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Prevention of Anaphylaxis: The Role of the Epinephrine Auto-Injector

Open AccessPublished:August 21, 2016DOI:https://doi.org/10.1016/j.amjmed.2016.07.018

      Highlights

      • Timely epinephrine injection prevents anaphylaxis-related hospitalization or death.
      • At-risk patients should carry 2 epinephrine auto-injectors, but many do not.
      • Prescription abandonment rates increase with higher out-of-pocket costs.
      • Limited or no cost sharing is required for preventive medications.
      • Classifying epinephrine auto-injectors as preventive would improve outcomes.

      Abstract

      Anaphylaxis is a life-threatening condition, with at-risk individuals remaining at chronic high risk of recurrence. Anaphylaxis is frequently underrecognized and undertreated by healthcare providers. The first-line pharmacologic intervention for anaphylaxis is epinephrine, and guidelines uniformly agree that its prompt administration is vital to prevent progression, improve patient outcomes, and reduce hospitalizations and fatalities. Healthcare costs potentially associated with failure to provide epinephrine (hospitalizations and emergency department visits) generally exceed those of its provision. At-risk patients are prescribed epinephrine auto-injectors to facilitate timely administration in the event of an anaphylactic episode. Despite guideline recommendations that patients carry 2 auto-injectors at all times, a significant proportion of patients fail to do so, with cost of medicine cited as one reason for this lack of adherence. With the increase of high-deductible healthcare plans, patient adherence to recommendations may be further affected by increased cost sharing. The recognition and classification of epinephrine as a preventive medicine by both the US Preventive Services Task Force and insurers could increase patient access, improve outcomes, and save lives.

      Keywords

      SEE RELATED EDITORIAL AND COMMENTARY pp. 1235 and 1237
      Clinical Significance
      • •Anaphylaxis is life threatening, underrecognized, and undertreated. Prompt epinephrine administration is integral to prevent hospitalizations and deaths.
      • •At-risk patients should carry 2 epinephrine auto-injectors, but many fail to do so.
      • •Adherence to medications decreases with the increased cost sharing associated with high-deductible healthcare plans.
      • •Classification of epinephrine auto-injectors as preventive medicines by the USPSTF and/or insurers would eliminate or reduce cost sharing, improving access and outcomes.
      Allergies are the sixth leading cause of chronic illness in the United States, affecting more than 50 million Americans and costing the healthcare system more than $18 billion annually.

      Centers for Disease Control and Prevention (CDC). Allergies. Available at: http://www.cdc.gov/healthcommunication/toolstemplates/entertainmented/tips/allergies.html. Accessed March 24, 2016.

