is strictly controlled, i.e. patients should not experience any symptoms. However, in daily practice, a considerable proportion of asthma patients continuously experience symptoms without consulting their physician . This raises the question of patient's preferences with regard to treatment aims. It is not yet known whether patients are willing to conform to the stringent treatment aim of strictly controlled asthma, especially if it results in high doses of asthma medication and an increased likelihood of concurrent side effects. These uncertainties hamper implementation of current guidelines and therefore a great diversity in treatment exists. Furthermore, discordance in patient's and medical treatment goals might result in unnecessary asthma symptoms and health care use.
A recent meta-analysis showed that FeNO guided treatment of asthma does not reduce the number of exacerbations; however it did reduce the daily dose of inhaled corticosteroids . Our study may extend these findings by providing further understanding of the cost-effectiveness and patient preferences of FeNO guided treatment of asthma.
We hypothesize that:
1) a treatment strategy aimed achieving at strictly controlled asthma is more (cost-)effective as compared to a treatment strategy aimed at sufficiently controlled asthma;
2) a treatment strategy aimed at achieving strictly controlled asthma is (cost-)effective when the treatment step is additionally guided by measurements of exhaled nitric oxide (NO) as compared to a treatment strategy aimed at strictly controlled asthma or sufficiently controlled asthma.
During the conduction of the trial the definition of asthma exacerbations has been changed. In our analysis we will use the definitions as proposed by the ATS/ERS task force . By incorporating internet-based graphic feedback on a patients' asthma control status and internet-based decision support based on current guidelines, we will enhance the feasibility and standardization of the treatment advice. The results of this study will provide insight into the potential discordance between patient's and medical treatment goals and the effect on health care costs from the societal perspective. The internet-based decision support methodology and results of our study may facilitate cost-effective implementation of future tailored treatment strategies for patients with mild to moderate asthma in primary care.
We thank Dr. W.B. van den Hout (Dept. Med. Decision Making, LUMC) and Prof. Dr. K.F. Rabe (Dept. Pulmonology, LUMC) for their contribution to the study protocol, as well as H.K. Reddel (Woolcock Institute of Medical Research, University of Sydney).
This study was supported by grants from:
Netherlands Organisation for Health Research and Development (ZON-MW, sub-programme Effects & Costs 80-82310-98-8627)
Netherlands Asthma Foundation (NAF 3.4.07.044)
Aerocrine (medical technology company; provided the FeNO meters; was not involved in conducting the study, nor will be in the analysis or reporting of results)
- Holgate ST, Price D, Valovirta E: Asthma out of control? A structured review of recent patient surveys. BMC Pulm Med. 2006, 6 (Suppl 1): s2-10.1186/1471-2466-6-S1-S2.View ArticlePubMedPubMed CentralGoogle Scholar
- Hoogendoorn M, Feenstra TL, Rutten-van Molken MP: Projections of future resource use and the costs of asthma and COPD in the Netherlands. Ned Tijdschr Geneeskd. 2006, 150: 1243-1250.PubMedGoogle Scholar
- Vermeire PA, Rabe KF, Soriano JB, Maier WC: Asthma control and differences in management practices across seven European countries. Respir Med. 2002, 96: 142-9. 10.1053/rmed.2001.1241.View ArticlePubMedGoogle Scholar
