Association of Dose of Inhaled Corticosteroids and Frequency of Adverse Events

Rationale: Inhaled corticosteroids (ICSs) are the cornerstone of asthma treatment and significantly improve morbidity and mortality. Adverse effects of oral corticosteroids are well documented, but less is known about ICS. Objectives: The aim of this study was to determine the risk of adverse effects from short-term ICS use in people with asthma. Methods: We conducted observational studies in adults with asthma using two different United Kingdom nationwide datasets: Clinical Practice Research Datalink Aurum and Clinical Practice Research Datalink GOLD. The exposure was incident ICS; the outcomes were a major adverse cardiac event (MACE), arrhythmia, pulmonary embolism (PE), and pneumonia over 12 months. Our main analyses used a cohort method with stabilized inverse probability treatment weighting to balance confounding between exposed and unexposed patients. Secondary analyses included nested case–control studies and self-controlled case series. ICS use was treated as both a categorical and a continuous variable. Absolute risk was estimated using weighted flexible parametric models. Measurements and Main Results: Among 162,202 patients in our main cohort, there was an association with all outcomes at the medium daily ICS dose or higher (hazard ratios [HRs] at 201–599 μg: MACE, 2.63 [95% confidence interval (CI), 1.66–4.15]; arrhythmia, 2.21 [95% CI, 1.60–3.04]; PE, 2.10 [95% CI, 1.37–3.22]; and pneumonia, 2.25 [95% CI, 1.77–2.85]; HRs at >600 μg: MACE, 4.63 [95% CI, 2.62–8.17]; arrhythmia, 2.91 [95% CI, 1.72–4.91]; PE, 3.32 [95% CI, 1.69–6.50]; and pneumonia, 4.09 [95% CI, 2.98–5.60]). There were no associations with lower doses of ICSs. Secondary analyses produced similar results. The number needed to harm using 12 months of ICS at 201 to 599 μg was as follows: MACE, 473 (95% CI, 344–754); arrhythmia, 567 (95% CI, 395–1,006); PE, 1,221 (95% CI, 744–3,388); and pneumonia, 230 (95% CI, 177–327). The number needed to harm using ICS at >600 μg was as follows: MACE, 224 (95% CI, 148–461); arrhythmia, 396 (95% CI, 228–1,523); PE, 577 (95% CI, 309–4,311); and pneumonia, 93 (95% CI, 69–141). Conclusions: Short-term use of low-dose ICS was not associated with adverse effects. Moderate to high daily ICS doses were associated with an increased risk, but low frequencies, of cardiovascular events, PE, and pneumonia. It is important for clinicians to adhere to guideline recommendations to use the lowest effective ICS dose.