Adverse outcomes from initiation of systemic corticosteroids for asthma: long-term observational study

Abstract

Purpose

Prior work suggests a threshold of four courses/year of systemic corticosteroid (SCS) therapy is associated with adverse consequences. The objective of this study was to investigate the onset of adverse outcomes beginning at SCS initiation in a broad asthma population.

Patients and methods

This historical matched cohort study utilized anonymized, longitudinal medical record data (1984–2017) of patients (≥18 years) with active asthma. Matched patients with first SCS prescription (SCS arm) and no SCS exposure (non-SCS arm) were followed until first outcome event. Associations between time-varying exposure measures and onset of 17 SCS-associated adverse outcomes were estimated using Cox proportional hazard regression, adjusting for confounders, in separate models.

Results

We matched 24,117 pairs of patients with median record availability before SCS initiation of 9.9 and 8.7 years and median follow-up 7.4 and 6.4 years in SCS and non-SCS arms, respectively. Compared with patients in the non-SCS arm, patients prescribed SCS had significantly increased risk of osteoporosis/osteoporotic fracture (adjusted hazard ratio 3.11; 95% CI 1.87–5.19), pneumonia (2.68; 2.30–3.11), cardio-/cerebrovascular diseases (1.53; 1.36–1.72), cataract (1.50; 1.31–1.73), sleep apnea (1.40; 1.04–1.86), renal impairment (1.36; 1.26–1.47), depression/anxiety (1.31; 1.21–1.41), type 2 diabetes (1.26; 1.15–1.37), and weight gain (1.14; 1.10–1.18). A dose-response relationship for cumulative SCS exposure with most adverse outcomes began at cumulative exposures of 1.0–<2.5 g and for some outcomes at cumulative exposures of only 0.5–<1 g (vs >0–<0.5 g reference), equivalent to four lifetime SCS courses.

Conclusion

Our findings suggest urgent need for reappraisal of when patients need specialist care and consideration of nonsteroid therapy.

Keywords:

• adverse outcomes
• asthma
• cumulative exposure
• oral corticosteroids
• systemic corticosteroids

Acknowledgments

This study was funded by AstraZeneca. We thank Aruni Seneviratna and Shreyasee Pradhan for their contributions to the project management for this study and Derek Skinner for his contributions to the data acquisition and handling. Writing and editorial support was provided by Elizabeth V. Hillyer, DVM, supported by the Observational and Pragmatic Research Institute Pte. Ltd (OPRI).

Author contributions

All authors contributed to the study conception and design, data acquisition, and data analysis and interpretation. All authors contributed to critically revising the manuscript and approved the final version prior to submission. All authors agree to be accountable for all aspects of the work and to ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

Disclosures

DBP has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through OPRI) from Aerocrine, AKL Research and Development Ltd, AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Mylan, Mundipharma, Napp, Novartis, Pfizer, Respiratory Effectiveness Group, Teva Pharmaceuticals, Theravance, UK National Health Service, and Zentiva; payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Skyepharma, and Teva Pharmaceuticals; payment for manuscript preparation from Mundipharma and Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma and Novartis; payment for travel/accommodation/meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva Pharmaceuticals, and Zentiva; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of OPRI (Singapore); and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation program me, and Health Technology Assessment. FT, XX, and TNT are employees and shareholders of AstraZeneca, which supplied the funding for this study. JV and MK are employees of OPRI, and JLZJ at the time of the study was an employee of OPRI, which conducted this study and which has conducted paid research in respiratory disease on behalf of the following organizations in the past 5 years: Aerocrine, AKL Research and Development Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva (a Sanofi company).