Abstract
First-line controller combination therapy for the management of asthma is a low-dose inhaled corticosteroid (LD-ICS) + a long-acting β-agonist (LABA), and second-line options are a LD-ICS + a leukotriene receptor antagonist (LTRA), LD-ICS + sustained-release theophylline (SR-T), and a medium-/high-dose ICS (HD-ICS). The purpose of this review is to assess the various second-line combination therapy options for the management of asthma. We systematically reviewed randomized controlled trials (RCTs) in adult patients with asthma, extracting and synthesizing data from eligible articles on study design, duration, randomization, blinding, withdrawal, run-in period, type of analysis, and names and doses of drugs. The primary outcome measure was change in percentage predicted forced expiratory volume in 1 second (% FEV1), and the secondary outcome was frequency of asthma exacerbations. Nine RCTs (three blinded and six open-label trials) were selected for the review. One study investigated LD-ICS + LTRA compared with HD-ICS, two studies investigated LD-ICS + SR-T compared with HD-ICS, and five studies investigated LD-ICS + LTRA compared with LD-ICS + SR-T. Only one of the nine RCTs compared all treatment options as mentioned in Global Initiative for Asthma (GINA) guidelines. Seven RCTs examined the primary outcome (change in % FEV1). No significant difference was observed (four RCTs; % FEV1) between LD-ICS + LTRA and LD-ICS + SR-T, but one RCT reported better clinical improvement with LD-ICS + LTRA than with LD-ICS + SR-T (% FEV1). Likewise, similar clinical effects (two RCTs) were observed between LD-ICS + SR-T and HD-ICS, one based on % FEV1 and the other based on exacerbation improvement. One RCT concluded that LD-ICS + LTRA was an effective and well-tolerated alternative to HD-ICS (exacerbation improvement). LD-ICS + LTRA resulted in greater clinical improvement when comparing all second-line treatment options in one RCT (% FEV1 and exacerbation improvement). All nine studies had a high risk of bias according to a modified Cochrane risk-of-bias tool for quality assessment of RCTs. Existing RCTs provide low-quality evidence of the superiority of second-line controller options for asthma management. This systematic review recommends that clinically relevant, stringently designed RCTs with appropriate sample sizes and durations are conducted to identify the best second-line controller option.
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