Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD.There is a considerable amount of evidence that supports the possibility of an increased risk of pneumonia associated with prolonged use of inhaled corticosteroids ICS in patients with chronic obstructive pulmonary disease COPD. However, as yet, no statistically significant increase in pneumonia-related day mortality in patients on ICS has been demonstrated. The lack of objective pneumonia definitions and radiological confirmations have been a major source of bias, because of the similarities in clinical presentation between pneumonia and acute exacerbations of COPD. One of the newer fluticasone risk-to-benefit ratio of inhaled corticosteroids in patients with copd studies overcomes these limitations and also provides an assessment of a range of doses, suggesting that the therapeutic window is quite narrow and that conventional dosing has probably been too high, although the absolute risk may be different medicines for low testosterone to other drugs. Newer studies were not able to rule out budesonide as responsible for pneumonia, as previous evidence suggested, and there is still need for evidence from head-to-head comparisons in order to better assess possible intra-class differences.
Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. - PubMed - NCBI
It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use. Subjects were identified using the Quebec health insurance databases and followed through or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia.
A nested case—control analysis was used to estimate the rate ratio RR of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity. The rate of serious pneumonia was higher with fluticasone RR 2.
The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials. Inhaled corticosteroids are known to increase the risk of developing pneumonia in patients with chronic obstructive pulmonary disease COPD , but it is unclear whether this risk varies for different agents, particularly fluticasone and budesonide.
The risk of patients with COPD developing serious pneumonia is particularly elevated and dose related with fluticasone use and much lower with budesonide. Inhaled corticosteroids ICS are commonly used for the treatment of asthma and chronic obstructive pulmonary disease COPD , though their effectiveness for the latter remains controversial. With respect to pneumonia, however, there remain uncertainties as to whether ICS all carry a similar increased risk and whether the effect is dose related.
We conducted a population-based cohort study of treated patients with COPD to assess whether the different ICS vary in their risk of pneumonia and to evaluate the dose—response effects.
The databases contain information on demographics and all medical services rendered for all residents of the Province. These databases have been used previously to conduct epidemiological studies of the risks of ICS. The source population for this study consisted of all subjects who, between and , were dispensed at least one prescription for any of the following respiratory medications: Subjects with a mention of asthma, either as primary or secondary diagnosis during a hospitalisation, or using nedocromil, ketotifen, cromolyn or antileukotrienes, were excluded.
All subjects in the cohort were followed from cohort entry, taken as the date of the third prescription, until the first hospitalisation for pneumonia, death, end of RAMQ drug coverage, or 31 March In view of the large size of the cohort and the time-varying nature of ICS prescriptions, a nested case—control analysis within the cohort was performed.
Cases of serious pneumonia were defined as a hospitalisation for or death from pneumonia. The first hospitalisation with an admission or primary diagnosis of pneumonia of any cause, including influenza, was identified in the RAMQ hospitalisation database International Classification of Diseases ICD -9 codes — For outpatients, deaths with pneumonia as a principal cause were identified.
The date of admission or outpatient death was called the index date. When less than 10 potential controls were available for a case, all members of the risk set were included as controls for that case.
All prescriptions for ICS, alone or in a combination inhaler, dispensed between cohort entry and the index date were identified. These include inhaled beclomethasone, fluticasone, budesonide, triamcinolone and flunisolide.
All doses of ICS were converted to fluticasone-equivalent doses on the basis of relative topical potency and what experts consider to be comparable doses according to the National Asthma Education Expert Panel report 2 see figure 3—5b and 3—5c in that report and the Canadian asthma consensus statement see table 8 in that statement. The RRs were adjusted for age matched by design , sex, severity of respiratory disease, and other conditions associated with a risk of pneumonia.
Comorbidity included cardiac disease defined by a prescription for cardiotropes, antihypertensives, diuretics or vasodilators; diabetes defined by insulin or oral hypoglycaemic agents; central nervous system drugs included benzodiazepines, major tranquillizers, anticonvulsants and drugs for parkinsonism; osteoporosis drugs included calcium, vitamin D and biphosphonates; antirheumatic drugs included gold salts, methotrexate, azathioprine, hydroxychloroquine and chloroquine.
Non-steroidal anti-inflammatory drugs, antidepressive agents and narcotics were considered as separate categories. Current ICS users were also classified as users of fluticasone, budesonide or other ICS beclomethasone, flunisolide or triamcinolone. Dose—response was assessed using the fluticasone-equivalent daily dose of current users classified as high, moderate and low.
It was further analysed by modelling the actual current fluticasone-equivalent daily dose continuously using cubic splines models.
These models fit the dose—response curve using a cubic polynomial function separately within four mutually exclusive dose intervals, then imposing that the curves join at boundaries to generate a smooth continuous dose—response function.
A sensitivity analysis was performed by stratifying by prior COPD hospitalisation to address the possible inaccuracy of the COPD definition of our cohort and the fact that budesonide was most likely used more frequently for asthma in Quebec at the time of this study. This is because, while neither budesonide nor fluticasone was indicated for use in COPD, the fluticasone—salmeterol combination was approved and therefore promoted for COPD during the time period under study while the budesonide—formoterol combination was not.
