Step 4: Stick Or Twist? a Review of Asthma Therapy
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BMJ Open Resp Res: first published as 10.1136/bmjresp-2016-000143 on 6 September 2016. Downloaded from Asthma Step 4: stick or twist? A review of asthma therapy Mariel G Slater,1 Ian D Pavord,2 Dominick E Shaw3 To cite: Slater MG, ABSTRACT may lead to reduced control include poor Pavord ID, Shaw DE. Step 4: Many people with asthma do not achieve disease inhaler technique, non-adherence to medica- stick or twist? A review of control, despite bronchodilators and inhaled BMJ Open tion, exposure to trigger factors and incor- asthma therapy. corticosteroid therapy. People with uncontrolled Resp Res 2016;3:e000143. rect prescribing. asthma are at higher risk of an asthma attack and doi:10.1136/bmjresp-2016- According to the BTS/SIGN guidance, death, with mortality rates estimated at 1000 deaths/ 000143 patients with uncontrolled asthma should year in England and Wales. The recent National Review fi of Asthma Deaths (NRAD) report, ‘Why asthma still have treatment intensi ed by escalating up kills’, recommended that patients at step 4 or 5 of the the treatment steps until control is achieved Received 19 April 2016 ‘ British Thoracic Society/Scottish Intercollegiate for at least 3 months, at which point step- Revised 4 July 2016 ’ Accepted 6 July 2016 Guidelines Network (BTS/SIGN) guidance must be ping down treatment should be considered referred to a specialist asthma service. This article (figure 1).3 Patients at step 4 are uncon- reviews the 2014 evidence base for therapy of asthma trolled, despite receiving at least 800 µg ICS patients at BTS/SIGN step 4 of the treatment cascade, per day (beclometasone dipropionate (BDP) in response to key findings of the NRAD report and or equivalent) plus a LABA (or other con- lack of preferred treatment option at this step. troller medication such as theophylline if LABA is not deemed effective at step 3). Recommended treatment options at this step by copyright. are: increasing the dose of ICS up to INTRODUCTION 2000 µg/day; adding a leukotriene receptor It is estimated that ∼300 million people have β antagonist (LTRA); theophylline; 2 adrener- asthma worldwide, with expectations that this gic receptor agonist tablet; tiotropium fi 12 gure will rise to 400 million by 2025. The bromide soft mist inhaler. However, there is severity of disease varies and patients with no algorithm to suggest which treatment severe asthma (requiring treatment at steps 4 should be tried first and it is unclear and 5 of the British thoracic Society/Scottish whether one treatment is more efficacious http://bmjopenrespres.bmj.com/ Intercollegiate Guidelines Network (BTS/ than another. Furthermore, it is important to 3 4 SIGN) guideline) often suffer from a worse try and achieve disease control without quality of life, asthma attacks, hospitalisations resorting to oral steroids which are linked 5 and are at higher risk of death. It is thought with osteoporosis, adrenal suppression, ∼ that 4% of people with asthma suffer from weight gain and diabetes.11 6 true severe refractory disease and studies Despite national and international have shown that this subgroup of patients evidence-based guidelines, the optimal man- impart a disproportionate pharmaco- agement strategy in severe asthma is still economic burden, with mean UK annual unclear due to lack of robust clinical data. treatment costs reaching between £2912 and Here, we focus on treatment options at step 7 1Medical Department, £4217 per patient. 4, given the recent National Review of on September 29, 2021 by guest. Protected Boehringer Ingelheim Ltd, The goal of asthma treatment is to achieve Asthma Deaths (NRAD) report recommen- Bracknell, Berkshire, UK disease control, which is assessed by clinical 12 2 dation for specialist referral and lack of Nuffield Department of measures and risk (of an asthma attack and clarity at this step (a review of pharmaco- Medicine Research Building, of medication side effects). Poor control is University of Oxford, Oxford, logical therapy at each individual treatment 13 Oxfordshire, UK linked with asthma attacks, which in turn are step has been published elsewhere). 3Division of Respiratory associated with poor future control and Medicine, University of healthcare usage.89In the UK, it is estimated Nottingham, Nottingham City that ∼65% of patients on at least an inhaled METHOD Hospital, Nottingham, UK β corticosteroid (ICS) with a long-acting 2 A literature review of randomised controlled Correspondence to adrenergic agonist (LABA) (BTS/SIGN step clinical trials (RCTs) of each asthma therapy 10 Dr Dominick Shaw; dominic. 