Elsevier

Clinical Therapeutics

Volume 33, Issue 10, October 2011, Pages 1413-1432
Clinical Therapeutics

Pharmaceutical economics & health policy
Review article
Incidence and US Costs of Corticosteroid-Associated Adverse Events: A Systematic Literature Review

The data in this article were previously presented in poster form at the Annual Meeting of the American College of Rheumatology, November 6–11, 2010, Atlanta, Georgia.
https://doi.org/10.1016/j.clinthera.2011.09.009Get rights and content

Abstract

Objective

The objective of this systematic literature review was to evaluate the incidences and risks for adverse events (AEs) associated with oral and parenteral corticosteroids. An assessment was performed to estimate the costs of such AEs.

Methods

A systematic review of literature published from 2007 to 2009 was conducted to identify the incidence rates and risk ratios of corticosteroid-related AEs. The review protocol was developed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The literature search was expanded to include additional search terms for psychiatric conditions, infections, and peptic ulcers. Costs obtained from a separate narrative literature review were applied to AEs likely to affect third-party payers in the United States.

Results

A total of 357 publications were identified from the primary (n = 323) and secondary (n = 34) searches. Of these, 310 were excluded because they did not evaluate AEs related to corticosteroids, were an excluded publication type, or for other reasons. A final list of 47 studies were used for data extraction. Across patient populations, the most frequently reported corticosteroid-associated AEs were psychiatric events, infections, gastric conditions, and fractures. Corticosteroid-associated AEs reported to occur at an incidence >30% were sleep disturbances, lipodystrophy, adrenal suppression, metabolic syndrome, weight gain, and hypertension. Vertebral fractures were reported at an incidence of 21% to 30%. Dose-response relationships were documented for fractures, acute myocardial infarction, hypertension, and peptic ulcer. The costs of managing AEs that may occur with corticosteroids can be substantial. The literature reported 1-year per-patient costs of up to $26,471.80 for nonfatal myocardial infarction, and per-event costs as high as $18,357.90 for fracture. The findings from the present review should be interpreted cautiously due to several limitations, including the retrospective design of most of the studies identified, risk for confounding due to underlying disease activity or patient population, and the relatively small number of studies that reported each AE association. As this cost analysis was preliminary, a comprehensive pharmacoeconomic analysis should be undertaken to confirm the findings.

Conclusion

Based on the findings from this review, systemic corticosteroids are a common cause of AEs that may be costly to payers.

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

References (69)

  • M. Luppa et al.

    Cost-of-illness studies of depression: a systematic review

    J Affect Disord

    (2007)
  • A. Elixhauser et al.

    Adverse Drug Events in U.S. Hospitals, 2004

  • J.N. Hoes et al.

    Adverse events of low- to medium-dose oral glucocorticoids in inflammatory diseases: a meta-analysis

    Ann Rheum Dis

    (2009)
  • S. Raofi et al.

    Medication therapy in ambulatory medical care: United States, 2003–4National Center for Health Statistics

    Vital Health Stat

    (2006)
  • F. Buttgereit et al.

    Glucocorticoids in the treatment of rheumatic diseases: an update on the mechanisms of action

    Arthritis Rheum

    (2004)
  • A. Zonana-Nacach et al.

    Damage in systemic lupus erythematosus and its association with corticosteroids

    Arthritis Rheum

    (2000)
  • I. Karp et al.

    Recent corticosteroid use and recent disease activity: independent determinants of coronary heart disease risk factors in systemic lupus erythematosus?

    Arthritis Rheum

    (2008)
  • M. Pisu et al.

    The cost of glucocorticoid-associated adverse events in rheumatoid arthritis

    Rheumatology

    (2005)
  • D. Hailey et al.

    Study quality and evidence of benefit in recent assessments of telemedicine

    J Telemed Telecare

    (2004)
  • G.A. Akerkar et al.

    Corticosteroid-associated complications in elderly Crohn's disease patients

    Am J Gastroenterol

    (1997)
  • Avina-Zubieta JA, Abrahamowicz M, Choi HK, et al. Corticosteroids increase risk for acute myocardial infarction in...
  • Acute adverse reactions to prednisone in relation to dosage

    Clin Pharmacol Ther

    (1972)
  • E.S. Brown

    Mood changes during prednisone bursts in outpatients with asthma

    J Clin Psychopharmacol

    (2002)
  • C.F. Christiansen et al.

    Glucocorticoid use and risk of atrial fibrillation or flutter: a population-based, case-control study

    Arch Intern Med

    (2009)
  • G.A. Chrousos et al.

    Side effects of glucocorticoid treatmentExperience of the Optic Neuritis Treatment Trial

    JAMA

    (1993)
  • H.O. Conn et al.

    >Corticosteroids and peptic ulcer: meta-analysis of adverse events during steroid therapy

    J Intern Med

    (1994)
  • F. de Vries et al.

    Fracture risk with intermittent high-dose oral glucocorticoid therapy

    Arthritis Rheum

    (2007)
  • K. Dietrich et al.

    Glucocorticoid therapy and risk of bladder cancer

    Br J Cancer

    (2009)
  • S.F. Dowell et al.

    Severe varicella associated with steroid use

    Pediatrics

    (1993)
  • S. Einaudi et al.

    Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

    Pediatr Blood Cancer

    (2008)
  • L. Fardet et al.

    Corticosteroid-induced lipodystrophy is associated with features of the metabolic syndrome

    Rheumatology

    (2007)
  • L. Fardet et al.

    Corticosteroid-induced clinical adverse events: frequency, risk factors and patient's opinion

    Br J Dermatol

    (2007)
  • S.E. Gabriel et al.

    Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica

    Arthritis Rheum

    (1997)
  • J.R. Garcia-Berrocal et al.

    Adverse effects of glucocorticoid therapy for inner ear disorders

    ORL J Otorhinolaryngol Relat Spec

    (2008)
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