Inhaled corticosteroids (ICSs), when used in combination with long-acting bronchodilators, reduce the risk of exacerbations and improve health-related quality of life in patients with chronic obstructive pulmonary disease (COPD) compared with bronchodilator or ICS therapy alone. Potential side effects of ICSs include adverse effects on glycemic control, bone density, cataract formation, skin changes, oral candidiasis, and pulmonary infections. Pneumonia is observed at increased rates in COPD patients, in particular those with greater airflow limitation, low body mass index, advanced age, and male gender, and ICSs may increase this risk. Risk assessment is essential in selecting appropriate patients for ICS-containing therapy.
Key points
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Inhaled corticosteroids (ICSs) should not be prescribed as monotherapy in chronic obstructive pulmonary disease (COPD).
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Combination therapy with ICS and long-acting beta-agonist (LABA) results in reduced exacerbations compared with bronchodilator treatment alone and triple therapy with ICS/LABA, and a long-acting muscarinic antagonist offers further benefit, including a possible survival advantage in some patients.
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In patients with higher blood eosinophil counts, the use of ICSs is associated with a greater reduction in COPD exacerbations risk.
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ICSs are associated with an increased risk of pneumonia. COPD patients with the highest pneumonia risk are those with low body mass index, advanced age, male gender, and greater airflow obstruction, and ICS-containing treatments should be used with caution in these groups.
Introduction
The Global Burden of Disease Study recently has reported that chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, reaching this threshold approximately 10 years earlier than predicted. , Explanations for this rise are multifactorial and include the aging population and improved outcomes for cardiovascular disease and cancer. Additionally, no pharmacologic treatment has been definitively shown to improve COPD mortality, which also contributes. Other treatment goals for COPD include reducing the burden of disease by alleviating symptoms, improving health-related quality of life, reducing exacerbation frequency and severity, and preservation of lung function. , Achieving these goals is challenging due to the heterogeneity and complex pathobiology of the disease, which include dysregulation in immune activation, airflow obstruction due to bronchoconstriction, small airway fibrosis, emphysema and muco-obstruction, and dysfunction of the mucociliary escalator. , The presence of lung inflammation also promotes airway and alveolar tissue damage, airway remodeling, and airflow obstruction and contributes to the risk of exacerbations of COPD (ECOPD), which cause life-limiting symptoms and also are associated with loss of lung function, poor quality of life, and significant health care costs. ,
Anti-inflammatory therapeutics evaluated in COPD include inhaled corticosteroids (ICSs), oral glucocorticoids, phosphodiesterase inhibitors, antibiotics, statins, mucolytics, and monoclonal antibodies targeting inflammatory mediators, such as benralizumab and mepolizumab that target interleukin (IL)-5, among other drugs. , , The best studied of these approaches is the use of ICSs, alone and in combination with a long-acting beta-agonist (LABA) and with long-acting muscarinic antagonists (LAMAs). Although targeting lung inflammation with ICSs can have clinical benefits, including reducing the risk of exacerbations, it also can be associated with untoward effects.
Inhaled corticosteroid monotherapy
Although ICS therapy has a well-established role in the management of asthma, early studies in COPD patients were small and resulted in conflicting results. Subsequent more extensive studies suggested modest benefits on lung function, symptoms, and exacerbation risk but did not demonstrate effects on the rate of forced expiratory volume in the in the first second of expiration (FEV 1 ) decline and raised the possibility of a mortality disadvantage with long-term use.