3 upwards) remain uncontrolled. Potential recommended by the 2014 version of the [email protected] factors, other than severity of disease, that BTS/SIGN guidelines at step 4 was Slater MG, Pavord ID, Shaw DE. BMJ Open Resp Res 2016;3:e000143. doi:10.1136/bmjresp-2016-000143 1 BMJ Open Resp Res: first published as 10.1136/bmjresp-2016-000143 on 6 September 2016. Downloaded from Open Access by copyright. Figure 1 British thoracic Society/Scottish Intercollegiate Guidelines Network (BTS/SIGN) 2014 version of guidelines on the management of asthma: summary of stepwise management in adults.3 Reproduced from (SIGN 141: British Guideline on the Management of Asthma, BTS/SIGN, page 72, 2014) with permission from BMJ Publishing Group. β 15 performed. Evidence included studies used to form the by increasing 2 adrenergic receptor expression. guideline itself (trials published to August 2012), RCTs Clinical trials in asthma have shown that ICS reduce http://bmjopenrespres.bmj.com/ β and Cochrane reviews up to April 2016. Embase and exacerbations and short-acting 2 adrenergic receptor MEDLINE were searched using the primary search agonist (SABA) use and also improve FEV1 and asthma terms ‘asthma’ (title) AND adult AND the therapy being symptoms, across a range of disease severities.16 assessed (title), for example, ‘leukotriene receptor However, side effects such as adrenal suppression antagonist’ OR ‘pranlukast’ OR ‘montelukast’ OR ‘zafir- become more common as the dose increases due to lukast’. All ICS doses stated are BDP per day or equiva- increased systemic exposure,17 and therefore, it is recom- lent (µg) (low dose <400 µg, medium 400–800 µg and mended that treatment is titrated to achieve the lowest high dose ≥800 µg).14 dose possible to maintain disease control.3 It is thought that most clinical benefits from ICS occur at lower doses fi – and that few patients bene t from doses above 400 on September 29, 2021 by guest. Protected TREATMENT OPTIONS AT STEP 4 OF THE BTS/SIGN 800 µg, that is, the dose–response curve becomes flat- GUIDELINES tened and side effects occur more frequently at doses – Option 1: increasing the dose of ICS above 800 µg (figure 2).91721 However, some asthma ICS are the cornerstone of asthma therapy and are used patients, including smokers,22 23 do respond clinically to 24 throughout steps 2–5(figure 1).3 ICS exert their effects higher doses of ICS, which can be accompanied by a 25 through binding to glucocorticoid receptors of inflam- normal serum cortisol level: consequently, no matory and structural cells within the airways, initiating maximum effective dose can be defined. cellular signalling and downregulation of inflammatory gene transcription and inflammatory mediator release, Evidence: increasing ICS up to 2000 µg as well as upregulation of anti-inflammatory genes. ICS One option is to increase the dose of ICS from 800 µg may also indirectly lead to bronchodilation, either to doses up to and including 2000 µg. As far as we are through reduction in inflammatory cell obstruction or aware to date, there are no studies assessing the clinical 2 Slater MG, Pavord ID, Shaw DE. BMJ Open Resp Res 2016;3:e000143. doi:10.1136/bmjresp-2016-000143 BMJ Open Resp Res: first published as 10.1136/bmjresp-2016-000143 on 6 September 2016. Downloaded from Open Access control over placebo.32 A meta-analysis of six studies of montelukast add-on therapy in mild–moderate asthma showed improved effectiveness compared with ICS alone, with regard to symptoms and chances of an asthma attack.33 However, there are no studies in the BTS/SIGN guidance that specifically assess the addition of LTRA as an add-on maintenance therapy at step 4 compared with placebo or usual care, and guidelines extrapolate from studies in milder patients. More recent evidence includes a 6-week double-blind parallel group trial that assessed 80 mg zafirlukast two times a day in 368 symptomatic asthma patients on high- dose ICS (≥1200 µg) plus any usual therapy. The results showed improved morning/evening PEF, daytime symptom score, SABA use and exacerbation risk with LTRA over placebo.34 A second study randomised 37 Figure 2 For most patients with asthma airway response patients with symptomatic asthma already taking 800– becomes flatter after 1000 µg of inhaled corticosteroid, but 1200 µg ICS plus a bronchodilator to 225 mg pranlukast systemic activity (measured by serum cortisol levels) becomes steeper.17 Reproduced with permission from Professor Brian J two times a day or normal care over 4 weeks, which Lipworth. resulted in improved lung function, asthma symptoms, SABA use and eosinophil levels in the pranlukast arm.35 A similar study assessed 10 mg once daily montelukast as effectiveness of stepping up ICS in a step 4 patient popu- an add-on therapy to symptomatic asthma patients – lation (already on high-dose ICS (without oral steroids) taking 400 1600 µg ICS over 16 weeks and showed increased asthma control and SABA usage compared +LABA (or other add-on controller)), and the current 36 guidelines are largely extrapolated from studies in with placebo. In contrast, two short-term clinical 32627 studies of patients on high-dose ICS (≥1000 µg) showed patients at step 3.