short-term use of oral corticosteroids among adults in the ... · corticosteroid use is much less...

Confidential: For Review Only

Short-Term Use of Oral Corticosteroids Among Adults in the

United States

Journal: BMJ

Manuscript ID BMJ.2016.035125

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 22-Aug-2016

Complete List of Authors: Waljee, Akbar; VA Center for Clinical Management Research; University of Michigan, Institute for Healthcare Policy and Innovation Rogers, Mary; University of Michigan, Institute for Healthcare Policy and Innovation; University of Michigan Medical School, Department of Internal Medicine

Lin, Paul; University of Michigan, Healthcare Policy and Innovation Singal, Amit; University of Texas Southwestern, Stein, Joshua; University of Michigan Medical School, Institute for Healthcare Policy and Innovation; University of Michigan, Ophthalmology and Visual Sciences Marks, Rory; University of Michigan Medical School, Department of Internal Medicine Ayanian, John; University of Michigan School of Medicine, Internal Medicine; University of Michigan Institute of Health Care Policy and Innovation, Nallamothu, Brahmajee; University of Michigan Medical School, Institute for Healthcare Policy and Innovation; University of Michigan Medical

School, Division of Cardiovascular Medicine

Keywords: corticosteroid use, adverse events

https://mc.manuscriptcentral.com/bmj

BMJ


Short-Term Use of Oral Corticosteroids Among Adults in the United States

Akbar K. Waljee, M.D., M.S. (1,2,3)

Mary A. M. Rogers, PhD. (2,4)

Paul Lin, M.S. (2)

Amit G. Singal, M.D. (5)

Joshua D. Stein M.D., M.S. (2,6,7)

Rory M. Marks., M.B., B.S. (8)

John Z. Ayanian, M.D. M.P.P (2,4,7)

Brahmajee K. Nallamothu, M.D., M.P.H. (1,2,9)

1. VA Center for Clinical Management Research, Ann Arbor, MI

2. University of Michigan Medical School, Institute for Healthcare Policy and

Innovation, Ann Arbor, MI

3. University of Michigan Medical School, Department of Internal Medicine,

Division of Gastroenterology and Hepatology, Ann Arbor, MI


Division of General Medicine, Ann Arbor, MI

5. Department of Internal Medicine, University of Texas Southwestern Medical

Center, Dallas, TX

6. University of Michigan Medical School, Department of Ophthalmology and

Visual Science, Ann Arbor, MI

7. University of Michigan School of Public Health, Department of Health

Management and Policy, University of Michigan, Ann Arbor, MI


Division of Rheumatology, Ann Arbor, MI


Division of Cardiovascular Medicine, Ann Arbor, MI

Word Count: 3115

Abstract Word Count: 231

Corresponding Author Contact Information:

Akbar K. Waljee, M.D., M.S.

2215 Fuller Road

Gastroenterology 111D

Ann Arbor, MI 48105, USA

Phone: 734-845-5865

Fax: 734-845-3237

Email: [email protected]

Page 1 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


ABSTRACT Objective: To determine the frequency of prescriptions for short-term oral

corticosteroids and adverse events associated with their use.

Design: A retrospective cohort.

Setting: A nationwide dataset of private insurance claims.

Participants: Adults age 18 to 64 years old who were continuously enrolled from

2012 to 2014 in a nationwide administrative dataset.

Main Outcome Measures: Rates of short-term oral corticosteroid use defined as

<30 days duration. Incidence rate ratios of sepsis, venous thromboembolism, and

fracture were calculated using a (within-person) self-controlled case series, with 30

day and 31-90 day risk periods after drug initiation.

Results: Of 1,552,021 adults, 328,376 (21.2%) received at least one outpatient

prescription for short-term oral corticosteroids over the 3-year period. Use was more

frequent among older patients, women, and white adults, with significant regional

variation in use observed. The most common indications for use were upper

respiratory infections, spine conditions, and allergies. Prescriptions were provided by

a diverse range of specialties. Within 30 days of drug initiation, there was an increase

in rates of sepsis (incidence rate ratio [IRR]=2.46;95%CI:1.90,3.19), venous

thromboembolism (IRR=2.80; 95%CI: 2.32,3.39), and fracture (IRR=1.63; 95%CI:

1.49,1.79) that diminished over the subsequent 31-90 days. The increased risk

persisted even at prednisone-equivalent doses of <20 mg/day (IRR=2.05 sepsis,

IRR=2.89 venous thromboembolism, IRR=1.62 fracture; all p<0.001).

Page 2 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Conclusion: One in five American adults received short-term oral corticosteroids

during a three-year period with an associated increased risk of adverse events.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Complications with chronic use of corticosteroids include a wide spectrum of

effects on the cardiovascular, musculoskeletal, digestive, endocrine,

ophthalmic, skin, and nervous systems.

• However, the potential risks associated with the use of short-term oral

corticosteroids and their overall use in general population has not been fully

characterized.

WHAT THIS STUDY ADDS

• This study of 1.5 million privately-insured adults (18-64 years of age) in the

United States found that short-term oral corticosteroids in an outpatient setting

were used by one in every five patients over a three-year period (2012-2014).

• Within 30 days of corticosteroid initiation, the incidence of sepsis, venous

thromboembolism, and fracture increased by 1.6-2.8 fold above background

rates.

• Greater attention to initiating prescriptions of these drugs, tailoring doses to

clinical indications, and identifying alternatives for treatment may potentially

improve patient safety.