Paggiaro and colleagues reported that 6 months of monotherapy with fluticasone propionate (FP) resulted in increased 6-minute walking distance, improved symptom scores for cough and sputum production, and a reduction in the number of patients who suffered moderate or severe exacerbations compared with placebo (60% vs 86%, respectively; P <.001). Pauwels and colleagues reported that in COPD patients who continued to smoke, monotherapy with budesonide resulted in initial improvement in FEV 1 in the first 6 months of treatment compared with placebo but that the rates of decline in FEV 1 over 3 years in the 2 groups were similar. These studies were followed by a 3-year single-center, double-blind, randomized placebo-controlled study nested in the Copenhagen City Heart Study. In this trial, Vestbo and colleagues evaluated the effect of budesonide on the rate of FEV 1 decline in COPD patients and again found no clear treatment benefit at 3 years with ICS monotherapy. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study also reported no statistical difference in decline in FEV 1 with FP compared with placebo, although there was a 25% reduction in median annual exacerbation rate and lower decline in health status as measured by St George’s Respiratory Questionnaire with ICS therapy. The Towards a Revolution in COPD Health (TORCH) trial randomized more than 6000 patients with COPD to FP/salmeterol (SAL), SAL, FP, or placebo. FP monotherapy again was shown to reduce the rate of exacerbations versus placebo, but the risk of death at 3 years with FP actually was increased vs placebo (15.2% versus 16.0%, respectively; [hazard ratio (HR) 1.060; 95% CI, 0.886–1.268; P = .53]) and statistically significantly higher when FP compared with FP/SAL (16.0% versus 12.6%, respectively; P = .007). Although there have been additional studies of ICS monotherapy in subpopulations of COPD, including those with heightened cardiovascular risk, and there has been a suggestion that they may have an impact on lung function decline in those with elevated blood eosinophils, the results of the TORCH study strongly suggested that this strategy should not be used routinely. ,
Inhaled corticosteroid/long-acting beta-agonist therapy
Numerous studies have compared ICS/LABA to LABA or LAMA alone as well as to dual bronchodilator therapy and have examined a range of clinical outcomes, although the effects of ICS/LABA on exacerbations and mortality have been of greatest interest.
Exacerbations
Inhaled corticosteroid/long-acting beta-agonist versus long-acting beta-agonist
In TORCH, FP/SAL was associated with a reduction in moderate or severe ECOPD compared with placebo, FP, and SAL, with FP/SAL compared to SAL alone being the most clinically relevant comparison with a risk ratio of 0.88 (95% CI, 0.81–0.95) favoring combination treatment. Although there are differences in the ICSs tested as well as trial methodology and the populations enrolled, ICS/LABA repeatedly has been shown to reduce the rate of ECOPD by 10% to 25%. ,
Inhaled corticosteroid/long-acting beta-agonist versus long-acting muscarinic antagonist
The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) trial evaluated tiotropium therapy compared with FP/SAL for patients with severe and very severe COPD (mean FEV 1 39%) over 2 years and found no difference in annual exacerbation rate (rate ratio [RR] 0.967; 95% CI, 0.836–1.119; P = .656). FP/SAL was associated with better health status and a lower withdrawal rate, suggesting an overall advantage to ICS/LABA.
Inhaled corticosteroid/long-acting beta-agonist versus long-acting muscarinic antagonist/long-acting beta-agonist
The Indacaterol–Glycopyrronium versus Salmeterol–Fluticasone for COPD (FLAME) trial demonstrated the superiority of the LABA/LAMA for the endpoint of annual rate of moderate or severe COPD exacerbations (RR 0.83; 95% CI, 0.75–0.91; P <.001). These results contrast with those from the IMPACT study, which showed an exacerbation benefit of fluticasone furoate (FF)/vilanterol (VI) compared with umeclidinium (UMEC)/VI. This difference in outcome likely is explained by methodological differences between the trials, including the inclusion of a run-in period on tiotropium in FLAME and the fact that the population in IMPACT was at much higher exacerbation risk, with 54% have greater than or equal to 2 moderate to severe exacerbations and 26% with greater than or equal to 1 severe exacerbation requiring hospitalization. ,
Survival/Mortality
In TORCH, FP/SAL was associated with a trend toward a reduction in mortality (HR 0.825; 95% CI, 0.68–1.00; P = .052). Although the results did not reach statistical significance, a prespecified secondary analysis using Cox proportional hazard testing did suggest a survival advantage with FP/SAL compared with placebo (HR 0.811; 95% CI, 0.670–0.982; P = .03). There are several possible explanations for the study failing to definitively establish a mortality benefit, including lower than expected mortality and differential dropout in the placebo arm.
