Which ICS/LABA combinations for COPD confer the lowest risk of severe pneumonia?

In chronic obstructive pulmonary disease (COPD) patients initiating inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA) combinations, both budesonide (BUD)/formoterol (FOR) dry-powder inhalers (DPIs) and beclomethasone (BEC)/FOR metered-dose inhalers (MDIs) pose lower risks of severe pneumonia and severe adverse events (AEs) compared with fluticasone (FLU)/salmeterol (SAL) delivered using the same type of inhaler, as reported in a recent study.

However, BUD/FOR appears to confer the greatest protection against severe pneumonia when the average daily dose of ICS is factored in, according to the investigators.  

The current analysis included 7,015 FLU/SAL DPI users and 7,015 propensity-matched users of BUD/FOR DPI, as well as 5,107 FLU/SAL MDI users and 5,107 matched users of BEC/FOR MDI. The ICS daily dose was differentially distributed among the treatment groups; majority of users were exposed to a dose of 500 mcg in the FLU/SAL DPI group (88 percent), 1,000 mcg in the FLU/SAL MDI group (50 percent), 800 mcg in the BUD/FOR DPI group (51 percent) and 500 mcg in the BEC/FOR MDI group (61 percent).

Cox regression models showed that compared with FLU/SAL delivered via either device type, both BUD/FOR DPIs and BEC/FOR MDIs conferred lower risks of severe pneumonia (hazard ratio [HR], 0.83, 95 percent confidence interval [CI], 0.70–0.98 and HR, 0.69, 95 percent CI, 0.58–0.81, respectively) and severe AE (HR, 0.88, 95 percent CI, 0.78–0.99 and HR, 0.90, 95 percent CI, 0.84–0.96, respectively). [Chest 2019;doi:10.1016/j.chest.2019.12.006]

When the models were further controlled for the average daily ICS dose, the risk of severe pneumonia was consistently lower with BUD/FOR DPI but not with BEC/FOR MDI.

Additionally, use of lower vs higher average daily doses of FLU/SAL MDI and BEC/FOR MDI led to a 66- and 38-percent reduction, respectively, in the risk of severe pneumonia (adjusted HR, 1.66, 95 percent CI, 1.03–2.70 and adjusted HR, 1.38, 95 percent CI, 1.04–1.81, respectively).

The findings were consistent in most of the prespecified subgroups and across all sensitivity analyses.

According to the investigators, the differential risk of pneumonia observed across several ICS/LABA combinations might be explained by the distinct physicochemical and pharmacokinetic properties of each ICS.

“By carefully comparing all three ICSs and controlling for inhaler device type and ICS daily dose, we can better delineate the safety and effectiveness of different ICSs. FLU propionate is more lipophilic than BUD, and BEC is a lipophilic prodrug but rapidly converts to its active metabolites with lower lipophilicity when it contacts bronchial secretions,” they pointed out. [Br J Clin Pharmacol 2015;80:372-380]

“In general, a lipophilic ICS has a longer retention time within airway or lung tissue to exert local immunosuppression and reduce inflammation. On the other hand, the solubility of FLU propionate is much lower than that of BUD and the active form of BEC, resulting in a slower rate of particle dissolution and uptake into airway tissue,” they continued. [Eur Respir J 2017;doi:10.1183/13993003.00037-2017]

The use of a less soluble ICS (ie, FLU) should then lead to a higher proportion of undissolved particles in the airway lumen, potentially impairing macrophage function and consequently delaying clearance of bacteria from the airways and increasing the risk of pneumonia, as evidence suggests. [Int J Chron Obstruct Pulmon Dis 2017;12:3055-3064]

Despite the presence of several limitations, the current data highlight the importance of considering the properties of different ICSs and using the lowest effective dose when prescribing ICSs for COPD patients, the investigators said.