Page 3 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


INTRODUCTION

Corticosteroids are powerful anti-inflammatory drugs that have been used to treat a

variety of diseases for over seven decades dating back to their introduction for

rheumatoid arthritis in 1949.[1-5] A strong driver of corticosteroid use is the potent

symptomatic relief they provide to many patients. Yet, long-term use of

corticosteroids is generally avoided given the risks of serious acute complications

such as infection, venous thromboembolism, avascular necrosis and fracture, as well

as chronic diseases such as diabetes mellitus, hypertension, osteoporosis, and other

features of iatrogenic Cushing’s syndrome.[6-18] Indeed, corticosteroids are one of

the most common causes of hospitalization for drug-related adverse events,[19] and

optimizing their long-term use has been a major focus for clinical guidelines across

diverse specialties for many years.[20-26]

In contrast to long-term use, however, the risk of complications from short-term

corticosteroid use is much less understood, and there is largely insufficient evidence

to guide clinicians. In the outpatient setting, brief courses of oral corticosteroids are

often used to treat conditions with clearly defined inflammatory pathophysiology for

which there is clinical consensus for efficacy, such as asthma, chronic obstructive

lung disease, rheumatoid arthritis, inflammatory bowel disease.[27-31] Yet

anecdotally, corticosteroids are also used frequently in the short-term to treat many

other prevalent conditions where evidence is more lacking such as non-specific

musculoskeletal pain, rashes, and allergies. Despite such pervasive indications for

Page 4 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


their use, surprisingly little is known about the overall prescribing patterns of short-

term use of these drugs in the general adult population or their potential harm.

The purpose of this study is to characterize contemporary outpatient utilization of

short-term oral corticosteroids and the associated risks of adverse event, as prior

studies have mostly evaluated long-terms use and chronic complications. Given the

inherent challenges related to confounding by treatment selection when determining

risks, we employed a self-controlled case series approach that is increasingly being

used for population surveillance of drug and vaccine safety.[32,33] Using this

method, each individual serves as his or her own control allowing for comparisons of

adverse event rates during time periods after exposure to corticosteroids versus rates

during periods when not exposed.

METHODS

Study Design and population

The Clinformatics TM Data Mart Database (OptumInsight, Eden Prairie, Minnesota,

U.S.) contains comprehensive, de-identified records of enrollees covered through a

large nationwide healthcare insurer and its pharmacy services for outpatient drugs.

We identified all individuals, ages 18 to 64 years, who were continuously enrolled

between January 1, 2012 and December 31, 2014. Individuals who were 65 years or

older at any point during the study were excluded, due to their eligibility for the

federal Medicare program.

Page 5 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Patients were also required to have at least one year of continuous enrollment prior

to the study period (January 1, 2011 to December 31, 2011) to capture prior use of

corticosteroids and baseline comorbid conditions. To focus on new users, we

excluded those who received any oral corticosteroids during year 2011 (n=293,456).

In addition, the study cohort excluded enrollees exclusively receiving non-oral forms

of corticosteroids (e.g., corticosteroid inhalers, intravenous corticosteroids or intra-

articular injections only; n=98,914), oral Budesonide prescriptions (n=3,329), and

those with solid organ or bone marrow transplants, or malignancy (n=224,658) (see

Appendix Table 1). Finally, we limited the study cohort users to those who were

prescribed oral corticosteroids for less than 30 days cumulatively over the study

period (Figure 1). Non-users in the study cohort were defined as those without any

corticosteroid prescriptions who remained in the cohort after the above exclusions.

No additional patients were excluded from the study. Missing variables were

generally uncommon (< 1%) and classified into ‘unknown’ categories.

Procedures

For each enrollee, we obtained demographic information on age, gender,

race/ethnicity, highest level of education, and region of the country based on a

residential Zip code. Race and ethnicity were identified using information obtained

from public records (e.g.,driver’s license data), the surname and first names of the

beneficiary and the Census block of residence (E-Tech, Ethnic Technologies, LLC.,

South Hackensack, NJ). Studies comparing a similar approach with information

collected from self-report demonstrated a positive predictive value of 71%.[34]

Page 6 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Comorbid conditions were ascertained from outpatient and inpatient claims available

for each enrollee during the study period using International Classification of

Diseases, Ninth Revision (ICD-9-CM) diagnosis codes that were subsequently

grouped into Elixhauser categories.[35]

Our primary exposure of interest was an outpatient prescription for an oral

formulation of corticosteroids for less than 30 days in duration, as obtained from

detailed information in each pharmacy claim. To calculate standardized doses for

each patient, all corticosteroid formulations were converted into a daily dose based

on prednisone-equivalent doses (Appendix Table 2).[36-38] We also identified

multiple outpatient prescriptions for patients and tabulated the number of repeated

doses.

Among all patients in the study cohort, we identified the specialty type of the

prescribing physician and clinical conditions for which corticosteroids were

administered by linking a patient’s first prescription with the principal ICD-9-CM

diagnosis code in the outpatient claim closest to the date of the prescription. If the

closest claim was beyond 3 days from the prescription, we labeled this information as

‘unknown’ for that patient. Overall, we were able to link 216,266 of 328,376 (66%) of

prescribing physicians and 279,240 of 328,376 (85.0%) of patients who received a

prescription to an ICD-9-CM diagnosis code. Diagnosis codes were grouped using

Clinical Classification Software obtained from the Agency for Healthcare Research

and Quality (AHRQ).[35,39]

Page 7 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


We assessed three acute adverse events associated with short-term corticosteroid

use: sepsis, venous thromboembolism, and fractures. These events were identified

using ICD-9-CM diagnosis codes that reflected acute presentations with chronic or

personal history codes not included (Appendix Table 3). We specifically selected

these events as they represent a broad range of corticosteroid-related complications

varying from infectious to musculoskeletal to hematologic, and each can be reliably

identified in claims data with previous descriptions suggestions they can occur early

after drug initiation.[17,40-42] For sepsis, inpatient claims were used to reflect

hospitalization with a primary diagnosis for this condition to be most conservative at

linking to serious infections. For venous thromboembolism and fractures, we used

both outpatient and inpatient claims to identify events.

Statistical Methods

Baseline characteristics of short-term oral corticosteroid users and non-users were

tabulated by age (in year 2014), gender, race, education, region, and number of

Elixhauser comorbidities (grouped as 0, 1 to 2, and ≥3). Student t-tests and chi-

squared tests were used to assess differences by group. We used logit regression to

model corticosteroid use while simultaneously adjusting for these six baseline

characteristics. In addition, we ranked the most common reasons for visits associated

with the prescription, as well as specialty types of the prescribing providers.