All analyses were conducted using SAS V. The mean duration of follow-up was 5. The cases had more severe respiratory disease, with more prescriptions for respiratory drugs, including oral corticosteroids and antibiotics. The cases had a slightly higher prevalence of comorbidity. Characteristics of cases of hospitalised or fatal pneumonia and their matched controls selected from a cohort of patients with COPD. Characteristics of controls selected from cohort of patients with COPD, according to current use of fluticasone and budesonide.
Crude and adjusted rate ratios of serious pneumonia associated with current use, dose and past use of inhaled corticosteroids among patients with COPD. Crude and adjusted rate ratios of serious pneumonia associated with current use and dose of the different ICS among patients with COPD.
Crude and adjusted rate ratios of serious pneumonia associated with current use of fluticasone and budesonide, stratified by prior COPD hospitalisation. These elevated risks disappeared within a few months of stopping the use of ICS. Systemic corticosteroids have been associated with increased risks of pneumonia in patients with rheumatoid arthritis. Our findings confirm the observations of several randomised trials of varying durations and doses.
Our results confirm the subgroup analyses of the meta-analysis, suggesting that the risk is particularly elevated with high doses and start at short durations of use. Moreover, the risk of pneumonia did not increase with the dose of budesonide.
Furthermore, since a higher dose formulation was only available for the fluticasone—salmeterol combination, patients with more severe disease may have been more likely to have received a combination therapy containing fluticasone rather than budesonide. Therefore, data on this question from countries where budesonide has a greater market share would be a valuable addition to this evidence. There is good evidence supporting the effect of ICS on human pulmonary host defence, acting through several biological pathways, such as an inhibitory action on macrophage functions, a decrease in cytokine production and nitric oxide expression, which may lead to a failure to control infection.
Fluticasone is known to be more potent ie, greater effect on intracellular steroid receptors , more lipophilic and has a longer half life than budesonide. It is therefore not surprising that a greater risk of oropharyngeal side effects is found with fluticasone compared with budesonide.
Indeed, a more prolonged corticosteroid effect in the lungs and greater pulmonary retention will facilitate the local immunosuppressive action. This study has strengths and some limitations. In this study, we defined serious pneumonia as a hospitalisation with a primary diagnosis of pneumonia or death from pneumonia, but did not have proof that the diagnosis was based on radiographic findings as these are not recorded in the RAMQ databases. However, it is most likely that as a primary inpatient diagnosis, it was in fact supported by a radiographic finding.
To address confounding by COPD severity, we adjusted for the number of prescriptions for respiratory medications other than ICS, and for exacerbations as measured by prescriptions for oral corticosteroids, antibiotics, as well as prior hospitalisations for pneumonia and COPD exacerbation. Yet, residual confounding arising from unmeasured covariates can still be present. Of most concern is the possibility that budesonide may have been preferentially prescribed to patients with a lower risk of pneumonia, such as those with asthma or less severe COPD.
In this specific study, however, our main results, adjusted for differences in severity, are consistent with those of several randomised trials which are inherently free of confounding, albeit less powerful with smaller study populations.
Exposure to ICS was measured from dispensed prescriptions so that one must assume that the drugs were actually taken. However, not taking these medications would actually tend to underestimate the true risk increase. Nevertheless, our definition likely captured some patients with asthma. One can expect that this would reduce the estimate of risk of ICS since ICS do not appear to increase the risk of pneumonia in patients with asthma.
The dose—response effect with fluticasone that we found on the incidence of serious pneumonia, sustained over a long time, is important in the risk—benefit balance for patients with COPD. In conclusion, high and low doses of fluticasone in patients with COPD are associated with an important increase in the risk of serious pneumonia, while the risk with budesonide is comparatively low, even at high doses, though it needs further examination in light of recent data and the possibility that patients receiving budesonide are inherently at lower risk of pneumonia than those prescribed fluticasone.
Further investigations into why the two popular ICS fluticasone and budesonide have such different effects on the risk of pneumonia are warranted. Contributors SS acquired the data. All authors had full access to the data and SS is guarantor for the overall content. The funding agencies were not involved in the study design, data analysis and interpretation, or the preparation of the manuscript.
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Key messages What is the key question? What is the bottom line? Introduction Inhaled corticosteroids ICS are commonly used for the treatment of asthma and chronic obstructive pulmonary disease COPD , though their effectiveness for the latter remains controversial.
Study design The source population for this study consisted of all subjects who, between and , were dispensed at least one prescription for any of the following respiratory medications: Pneumonia cases and controls Cases of serious pneumonia were defined as a hospitalisation for or death from pneumonia.
ICS exposure All prescriptions for ICS, alone or in a combination inhaler, dispensed between cohort entry and the index date were identified. View inline View popup. Inhaled corticosteroids in COPD: Eur Respir J ; Suissa S , Barnes PJ. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med ; Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma.