Corticosteroids: do they damage the cardiovascular system?Incidence rates of adverse events in corticosteroid users and oxandrolone recovery. Incidence rate ratios for adverse events within 30 day and day risk periods after drug initiation. The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Prescriptions were provided by a diverse range of specialties. Within 30 days of corticostedoids initiation, there was an increase in rates of sepsis incidence rate ratio 5.
Glucocorticoids and Cardiovascular Disease
Incidence rates of adverse events in corticosteroid users and non-users. Incidence rate ratios for adverse events within 30 day and day risk periods after drug initiation. The most common indications for use were upper respiratory tract infections, spinal 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 5. 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 In contrast with long term use, however, the risk of complications from short term use is much less understood, and evidence is generally insufficient 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, and inflammatory bowel disease.
Despite such pervasive indications for use of oral corticosteroids, little is known about the prescribing patterns of short term use of these drugs in the general adult population, or their potential harm.
In this study we characterized short term use of oral corticosteroids in a contemporary outpatient population, and the risk of acute adverse events. We describe those who use oral corticosteroids in the short term in an outpatient setting and then report absolute incidence rates of adverse events in users and non-users. We chose three acute events listed as adverse events on the Food and Drug Administration mandated drug label for oral corticosteroids sepsis, venous thromboembolism, fracture.
Given the inherent challenges related to confounding, we employed a self controlled case series SCCS design. This design has been used to examine drug and vaccine safety. The Clinformatics DataMart database OptumInsight, Eden Prairie, MN contains comprehensive, deidentified records of enrollees covered through a large nationwide healthcare insurer and its pharmacy services for outpatient drugs.
All enrollees are included in a denominator file, regardless of whether they received services eg, clinic visits, drug prescriptions, hospital admissions. Those who were 65 years or older at any point during the study were excluded, owing to their eligibility for the federal Medicare program. Patients were also required to have at least one year of continuous enrollment before the study period 1 January to 31 December to capture past use of corticosteroids and baseline comorbid conditions.
Non-users in the study cohort were defined as those without any corticosteroid prescriptions who remained in the cohort after the exclusions. No additional patients were excluded from the study. For each enrollee, we obtained demographic information on age, sex, race or ethnicity, highest level of education, and region of the country based on a residential zip code.
Comorbid conditions were ascertained from outpatient and inpatient claims available for each enrollee during the study period using ICDCM international classification of diseases, ninth revision diagnosis codes that were subsequently grouped into Elixhauser categories.
Our primary exposure of interest was an outpatient prescription for an oral formulation of corticosteroids for less than 30 days, 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 see web appendix table 2.
If the closest claim was beyond three days from the prescription, we labeled this information for that patient as unknown. Diagnosis codes were grouped using clinical classification software obtained from the Agency for Healthcare Research and Quality.
We assessed three acute adverse events associated with short term corticosteroid use: These events were identified using ICDCM diagnosis codes that reflected acute presentations, with chronic or personal history codes not included see web appendix table 3.
We specifically selected these events as they represent a broad range of corticosteroid related acute complications. Each also has been listed on the FDA mandated drug label as possible adverse reactions, can be reliably identified in claims data, and has supporting evidence of pathogenesis early after drug initiation was available.
For venous thromboembolism and fractures, we used both outpatient and inpatient claims to identify events. Regional variation in corticosteroid use was graphed by census division.
We ranked the most common reasons for visits associated with the prescription, as well as specialty types of the prescribing providers. For the entire cohort we calculated incidence rates of adverse events per person years at risk for corticosteroid users and non-users.
Rates were also stratified by age, sex, and race. In addition, we calculated the cumulative risk of adverse events during the five to 90 day period after a clinic visit for corticosteroid users and non-users. To control for patient specific characteristics while investigating the risk of adverse events, we used a self controlled case series SCCS design.
To be conservative, we modified the SCCS design so that adverse events within a four day window of when the prescription was filled were excluded to remove those who might have potentially received the oral corticosteroid concomitantly with the adverse event. To preclude capturing multiple follow-up visits after the initial diagnosis of an adverse event, we only recorded the first event.
Those who experienced an adverse event in the prestudy period of were excluded to avoid detecting legacy effects from past episodes. Patients were excluded if they were admitted to hospital within a 14 day period before the corticosteroid prescription date so that potential effects related to a recent hospital admission would be removed.