Incidence rates of adverse events per 1000 person-years at risk were calculated and

stratified by age, gender and race. To control for patient-specific characteristics while

Page 8 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


investigating the risk of adverse events, we used a modified self-controlled case

series approach in corticosteroid users.[32,33,43] This method utilizes a within-

person design to compare the rates of events after corticosteroid use (5-30 days and

31-90 days after the prescription was filled) with the rates prior to use (Appendix

Figure 1).

To preclude capturing multiple follow-up visits after the initial diagnosis of an adverse

event, we only recorded the first event. Additionally, individuals who experienced an

adverse event in the pre-study period of 2011 were excluded to avoid detecting

legacy effects from prior episodes. Adverse events <5 days before or after the

recorded diagnosis were excluded to remove those who may have received the oral

corticosteroid concomitantly with the adverse event. Sensitivity analyses were

conducted by extending this period to a ±7-day window. In addition, individuals who

received repeated prescriptions within the 31-90 day were analyzed separately in a

sensitivity analysis since the timing of their exposures varied.

Incidence rate ratios (IRRs) were calculated using fixed (conditional) Poisson

regression, offset by the natural logarithm of the days at risk to correct for differences

in the lengths of observation. Effect modification by demographic factors (age,

gender, race) were assessed by an interaction term.

Analyses were conducted with SAS software, v9.4 (SAS Institute), and Stata/MP14.1

(StataCorp, College Station, TX). Two-tailed P values are reported for all analyses,

Page 9 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


with alpha=0.05. The Institutional Review Board of the University of Michigan

determined the study to be exempt from further review and waived the requirement

for informed consent.

Patient Involvement

Our study was a secondary data analysis and did not include any study participants.

No patients were involved in the research question or the outcome measures, and

they were not involved in the design and implementation of the study.

RESULTS

Among 1,552,021 adults in the study cohort, 328,376 (21.2%) received at least one

outpatient prescription for short-term oral corticosteroids during the three-year study

period. The mean age among users was 45.5 years (standard deviation [SD],11.6)

compared with 44.1 years (SD,12.2) for non-users (p<0.001). The median number of

days of use was 6 days (interquartile range [IQR], 6-12 days) with 47.4% receiving

treatment for ≥7 days. Overall, the median prednisone-equivalent daily dose was 20

mg per day (IQR,17.5-36.8 mg per day) with 23.4% receiving ≥40 mg per day. The

most common prescription written for oral corticosteroids was a 6-day

methylprednisolone “dosepak,” which accounted for 46.9% of all prescriptions during

the study period. Among corticosteroid users, 70.5% used only one prescription,

20.7% received two courses of treatment, 8.8% received three or more courses of

treatment. The average prescription count for those patients with 2 or more

prescription was 2.4 (±0.7).

Page 10 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Compared to non-users, short-term oral corticosteroid users were more often older,

women, white, educated, and had a greater number of comorbid conditions (Table 1).

People residing in the Pacific region had the lowest use of short-term oral

corticosteroids (12.4%), while people in the East South Central region and West

South Central region had the highest usage (29.4% and 27.6%, respectively). The

use of corticosteroids varied significantly across several of these baseline

characteristics even after multivariable adjustment (Table 2).

The most common indications for short-term oral corticosteroid use were upper

respiratory infections, spine conditions and intervertebral disc disorders, allergies,

bronchitis and (non-bronchitic) lower respiratory disorders (Appendix Table 4). These

five conditions were associated with approximately half of all prescriptions. The two

most common specialty types of physicians prescribing short-term oral

corticosteroids were family medicine and general internal medicine, accounting for a

majority of prescriptions (Appendix Table 4). These drugs were also frequently

prescribed by specialists in emergency medicine, otolaryngology and orthopedics.

Short-term Corticosteroids and Adverse Events

Rates of sepsis, venous thromboembolism, and fracture were significantly higher in

short-term oral corticosteroid users than in non-users (Table 3). The differences were

evident across age, gender and race strata. The unadjusted IRR for the association

between corticosteroids and sepsis was significant

Page 11 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


(IRR=1.85;95%CI:1.72,1.98;p<0.001), as was the association with venous

thromboembolism (IRR=1.87;95%CI:1.77,1.97;p<0.001) and fracture

(IRR=1.48(95%CI:1.45,1.51;p<0.001).

The results of the self-controlled case series are displayed in Table 4. Overall, there

were increased risks for sepsis, venous thromboembolism, and fracture within the

first 30 days after initiation of corticosteroids. This relationship was consistent across

doses. The long-term risk for adverse events diminished as the time from initial

exposure increased, although a modestly elevated risk remained significant for

venous thromboembolism and fracture at 90 days. For sepsis, only short-term (5-30

day) use was associated with increased risk.

To examine risks for particular types of patients, effect modification by age, gender

and race were explored. Men taking corticosteroids had a higher short-term risk of

venous thromboembolism than women (IRR=3.38,95%CI:2.63,4.34 for men;

IRR=2.21,95%CI:1.64,2.96 for women;p=0.031 interaction term), and whites had a

higher short-term risk of fractures than non-whites (IRR=1.77,95%CI:1.59,1.96 for

whites; IRR=1.24,95%CI;1.01,1.52 for non-whites;p=0.002 interaction term).

In sensitivity analyses, the time between when the prescription was filled and the

measurement of adverse events was extended to a ±7-day window (Appendix Table

5). The increased risks of sepsis, venous thromboembolism and fracture remained

despite extending the time window. In the sensitivity analysis of patients who

Page 12 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


received repeated prescriptions (Appendix Table 6), adverse event rates were

significantly elevated within the specific time windows in which the corticosteroid

prescriptions were filled.

DISCUSSION

In this large, population-based study of privately insured non-elderly adults in the

U.S., one in five individuals received a new outpatient prescription for short-term oral

corticosteroids over a three-year period. These drugs were used for a wide range of

conditions seen by generalist and specialist physicians, such as upper respiratory

infections, spine conditions, and allergies. Importantly, these prescriptions were

associated with significantly higher rates of sepsis, venous thromboembolism and

fracture despite being used for a relatively brief duration.