      Individuals in hyperallergic states are at chronic high risk for the occurrence of acute anaphylactic episodes, and as many as 49 million individuals are thought to be at risk in the United States.
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      Annual direct costs of anaphylaxis are estimated at $1.2 billion.
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      Economic burden of anaphylaxis in the United States.
      Anaphylactic episodes are serious, multisystem, life-threatening, and generalized or systemic hypersensitive or allergic reactions that are rapid in onset and potentially fatal.
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      Anaphylaxis may be immunologic (immunoglobulin E mediated or non–immunoglobulin E mediated) or nonimmunologic; both forms are referred to as “anaphylaxis” in this review, in line with international guidelines and consensus statements.
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      Risk factors for anaphylaxis include age,
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      World Allergy Organization
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      comorbidities (eg, asthma
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      Anaphylaxis–a practice parameter update 2015.
      ), and certain medications (eg, beta-blockers and angiotensin-converting enzyme inhibitors).
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      World Allergy Organization
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      Anaphylaxis occurs on a continuum and can begin with relatively minor symptoms before progressing, in an unpredictable manner, to a life-threatening condition.
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      World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis
      Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization.
      The most common signs and symptoms include changes in the skin (eg, itching, erythema, pruritus, urticaria, angioedema) and respiration (including bronchospasm, laryngeal edema, cough, respiratory arrest); effects on the gastrointestinal, cardiovascular, and central nervous systems also may be evident.
      • Kemp S.F.
      • Lockey R.F.
      • Simons F.E.
      World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis
      Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization.
      • Simons F.E.
      • Ardusso L.R.
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      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      Anaphylaxis often is underrecognized by healthcare professionals both in general practice and in emergency care,
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      2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.
      particularly if cutaneous signs and symptoms are not present (these are absent in 10%-20% of patients).
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      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      International guidelines concur that anaphylaxis is a medical emergency and requires rapid intervention.
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      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      • Simons F.E.
      • Ebisawa M.
      • Sanchez-Borges M.
      • et al.
      2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.
      Prompt treatment with epinephrine, the only first-line intervention for anaphylaxis, is recommended to prevent the progression of an anaphylactic episode.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      • Simons F.E.
      • Ebisawa M.
      • Sanchez-Borges M.
      • et al.
      2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.
      • Simons F.E.
      • Ardusso L.R.
      • Dimov V.
      • et al.
      World Allergy Organization
      World Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base.
      For patients experiencing an anaphylactic event, epinephrine is the only medication proven to prevent hospitalization and fatalities.
      • Simons F.E.
      • Ebisawa M.
      • Sanchez-Borges M.
      • et al.
      2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.
      Because the onset of anaphylaxis symptoms often occurs in the community setting,
      • Kemp S.F.
      • Lockey R.F.
      • Simons F.E.
      World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis
      Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization.
      at-risk patients should be prescribed epinephrine auto-injectors to provide rapid intramuscular administration of epinephrine.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.
      However, a large number of patients prescribed epinephrine auto-injectors do not have access to one at the time of an allergen exposure, leading to delayed medication administration and increased risk of progression to severe anaphylaxis.
      • Wood R.A.
      • Camargo Jr., C.A.
      • Lieberman P.
      • et al.
      Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.
      • Kaplan M.S.
      • Jung S.Y.
      • Chiang M.L.
      Epinephrine autoinjector refill history in an HMO.
      • Pumphrey R.S.
      Lessons for management of anaphylaxis from a study of fatal reactions.
      • Song T.T.
      • Worm M.
      • Lieberman P.
      Anaphylaxis treatment: current barriers to adrenaline auto-injector use.
      Currently, many high-deductible healthcare plans include epinephrine auto-injectors among those medications to which the plan's deductible applies rather than as a preventive medicine exempt from cost sharing. Because high deductibles and high cost sharing, such as those in high-deductible healthcare plans, may lead to decreased use of medical care,
      • Eaddy M.T.
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      • O'Day K.
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      How patient cost-sharing trends affect adherence and outcomes: a literature review.
      • Medford-Davis L.N.
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      • Dark C.
      The Patient Protection and Affordable Care Act's effect on emergency medicine: a synthesis of the data.
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      • et al.
      Low-socioeconomic-status enrollees in high-deductible plans reduced high-severity emergency care.
      • Kullgren J.T.
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      • Hinrichsen V.L.
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      Health care use and decision making among lower-income families in high-deductible health plans.
      the recognition and classification of epinephrine as a preventive medicine could improve patient access. Recommended preventive services or medications (ie, those graded A or B by the US Preventive Services Task Force [USPSTF]) are not subject to any cost-sharing requirements for the patient, (eg, deductibles, copayments) (as discussed next), as per the Patient Protection and Affordable Care Act 2010.

      Patient Protection and Affordable Care Act, 42 USC §18001 (2010).

      The role of epinephrine auto-injectors in the prevention of anaphylaxis progression and their potential classification as preventive by the USPSTF and inclusion on healthcare plan preventive medication lists are reviewed.

      Economic Burden of Anaphylaxis

      The reported incidence of anaphylaxis in the United States is 49.8 in 100,000 person-years,
      • Decker W.W.
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      • Manivannan V.
      • et al.
      The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project.
      with a lifetime prevalence of approximately 1.6% to 5.1%.
      • Wood R.A.
      • Camargo Jr., C.A.
      • Lieberman P.
      • et al.
      Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.
      Anaphylaxis represents an increasing burden on emergency departments and hospitals. One study reported a 2.23% annual increase in anaphylaxis-related hospitalizations from 1999 to 2009, reaching 25.1 per million population annually.
      • Ma L.
      • Danoff T.M.
      • Borish L.
      Case fatality and population mortality associated with anaphylaxis in the United States.
      The same authors calculated that, from 2006 to 2009, the number of anaphylaxis-related emergency department presentations without hospital admission ranged from 17,735 to 21,822.
      • Ma L.
      • Danoff T.M.
      • Borish L.
      Case fatality and population mortality associated with anaphylaxis in the United States.
      From 1999 to 2009, anaphylaxis-related deaths totaled 2229 (0.69 per million population), with the annual number of deaths ranging from 186 to 225 (0.63-0.76 per million population).
      • Ma L.
      • Danoff T.M.
      • Borish L.
      Case fatality and population mortality associated with anaphylaxis in the United States.
      However, healthcare providers frequently underreport anaphylaxis because of the unexpected nature of the event, a lack of accurate diagnosis, and a lack of accurate diagnostic coding.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Sclar D.A.
      • Lieberman P.L.
      Anaphylaxis: underdiagnosed, underreported, and undertreated.
      • Academy of Managed Care Pharmacy
      Proceedings of the AMCP Integrated Care Summit: population health and quality improvement in anaphylaxis.
      This means that currently reported rates of anaphylaxis prevalence and associated mortality are likely to be underestimates. In addition, inaccurate coding makes it difficult for payers to accurately determine the costs of treating anaphylaxis versus the costs associated with preventive measures.
      • Academy of Managed Care Pharmacy
      Proceedings of the AMCP Integrated Care Summit: population health and quality improvement in anaphylaxis.
      Of the estimated annual direct anaphylaxis costs of $1.2 billion, $294 million relates to epinephrine costs. Indirect expenditures are estimated at $609 million.
      • Sclar D.
      • Cohen L.
      • Robison L.
      Economic burden of anaphylaxis in the United States.
      A survey of caregivers of children with a food allergy estimated direct medical costs (including emergency department visits and hospitalizations) to be higher, at $3.7 billion per year.
      • Gupta R.
      • Holdford D.
      • Bilaver L.
      • et al.
      The high economic burden of childhood food allergy in the United States.
      In a review of literature and healthcare databases, epinephrine costs amounted to less than 9% of the total direct costs of treating patients with food allergy and anaphylaxis, whereas emergency department visits accounted for 20% of direct costs.
      • Patel D.A.
      • Holdford D.A.
      • Edwards E.
      • Carroll N.V.
      Estimating the economic burden of food-induced allergic reactions and anaphylaxis in the United States.

