Abstract
Background
The prescribing pattern of epinephrine over time is an indicator of the secular trend of anaphylaxis. However, it is not well known in a population level in the United States.
Objective
To evaluate the trend of prescriptions for epinephrine auto-injectors in Olmsted County, MN residents.
Methods
Outpatient prescriptions for epinephrine were identified among residents of Olmsted County, Minnesota, between January 1, 2004 and December 31, 2010. We used the first prescription per patient per year, and the first prescription per patient during the study period to calculate incidence rates. Incidence rates per 100,000 person-years were calculated using patients prescribed epinephrine per year as the numerator and age- and sex-specific counts of the population of Olmsted County as the denominator. The relationships of age group, sex, and year of prescription with incidence rates were assessed by fitting Poisson regression models using the SAS procedure GENMOD.
Results
The overall incidence rate of epinephrine auto-injector prescriptions during the study period was 757 per 100,000 person-years (95% CI 740–774). The prescription rates per patient per year increased over time, with an annual rate of increase of 8% (p<0.001), but the rates per patient remained stable (p=0.077). For each year, incidence rates overall were higher in women compared to men (p<0.001). From ages 0–19, incidence rates were higher in boys compared to girls. At age 20 and above, incidence rates were higher in women compared to men.
Conclusion
The overall rate of epinephrine auto-injector prescriptions increased, but the rate of first time prescriptions was stable from 2005–2010. In childhood, boys were more likely to receive a prescription than girls, but this reversed in later ages.
Keywords: Anaphylaxis, epinephrine auto-injector, epidemiology, incidence rate
INTRODUCTION
Epinephrine auto-injectors are the first line therapy for anaphylaxis and can be administered by laypeople or healthcare providers for the emergency management of anaphylaxis. 1, 2 Since epinephrine auto-injectors are primarily prescribed to treat or prevent anaphylaxis and related allergic reactions, the prescription trends over time can be used as an indicator of the overall prevalence of patients who have experienced or are at risk of experiencing anaphylaxis. 3
Trends of epinephrine auto-injector prescriptions in the United States, however, are not well known. 4 The Rochester Epidemiology Project (REP) is a record linkage system that connects and indexes the records of virtually all providers of medical care in Olmsted County, Minnesota. 4–7 Prescription data have become available as a part of the REP since 2003. 8 Thus, evaluating trends of prescribing for epinephrine auto-injectors within the REP will provide an additional method of estimating the prevalence of patients who have experienced or are at risk of anaphylaxis in Olmsted County, Minnesota.
In this study, we used the REP research infrastructure to determine the trends of epinephrine auto-injector prescriptions in Olmsted County residents over a 7-year period, 2004 – 2010. We hypothesized that the number of prescriptions per year would increase, suggesting an increasing prevalence of anaphylaxis in Olmsted County, MN.
METHODS
Study population
All Olmsted County residents identified by REP census between January 1, 2003 and December 31, 2010 who had given permission for their medical records to be used for research were included in the study. A previous study showed that the record linkage system through the REP captures 98.7% of the population of Olmsted County by US census, and the age and sex distributions were nearly identical to US census estimates.9 The prescription data captures above 80–90 percent from Mayo Clinic and Olmsted Medical Center, two large healthcare organizations in Olmsted County. A previous study suggested that some non-critical medications may be under-counting but still accurately describe trends. 8 St. Sauver et al. reported that age, sex, and ethnic characteristics of Olmsted County were similar to those of the state of Minnesota and the Upper Midwest, however, Olmsted County was less ethnically diverse than the entire US population, more highly educated, and wealthier.9 Additional details of REP studies have been published elsewhere. 9–12 The study was approved by the Institutional Review Boards of both Mayo Clinic and Olmsted Medical Center.
Prescription records
Outpatient prescriptions between January 1, 2003, and December 31, 2010 were obtained from the Mayo Clinic and Olmsted Medical Center in Rochester MN. These two institutions provide nearly all of the health care for Olmsted County residents. 9, 10, 12, 13 Both institutions use electronic prescription systems in outpatient settings. Epinephrine auto-injectors were available in twenty-nine prescription formularies. All prescriptions were mutually exclusive, and individuals who received multiple prescriptions within available formularies were counted only once per year for each year during the study period, and first time prescriptions were also counted once per patient for each year, and once per patient during the study period. We counted each prescription only once whether it was for a single autoinjector or 2-pak. We did not account for refills or duration of medication use.