Estimates of corticosteroid utilization 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 medications taken within

the previous 30 days.[7] Their findings indicated a mean duration of corticosteroid

use exceeding 4 years among users – thus capturing a larger proportion of chronic

treatment, but potentially underreporting short-term use. Furthermore, although their

analyses were weighted, the actual sample of corticosteroid users included only 356

individuals. Our longitudinal analysis of 1.5 million insured Americans demonstrated

an incidence of approximately 7% for short-term oral corticosteroid use on a yearly

basis.

Page 13 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


While the long-term complications of chronic corticosteroid use are well appreciated,

there is a paucity of clinical data regarding the potential short-term adverse effects of

corticosteroid use despite the existence of pathophysiological evidence suggesting

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 (e.g peripheral white blood cells) within the first day after drug ingestion that

were noticeable with 10 mg, 25 mg, and 60 mg doses.[44,45] Rapid alteration in

markers of bone metabolism have also been documented with the initiation of

corticosteroid use; mean serum concentrations of osteocalcin and both procollagen I

N- and C-terminal peptides were significantly decreased in the early weeks after

starting prednisone.[46] The mechanisms underlying the increase in venous

thromboembolism are not fully known although infection is a common trigger of

thrombosis,[47] suggesting that both venous thromboembolism and sepsis may be

mediated through changes in the immune system. Further work is certainly needed to

clarify whether and how our observations in this large population may be linked to

potential causal pathways.

Our findings are particularly concerning 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 of time

to prevent adverse events. [24,25] However, we found that even short durations of

Page 14 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


oral corticosteroid use, regardless of dose, were associated with increased risks of

adverse events and that few patients were on 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 time 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 medications in brief

courses. This raises the need for early general medical education of clinicians

regarding 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. Indeed, a

surprising finding was that the most common prescribers were not subspecialists like

rheumatologists that 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 infections, spine

conditions and allergies that often have marginal benefit and for which alternate

treatments may be simiarly effective and safer. For example, a multimodal pain

treatment regimen can be used to treat spinal pain and non-sedating anti-histamines

can be used for allergies. An examination of potential determinants of corticosteroid

Page 15 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


use will be needed to inform future intervention strategies. If corticosteroid use is

driven by patient preferences, education regarding potential harms should be

expanded. If prescriptions are primarily driven by provider decisions, decision support

tools to identify alternatives to corticosteroids (e.g. non-steroidal anti-inflammatory

drugs (NSAIDS) for acute gout[30] or tricyclic antidepressants for neuropathic

pain[48]) may be a more effective approach.

Our study has several limitations. 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 may have misclassified some

treatment indications and specialties. Second, 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. Third, we did not evaluate all of the possible adverse events

linked to oral corticosteroids, focusing instead on three diverse conditions. 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

hospitalization for sepsis, ignoring less serious but likely important infections, and did

not assess some adverse events like behavioural 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. Finally, although we used a within-person

approach to control for genetic predisposition, health-related behaviors, and co-

morbid conditions, we may have been unable to capture time-varying confounders

during this specific study period leading to concerns regarding residual confounding.

Page 16 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Assumptions of the self-controlled case series 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 prior events on subsequent drug use (if this

occurred) yielded IRRs that may be somewhat conservative and closer to the null.

Survival bias was not an issue since, by design, all patients were alive during the

time periods when the outcomes were measured (i.e., the comparator period was

prior to the first use of corticosteroids).

In conclusion, oral corticosteroids are frequently prescribed for short-term use in the

U.S. for a variety of common conditions and by numerous provider specialites

Over a 3-year period, approximately 1 in 5 American adults used oral corticosteroids

for a duration of less than 30 days. The short-term use of these drugs was associated

with increased rates of sepsis, venous thromboembolism, and fracture – even at the

low doses. Greater attention to initiating prescriptions of these drugs, tailoring doses

to clinical indications, and identifying alternatives for treatment may improve patient

safety.

Page 17 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Author Contributions: Dr. Waljee and Dr. Nallamouth had full access to al the data

in the study and take responsibility for the integrity of the data and the accuracy of

the data analysis.

Study concept and design: Waljee,

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Waljee, Nallamothu.

Figures: Waljee, Rogers, Lin.

Criticial revision of the manuscript: All authors.

Final approval: All authors.

Funding: AKW is supported by a career development grant award (CDA 11-217)

from the United States Department of Veterans Affairs Health Services Research and

Development Service. JDS is supported by grants from Research to Prevent

Blindness and W.K. Kellogg Foundation. Data acquisition, statistical and

administrative support was supported by the Institute for Healthcare Policy and

Innovation at the University of Michigan. These funders had no role in study design,

data collection, data analysis, data interpretation, or writing of the report.

Competing interests: All authors have completed the ICMJE uniform disclosure

form at www.icmje.org/coi_disclosure.pdf and declare: no support from any

organisation for the submitted work. AKW is supported by a career development

grant award (CDA 11-217) from the United States Department of Veterans Affairs

Health Services Research. JDS is supported by grants from Research to Prevent

Blindness and W.K. Kellogg Foundation. AGS reports personal fees from Bayer

Pharmaceuticals and a grant from Gilead pharmaceuticals outside the submitted

Page 18 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


work; no financial relationships with any organisations that might have an interest in

the submitted work in the previous three years; no other relationships or activities that

could appear to have influenced the submitted work.

Disclaimer: The authors are solely responsible for the design, conduct, data

analyses, and drafting and editing of the manuscript and its final content. The

contents do not represent the views of the U.S. Department of Veterans Affairs or the

United States Government.

The Corresponding Author has the right to grant on behalf of all authors and does

grant on behalf of all authors, a non-exclusive licence to the Publishers and its

licensees in perpetuity, in all forms, formats and media (whether known now or

created in the future), to i) publish, reproduce, distribute, display and store the

Contribution, ii) translate the Contribution into other languages, create adaptations,

reprints, include within collections and create summaries, extracts and/or, abstracts

of the Contribution, iii) create any other derivative work(s) based on the Contribution,

iv) to exploit all subsidiary rights in the Contribution, v) the inclusion of electronic links

from the Contribution to third party material where-ever it may be located; and, vi)

licence any third party to do any or all of the above.