      Importance of Prompt Treatment of Anaphylaxis

      Guidelines and consensus statements emphasize the importance of prompt initial administration of epinephrine for the treatment of anaphylaxis.
      • Kemp S.F.
      • Lockey R.F.
      • Simons F.E.
      World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis
      Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      • Simons F.E.
      • Ebisawa M.
      • Sanchez-Borges M.
      • et al.
      2015 update of the evidence base: World Allergy Organization anaphylaxis guidelines.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      • Simons F.E.
      • Ardusso L.R.
      • Dimov V.
      • et al.
      World Allergy Organization
      World Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base.
      Some authors have specified that epinephrine is indicated in patients with “impending anaphylaxis”
      • Fineman S.M.
      • Bowman S.H.
      • Campbell R.L.
      • et al.
      Addressing barriers to emergency anaphylaxis care: from emergency medical services to emergency department to outpatient follow-up.
      or should be administered “sooner rather than later.”
      • Kemp S.F.
      Office approach to anaphylaxis: sooner better than later.
      Members of the Anaphylaxis Practice Parameter Workgroup, commissioned by the Joint Task Force on Practice Parameters, recommend immediate treatment with epinephrine to prevent symptom progression and the occurrence of more severe anaphylaxis.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      Delayed epinephrine administration leads to worse outcomes and fatalities.
      • Kemp S.F.
      • Lockey R.F.
      • Simons F.E.
      World Allergy Organization ad hoc Committee on Epinephrine in Anaphylaxis
      Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization.
      • Simons F.E.
      • Ardusso L.R.
      • Dimov V.
      • et al.
      World Allergy Organization
      World Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base.
      • Fleming J.T.
      • Clark S.
      • Camargo Jr., C.A.
      • Rudders S.A.
      Early treatment of food-induced anaphylaxis with epinephrine is associated with a lower risk of hospitalization.
      A UK study found that of all anaphylaxis fatalities occurring in a 6-year period, only 14% of the victims had received epinephrine before cardiac arrest.
      • Pumphrey R.S.
      Lessons for management of anaphylaxis from a study of fatal reactions.
      In a 14-month US study of fatal or near-fatal food-induced anaphylaxis in children and adolescents, only 33% of the patients with a fatal reaction received epinephrine within 1 hour of allergen exposure, whereas none of the patients with a near-fatal reaction received epinephrine at the first sign of symptoms.
      • Sampson H.A.
      • Mendelson L.
      • Rosen J.P.
      Fatal and near-fatal anaphylactic reactions to food in children and adolescents.
      Although 50% of the patients with a fatal reaction had been previously prescribed epinephrine auto-injectors, none had them available at the time of the reaction. In addition to the risk of fatality, failure to promptly administer epinephrine may increase the likelihood of biphasic anaphylaxis, in which symptoms recur 1 to 72 hours (typically within 8-10 hours) after resolution of the initial symptoms.
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      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.