Statistical analysis
First, we selected the first prescription per patient per year to estimate incidence, then described first prescription per patient during the study period. Trends for first time prescriptions were analyzed from 2004–2010 to allow for a one year wash out period to be able to account for patients who had received a prescription the year before. Prescriptions in 2003 were removed to account for a wash out period during the first 12 months of the study. Incidence rates per 100,000 person-years were calculated using patients prescribed epinephrine as the numerator, and age- and sex-specific counts of the population of Olmsted County as the denominator. The denominators were obtained from a complete enumeration of the Olmsted County population provided by the Rochester Epidemiology Project.14 Because the population of Olmsted County is nearly all white, incidence rates were directly age- and sex-adjusted to the structure of the 2010 US white population. Patients were grouped by age into those 0–9, 10–19, 20–29, 30–39, 40–49, 50–59, and 60+ years old.
The relationships of age group, sex, and year of prescription with incidence rates were assessed by fitting Poisson regression models using the SAS procedure GENMOD. Statistical analyses were performed using version 9.3 of the SAS software package (SAS Institute; Cary, NC). All hypothesis tests were two-sided, and p-values <0.05 were considered statistically significant.
RESULTS
Overall findings
A total of 7991 prescriptions among 3801 patients from 2004–2010 were identified in Olmsted County. The mean age at the first prescription per year was 31.5 years [median 30 years; interquartile range (IQR) 11–50; range 0–97]. Table 1 shows the number of prescriptions each year and the demographics of the patients who received the prescriptions. The greatest number of prescriptions was written for persons age 0–9 years, followed by 10–19 years. Appendix Table shows the number of prescriptions per patient for each year. Seven hundred twenty-five patients had one prescription in 2004; 80 patients had two prescriptions although only the first one was analyzed. There does appear to be an increase in the proportion of patients with more than one prescription during the course of a year (p<0.001). In 2004, 11% of the patients had more than one prescription compared with 17% in 2010. Women received 56% of prescriptions overall. The overall age- and sex-adjusted incidence rate for this analysis was 757 per 100,000 person-years (95% CI 740–774). Age-adjusted rates for women and men were 841 (95% CI 816–866) and 664 (95% CI 642–689) per 100,000 person-years, respectively.
Table 1.
Summary and demographic characteristics of patients receiving epinephrine auto-injector prescriptions in Olmsted County, MN from January 1, 2004 to December 31, 2010. (N=7991)
| Feature | N (%) |
|---|---|
| Age in years | |
| 0–9 | 1752 (22) |
| 10–19 | 1277 (16) |
| 20–29 | 930 (12) |
| 30–39 | 952 (12) |
| 40–49 | 1069 (13) |
| 50–59 | 1068 (13) |
| 60+ | 943 (12) |
| Sex | |
| Female | 4488 (56) |
| Male | 3503 (44) |
| Race | |
| Black | 213 (3) |
| Asian | 349 (4) |
| Hawaiian/Pacific Islander | 16 (<1) |
| American Indian | 19 (<1) |
| Other/mixed | 358 (4.5) |
| Undisclosed | 98 (1) |
| White | 6938 (87) |
| Year | |
| 2004 | 819 (10) |
| 2005 | 918 (11) |
| 2006 | 1121 (14) |
| 2007 | 1168 (15) |
| 2008 | 1231 (15) |
| 2009 | 1290 (16) |
| 2010 | 1444 (18) |
Appendix Table.
Number of prescriptions per patient, from 2004 to 2010
| Year | Number of prescriptions per patient | |||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | |
| 2004 | 725 | 80 | 11 | 2 | 1 | 0 |
| 2005 | 805 | 99 | 11 | 2 | 0 | 1 |
| 2006 | 997 | 110 | 13 | 1 | 0 | 0 |
| 2007 | 1015 | 133 | 17 | 3 | 0 | 0 |
| 2008 | 1094 | 119 | 15 | 3 | 0 | 0 |
| 2009 | 1085 | 170 | 28 | 5 | 2 | 0 |
| 2010 | 1200 | 205 | 29 | 5 | 5 | 0 |
Prescription rate by age and sex
Incidence rates by age are summarized in Table 2 and shown in Figure 1. Incidence rates differed by age group (p<0.001) and by sex (p<0.001), and increased over time (p<0.001). The highest prescription rate was among boys aged 0–9 years. Prescription incidence rates were higher in boys aged 0–19 years compared to girls; however after age 19, incidence rates were higher in women compared to men.
Table 2.
Rates of epinephrine auto-injector prescriptions by age.
| Age in years | Women | Men | Both | |||
|---|---|---|---|---|---|---|
| N | Rate* | N | Rate* | N | Rate† | |
| 0–9 | 641 | 875 | 1111 | 1445 | 1752 | 1167 |
| 10–19 | 543 | 796 | 734 | 1041 | 1277 | 921 |
| 20–29 | 625 | 709 | 305 | 417 | 930 | 577 |
| 30–39 | 604 | 947 | 348 | 512 | 952 | 684 |
| 40–49 | 749 | 966 | 320 | 445 | 1069 | 716 |
| 50–59 | 676 | 1018 | 392 | 650 | 1068 | 843 |
| 60+ | 650 | 720 | 293 | 409 | 943 | 582 |
| Total | 4488 | 841 | 3503 | 664 | 7991 | 757 |
Rates per 100,000 person-years age-adjusted to 2010 US white population.
