Pharmaceutical economics & health policyReview articleIncidence and US Costs of Corticosteroid-Associated Adverse Events: A Systematic Literature Review
Introduction
Corticosteroids are important and commonly used medications because of their potent anti-inflammatory and immunosuppressive properties. Systemic corticosteroids are a mainstay of treatment for many conditions, including rheumatologic conditions (eg, rheumatoid arthritis, temporal arteritis, polymyalgia rheumatica, systemic lupus erythematosus [SLE]), allergic reactions, hepatitis, obstructive lung diseases (eg, asthma, chronic obstructive pulmonary disease), and inflammatory bowel diseases (eg, ulcerative colitis, Crohn's disease).1, 2 Systemic corticosteroids are also widely used as a part of the immunosuppressive regimen after organ transplantation and in oncology as a part of chemotherapy.2 In 2003–2004, corticosteroids were the 19th most commonly mentioned (ie, ordered, supplied, administered, or continued) class of drug at ambulatory care visits, used by an estimated 141.7 per 1000 persons in the United States.3 Prednisone was the 15th most commonly mentioned drug in US ambulatory care visits, with 16.6 million mentions, or ∼1% of all mentions of drugs.3 Corticosteroids have dose-related anti-inflammatory and immunomodulatory effects that are mediated primarily by genomic mechanisms activated by corticosteroid binding to glucocorticoid receptors.4 The direct relationship between corticosteroid dosage and degree of glucocorticoid receptor saturation is thought to explain the observation that clinical activity generally increases with increasing corticosteroid dosage (Table I).4 Likewise, the nonspecific nongenomic activity of corticosteroids appears to play an increasing role in the therapeutic effect as dosage increases.4
Although corticosteroids are effective anti-inflammatory and immunomodulatory agents, they exact a toll with respect to adverse events (AEs) and toxicities. Corticosteroids have been associated with AEs that are common and may be severe or life-threatening. According to data from the Healthcare Cost and Utilization Project (HCUP),1 corticosteroids were the most common specific cause of drug-related AEs, accounting for 10.3% of all drug-related AEs and 141,000 hospital stays in the United States in 2004. The contribution of corticosteroids to morbidity is illustrated by findings in patients with SLE, who may be prescribed long-term corticosteroids. In the Hopkins Lupus Cohort Study (n = 539),5 the cumulative dose of prednisone was associated with osteoporotic fractures (relative risk [RR] = 2.5), symptomatic coronary artery disease (CAD) (RR = 1.7), and cataracts (RR = 1.9). Each 2-month period of exposure to high-dose prednisone (defined as ≥60 mg/d for ≥2 months) was associated with a 1.2-fold increase in the risks for avascular necrosis and stroke. In a study based on a review of medical records from 11,359 clinic visits in 310 patients with SLE at the Montreal General Hospital, Montreal, Quebec, Canada, the past-year corticosteroid dose was found to be a predictor of the 2-year risk for CAD, and the 8 risk factors for CAD.6
Although the product costs of corticosteroids are relatively low, their total direct and indirect costs may be considerably higher than the price of the drugs themselves when the cost of managing short- and long-term AEs is considered. The cost of corticosteroid-associated AEs has been evaluated in few studies, each having limited representativeness or generalizability with respect to factors such as patient population and country (ie, variability in currency, costs of medical services, and treatment patterns).7, 8 Information on the costs of corticosteroid-associated AEs is important to physicians and payers in evaluating treatment strategies for conditions for which corticosteroids are prescribed. The present investigation evaluated the incidences of and risks for AEs associated with oral and parenteral corticosteroids in the general population, using a systematic review of interventional and observational studies published in the medical literature. A narrative review was used for determining the costs of the AEs likely to affect third-party payers in the United States.
Section snippets
Methods
The present study was an extension and amplification of a review of the medical literature published from 1990 to 20077 of the costs attributable to corticosteroid-associated AEs based on population rates and costs in the United Kingdom, conducted by Manson et al.7 Although that study reviewed costs in the United Kingdom, it was chosen as a foundation for this US-focused initiative because of its recency and its comprehensiveness relative to other assessments of corticosteroid-associated AEs.
Study Disposition and Characteristics
The Figure shows the disposition of publications identified for the analysis. The number of unique, potentially relevant publications identified and screened for retrieval was 323, of which 47 (27 from the primary search, 20 from the secondary search) were included in the data extraction.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 More than half of the
Discussion
Corticosteroids are an integral aspect of management of many autoimmune and inflammatory conditions. Although corticosteroids have been reported to have substantial clinical benefit in many diseases, they have been associated with AEs, particularly with long-term treatment. The findings from this review support that systemic corticosteroids are a common cause of AEs. AEs reported with particularly high frequency (>30% of patients) with corticosteroids included sleep disturbances, lipodystrophy,
Conclusions
Based on findings from this literature review, systemic corticosteroids are a common cause of AEs that range from bothersome to patients to severe or life-threatening. Corticosteroid-induced AEs such as sleep disturbances, lipodystrophy, hypertension, and adrenal suppression were reported with high frequency; while the absolute incidence was low for other AEs (eg, acute myocardial infarction and infections), corticosteroids were still significantly associated with a greater risk of development.
Acknowledgments
The authors would like to thank Jane Saiers, PhD (The WriteMedicine, Inc.) for assistance with writing this manuscript.
This work was supported by GlaxoSmithKline. GlaxoSmithKline and Human Genome Sciences funded the conduct of this review. Author disclosures are as follows: Dr. Sarnes is an employee of Xcenda, LLC, which received funding from GlaxoSmithKline and Human Genome Sciences to conduct this research. Drs. Kan and Bass are employees of GlaxoSmithKline, and Dr. Dennis is an employee of
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Affiliation at the time of writing.