A post hoc analysis of the TORCH study did demonstrate that in those patients treated for cardiovascular disease and with moderate airflow limitation (FEV 1 >50%), FP/SAL reduced the risk of cardiovascular adverse events compared with placebo. These data suggested the possibility of ICS/LABA being especially beneficial to those with heightened cardiovascular risk. This hypothesis was tested in the Study to Understand Mortality and Morbidity in COPD (SUMMIT) that enrolled patients with moderate COPD and heightened cardiovascular risk and randomized them to FF, VI, their combination (FF/VI), or placebo. The study was designed to evaluate the effect of FF/VI on all-cause mortality, but cardiovascular events and exacerbations also were examined. All-cause mortality was unaffected by FF/VI compared with placebo (HR 0.88; 95% CI, 0.74–1.04) and although there was also no impact of any active treatment on cardiovascular outcomes, there was no evidence of an adverse effect. Prespecified secondary analyses demonstrated that FF/VI reduced the risk of exacerbations compared with placebo and that FF-containing treatments might slow the rate of FEV 1 decline. , The study also demonstrated an important link between exacerbations and cardiovascular events as the HR for cardiovascular events after ECOPD was increased, particularly in the first 30 days (HR 3.8; 95% CI, 2.7–5.5) and remained elevated for up to 1 year.
The INSPIRE trial examined survival as a safety endpoint and demonstrated that FP/SAL was associated with a reduction in mortality compared with tiotropium (3% vs 6%, respectively; P = .032). Additionally, Cox proportional hazards model for time to death on treatment showed a 52% reduction in the risk of death in those randomized to FP/SAL (HR 0.48; 95% CI, 0.27–0.85; P = .012). ,
Trials of triple therapy with inhaled corticosteroid/long-acting beta-agonist/long-acting muscarinic antagonist
The recent development of single-inhaler triple therapies has prompted a series of clinical trials testing the effects of maximal inhaled treatment with an emphasis on exacerbations.
Exacerbations
The Informing the Pathway of COPD Treatment (IMPACT) trial evaluated the effect of triple therapy with FF/VI/UMEC versus both FF/VI and UMEC/VI in more than 10,000 patients with symptomatic COPD and a history of exacerbations. There was a lower rate of moderate and severe COPD exacerbations with triple therapy compared with UMEC/VI (RR 0.75; 95% CI, 0.70–0.81; P <.001) as well as a lower rate of COPD-related hospitalizations (RR 0.66; 95% CI, 0.56–0.78; P <.001). The efficacy and safety of fixed triple inhaler therapy also was demonstrated in TRILOGY as well as TRINITY, where the combination of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G) showed a 23% reduction in moderate/severe exacerbations versus ICS/LABA (BDP/FF) (RR 0.77; 95% CI, 0.65–0.92; P = .005) and 20% reduction versus LAMA (tiotropium) (RR 0.80; 95% CI 0.69–0.92; P = 0.0025) in symptomatic severe/very severe COPD patients with an exacerbation history. ,
Similar to IMPACT, the Extrafine Inhaled Triple Therapy versus Dual Bronchodilator Therapy in Chronic Obstructive Pulmonary Disease (TRIBUTE) study also compared triple ICS-containing therapy versus LABA/LAMA in patients with severe/very severe COPD at risk for ECOPD. , BDP/FF/G reduced the risk of moderate/severe exacerbations compared with indacaterol/GLY (annual exacerbation rate of 0.50 vs 0.59 events, respectively, per patient-year: RR 0.848; 95% CI, 0.723–0.995; P = .043). Although the overall rate of exacerbations and the relative benefit of triple therapy were less than observed in IMPACT, the results still suggest a clinically relevant advantage.