      Inadequate Treatment of Anaphylaxis

      Despite clear recommendations for prompt epinephrine administration, recognition of anaphylaxis is often inconsistent and many patients receive inadequate management. A review of a national database demonstrated that 57% of anaphylactic episodes are not recognized in the emergency department,
      • Ross M.P.
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      • Street D.
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      Analysis of food-allergic and anaphylactic events in the National Electronic Injury Surveillance System.
      whereas another study reports that anaphylaxis is underrecognized in both emergency departments and urgent care centers.
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      • Coffman A.
      • Erwin E.
      • Mikhail I.
      Variability in the recognition and management of food induced anaphylaxis in pediatric emergency departments and urgent care centers.
      Overall, this lack of recognition and management of anaphylaxis means that patients often do not receive first-line epinephrine treatment. For example, in a study of pediatric patients with food-induced anaphylaxis, only 61% received epinephrine (either pre- or postadmission). The median length of emergency department stay was shorter for those patients who received epinephrine before admission to the emergency department (3 vs 4 hours, P = .03), and these patients also were less likely to be hospitalized (17% vs 43%, P <.001).
      • Fleming J.T.
      • Clark S.
      • Camargo Jr., C.A.
      • Rudders S.A.
      Early treatment of food-induced anaphylaxis with epinephrine is associated with a lower risk of hospitalization.
      Likewise, other studies in pediatric patients have shown that as few as 33% to 50% of anaphylactic patients admitted to the emergency department receive epinephrine.
      • Gaspar A.
      • Santos N.
      • Piedade S.
      • et al.
      One-year survey of paediatric anaphylaxis in an allergy department.
      • Hemler J.A.
      • Sharma H.P.
      Management of children with anaphylaxis in an urban emergency department.
      In a 12-year study of 12.4 million emergency department visits for allergic reactions and anaphylaxis, only 50% of patients with the most severe reactions received epinephrine.
      • Gaeta T.J.
      • Clark S.
      • Pelletier A.J.
      • Camargo C.A.
      National study of US emergency department visits for acute allergic reactions, 1993 to 2004.
      Instead of receiving first-line epinephrine treatment, patients often were treated with second-line therapies, including antihistamines and glucocorticoids.
      • Fleming J.T.
      • Clark S.
      • Camargo Jr., C.A.
      • Rudders S.A.
      Early treatment of food-induced anaphylaxis with epinephrine is associated with a lower risk of hospitalization.
      • Hemler J.A.
      • Sharma H.P.
      Management of children with anaphylaxis in an urban emergency department.
      • Gaeta T.J.
      • Clark S.
      • Pelletier A.J.
      • Camargo C.A.
      National study of US emergency department visits for acute allergic reactions, 1993 to 2004.
      However, these medications only treat the cutaneous symptoms of anaphylaxis and do not prevent or relieve life-threatening upper airway obstruction.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      Furthermore, they may require several hours to take effect, limiting their utility in the early hours of an anaphylactic episode.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.

      Adherence

      Anaphylaxis has a high risk of recurrence (estimated to be 30%-43%),
      • Armstrong N.
      • Wolff R.
      • van Mastrigt G.
      • et al.
      A systematic review and cost-effectiveness analysis of specialist services and adrenaline auto-injectors in anaphylaxis.
      and long-term preventive measures are a key element of patient care. Discharge from the emergency department represents the transition to long-term management, and emergency department practitioners play a pivotal role in this step.
      • Fineman S.M.
      • Bowman S.H.
      • Campbell R.L.
      • et al.
      Addressing barriers to emergency anaphylaxis care: from emergency medical services to emergency department to outpatient follow-up.
      Long-term management approaches initiated at discharge should include patient education,
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      allergen avoidance,
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      • Kemp S.F.
      Office approach to anaphylaxis: sooner better than later.
      referral to an allergy specialist,
      • Kemp S.F.
      Office approach to anaphylaxis: sooner better than later.
      and the provision of epinephrine auto-injectors.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      • Kemp S.F.
      Office approach to anaphylaxis: sooner better than later.
      Current guidelines recommend that at-risk patients carry 2 epinephrine auto-injectors at all times (because anaphylactic episodes can be biphasic, necessitating the administration of 2 doses of epinephrine).
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      International consensus on (ICON) anaphylaxis.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      • Boyce J.A.
      • Assa'ad A.
      • Burks A.W.
      • et al.
      NIAID-Sponsored Expert Panel
      Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel.
      However, many patients do not have access to an auto-injector at the time of recurrence. In one survey, 52% of patients who had previously experienced anaphylaxis had never received a self-injectable epinephrine prescription, and 60% did not have an auto-injector available.
      • Wood R.A.
      • Camargo Jr., C.A.
      • Lieberman P.
      • et al.
      Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States.
      Other authors have cited even lower figures, with an observational study reporting that only 9% to 28% of patients requiring epinephrine auto-injectors carried one with them.
      • Sánchez J.
      Anaphylaxis. How often patients carry epinephrine in real life?.
      In a study of 14,677 patients in a large health maintenance organization who had received a prescription for an epinephrine auto-injector, only 11% refilled consistently.
      • Kaplan M.S.
      • Jung S.Y.
      • Chiang M.L.
      Epinephrine autoinjector refill history in an HMO.
      Medication cost has been shown to play a critical role in patient nonadherence.
      • Goldman D.P.
      • Joyce G.F.
      • Zheng Y.
      Prescription drug cost sharing: associations with medication and medical utilization and spending and health.
      Cost of a medication and lack of insurance coverage for a medication are among the most common reasons cited by patients for failing to fill or refill a prescription.
      • Kennedy J.
      • Tuleu I.
      • Mackay K.
      Unfilled prescriptions of medicare beneficiaries: prevalence, reasons, and types of medicines prescribed.
      A review of studies analyzing the relationship between patient cost sharing and adherence estimated that, for each dollar increase in patient copayments, adherence decreases by 0.4%.
      • Eaddy M.T.
      • Cook C.L.
      • O'Day K.
      • et al.
      How patient cost-sharing trends affect adherence and outcomes: a literature review.
      Moreover, reduction in out-of-pocket expenses has been identified as a strategy to improve adherence among patients with chronic conditions.
      • Viswanathan M.
      • Golin C.E.
      • Jones C.D.
      • et al.
      Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review.
      This relationship between cost and adherence extends to anaphylaxis treatment. When allergists were surveyed about the medication concerns of patients with anaphylaxis, 56% listed the cost of the epinephrine auto-injector as a patient concern and 38% cited patient financial inability to fill the prescription for the epinephrine auto-injector as one of the most frequent reasons why patients fail to carry an auto-injector with them.
      • Fineman S.
      • Dowling P.
      • O'Rourke D.
      Allergists' self-reported adherence to anaphylaxis practice parameters and perceived barriers to care: an American College of Allergy, Asthma, and Immunology member survey.
      Furthermore, 78% of allergists surveyed stated that their patients were likely to use an expired epinephrine auto-injector if they were unable to afford a new epinephrine auto-injector.
      • Fineman S.
      • Dowling P.
      • O'Rourke D.
      Allergists' self-reported adherence to anaphylaxis practice parameters and perceived barriers to care: an American College of Allergy, Asthma, and Immunology member survey.
      Claims data also suggest that financial considerations may represent a barrier to epinephrine auto-injector use in the United States. For example, abandonment rates of the EpiPen (Mylan, Canonsburg, Pa) auto-injector increase in relation to patient cost; more than 50% of EpiPen prescriptions are abandoned when patient cost exceeds $300 (Figure).

