In this large, population based study of privately insured non-elderly (<64 years) adults in the US, one in five received a new outpatient prescription for short term use of oral corticosteroids over a three year period. These drugs were used for a wide range of conditions, such as upper respiratory tract infections, spinal conditions, and allergies and were commonly prescribed by both generalist and specialist physicians. Importantly, these prescriptions were associated with statistically significantly higher rates of sepsis, venous thromboembolism, and fracture despite being used for a relatively brief duration.

Though the long term complications of chronic corticosteroid use are well known, there is a paucity of clinical data on the potential short term adverse effects of corticosteroid use, despite the existence of pathophysiological evidence suggesting possible early changes after drug initiation. For example, the impact of corticosteroids on the immune system has been widely studied, and in randomized controlled trials of prednisone (versus placebo) in healthy adults there were effects on peripheral cell lines (eg, peripheral white blood cells) within the first day after drug ingestion that were noticeable with 10 mg, 25 mg, and 60 mg doses. 48 49 Rapid alteration in markers of bone metabolism has also been documented with the initiation of corticosteroid use; mean serum concentrations of osteocalcin and both serum propeptide of type I N-terminal and C-terminal procollagen were statistically significantly decreased in the early weeks after starting prednisone. 43 The mechanisms underlying the increase in venous thromboembolism are not fully known. However, infection is a common trigger of thrombosis, 50 suggesting that both venous thromboembolism and sepsis may be potentially mediated through changes in the immune system. Further work is needed to clarify whether and how our observations in this large population may be linked to potential causal pathways.

Estimates of corticosteroid use from cross sectional studies range from 0.5% to 1.2% over various study periods. 7 9 10 An analysis of the National Health and Nutrition Examination Survey described self reported use of drugs taken within the previous 30 days. 7 Its findings indicated a mean duration of corticosteroid use exceeding four years among users—thus capturing a larger proportion of chronic treatment but potentially underreporting short term use. Furthermore, although the analyses were weighted, the actual sample of corticosteroid users included only 356 people. In our longitudinal analysis of 1.5 million insured Americans, the incidence was approximately 7% for short term oral corticosteroid use on a yearly basis.

Strengths and limitations of this study

Our findings are particularly of concern given the large number of patients exposed to short term oral corticosteroids in the general adult population. Clinical guidelines typically recommend using the lowest dose of steroids for the shortest period to prevent adverse events.2425 However, we found that even short durations of use, regardless of dose, were associated with increased risks of adverse events and that few patients were using very low doses. Only 6.3% of the prescriptions were for a prednisone equivalent dose of less than 17.5 mg/day, and 1.0% of prescriptions were for less than 7.5 mg/day; therefore, we were unable to examine events in patients given very low doses for short periods. A major reason for the higher than expected doses was the widespread use of “fixed dose” methylprednisolone dosepaks that are tapered over a short period. These dosepaks offer ease of use but do not permit the individualization of drug dosing to minimize exposure.

A substantial challenge to improving use of oral corticosteroids will be the diverse set of conditions and types of providers who administer these drugs in brief courses. This raises the need for early general medical education of clinicians about the potential risks of oral corticosteroids and the evidence basis for their use, given that use may not be specific to a particular disease or specialty. Suprisingly, the most common prescribers were not subspecialists, such as rheumatologists, who are most experienced with treating inflammatory conditions and the long term use of these drugs. We also found that the most common indications for corticosteroid use included conditions such as upper respiratory tract infections, spinal conditions, and allergies, which often have marginal benefit and for which alternate treatments may be similarly effective and safer. For example, a multimodal pain treatment regimen can be used to treat spinal pain, and non-sedating antihistamines can be used for allergies. An examination of potential determinants of corticosteroid use will be needed to inform future intervention strategies. If corticosteroid use is driven by patient preferences, education on the potential harms should be expanded. If prescriptions are primarily driven by provider decisions, decision support tools to identify alternatives to corticosteroids (eg, non-steroidal anti-inflammatory drugs for acute gout30 or tricyclic antidepressants for neuropathic pain51) may be a more effective approach, but additional studies will be required to substantiate these possible alternatives as some of these drugs are available over the counter.

Our study has several limitations. Firstly, our cohort only includes commercially insured adults and excludes patients aged more than 64 years, which potentially limits the generalisability of our findings. We focused on younger adults as these individuals tend to have fewer comorbid conditions, and therefore our findings may be less likely to be biased by the high prevalence of age related comorbid conditions. Although our reference population is commercially insured adults, we have no reason to suspect this characteristic should bias a possible association between corticosteroid use and adverse events. Secondly, we determined the indication for corticosteroid use and the specific provider prescribing the drug by linking outpatient claims recorded most closely to the prescription date; thus we might have misclassified some treatment indications and specialties. Thirdly, we were unable to adequately assess the risks of adverse events at very low doses of corticosteroids, given the infrequency of use at these doses.

Fourthly, we did not evaluate all of the possible adverse events linked to oral corticosteroids but focused on three acute adverse reactions. This makes our findings even more striking as they are likely a conservative estimate of the associated risks of adverse events. For example, we only focused on hospital admissions for sepsis, ignoring less serious but likely important infections, and we did not assess some adverse events such as behavioral or psychiatric conditions. In addition, a dose- response trend was not seen and may reflect our selection criteria of using prescriptions of less than 30 days. Fifthly, although we used a within person approach to control for genetic predisposition, health related behaviors, and comorbid conditions and adjusted for time varying use of different drugs, other time varying factors could be differentially distributed between the risk and baseline periods. However, the incidence rate ratios were strong (many >3.0) so that any residual confounding would have to be appreciable to fully explain our findings. Assumptions of the SCCS design were mitigated by using only the first event for each of the three outcomes, and therefore independence of recurrent events and the potential influence of past events on subsequent drug use (if this occurred) yielded incidence rate ratios that might be somewhat conservative. Survival bias was not an issue since by design all patients were alive during the periods when the outcomes were measured (ie, the comparator period was before the first use of corticosteroids).