Survival/Mortality
In IMPACT, triple inhaled therapy with ICFF/VI/UMEC was associated with a signal toward a reduction in all-cause mortality compared with UMEC/VI. Although assessment of the mortality signal in IMPACT should be interpreted with caution because it was not the primary outcome, the trial is invaluable because of its meticulous adjudication of clinical events and the assessment of outcomes both on and off treatment and after capture of the vital status on all but 42 (0.4%) patients. With time to on-treatment all-cause mortality as a prespecified endpoint, the HR for FF/VI/UMEC versus UMEC/VI was 0.58 (95% CI, 0.38–0.88; unadjusted P = .011). Similar results were observed when the analysis included data after patients stopped treatment (HR 0.71; 95% CI, 0.51–0.99; P = .043) and when the vital status was available for 99.6% of randomized subjects (HR 0.72; 95% CI, 0.53–0.99; P = .042). , A pooled analysis of the TRILOGY, TRINITY, and TRIBUTE studies evaluated mortality as a safety outcome and found that the risk of nonrespiratory mortality was lower with ICS-containing treatments compared with treatment without ICSs (HR 0.65%; 95% CI; 0.43–0.97; P = .037)
Although no study has demonstrated an advantage to ICS-containing therapy with mortality as the primary endpoint, the weight of the evidence suggests that there may be a benefit in a subset of patients, likely those with more severe disease, significant symptoms, and exacerbation risk.
Risks/safety
Population-based studies and analyses of randomized controlled trials (RCTs) have shown that ICS therapy has untoward effects that include changes in bone density, oral candidiasis, insulin resistance, skin changes, and adrenal suppression as well as increased risk of pneumonia and mycobacterial infections ( Table 1 ).
| Randomized Controlled Trial | Observational/Case-Control Study | Systematic Review | |
|---|---|---|---|
| Pneumonia | ✓✓✓ | ✓✓✓ | ✓✓✓ |
| Mycobacterial infections | ✓ | ✓ | |
| Diabetes | ✓ | ||
| Bone density | (No effect on fracture risk) | ✓✓ | ✓✓ |
Pneumonia Risk
COPD patients are at increased risk of community-acquired pneumonia as well as increased risk of death from pneumonia. Risk factors for pneumonia in COPD include older age, lower body mass index (BMI), male gender, lower FEV 1 , prior pneumonia, and ICS use, although the magnitude of additional risk attributable to ICSs is uncertain. There also has been substantial interest in the use of blood eosinophils as a predictor of pneumonia, but most studies have shown either no association or an association only with very low eosinophil counts. , There also is significant variability in pneumonia rates across studies with differences in study populations, study design, the ICS included, and varied definitions of pneumonia that complicate comparisons. Despite these challenges, a Cochrane review has concluded that pneumonia is a class-related risk of ICS.
The TORCH study reported increased pneumonia risk in the FF-containing treatment groups, and although this was not a prespecified outcome and chest radiographs were not required for diagnosis, the same trend has been observed in subsequent RCTs of ICS-containing therapies, including those where pneumonia events were adjudicated. , ,
Although the weight of the evidence suggests that ICSs increase the risk of any pneumonia, this does not seem to increase pneumonia-related or all-cause mortality. There also are data to suggest that outcomes for COPD patients admitted with pneumonia are better in those taking ICSs as outpatients and that there may be a double effect of the drugs, including both an adverse effect and an additional unidentified mitigating effect. Additionally, in order to determine overall risk-benefit, the risk of ICS-related pneumonia has to be compared and counterbalanced with the ICS-related reduction in acute exacerbations. Data from IMPACT and TRIBUTE show that the rate of ECOPD is approximately 10-fold higher than the rate of pneumonia and, thus, the small increase in pneumonia risk with ICSs may be offset by the exacerbation benefit, although the decision to use ICSs must be individualized.
Mycobacterial Risk
Recent population-based studies suggest that COPD patients on ICSs are at an increased risk of nontuberculous mycobacterial (NTM) infections. , In a large population-based study in Canada, Brode and colleagues found that there was an association between NTM and ICS use in patients with obstructive lung disease (asthma, COPD, and asthma-COPD overlap). When selected for COPD patients, the investigators found an adjusted odds ratio of 1.96 (95% CI, 1.62–2.36). Similar findings were seen in a population-based case-control study in Denmark that verified that COPD is a risk factor for NTM, and ICS therapy further increases the risk. This effect of ICSs on mycobacterial risk has not been demonstrated in a randomized clinical trial.