      IMS Formulary Impact Analyzer Report: EpiPen claims data October 2014 to October 2015. Data on file, Mylan.

      Figure
      FigureAbandonment rates with increasing patient cost of the EpiPen (Mylan, Canonsburg, Pa) (October 2014 to October 2015).

      IMS Formulary Impact Analyzer Report: EpiPen claims data October 2014 to October 2015. Data on file, Mylan.

      Epinephrine Auto-Injector as a Preventive Medication

      The US Treasury Department defines medications as preventive “when taken by a person who has developed risk factors for a disease that has not yet manifested itself or not yet become clinically apparent (ie, asymptomatic) or to prevent the reoccurrence of a disease from which a person has recovered.”

      Internal Revenue Service. Internal Revenue Bulletin: 2004-33. Notice 2004-50. Available at: https://www.irs.gov/irb/2004-33_IRB/ar08.html#d0e1823. Accessed March 20, 2016.

      Recommended practices for prevention, trigger avoidance, and treatment indicate that anaphylaxis is a chronic condition with occasional, potentially severe symptom recurrence.
      • Sclar D.A.
      • Lieberman P.L.
      Anaphylaxis: underdiagnosed, underreported, and undertreated.
      Patients with allergies have risk factors for anaphylaxis, including a previous allergic reaction, comorbidities such as asthma, and treatment with certain medications.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      Furthermore, patients who have recovered from anaphylaxis are at risk for reappearance of symptoms in a future episode.
      • Lieberman P.
      • Nicklas R.A.
      • Randolph C.
      • et al.
      Anaphylaxis–a practice parameter update 2015.
      Preventive anaphylaxis care (ie, filling an epinephrine auto-injector prescription or visiting an allergist/immunologist) in the year before an anaphylactic event has been associated with a lower risk of severe anaphylaxis.
      • Clark S.
      • Wei W.
      • Rudders S.A.
      • Camargo Jr., C.A.
      Risk factors for severe anaphylaxis in patients receiving anaphylaxis treatment in US emergency departments and hospitals.
      These data support the classification of epinephrine, the only first-line, lifesaving treatment for anaphylaxis, as a preventive medication.

      Preventive Medicine and High-Deductible Healthcare Plans

      The USPSTF is an independent, volunteer expert panel that makes evidence-based recommendations on clinical preventive procedures, services, and therapies.

      US Preventive Services Task Force (USPSTF). About the USPSTF. Available at: http://www.uspreventiveservicestaskforce.org/Page/Name/about-the-uspstf. Accessed June 7, 2016.