Page 19 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


References 1 Spies TD, Stone RE. Deoxycortone with ascorbic acid versus

adrenocorticotropic hormone in rheumatoid arthritis. Lancet 1949;2:1219–21.

2 Bunim JJ, Pechet MM, Bollet AJ. Studies on metacortandralone and metacortandracin in rheumatoid arthritis; antirheumatic potency, metabolic effects, and hormonal properties. JAMA 1955;157:311–8. doi:10.1001/jama.1955.02950210007003

3 Carone FA, Liebow AA. Acute pancreatic lesions in patients treated with ACTH and adrenal corticoids. N Engl J Med 1957;257:690–7. doi:10.1056/NEJM195710102571502

4 Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med 2005;353:1711–23. doi:10.1056/NEJMra050541

5 Herzog HL, Nobile A, Tolksdorf S, et al. New antiarthritic steroids. Science 1955;121:176.

6 Gudbjornsson B, Juliusson UI, Gudjonsson FV. Prevalence of long term steroid treatment and the frequency of decision making to prevent steroid induced osteoporosis in daily clinical practice. Ann Rheum Dis 2002;61:32–6. doi:10.1136/ard.61.1.32

7 Overman RA, Yeh J-Y. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res (Hoboken) 2013;65:294–8. doi:10.1002/acr.21796

8 Sarnes E, Crofford L, Watson M, et al. Incidence and US costs of corticosteroid-associated adverse events: a systematic literature review. Clin Ther 2011;33:1413–32. doi:10.1016/j.clinthera.2011.09.009

9 van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oral corticosteroids in the United Kingdom. QJM 2000;93:105–11.

10 Walsh LJ, Wong CA, Pringle M, et al. Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study. BMJ 1996;313:344–6.

11 Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004;141:764–70.

12 Gurwitz JH, Bohn RL, Glynn RJ, et al. Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med 1994;154:97–101.

Page 20 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


13 Stuijver DJF, Majoor CJ, van Zaane B, et al. Use of oral glucocorticoids and the risk of pulmonary embolism: a population-based case-control study. Chest 2013;143:1337–42. doi:10.1378/chest.12-1446

14 Curtis JR, Westfall AO, Allison J, et al. Population-based assessment of adverse events associated with long-term glucocorticoid use. Arthritis Rheum 2006;55:420–6. doi:10.1002/art.21984

15 del Rincón I, Battafarano DF, Restrepo JF, et al. Glucocorticoid dose thresholds associated with all-cause and cardiovascular mortality in rheumatoid arthritis. Arthritis Rheumatol 2014;66:264–72. doi:10.1002/art.38210

16 Dessein PH, Joffe BI, Stanwix AE, et al. Glucocorticoids and insulin sensitivity in rheumatoid arthritis. J Rheumatol 2004;31:867–74.

17 Johannesdottir SA, Horváth-Puhó E, Dekkers OM, et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 2013;173:743–52. doi:10.1001/jamainternmed.2013.122

18 Davis JM, Maradit Kremers H, Crowson CS, et al. Glucocorticoids and cardiovascular events in rheumatoid arthritis: a population-based cohort study. Arthritis Rheum 2007;56:820–30. doi:10.1002/art.22418

19 Weiss AJ, Elixhauser A, Bae J, et al. Origin of adverse drug events in US hospitals, 2011. 2013.http://www.ncbi.nlm.nih.gov/books/NBK169247/ (accessed 13 Mar2016).

20 Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010;62:1515–26. doi:10.1002/acr.20295

21 Melmed GY, Siegel CA. Quality improvement in inflammatory bowel disease. Gastroenterol Hepatol (N Y) 2013;9:286–92.

22 Gerritsen AAM, de Krom MCTFM, Struijs MA, et al. Conservative treatment options for carpal tunnel syndrome: a systematic review of randomised controlled trials. J Neurol 2002;249:272–80.

23 Goldberg H, Firtch W, Tyburski M, et al. Oral steroids for acute radiculopathy due to a herniated lumbar disk: a randomized clinical trial. JAMA 2015;313:1915–23. doi:10.1001/jama.2015.4468

24 Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–65. doi:10.1164/rccm.201204-0596PP

Page 21 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


25 National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J. Allergy Clin. Immunol. 2007;120:S94–138. doi:10.1016/j.jaci.2007.09.043

26 Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 2016;68:1–26. doi:10.1002/art.39480

27 Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma. N Engl J Med 1986;314:150–2. doi:10.1056/NEJM198601163140304

28 Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999;340:1941–7. doi:10.1056/NEJM199906243402502

29 Akdis CA, Akdis M, Bieber T, et al. Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. Blackwell Publishing Ltd 2006. 969–87. doi:10.1111/j.1398-9995.2006.01153.x

30 Rainer TH, Cheng CH, Janssens HJEM, et al. Oral prednisolone in the treatment of acute gout: a pragmatic, multicenter, double-blind, randomized trial. Ann Intern Med 2016;164:464–71. doi:10.7326/M14-2070

31 Margolin ML, Krumholz MP, Fochios SE, et al. Clinical trials in ulcerative colitis: II. Historical review. The American journal of gastroenterology 1988;83:227–43.

32 Schneeweiss S, Avorn J. A review of uses of health care utilization databases for epidemiologic research on therapeutics. J Clin Epidemiol 2005;58:323–37. doi:10.1016/j.jclinepi.2004.10.012

33 Whitaker HJ, Farrington CP, Spiessens B, et al. Tutorial in biostatistics: the self-controlled case series method. Stat Med 2006;25:1768–97. doi:10.1002/sim.2302

34 DeFrank JT, Bowling JM, Rimer BK, et al. Triangulating differential nonresponse by race in a telephone survey. Prev Chronic Dis 2007;4:A60.

35 Elixhauser A, Steiner C, Harris DR, et al. Comorbidity measures for use with administrative data. Med Care 1998;36:8–27.