Fractures and Bone Density
A long-standing concern for ICS therapy is an effect on bone density and fracture risk. Osteoporosis is significant comorbidity in COPD, and patients not on ICS therapy are estimated to have a prevalence of ranging from 10% to 33%. The systemic bioavailability of most ICS molecules is believed to be minimal, but the effects of very long exposure have not been studied adequately. In the Lung Health Study, after 3 years of ICS therapy with triamcinolone, a significant number of patients had reduced bone density in the femoral neck and lumbar spine compared with placebo. These findings were not observed in other studies, and no RCT has demonstrated a significant increase in fracture risk. The effects of ICSs on bone density likely are both dose dependent and time dependent and many patients started on the drugs take them for far longer than has been studied. It, therefore, is advisable that ICS dose and duration be minimized, therapy limited to those who will receive benefit, and individuals monitored for adverse bone effects.
Glycemic Control/Insulin Resistance
Diabetes is a common comorbid condition in patients with COPD; thus, understanding the effect of ICSs on glycemic control is essential. A case-control study in patients with asthma or COPD reported that ICS use was associated with an increased risk of new-onset diabetes and diabetes progression, with a clear dose-response relationship. In a UK-based historical matched cohort study, Price and colleagues evaluated the change in hemoglobin (Hb) A 1c in COPD patients with coexisting diabetes who were taking ICSs over 12 months to 18 months relative to a non-ICS cohort. The adjusted difference in change in HbA 1c was 0.16% (95% CI, 0.05%–0.27%), suggesting that patients using ICSs had worse diabetes control. Another cohort study noted small changes in serum glucose (ranging from 2 mg/dL to 5 mg/dL) without an increased risk of developing diabetes, even though the clinical relevance of this effect is unclear. Additional studies are needed to determine the overall impact of ICSs on long-term glycemic control.
Adrenal Suppression
Systemic administration of glucocorticoids causes hypothalamic-pituitary-adrenal (HPA) axis suppression by reducing corticotropin production, which reduces cortisol secretion by the adrenal gland. The degree of HPA suppression is dependent on dose, duration, frequency, and timing of glucocorticoid administration; however, there have been no data to suggest that doses delivered with inhaled corticosteroids have a meaningful clinical impact on the HPA axis for most patients.
Risk-benefit considerations
The selection of patients for ICS-containing therapy requires an assessment of their likelihood of receiving a benefit, most clearly in reducing exacerbation risk and the risk of hospitalization, and their propensity to suffer ICS-related side effects. As discussed previously, older age, low BMI, lower lung function, and male sex increase the risk of pneumonia in COPD but may not preclude treatment with ICSs if the potential for exacerbation prevention is more significant. Several studies suggest that sputum eosinophilia, although not readily available in most clinical settings, may serve as a predictive biomarker of response to corticosteroids in patients with COPD. , Although sputum eosinophils correlate well with exacerbations and ICS benefit, findings from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) suggest that the use of blood eosinophils as a surrogate may perform poorly due to weak association between sputum and blood eosinophilia. This contrasts with data from several RCTs that demonstrate a clear association between greater eosinophil count and both the risk of exacerbations and the magnitude of ICS benefit. A post hoc analysis of pooled phase III data also showed that patients with a peripheral blood eosinophil count of at least 100 cells/μL with at least 1 exacerbation in the preceding year had a reduction in exacerbations with ICS/LABA therapy (RR 0.75; 95% CI, 0.57–0.99; P = .015), with the most significant treatment effect noted in those with the highest level of blood eosinophils. , IMPACT and TRIBUTE had a predefined analysis based on blood eosinophilia that showed more significant treatment effects to ICSs with eosinophil level greater than 150 cells/μL to 200 cells/μL, although in smokers the threshold for benefit may be higher. , Pascoe and colleagues redemonstrated a direct relationship between ECOPD reduction and higher peripheral eosinophil count; however, there was not a clear association between pneumonia with baseline blood eosinophils. Based on available data, it is reasonable to consider ICS use in those patients with frequent and severe exacerbations and consider avoiding in patients with a history of frequent cases of pneumonia. There also may be a role for examining sputum culture data to select ICS candidates, because chronic bronchial infection also may increase pneumonia risk ( Box 1 ).
