Does Short-Term Oral Steroid Use Carry Serious Risk?
Clinical Context
Corticosteroids are potent anti-inflammatory drugs that are highly effective for symptomatic relief of rheumatologic and other conditions and that have been in widespread use for more than 7 decades. Long-term corticosteroid use is associated with a wide variety of cardiovascular, musculoskeletal, digestive, endocrine, ophthalmic, skin, and nervous system effects, including acute infection, venous thromboembolism, avascular necrosis, and fracture, as well as chronic diabetes mellitus, hypertension, osteoporosis, and iatrogenic Cushing syndrome.
To date, the overall use of short-term oral corticosteroids in a general population and potential associated risks have not been completely described. The goals of this retrospective cohort study and self-controlled case series were to evaluate the frequency of prescriptions for short-term oral corticosteroid use in an outpatient setting and associated adverse events of sepsis, venous thromboembolism (VTE), and fractures.
Study Synopsis and Perspective
The millions of Americans prescribed short-term oral corticosteroids are taking a dose of risk along with their medication, according to a cohort study of more than 1.5 million adults.
Within 30 days of initiating these drugs, even at relatively low doses, users had a nearly 2-fold increased risk for fracture, a 3-fold increased risk for VTE, and a 5-fold increased risk for sepsis.
"Greater attention to initiating prescriptions of these drugs and monitoring for adverse events may potentially improve patient safety," write Akbar K. Waljee, MD, an assistant professor of gastroenterology at the University of Michigan in Ann Arbor, and colleagues. They present their findings in an article published April 12 in the BMJ.
They found that more than 1 in 5 adults included in the Clinformatics DataMart, a large national database of commercial insurance claims, received prescriptions for short-term oral corticosteroids during the 3-year study, which ran from January 1, 2012, to December 31, 2014.
Although corticosteroids are among the most common cause for hospitalization for drug-related adverse events, and various specialties have long focused on optimizing their long-term use, the short-term risks associated with the drugs have been less carefully studied.
"Although physicians focus on the long-term consequences of steroids, they don't tend to think about potential risks from short-term use," said Dr Waljee in a university news release. "We see a clear signal of higher rates of these three serious events within 30 days of filling a prescription. We need to understand that steroids do have a real risk and that we may use them more than we really need to. This is so important because of how often these drugs are used."
Of 1,548,945 adults 18 to 64 years old included in the database, 327,452 (21.1%) received at least 1 outpatient prescription for short-term oral corticosteroids (≤30 days). The mean age of users was 45.5 years (standard deviation [SD], 11.6 years) compared with 44.1 years (SD, 12.2 years) for nonusers (P<.001). The median duration of use was 6 days (interquartile range, 6-12 days).
The 6 most common indications for the drugs were upper respiratory tract infections, spinal conditions, intervertebral disk disorders, allergies, bronchitis, and nonbronchitic lower respiratory tract disorders. Together, those indications accounted for about half of all prescriptions. The 2 most common physician specialties prescribing short-term oral corticosteroids were family medicine and general internal medicine.
Nearly half (46.9%) of recipients were prescribed a 6-day prepackaged methylprednisolone "dosepak," which tapers the dose from highest to lowest. Dr Waljee noted in the news release that although individual oral steroid pills can cost less than a dollar each for a 7-day course, the prepackaged version may cost several times that and often initiates therapy with a higher high dose than may be necessary.
Use was more frequent among older patients, women, and white adults, with significant regional variation (all P<.001).
Within 30 days of drug initiation, there was an increase in incidence rate of the following: sepsis, with a rate ratio of 5.30 (95% confidence interval [CI], 3.80-7.41); VTE, with a rate ratio of 3.33 (95% CI, 2.78-3.99); and fracture, with a rate ratio of 1.87 (95% CI, 1.69-2.07).
The increased risk persisted at prednisone equivalent doses of less than 20 mg/day, with an incidence rate ratio (IRR) of 4.02 for sepsis, 3.61 for VTE, and 1.83 for fracture (all P<.001).
Rate ratios decreased during the following subsequent 31 to 90 days, however.
Although rare, hospitalizations were also more frequent in users than nonusers, with 0.05% of users admitted for sepsis compared with 0.02% of nonusers. For blood clots, the admission rate was 0.14% vs 0.09%, and for fractures, it was 0.51% vs 0.39%.