Adjustment was made for time varying covariates related to concomitant drug use. In these analyses, the most commonly used classes of drugs 42 classes were coded for each period and included in the full model; only those drug classes associated with each outcome sepsis, venous theomboembolism, fracture were retained in the final models. Fixed conditional Poisson regression was used to calculate incidence rate ratios, 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, sex, race were assessed by an interaction term. We performed an analysis to deal with concerns that we were simply detecting more adverse events as a result of exposure to medical care rather than exposure to corticosteroids.
For this analysis, we compared 30 day rates of hospital admissions for sepsis, venous thromboembolism, and fractures after a clinic visit in patients with matched diagnoses who did not receive corticosteroids and those who did receive corticosteroids after adjusting for age, sex, and race. Secondly, we used the cohort from the SCCS design and recalculated the incidence rate ratios after stratification by respiratory conditions or musculoskeletal conditions.
These analyses assessed whether adverse events were being driven potentially by misdiagnosis eg, sepsis may be more common because pneumonia is misdiagnosed as asthma, or fracture may be more common because vertebral fracture is misdiagnosed as back strain. Thirdly, in another sensitivity analysis we excluded patients who were using concomitant non-oral forms of corticosteroids.
Lastly, we extended the four day period around the date of the prescription being filled to a seven day period. Analyses were conducted with SAS software, v9.
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.
No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community. The mean age for users was Among corticosteroid users, For those patients with two or more prescriptions, the average prescription count was 2.
People residing in the Pacific region had the lowest use of short term oral corticosteroids Demographic characteristics of participants according to short term use or non-use of oral corticosteroids. The most common indications for short term oral corticosteroid use were upper respiratory tract infections, spinal conditions, and intervertebral disc disorders, allergies, bronchitis, and non-bronchitic lower respiratory tract disorders see web appendix table 4.
These five conditions were associated with about 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 most prescriptions see web appendix table 4.
These drugs were also frequently prescribed by specialists in emergency medicine, otolaryngology, and orthopedics. The differences were evident across age, sex, and race stratums. Fractures were the most common complication in users 21 events for every users annually , followed by venous thromboembolism 5 events for every users annually and hospital admissions for sepsis 2 events for every users annually. Incidence rates of adverse events by short term use of oral corticosteroids.
The absolute risk of an adverse event during the five to 90 day period after a clinic visit was calculated.
For those patients with a visit, the risk of hospital admission for sepsis was 0. The risk of venous thromboembolism was 0. Overall, risks for sepsis, venous thromboembolism, and fracture increased within the first 30 days after initiation of corticosteroids. For example, the risk of hospital admission for sepsis increased fivefold above baseline risk after oral corticosteroids were used.
This relation was consistent across doses. The long term risk for adverse events days diminished as the time from initial exposure increased. Incidence rate ratios for adverse events associated with short term use of oral corticosteroids. To examine risks for particular types of patients, we explored effect modification by age, sex, and race.
No significant effect modification was found after adjustment for time varying covariates, except for race; white patients had a higher short term risk of fractures than non-white patients incidence rate ratio 2. Web appendix table 5 displays the results of our analysis of 30 day rates of hospital admission for sepsis, venous thromboembolism, and fractures after a clinic visit in patients with matched diagnoses who did not receive corticosteroids and those who did receive corticosteroids after adjusting for age, sex, and race.
It shows consistently higher incidence rates of adverse events in the patients who received corticosteroids. The 30 day risk of venous thromboembolism, fracture, and hospital admission for sepsis was statistically significantly increased for patients presenting with both respiratory conditions and musculoskeletal conditions. When we excluded patients using concomitant non-oral forms of corticosteroids from the analyses, the results were similar see web appendix table 6. In the day window the incidence rate ratio for sepsis was 4.
Extending the four day period around the date of prescription to a seven day period also did not appreciably change the results see web appendix table 7. The incidence rate ratio for sepsis was 4. Incidence rate ratios for adverse events associated with short term use of oral corticosteroids, by reason for medical visit. 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. Estimates of corticosteroid use from cross sectional studies range from 0.
Furthermore, although the analyses were weighted, the actual sample of corticosteroid users included only people. In our longitudinal analysis of 1. 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.
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. 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. 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.