- Rabe KF, Vermeire PA, Soriano JB, Maier WC: Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J. 2000, 16: 802-807. 10.1183/09031936.00.16580200.View ArticlePubMedGoogle Scholar
- Geijer RMM, Chavannes NH, Muris JWM, Sachs APE, Schermer T, Smeele IJM, Thoonen B, Van der Molen T, Van Schayck CP, Van Weel C, Kolnaar BGM, Grol MH: NHG standaard Astma bij volwassenen. Huisarts Wet. 2007, 50: 537-551. 10.1007/BF03085239.View ArticleGoogle Scholar
- Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and Prevention. NHLBI/WHO workshop report. 2006, National Institutes of Health, National Heart, Lung and Blood Institute, accessed September 2008, [http://www.ginasthma.org]Google Scholar
- Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR: Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999, 14: 902-907. 10.1034/j.1399-3003.1999.14d29.x.View ArticlePubMedGoogle Scholar
- Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE: Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004, 170: 836-844. 10.1164/rccm.200401-033OC.View ArticlePubMedGoogle Scholar
- O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, Ekstrom T, Bateman ED: Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005, 171: 129-136.View ArticlePubMedGoogle Scholar
- Reddel HK: Goals of asthma treatment: how high should we go?. Eur Respir J. 2004, 24: 715-717. 10.1183/09031936.04.10104904.View ArticlePubMedGoogle Scholar
- Briggs AH, Bousquet J, Wallace MV, Busse WW, Clark TJ, Pedersen SE, Bateman ED: Cost-effectiveness of asthma control: an economic appraisal of the GOAL study. Allergy. 2006, 61: 531-536. 10.1111/j.1398-9995.2006.01038.x.View ArticlePubMedGoogle Scholar
- Akazawa M, Stempel DA: Single-inhaler combination therapy for asthma: a review of cost effectiveness. Pharmacoeconomics. 2006, 24: 971-988. 10.2165/00019053-200624100-00005.View ArticlePubMedGoogle Scholar
- Pavord ID, Shaw D: The use of exhaled nitric oxide in the management of asthma. J Asthma. 2008, 45: 523-531. 10.1080/02770900801978557.View ArticlePubMedGoogle Scholar
- Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O'Connor GT, Morgan WJ, Kattan M, Pongracic JA, Teach SJ, Bloomberg GR, Eggleston PA, Gruchalla RS, Kercsmar CM, Liu AH, Wildfire JJ, Curry MD, Busse WW: Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial. Lancet. 2008, 372: 1065-1072. 10.1016/S0140-6736(08)61448-8.View ArticlePubMedPubMed CentralGoogle Scholar
- Smith AD, Cowan JO, Brassett KP, Herbison GP, Taylor DR: Use of exhaled nitric oxide measurements to guide treatment in chronic asthma. N Engl J Med. 2005, 352: 2163-2173. 10.1056/NEJMoa043596.View ArticlePubMedGoogle Scholar
- Shaw DE, Berry MA, Thomas M, Green RH, Brightling CE, Wardlaw AJ, Pavord ID: The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial. Am J Respir Crit Care Med. 2007, 176: 231-237. 10.1164/rccm.200610-1427OC.View ArticlePubMedGoogle Scholar
- Van der Meer V, Rikkers-Mutsaerts ER, Sterk PJ, Thiadens HA, Assendelft WJ, Sont JK: Compliance and reliability of electronic PEF monitoring in adolescents with asthma. Thorax. 2006, 61: 457-458. 10.1136/thx.2005.054619.View ArticlePubMedPubMed CentralGoogle Scholar
- Van den Nieuwenhof L, Schermer T, Eysink P, Halet E, van Weel C, Bindels P, Bottema B: Can the Asthma Control Questionnaire be used to differentiate between patients with controlled and uncontrolled asthma symptoms? A pilot study. Fam Pract. 2006, 23: 674-681. 10.1093/fampra/cml041.View ArticlePubMedGoogle Scholar
- Puffer S, Torgerson DJ, Watson J: Cluster randomized controlled trials. J Eval Clin Pract. 2005, 11: 479-483. 10.1111/j.1365-2753.2005.00568.x.View ArticlePubMedGoogle Scholar