36 Meikle AW, Tyler FH. Potency and duration of action of glucocorticoids. Effects of hydrocortisone, prednisone and dexamethasone on human pituitary-adrenal function. Am J Med 1977;63:200–7. doi:10.1016/0002-9343(77)90233-9

Page 22 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


37 Dixon JS. Second-Line Agents in the Treatment of Arthritis. Informa Health Care 1991.

38 Singer M, Webb A. Oxford Handbook of Critical Care. Oxford University Press 2009.

39 Elixhauser A, Steiner C, Palmer L. Clinical Classifications Software (CCS), 2014. U.S. Agency for Healthcare Research and Quality. http://www.hcup-us.ahrq.gov/toolssoftware/ccs/ccs.jsp (accessed 13 Mar2016).

40 Migita K, Arai T, Ishizuka N, et al. Rates of serious intracellular infections in autoimmune disease patients receiving initial glucocorticoid therapy. PLoS ONE 2013;8:e78699. doi:10.1371/journal.pone.0078699

41 Dovio A, Perazzolo L, Osella G, et al. Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. J Clin Endocrinol Metab 2004;89:4923–8. doi:10.1210/jc.2004-0164

42 Pearce G, Ryan PF, Delmas PD, et al. The deleterious effects of low-dose corticosteroids on bone density in patients with polymyalgia rheumatica. Br J Rheumatol 1998;37:292–9. doi:10.1093/rheumatology/37.3.292

43 Gagne JJ, Fireman B, Ryan PB, et al. Design considerations in an active medical product safety monitoring system. Pharmacoepidemiol Drug Saf 2012;21:32–40. doi:10.1002/pds.2316

44 Hahn BH, MacDermott RP, Jacobs SB, et al. Immunosuppressive effects of low doses of glucocorticoids: effects on autologous and allogeneic mixed leukocyte reactions. J Immunol 1980;124:2812–7.

45 Kauh E, Mixson L, Malice M-P, et al. Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals. Eur J Endocrinol 2012;166:459–67. doi:10.1530/EJE-11-0751

46 Ton FN, Gunawardene SC, Lee H, et al. Effects of low-dose prednisone on bone metabolism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2005;20:464–70. doi:10.1359/JBMR.041125

47 Rogers MAM, Levine DA, Blumberg N, et al. Triggers of hospitalization for venous thromboembolism. Circulation 2012;125:2092–9. doi:10.1161/CIRCULATIONAHA.111.084467

48 Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatr 2010;81:1372–3. doi:10.1136/jnnp.2008.144964

Page 23 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Table Titles and Figure Legends: Table 1. Demographic Characteristics of Short-Term Oral Corticosteroid Users and Non-Users Table 2. Adjusted Odds Ratios for Short-Term Oral Corticosteroid Use Table 3. Incidence Rates of Adverse Events Among Short-Term Oral Corticosteroid Users and Non-Users Table 4. Incidence Rate Ratios for Adverse Events Associated with Short-Term Oral Corticosteroid Use Figure 1. Flow Diagram of Study Inclusion and Exclusion Criteria Appendix Table 1. ICD-9-CM Diagnosis Codes to Exclude Potential Chronic Corticosteroid Users Appendix Table 2. Equivalent Doses of Oral Corticosteroids Appendix Table 3. ICD-9-CM Diagnosis Codes to Identify Potential Adverse Events Associated with Oral Corticosteroid Use Appendix Table 4. Diagnoses and Prescribing Physicians Associated with Short-Term Corticosteroid Use, 2012-2014 Appendix Table 5. Incidence Rate Ratios for Adverse Events using a 7-day Window Appendix Table 6. Incidence Rate Ratios for Adverse Events in Patients using Subsequent Corticosteroid Prescriptions within the 90-day Window Appendix Figure 1. Structure of Study Design for Self-Controlled Case Series

Page 24 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Table 1. Demographic Characteristics of Short-Term Oral Corticosteroid Users and Non-Users

n Column % Row % n Column % Row %

328376 100% 21�2% 1223645 100% 78�8%

18 to < 25 22857 7.0% 16�6% 114994 9�4% 83�4%

25 to < 35 40564 12�4% 17�9% 185483 15�2% 82�1%

35 to < 45 79845 24�3% 21�9% 285514 23�3% 78�1%

45 to < 55 98651 30.0% 22�4% 341178 27�9% 77�6%

55 to < 65 86459 26�3% 22�6% 296476 24�2% 77�4%

Female 168571 51�3% 23�9% 538083 44.0% 76�1%

Male 159805 48�7% 18�9% 685562 56.0% 81�1%

White - Non-Hispanic 239877 73�1% 22�1% 845803 69�1% 77�9%

Hispanic 33738 10�3% 19�3% 140835 11�5% 80�7%

Black - Non-Hispanic 29830 9�1% 20�5% 115565 9�4% 79�5%

Asian 10397 3�2% 14�4% 61887 5�1% 85�6%

Unknown 14534 4�4% 19�6% 59555 4�9% 80�4%

< 12th Grade 1322 0�4% 17�1% 6410 0�5% 82�9%

High School Graduate 86023 26�2% 22�5% 295993 24�2% 77�5%

Some College 176916 53�9% 21�2% 656508 53�7% 78�8%

College Graduate or Higher 61844 18�8% 19�6% 253361 20�7% 80�4%

Unknown 2271 0�7% 16�6% 11373 0�9% 83�4%

0 103248 31�4% 14�5% 611247 50.0% 85�5%

1-2 137586 41�9% 24�7% 418662 34�2% 75�3%

≥3 87542 26�7% 31�1% 193736 15�8% 68�9%

New England 7918 2�4% 17.0% 38785 3�2% 83.0%

Middle Atlantic 20150 6�1% 18�1% 91321 7�5% 81�9%

South Atlantic 82912 25�3% 22�9% 278755 22�8% 77�1%

East North Central 54802 16�7% 21�1% 205445 16�8% 78�9%

East South Central 14937 4�6% 29�4% 35842 2�9% 70�6%

West North Central 36123 11.0% 18�9% 155505 12�7% 81�1%

West South Central 66489 20�3% 27�6% 174548 14�3% 72�4%

Mountain 28963 8�8% 18�2% 130609 10�7% 81�8%

Pacific 15808 4�8% 12�4% 111502 9�1% 87�6%

Unknown 274 0�1% 17�1% 1333 0�1% 82�9%

Census Division

Education

Race

Steroid Users Non-Steroid Users

Age (years)