      Recommendations are updated regularly on the basis of evidence level and cost:benefit ratio,

      US Preventive Services Task Force (USPSTF). About the USPSTF. Available at: http://www.uspreventiveservicestaskforce.org/Page/Name/about-the-uspstf. Accessed June 7, 2016.

      with services being graded A to D or I accordingly (Table 1).

      US Preventive Services Task Force (USPSTF). Grade definitions. Available at: http://www.uspreventiveservicestaskforce.org/Page/Name/grade-definitions. Accessed March 20, 2016.

      The USPSTF recommends that those services receiving grades A or B should be offered or provided to patients. Grade A services are those where there is a high certainty of substantial net benefit, and Grade B services have either a moderate certainty of moderate or substantial benefit or a high certainty of moderate benefit (Table 1).

      US Preventive Services Task Force (USPSTF). Grade definitions. Available at: http://www.uspreventiveservicestaskforce.org/Page/Name/grade-definitions. Accessed March 20, 2016.

      Table 1US Preventive Services Task Force Grade Definitions

      US Preventive Services Task Force (USPSTF). Grade definitions. Available at: http://www.uspreventiveservicestaskforce.org/Page/Name/grade-definitions. Accessed March 20, 2016.

      GradeDefinitionRecommendations
      AThe USPSTF recommends. High certainty of substantial net benefit.Offer or provide this service.
      BThe USPSTF recommends. High certainty of moderate net benefit or moderate certainty of moderate to substantial net benefit.Offer or provide this service.
      CThe USPSTF recommends selectively offering/providing to individual patients on the basis of professional judgment and patient preferences. Moderate certainty of small net benefit.Offer or provide this service for selected patients depending on individual circumstances.
      DThe USPSTF recommends against. Moderate or high certainty of no net benefit or that harms outweigh benefits.Discourage use.
      IThe USPSTF concludes that current evidence is insufficient to assess benefits and harms. Evidence is lacking, of poor quality, or conflicting.Read the clinical considerations section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.
      USPSTF = US Preventive Services Task Force.
      Per the Patient Protection and Affordable Care Act 2010,

      Patient Protection and Affordable Care Act, 42 USC §18001 (2010).

      the cost of those preventive drugs that are given USPSTF grade A or B ratings is covered in healthcare insurance plans, including in high-deductible healthcare plans. To grade preventive medications, the USPSTF evaluates all available peer-reviewed evidence, often including data from randomized controlled trials. However, in the case of some preventive medications recommended by the USPSTF (eg, folic acid for the prevention of neural tube defects), the evidence base contains only limited numbers of randomized controlled trials because of the nature of the medication.
      • US Preventive Services Task Force
      Folic acid for the prevention of neural tube defects: U.S. Preventive Services Task Force recommendation statement.
      In the case of epinephrine, which was introduced before the advent of randomized controlled trials,
      • Simons F.E.
      • Ardusso L.R.
      • Bilò M.B.
      • et al.
      World Allergy Organization
      World allergy organization guidelines for the assessment and management of anaphylaxis.
      it would be unethical to assess efficacy in placebo-controlled or comparator randomized controlled trials (ie, it would not be ethical to withhold epinephrine when it is the only first-line medication and the only medication known to prevent fatalities).
      • Sheikh A.
      • Simons F.E.
      • Barbour V.
      • Worth A.
      Adrenaline auto-injectors for the treatment of anaphylaxis with and without cardiovascular collapse in the community.
      • McLean-Tooke A.P.
      • Bethune C.A.
      • Fay A.C.
      • Spickett G.P.
      Adrenaline in the treatment of anaphylaxis: what is the evidence?.
      Partial coverage and high copayments are associated with decreased uptake of preventive services and poorer patient outcomes.
      • Curry S.J.
      • Grothaus L.C.
      • McAfee T.
      • Pabiniak C.
      Use and cost effectiveness of smoking-cessation services under four insurance plans in a health maintenance organization.
      • Faulkner L.A.
      • Schauffler H.H.
      The effect of health insurance coverage on the appropriate use of recommended clinical preventive services.
      Therefore, classification of medications as preventive (grades A or B) by the USPSTF and subsequent exemption from deductibles in healthcare plans, including high-deductible healthcare plans, would be expected to increase use. In the case of epinephrine auto-injectors, an increase in the number of patients filling prescriptions should improve access at the time of an anaphylactic episode and avoid delay in epinephrine initiation, thereby reducing hospitalizations, fatalities, and treatment costs.
      High-deductible healthcare plan enrollment has increased each year, covering up to 19.7 million individuals in the United States in November 2015.

      America's Health Insurance Plans (AHIP). New census survey shows continued growth in HSA enrollment. Available at: https://ahip.org/new-census-survey-shows-continued-growth-in-hsa-enrollment/. Accessed June 7, 2016.