- Humbert M, Holgate S, Boulet LP, Bousquet J: Asthma control or severity: that is the question. Allergy. 2007, 62: 95-101.PubMedGoogle Scholar
- Taylor DR, Pijnenburg MW, Smith AD, De Jongste JC: Exhaled nitric oxide measurements: clinical application and interpretation. Thorax. 2006, 61: 817-827. 10.1136/thx.2005.056093.View ArticlePubMedPubMed CentralGoogle Scholar
- Schellevis FC, de Bakker DH, Verheij RA, Hingstman L: Hoe is de huisartsenzorg georganiseerd?. Volksgezondheid Toekomst Verkenning, Nationaal Kompas Volksgezondheid. 1999, Bilthoven: RIVMGoogle Scholar
- Juniper EF, Bousquet J, Abetz L, Bateman ED: Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med. 2006, 100: 616-621. 10.1016/j.rmed.2005.08.012.View ArticlePubMedGoogle Scholar
- Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J: Standardisation of spirometry. Eur Respir J. 2005, 26: 319-338. 10.1183/09031936.05.00034805.View ArticlePubMedGoogle Scholar
- ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005, 171: 912-930.Google Scholar
- Alving K, Janson C, Nordvall L: Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children. Respir Res. 2006, 7: 67-10.1186/1465-9921-7-67.View ArticlePubMedPubMed CentralGoogle Scholar
- Dressel H, de la MD, Reichert J, Ochmann U, Petru R, Angerer P, Holz O, Nowak D, Jorres RA: Exhaled nitric oxide: independent effects of atopy, smoking, respiratory tract infection, gender and height. Respir Med. 2008, 102: 962-969. 10.1016/j.rmed.2008.02.012.View ArticlePubMedGoogle Scholar
- Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A: Differences between asthma exacerbations and poor asthma control. Lancet. 1999, 353: 364-369. 10.1016/S0140-6736(98)06128-5.View ArticlePubMedGoogle Scholar
- Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG: Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet. 2006, 368: 744-753. 10.1016/S0140-6736(06)69284-2.View ArticlePubMedGoogle Scholar
- Van den Hout WB, Tijhuis GJ, Hazes JM, Breedveld FC, Vliet Vlieland TP: Cost effectiveness and cost utility analysis of multidisciplinary care in patients with rheumatoid arthritis: a randomised comparison of clinical nurse specialist care, inpatient team care, and day patient team care. Ann Rheum Dis. 2003, 62: 308-315. 10.1136/ard.62.4.308.View ArticlePubMedPubMed CentralGoogle Scholar
- Foundation for Accountability: FACCT quality measurement guide. Adult asthma version 2.0. 1999, [http://www.facct.org/doclibFiles/documentFile_118.pdf.]Google Scholar
- Broadbent E, Petrie KJ, Main J, Weinman J: The brief illness perception questionnaire. J Psychosom Res. 2006, 60: 631-637. 10.1016/j.jpsychores.2005.10.020.View ArticlePubMedGoogle Scholar
- Horne R, Weinman J, Hankins M: The beliefs about medicines questionnaire: The development and evaluation of a new method for assessing the cognitive representation of medicine. Psychol Health. 1999, 14: 1-24. 10.1080/08870449908407311.View ArticleGoogle Scholar
- Fialko L, Garety PA, Kuipers E, Dunn G, Bebbington PE, Fowler D, Freeman D: A large-scale validation study of the Medication Adherence Rating Scale (MARS). Schizophr Res. 2008, 100: 53-59. 10.1016/j.schres.2007.10.029.View ArticlePubMedGoogle Scholar
- Menckeberg TT, Bouvy ML, Bracke M, Kaptein AA, Leufkens HG, Raaijmakers JA, Horne R: Beliefs about medicines predict refill adherence to inhaled corticosteroids. J Psychosom Res. 2008, 64: 47-54. 10.1016/j.jpsychores.2007.07.016.View ArticlePubMedGoogle Scholar
- Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE: Measuring quality of life in asthma. Am Rev Respir Dis. 1993, 147: 832-838.View ArticlePubMedGoogle Scholar