Overall

Gender

Elixhauser Comorbidity

Page 25 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Table 2. Adjusted Odds Ratios for Short-Term Oral Corticosteroid Use

OR p-value

18 to < 25

25 to < 35 1�08 1�07 1�10

35 to < 45 1�28 1�26 1�30

45 to < 55 1�18 1�16 1�20

55 to < 65 1�07 1�04 1�08 <0�001

Female

Male 1�27 1�26 1�28 <0�001

White - Non-Hispanic

Hispanic 0�81 0�80 0�82

Black - Non-Hispanic 0�74 0�73 0�75

Asian 0�67 0�66 0�69

Unknown 0�92 0�90 0�93 <0�001

< 12th Grade

High School Graduate 1�26 1�18 1�34

Some College 1�27 1�20 1�35

College Graduate or Higher 1�25 1�17 1�33

Unknown 0�92 0�85 0�99 <0�001

0

1-2 1�90 1�88 1�92

≥3 2�62 2�59 2�65 <0�001

New England

Middle Atlantic 1�11 1�07 1�14

South Atlantic 1�53 1�49 1�57

East North Central 1�36 1�33 1�40

East South Central 2�08 2�02 2�15

West North Central 1�18 1�15 1�21

West South Central 2�02 1�97 2�07

Mountain 1�12 1�09 1�15

Pacific 0�78 0�76 0�80

Unknown 1�07 0�93 1�22 <0�001

Reference

Reference

Census Division

95% CI

Age (years)

Gender

Education

Race

Elixhauser Comorbidity

Reference

Reference

Reference

Reference

Page 26 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Table 3. Incidence Rates and Incidence Rate Ratios of Adverse Events Among Short-Term Oral Corticosteroid Users and Non-Users

Incidence

in Users

(95% CI)*

Incidence in

Non-Users

(95% CI)*

Incidence

Rate Ratio

(95% CI)

Incidence

in Users

(95% CI)*

Incidence in

Non-Users

(95% CI)*

Incidence

Rate Ratio

(95% CI)

Incidence

in Users

(95% CI)*

Incidence in

Non-Users

(95% CI)*

Incidence

Rate Ratio

(95% CI)

Overall 1.8 (1.7, 1.9) 1.0 (1.0, 1.0) 1.8 (1.7, 2.0) 3.3 (3.1, 3.5) 1.8 (1.7, 1.8) 1.9 (1.8, 2.0) 20.9 (20.5, 21.3) 14.1 (14.0, 14.2) 1.5 (1.4, 1.5)

Age (years)

18 to < 25 0.8 (0.6, 1.2) 0.5 (0.4, 0.6) 1.6 (1.1, 2.4) 0.9 (0.6, 1.3) 0.4 (0.4, 0.5) 2.0 (1.3, 3.0) 21.1 (19.6, 22.7) 14.9 (14.5, 15.3) 1.4 (1.3, 1.5)

25 to < 35 0.9 (0.7, 1.2) 0.5 (0.4, 0.6) 1.9 (1.4, 2.5) 1.4 (1.2, 1.7) 0.8 (0.7, 0.9) 1.8 (1.4, 2.2) 16.3 (15.3, 17.3) 11.7 (11.4, 12.0) 1.4 (1.3, 1.5)

35 to < 45 1.0 (0.8, 1.2) 0.6 (0.5, 0.6) 1.8 (1.4, 2.2) 2.4 (2.2, 2.7) 1.3 (1.2, 1.4) 1.9 (1.6, 2.1) 17.5 (16.8, 18.3) 11.8 (11.6, 12.1) 1.5 (1.4, 1.6)

45 to < 55 1.8 (1.6, 2.0) 1.0 (1.0, 1.1) 1.7 (1.5, 2.0) 3.7 (3.4, 4.0) 2.0 (1.9, 2.1) 1.8 (1.7, 2.0) 20.3 (19.6, 21.0) 13.6 (13.3, 13.8) 1.5 (1.4, 1.6)

55 to < 65 3.3 (3.0, 3.6) 1.8 (1.8, 1.9) 1.8 (1.6, 2.0) 5.2 (4.8, 5.6) 3.1 (2.9, 3.2) 1.7 (1.6, 1.9) 26.7 (25.8, 27.6) 18.1 (17.8, 18.4) 1.5 (1.4, 1.5)

Gender

Female 1.7 (1.6, 1.9) 0.9 (0.9, 1.0) 1.9 (1.7, 2.1) 3.2 (3.0, 3.4) 1.8 (1.7, 1.8) 1.8 (1.7, 2.0) 22.5 (21.9, 23.1) 14.7 (14.5, 14.9) 1.5 (1.5, 1.6)

Male 1.9 (1.8, 2.1) 1.0 (1.0, 1.1) 1.8 (1.7, 2.0) 3.4 (3.2, 3.6) 1.8 (1.7, 1.8) 1.9 (1.8, 2.1) 19.1 (18.6, 19.7) 13.6 (13.5, 13.8) 1.4 (1.4, 1.4)

Race

Nonwhite 2.0 (1.7, 2.2) 1.1 (1.0, 1.2) 1.8 (1.6, 2.0) 3.3 (3.0, 3.6) 1.6 (1.5, 1.7) 2.1 (1.9, 2.3) 18.0 (17.3, 18.8) 11.8 (11.6, 12.0) 1.5 (1.5, 1.6)

White 1.8 (1.6, 1.9) 0.9 (0.9, 1.0) 1.9 (1.7, 2.1) 3.3 (3.1, 3.5) 1.8 (1.8, 1.9) 1.8 (1.7, 1.9) 21.9 (21.4, 22.4) 15.1 (15.0, 15.3) 1.4 (1.4, 1.5)

*per 1000 person-years at risk.