      High-deductible healthcare plans have high annual deductibles and out-of-pocket limits. However, high patient cost sharing is associated with decreased treatment adherence,
      • Eaddy M.T.
      • Cook C.L.
      • O'Day K.
      • et al.
      How patient cost-sharing trends affect adherence and outcomes: a literature review.
      delayed presentation,
      • Lieu T.A.
      • Solomon J.L.
      • Sabin J.E.
      • et al.
      Consumer awareness and strategies among families with high-deductible health plans.
      and adverse outcomes, particularly among low-income patients in high-deductible healthcare plans.
      • Medford-Davis L.N.
      • Eswaran V.
      • Shah R.M.
      • Dark C.
      The Patient Protection and Affordable Care Act's effect on emergency medicine: a synthesis of the data.
      • Wharam J.F.
      • Zhang F.
      • Landon B.E.
      • et al.
      Low-socioeconomic-status enrollees in high-deductible plans reduced high-severity emergency care.
      • Kullgren J.T.
      • Galbraith A.A.
      • Hinrichsen V.L.
      • et al.
      Health care use and decision making among lower-income families in high-deductible health plans.
      Insurers offer full coverage of the cost of preventive medications with USPSTF grade A or B ratings, and they have latitude to expand their list of preventive medicines beyond this automatic inclusion, providing that the medication conforms to the Internal Revenue Service definition of a preventive medication. For classification as preventive within a high-deductible healthcare plan policy, medications must qualify for reimbursement as part of a health savings account and cannot include those used to treat an existing illness, injury, or condition.

      Internal Revenue Service. Internal Revenue Bulletin: 2004-15. Notice 2004-23. Available at: https://www.irs.gov/irb/2004-15_IRB/ar10.html#d0e967. Accessed March 20, 2016.

      In the absence of a specific Internal Revenue Service–defined list,

      Internal Revenue Service. Internal Revenue Bulletin: 2004-33. Notice 2004-50. Available at: https://www.irs.gov/irb/2004-33_IRB/ar08.html#d0e1823. Accessed March 20, 2016.

      some high-deductible healthcare plan preventive medication lists can be broad and may include such medications as heart failure and diabetes medications, asthma inhalers, blood-thinning agents, and statins.

      Express Scripts. 2015 Preventive drug list for Pitney Bowes PPO and health fund PPO options. Available at: https://www.express-scripts.com/art/open_enrollment/PitneyBowesACAPreventiveDrugList.pdf. Accessed April 21, 2016.

      Express Scripts. Express Scripts preventive medications list for Boeing. Available at: https://www.express-scripts.com/art/open_enrollment/PDL4833D.pdf. Accessed April 21, 2016.

      BCBS Arizona. Guidance regarding waiver of deductible for preventive medications covered under high deductible health plans designed for use with a health savings account. Available at: https://www.azblue.com/∼/media/azblue/files/pharmacy-forms-mastery-directory/all-other/other-forms-and-resources/hsa-preventive-drug-list.pdf. Accessed April 21, 2016.

      Preventive drugs and services have been shown to be cost-effective in many cases,
      • Maciosek M.V.
      • Coffield A.B.
      • Edwards N.M.
      • et al.
      Priorities among effective clinical preventive services: results of a systematic review and analysis.
      and employers cite increased productivity and decreased costs among their reasons for providing preventive services coverage in employee healthcare plans.
      • Bondi M.A.
      • Harris J.R.
      • Atkins D.
      • et al.
      Employer coverage of clinical preventive services in the United States.
      One survey reported that large employers with health savings account–qualified high-deductible healthcare plans were particularly likely to use a liberal definition of preventive medications, with 57% of high-deductible healthcare plans covering preventive medications at 100% in 2013, up from 46% in 2012.

      Wojcik J. IRS' lack of definitive drugs list has firms fully covering maintenance meds. Available at: http://www.businessinsurance.com/article/20141109/NEWS03/311099985/irs-lack-of-definitive-drugs-list-has-firms-fully-covering. Accessed March 24, 2016.

      Inclusion of Epinephrine Auto-Injector in Healthcare Plans

      The evidence presented suggests that the risk of epinephrine auto-injector prescription abandonment could be diminished by inclusion of epinephrine auto-injectors in preventive medication lists. A review of high-deductible healthcare plans listed under health exchanges in the Managed Markets Insight and Technology database showed that the EpiPen 2-Pak was classed as a tier 1 to 2 product in 67% of plans, classed as a tier 3 to 4 product in 6% of plans, “approved” in 5% of plans, and not reimbursed in 22% of plans (Table 2).

      Managed Markets Insight & Technology (MMIT). Managed Markets Insight & Technology (MMIT) formulary database. Available at: https://formularylookup.com. Accessed July 9, 2015.

      However, examples of epinephrine auto-injectors being listed as preventive medications, exempt from high deductibles, in high-deductible healthcare plans are limited.