- Brazier J, Usherwood T, Harper R, Thomas K: Deriving a preference-based single index from the UK SF-36 Health Survey. J Clin Epidemiol. 1998, 51: 1115-1128. 10.1016/S0895-4356(98)00103-6.View ArticlePubMedGoogle Scholar
- Revicki DA, Leidy NK, Brennan-Diemer F, Sorensen S, Togias A: Integrating patient preferences into health outcomes assessment: the multiattribute Asthma Symptom Utility Index. Chest. 1998, 114: 998-1007. 10.1378/chest.114.4.998.View ArticlePubMedGoogle Scholar
- Stiggelbout AM, de Haes JC: Patient preference for cancer therapy: an overview of measurement approaches. J Clin Oncol. 2001, 19: 220-230.PubMedGoogle Scholar
- Dolan P: Modeling valuations for EuroQol health states. Med Care. 1997, 35: 1095-1108. 10.1097/00005650-199711000-00002.View ArticlePubMedGoogle Scholar
- Szende A, Svensson K, Stahl E, Meszaros A, Berta GY: Psychometric and utility-based measures of health status of asthmatic patients with different disease control level. Pharmacoeconomics. 2004, 22: 537-547. 10.2165/00019053-200422080-00005.View ArticlePubMedGoogle Scholar
- Walters SJ, Brazier JE: Comparison of the minimally important difference for two health state utility measures: EQ-5D and SF-6D. Qual Life Res. 2005, 14: 1523-1532. 10.1007/s11136-004-7713-0.View ArticlePubMedGoogle Scholar
- Willan AR: Analysis, sample size, and power for estimating incremental net health benefit from clinical trial data. Control Clin Trials. 2001, 22: 228-237. 10.1016/S0197-2456(01)00110-6.View ArticlePubMedGoogle Scholar
- Schermer TR, Thoonen BP, van den BG, Akkermans RP, Grol RP, Folgering HT, van Weel C, van Schayck CP: Randomized controlled economic evaluation of asthma self-management in primary health care. Am J Respir Crit Care Med. 2002, 166: 1062-1072. 10.1164/rccm.2105116.View ArticlePubMedGoogle Scholar
- Campbell MK, Thomson S, Ramsay CR, MacLennan GS, Grimshaw JM: Sample size calculator for cluster randomized trials. Comput Biol Med. 2004, 34: 113-125. 10.1016/S0010-4825(03)00039-8.View ArticlePubMedGoogle Scholar
- Van Den Brink M, Van Den Hout WB, Stiggelbout AM, Van De Velde CJ, Kievit J: Cost measurement in economic evaluations of health care: Whom to ask?. Med Care. 2004, 42: 740-746. 10.1097/01.mlr.0000132351.78009.a1.View ArticlePubMedGoogle Scholar
- Oostenbrink JB, Koopmanschap MA, Rutten FF: Standardisation of costs: the Dutch Manual for Costing in economic evaluations. Pharmacoeconomics. 2002, 20: 443-454. 10.2165/00019053-200220070-00002.View ArticlePubMedGoogle Scholar
- Lamers LM, McDonnell J, Stalmeier PF, Krabbe PF, Busschbach JJ: The Dutch tariff: results and arguments for an effective design for national EQ-5D valuation studies. Health Econ. 2006, 15: 1121-1132. 10.1002/hec.1124.View ArticlePubMedGoogle Scholar
- van den Nieuwenhof L, Schermer T, Heins M, Grootens J, Eysink P, Bottema B, van Weel C, Bindels P: Tracing uncontrolled asthma in family practice using a mailed asthma control questionnaire. AnnFam Med. 2008, 6 (Suppl 1): s16-s22.Google Scholar
- Petsky HL, Cates CJ, Lasserson TJ, Li AM, Turner C, Kynaston JA, Chang AB: A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils). Thorax.Google Scholar
- Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, de Jongste JC, Kerstjens HA, Lazarus SC, Levy ML, O'Byrne PM, Partridge MR, Pavord ID, Sears MR, Sterk PJ, Stoloff SW, Sullivan SD, Szefler SJ, Thomas MD, Wenzel SE, American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations: An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009, 180: 59-99. 10.1164/rccm.200801-060ST.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/11/53/prepub
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