Sepsis Venous Thromboembolism Fractures

Page 27 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Table 4. Incidence Rate Ratios for Adverse Events Associated with Short-Term Oral Corticosteroid Use

Median Dose

(mg/day)

Median duration (days)*

5-30 days† 31-90 days†

Adverse Event IRR 95% CI P value IRR 95% CI P value

All doses vs No corticosteroids

Sepsis 20 6 2.46 1.90, 3.19 <0.001 1.01 0.77, 1.31 0.957

Venous thromboembolism 20 6 2.80 2.32, 3.39 <0.001 1.45 1.21, 1.74 <0.001

Fracture 20 6 1.63 1.49, 1.79 <0.001 1.12 1.03, 1.21 0.006

Dose: <20 mg/day vs 0 mg/day

Sepsis 17.5 6 2.05 1.37, 3.06 <0.001 0.98 0.67, 1.45 0.931

Venous thromboembolism 17.5 6 2.89 2.20, 3.79 <0.001 1.23 0.93, 1.62 0.149

Fracture 17.5 6 1.62 1.42, 1.84 <0.001 1.09 0.98, 1.22 0.122 Dose: 20-39 mg/day vs 0 mg/day

Sepsis 30 7 2.92 1.99, 4.28 <0.001 1.01 0.66, 1.53 0.981

Venous thromboembolism 33.3 7 2.31 1.68, 3.17 <0.001 1.54 1.17, 2.03 0.002

Fracture 35 7 1.65 1.42. 1.91 <0.001 1.08 0.95, 1.23 0.247

Dose: >40 mg/day vs 0 mg/day

Sepsis 60 5 2.59 1.25, 5.36 0.010 1.11 0.54, 2.29 0.782

Venous thromboembolism 60 5 4.27 2.60, 7.02 <0.001 2.05 1.26, 3.35 0.004

Fracture 60 5 1.63 1.23, 2.16 0.001 1.37 1.10, 1.71 0.005

* Median number of days taking steroids.

† Number of days from date when corticosteroid prescription was filled.

Reference period was 5 to 180 days prior to prescription date.

Page 28 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Figure 1. Flow Diagram of Study Inclusion and Exclusion Criteria

Page 29 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Appendix Table 1. ICD-9-CM Diagnosis Codes to Exclude Potential Chronic Corticosteroid Users

• Malignant Related: 140.XX-209.3X, 209.7X, 230.X-234.X, 258.02, 258.03, 511.81, 789.51, 795.01-795.06, 795.10-795.14, 795.16, 796.70-796.74, 796.76, V10.XX, V58.0, V58.1X, V66.1, V66.2, V67.1, V67.2, V71.1

• Transplant Related: v42.XX

Page 30 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Appendix Table 2. Equivalent Doses of Oral Corticosteroids

Equivalent Dose

Corticosteroid

0.6 mg Betamethasone

0.75 mg Dexamethasone

4 mg Methylprednisolone

4 mg Triamcinolone

5 mg Prednisone

5 mg Prednisolone

20 mg Hydrocortisone

25 mg Cortisone

Page 31 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Appendix Table 3. ICD-9-CM Diagnosis Codes to Identify Potential Adverse Events Associated with Oral Corticosteroid Use

• Fracture: 805.XX, 807.XX, 808.XX, 809.X, 810.XX, 811.XX, 812.XX, 813.XX, 814.XX, 815.XX, 816.XX, 817.X, 818.X, 819.X, 820.XX, 821.XX, 822.X, 823.XX, 824.X, 825.XX, 826.X, 827.X, 828.X, 829.X

• Venous thromboembolism (VTE) : 452, 453.X (except chronic VTE 453.5X and 453.7X)

• Sepsis Only: 785.52, 995.91, 995.92

Page 32 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Appendix Table 4. Diagnoses and Prescribing Physicians Associated with Short-Term Corticosteroid Use, 2012-2014

Ranking Frequency Percentage

Upper Respiratory Infection 1 44007 15�8%

Spine Conditions 2 31162 11�2%

Allergy 3 29200 10�5%

Bronchitis 4 18780 6�7%

Lower Respiratory Disorders (non-bronchitis) 5 13565 4�9%

Connective Tissue Disorders 6 13304 4�8%

Upper Respiratory Disorders 7 11632 4�2%

Joint Disorders 8 9453 3�4%

Asthma 9 8029 2�9%

Skin Disorders 10 7051 2�5%

Family Practice 1 97919 45�3%

Internal Medicine 2 37997 17�6%

Emergency Medicine 3 14931 6�9%

Otolaryngology 4 10449 4�8%

Orthopedics 5 9674 4�5%

Diagnosis Group

Physician Specialty

Page 33 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Appendix Table 5. Incidence Rate Ratios for Adverse Events using a 7-day Window

IRR 95% CI P value IRR 95% CI P value

Sepsis 2�21 1�66, 2�95 <0�001 1�15 0�88, 1�51 0�299

Venous thromboembolism 2�60 2�12, 3�19 <0�001 1�57 1�30, 1�88 <0�001

Fracture 1�44 1�30, 1�59 <0�001 1�15 1�07, 1�25 <0�001

* Number of days from date when corticosteroid prescription was filled�

Reference period was 8 to 180 days prior to prescription date�

8-30 days* 31-90 days*

Page 34 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Appendix Table 6. Incidence Rate Ratios for Adverse Events in Patients using Subsequent Corticosteroid Prescriptions within the 90-day Window

IRR 95% CI P value

Sepsis

Additional prescriptions in 31-90 day period 3�00 1�19, 7�57 0�02

Venous thromboembolism


Fracture


* Number of days from date when corticosteroid prescription was filled� Reference

period was 5 to 180 days prior to prescription date�

31-90 days*

Page 35 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960


Appendix Figure 1. Structure of Study Design for Self-Controlled Case Series

Adverse events Adverse events

+ 4-daywindow

Time 0, when corticosteroid prescription was filled

31 to 90 days-5 days to -180 days 5 to 30 days

Page 36 of 36


BMJ

123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960

short-term use of oral corticosteroids among adults in the ... · corticosteroid use is much less...

Documents