Rates per 100,000 person-years age- and sex-adjusted to 2010 US white population.
Figure 1.
Rates of self-injectable epinephrine prescriptions overall and by age and sex
Incidence rates by year are summarized in Table 3 and shown in Figure 2, and incidence rates of first time prescriptions during the study period in Figure 3, 4. Over the study period, there was a 69% increase in the rate of prescriptions from 555 to 939 per 100,000 person years. The incidence rate ratio for the trend of incidence rates over time was 1.080 (95% CI 1.068–1.092), indicating that rates increased by 8.0% per year (Figure 2). The overall prescription rate increased in all age groups from 2004–2010 (p <0.001). There was no evidence of a statistically significant difference in the rates of increase between different age groups (p=0.17). First time prescription rate decreased during 2004–2010 (p<0.001), otherwise relatively stable (p=0.077) from 2005–2010, yet there was evidence that incidence rates differed by age group (p<0.001), differed by sex (p<0.001) (Figure 3, 4). Women received more prescriptions than men throughout the study period (Figure 3). Men received more prescriptions than women up to age 19, but this reversed in the older age (Figure 4).
Table 3.
Epinephrine auto-injector prescription rates by year
| Year | Women | Men | Both | |||
|---|---|---|---|---|---|---|
| N | Rate* | N | Rate* | N | Rate† | |
| 2004 | 483 | 650 | 336 | 454 | 819 | 555 |
| 2005 | 510 | 679 | 409 | 545 | 918 | 616 |
| 2006 | 625 | 832 | 496 | 659 | 1121 | 751 |
| 2007 | 650 | 840 | 518 | 686 | 1168 | 767 |
| 2008 | 687 | 895 | 544 | 712 | 1231 | 808 |
| 2009 | 716 | 923 | 574 | 746 | 1290 | 840 |
| 2010 | 817 | 1043 | 627 | 825 | 1444 | 939 |
Rate per 100,000 person-years age-adjusted to 2010 US white population.
Rate per 100,000 person-years age- and sex-adjusted to 2010 US white population.
Figure 2.
Rates of self-injectable epinephrine prescriptions overall and by sex, 2004–2010
Figure 3.
The incidence rate of first-time self-injectable epinephrine prescriptions overall and by sex, 2004–2010
Figure 4.
The incidence rate of first time epinephrine prescriptions by age and sex
DISCUSSION
Statement of principle findings
The overall age- and sex-adjusted incidence rate for this population of patients in Olmsted County, Minnesota was 757 per 100,000 person-years. Although, overall, the rate of prescriptions was higher in women than in men, prescription rates were higher in boys age 0–19 years compared to girls. There was an approximately 8% increase in prescription rates each year over the 7-year study period. However, first time prescriptions per patient during the study period remained relatively stable.
Strengths and limitations
The primary strength of our study is the ability to obtain a population-based estimate of epinephrine auto-injector prescriptions over a 7-year period. Through the Rochester Epidemiology Project collaborations within Olmsted County, we were able to identify above 80–90 percent of all the prescriptions from Mayo Clinic and Olmsted Medical Center, two large healthcare organizations in Olmsted County from 2004 to 2010. Prescription data can be used to help delineate trends of anaphylaxis care and infer anaphylaxis incidence rates.
Our study has several potential limitations. First, the study was conducted in a predominantly white community, and the study findings may not generalize to other more diverse settings. Second, prescription data were available for outpatients including those given at the time of discharge from hospital or emergency department; however we were unable to estimate the use of epinephrine autoinjector in the inpatient setting. Furthermore, we were unable to determine the type of provider who provided the prescription such as an allergist/immunologist, primary care provider, or ED provider. Third, our prescription data are not linked to the prescriber, and therefore we are not able to describe prescribing trends among different specialties. Fourth, we were not able to capture prescriptions that were called in or handwritten. However, we estimate that these would represent a small proportion of the prescriptions. Fifth, the prescription data does not include dispensing or insurance coverage information. Sixth, the prescription data does not have an overall trend of other prescriptions, and it is not certain that the trend increase in epinephrine prescription is unique, or it possibly mirrors a general rise in all-cause prescriptions over the period. It is noteworthy that prescriptions for epinephrine autoinjectors written for prophylaxis among patients taking Omalizumab could potentially confound the findings. However, only 30 patients during the study period were prescribed Omalizumab, and 19 of these patients were also prescribed epinephrine. Therefore, we believe that 19 patients, or 0.5% of the cohort, are unlikely to confound our results. Finally, epinephrine prescriptions do not necessarily indicate treatment of anaphylaxis, as clinicians often prescribe epinephrine to address potential exposure to inciting triggers rather than clinical signs or symptoms.