Dr Waljee and colleagues found it significant that the most frequent corticosteroid prescribers were not rheumatologists or other subspecialists experienced in treating inflammatory conditions long-term. "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," they write. "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."
On the basis of these findings, Dr Waljee recommended prescribing the smallest possible amount of corticosteroids for treating the condition in question. "If there are alternatives to steroids, we should...use those when possible," he said in the release. "Steroids may work faster, but they aren't as risk-free as you might think."
This study was partly supported by the University of Michigan's Institute for Healthcare Policy. The authors have disclosed no relevant financial relationships.
BMJ. 2017;357:j1415.[1]
Study Highlights
Of 1,548,945 adults 18 to 64 years old who were continuously enrolled from 2012 to 2014 in a nationwide dataset of private insurance claims, 327,452 (21.1%) received 1 or more outpatient prescriptions for short-term (<30 days) oral corticosteroid use during these 3 years.
Annual incidence was approximately 7%.
Short-term oral corticosteroid users were slightly older than nonusers (mean age, 45.5±11.6 vs 44.1±12.2 years; P<.001) and used steroids for a median duration of 6 days (interquartile range, 6-12 days).
Older patients, women, and white adults had higher rates of use than the general population, with significant regional variation (P<.001 for all).
Upper respiratory tract infections, spinal conditions, intervertebral disc disorders, allergies, bronchitis, and nonbronchitic lower respiratory tract conditions were the leading indications for use, accounting for approximately half of all prescriptions.
Providers from a wide range of specialties, particularly family medicine and general internal medicine, issued prescriptions for a wide range of conditions.
Only 6.3% of prescriptions were for a prednisone equivalent dose of less than 17.5 mg/day, and only 1.0% for less than 7.5 mg/day; 46.9 % were for a 6-day prepackaged methylprednisolone "dosepak" allowing tapering, but at higher cost and higher starting dose than may be needed.
A within-person approach for assessing adverse events controlled for genetic predisposition, health-related behaviors, and comorbidities and adjusted for time-varying use of different drugs
Within 30 days of starting oral corticosteroids, incidence rates of adverse events increased, with a subsequent decrease during the next 31 to 90 days.
IRRs were 5.30 for sepsis (95% CI, 3.80-7.41), 3.33 for VTE (95% CI, 2.78-3.99), and 1.87 for fracture (95% CI, 1.69-2.07).
Increased risk was still present at prednisone equivalent doses of less than 20 mg/day (IRR, 4.02 for sepsis, 3.61 for VTE, and 1.83 for fracture; all P<.001).
Hospitalizations were rare, but more frequent with corticosteroids (for sepsis, 0.05% vs 0.02%; for VTE, 0.14% vs 0.09%; and for fractures, 0.51% vs 0.39%).
On the basis of their findings, the investigators concluded that 20% of adults in a commercially insured US plan received prescriptions for short-term oral corticosteroid use during a 3-year period, with associated increased risk for adverse events.
Pathophysiologic evidence suggests possible early changes after starting corticosteroids, with immune system effects on peripheral cell lines within the first day and rapid changes in markers of bone metabolism.
Mechanisms underlying the increase in VTE are not fully understood, but it may be potentially mediated through immune system changes.
Further research should assess potential causal pathways.
Early general medical education of clinicians should highlight the potential risks of oral corticosteroids and the evidence supporting their use, given that use may not be specific to a particular disease or specialty.
The most common indications for corticosteroid use included conditions for which there is little benefit and for which other treatments may be similarly effective and safer.
Evaluating potential predictors of corticosteroid use, such as patient preferences or provider decisions, should help guide future intervention strategies.
Study limitations include lack of generalizability to other settings and to patients older than 64 years, possible misclassification of some treatment indications and specialties, failure to assess all possible adverse events of oral corticosteroids, and possible residual confounding.
In addition, very few patients were given very low doses for short periods, largely caused by dosepaks that facilitate tapering but hinder individualization of dose regimens.
Clinical Implications
During a 3-year period, more than 1 in 5 adults in a commercially insured US plan used oral corticosteroids for less than 30 days, based on a retrospective study.
Short-term oral corticosteroid use, even at relatively low doses, was linked to increased rates of sepsis, VTE, and fracture. Additional studies are needed to identify optimal use of corticosteroids and to explore whether treatment alternatives may improve patient safety.
Implications for the Healthcare Team: Greater attention to using caution when starting oral corticosteroids and monitoring for adverse events may potentially improve patient safety.