      BCBS Arizona. Guidance regarding waiver of deductible for preventive medications covered under high deductible health plans designed for use with a health savings account. Available at: https://www.azblue.com/∼/media/azblue/files/pharmacy-forms-mastery-directory/all-other/other-forms-and-resources/hsa-preventive-drug-list.pdf. Accessed April 21, 2016.

      Table 2High Deductible Health Plan Raw Formulary Status of EpiPen (Mylan, Canonsburg, Pa) 2-Pak in Health Exchanges
      Numbers are based on a search of the publicly available website www.formularylookup.com. Exchanges contain dynamic information and are updated frequently, so the exact percentages of plans listed here have likely changed since the original search was conducted in July 2015.
      (N = 100)

      Managed Markets Insight & Technology (MMIT). Managed Markets Insight & Technology (MMIT) formulary database. Available at: https://formularylookup.com. Accessed July 9, 2015.

      Tier 1 (% of Plans)Tier 2 (% of Plans)Tier 3 (% of Plans)Tier 4 (% of Plans)Approved (% of Plans)Not Reimbursed (% of Plans)
      16651522
      Numbers are based on a search of the publicly available website www.formularylookup.com. Exchanges contain dynamic information and are updated frequently, so the exact percentages of plans listed here have likely changed since the original search was conducted in July 2015.

      Conclusions

      Allergy is an important and prevalent condition in the United States, which puts hyperallergic patients at chronic risk of anaphylaxis. Timely recognition of anaphylactic episodes and prompt administration of first-line epinephrine are integral to prevent symptom progression, hospitalization, and death. But current recognition and treatment of anaphylaxis are inadequate, with epinephrine administration frequently delayed or not given as first-line medication. Guidelines recommend that patients carry 2 epinephrine auto-injectors; however, a significant proportion of patients fail to do so. Overall medication costs are one of the factors driving this patient nonadherence, as demonstrated in Figure 1; because a medication's price (ie, that paid to a manufacturer) contributes to overall medication costs, price is also a factor in patient nonadherence. Reduction of the price, therefore, would be expected to improve adherence.
      Considering the cost of auto-injectors compared with the costs of emergency department visits and hospitalizations associated with failure to treat anaphylaxis appropriately, these findings suggest preventive treatment of anaphylaxis with an epinephrine auto-injector would be cost-effective.
      Epinephrine auto-injectors are currently included in the deductibles of many healthcare plans, which, coupled with the negative impact of high cost sharing, often decreases patient adherence. With more patients enrolling in high-deductible healthcare plans, fewer of them may be willing or able to obtain epinephrine auto-injectors. However, the classification of epinephrine auto-injectors as a grade A or B preventive medicine by the USPSTF and inclusion on preventive medication lists could be expected to increase patient access to first-line anaphylaxis treatment, improving outcomes and decreasing fatalities.

      Acknowledgments

      Hannah Mace, MPharmacol (Ashfield Healthcare, Haddam, Conn), drafted an initial manuscript outline based upon author direction and revised subsequent drafts to incorporate author comments, and Mary Kacillas and Paula Stuckart (Ashfield Healthcare) copyedited and styled the article per Journal requirements.

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      Linked Article

      • A Sticky Problem: Dealing with Industry Under Unpleasant Circumstances
        The American Journal of MedicineVol. 129Issue 12
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          In this issue of the American Journal of Medicine, Dr Leonard Fromer appropriately calls for easier access to potential lifesaving therapy, the epinephrine auto injector, for patients with severe allergic reactions. The editor and the staff of the AJM strongly support the concept that epinephrine auto injectors should be made affordable and easily accessible for patients who are at risk for developing life threatening allergic reactions. I have personally known patients, friends, and family whose lives were likely saved by an injection of epinephrine from an auto injector.
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      • The Tragedy of the Commons – Drug Shortages and Our Patients' Health
        The American Journal of MedicineVol. 129Issue 12
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          There has been, rightfully, a great deal of controversy related to the EpiPen pricing issue1; a preparation sold for $83 by Merck (Rockville, Md) a decade ago is now priced at $600. The fury directed at the company now marketing this drug-delivery device – Mylan (Canonsburg, Pa) – came from patients, families, and legislators; lives are on the line, people suffering from anaphylaxis will die if they do not have rapid access to epinephrine. The response of Mylan was, initially, to shrug their shoulders: it is capitalism after all.
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      • Ethics, Morality, and Consulting: The Moral Problem of the Commons
        The American Journal of MedicineVol. 130Issue 2
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          We read with great dismay the review article published in The American Journal of Medicine under the name of Leonard Fromer.1 Dismay that this respected source of medical and social information, by publishing the aforementioned piece, has done a disservice to its readers and our country. The authors of this piece frontally attack the “Fiscal Commons” of the United States, and indirectly, the pocketbooks of our citizens.
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