Interpretation of findings
To our knowledge, this is the first population-based study to address the trends of epinephrine auto-injector prescriptions in the United States over time. For each year of the study period, rates of epinephrine auto-injector prescriptions were higher in women overall compared to men. The highest rates were observed among patients age 0–9 years during which boys received more than girls. However, women received more prescriptions than men in the older age groups. These findings are consistent with the findings of Simon et al. who studied the population of Manitoba, Canada from 1995–2000. 3 Our demographic findings for epinephrine auto-injectors are also consistent with the demographics observed in prior epidemiological studies of anaphylaxis.4, 15–17 Overall, we found that epinephrine auto-injector prescription rates were higher in women, which is consistent with findings by Decker et al. who reported that overall rates of anaphylaxis were higher in women than in men. 4 Mulla et al. reported a finding of higher hospitalization among women than men with anaphylaxis in Florida. 16 Our study showed a higher rate of epinephrine auto-injectors prescriptions for boys age 0–9 compared to girls and higher rates in women over age 20 compared to men. Similar trends have been demonstrated in studies of anaphylaxis-related hospitalizations. 15–17 Another study from Australia demonstrated that more boys were hospitalized than girls for angioedema, urticaria and anaphylaxis, but this reversed in older ages. 17 A higher rate of anaphylaxis hospitalization for males under 20 years of age was also reported in the US. 15
Incidence rates of prescription were adjusted for population counts by definition. Taken together, the consistency of our findings with extant literature suggests that epinephrine auto-injectors can be used to estimate of the burden of anaphylaxis in a population. 4,18,19
Lastly, our study showed that the prescription rate increased 8% per year during the study period (69% increase overall), yet the rate of first time prescription in our cohort during the study period was relatively stable. Pharmacy data from Australia showed a 300% increase in epinephrine auto-injector prescriptions from 1998–2002.20 A study from Israel also showed that epinephrine auto-injector prescriptions increased by 76% from 1997 to 2004.21 Similarly, national healthcare data from the United Kingdom showed a 97% increase in epinephrine auto-injector prescriptions along with increased diagnoses of anaphylaxis between 2001 and 2005. 22 These studies reported the crude rate of prescriptions. Thus, our data are consistent with worldwide trends showing increasing rates of epinephrine auto-injector prescriptions, which reflects the increasing prevalence of anaphylaxis. The findings of relatively constant trend for first- time prescriptions during the study period suggests that providers are providing refills of epinephrine prescriptions although it is unknown whether newly diagnosed cases of anaphylaxis patients are receiving necessary prescriptions.
CONCLUSION AND FUTURE DIRECTIONS
Outpatient prescriptions of epinephrine auto-injectors showed an overall increase in all age groups from 2004–2010 in Olmsted County. However, first time prescriptions per patient during the study period remained relatively stable. Rates of increase may be related to increased burden of allergic disease, especially food allergy in young patients, increased public awareness, as well as increasing recognition and frequency of diagnosis by healthcare providers. Further studies are needed to clearly determine if these trends continue and the appropriateness of epinephrine auto-injector prescribing patterns.
Highlights Box.
1. What is already known about this topic?
The prescription trend of epinephrine auto-injector can be an indicator of the prevalence of patients who have experienced or are at risk of anaphylaxis.
2. What does this article add to our knowledge?
The incidence rate of epinephrine auto-injector prescriptions increased from 2004–2010. In childhood, boys were more likely to receive a prescription than girls, but this reversed in later ages.
3. How does this study impact current management guidelines
Rates of increased epinephrine auto-injector may be related to increased burden of allergic disease, especially food allergy in young patients, increased public awareness, as well as increasing recognition and frequency of diagnosis by healthcare providers.
Acknowledgments
We appreciate the valuable input from Hirohito Kita, MD, PhD, James Li, MD, PhD and Amy Weaver MPH at the Mayo Graduate School. This study was made possible using the resources of the Rochester Epidemiology Project, which is supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676, and by CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
Abbreviations
- REP
Rochester Epidemiology Project
- IQRs
interquartile ranges
- CI
Confidence interval
- ED
Emergency department
Footnotes
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Contributor Information
Sangil Lee, Clinical instructor, Department of emergency medicine, Mayo Clinic Health System.
Erik P Hess, Associate professor, Department of emergency medicine, Mayo Clinic.
Christine Lohse, Department of emergency medicine, Mayo Clinic.
Dante Lucas S Souza, Department of emergency medicine, Mayo Clinic.
Ronna L Campbell, Assistant professor, Department of emergency medicine, Mayo Clinic.
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