Long-Acting Beta Agonists vs. Leukotriene Receptor Antagonists in Older Adults with Persistent Asthma

Cost-Utility Analysis of Long-Acting Beta Agonists versus Leukotriene Receptor Antagonists in Older Adults with Persistent Asthma Receiving Concomitant Inhaled Corticosteroid Therapy ShoroqAltawalbeh, PharmD, PhD Assistant Professor of Clinical Pharmacy Faculty of Pharmacy Jordan University of Science and Technology 1

Outline Introduction Objectives Methods Results Summary & clinical implication Future directions Acknowledgement 2

Asthma in Older Adults Frequent coexistence of comorbid conditions Poor recall and perception of symptoms Depressive symptoms Reduced psychological and physical quality of life Physical disability Low adherence and treatment side effects Gillman A, Douglass JA. Asia Pac Allergy 2012;2:101-8. Lee JA, P LR, Berg JP. J Asthma 2014;51:399-404. 3

Asthma Epidemiology in Older Adults Prevalence estimated to be greater than 10% Public health concern The population of older adults is increasing rapidly Gillman A, Douglass JA. Asia Pac Allergy 2012;2:101-8. Song WJ, Cho SH.. Allergy Asthma Immunol Res 2015;7:431-9 4

Poor Asthma Outcomes in Older Adults Compared to younger adults: Poor asthma control OR = 2.18 (1.28-3.72)1 More asthma hospitalizations 4.5 versus 2.3 hospitalization / 100,000 persons2 Half of all asthma-related deaths occurred in individuals over 65 years old3 More asthma-related deaths $1490 vs $773 ( 50% inpatient & 35% medications)4 Higher asthma-related expenditures 1-Kampe M et al.Eur Clin Respir J 2014:1:1-9 2-Moorman J, Rudd R, Johnson C, et al. MMWR Surveill Summ. 2007;56:1-54 3-Stupka E, deShazo R. Am J Med 2009;122:6-11. 4- Plaza V, Serra-Batlles J, Ferrer M, et al. Respiration 2000;67:65-70 5

Asthma Treatment; Stepwise Approach 6

Asthma Treatment: The Add-on Challenge The latest GINA guidelines recommended: When asthma symptoms are not well-controlled on low dose ICS, LABA is the first line add-on treatment. LTRA is an alternative. Asthma treatments are still understudied in older adults Excluded from clinical trials. Different add-on treatments were not directly compared in older adults. The evidence for treatment of asthma in older patients is mostly based on research conducted in younger adults or age-pooled populations Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. 2014. Gillman A, Douglass JA. Asia Pac Allergy 2012;2:101-8. Travers J, Marsh S, Williams M, et al. Thorax 2007;62:219-23 7

Long Acting Beta Agonists (LABA) Add-on Concens An effective asthma treatment Understudied in older adults Concerns in question: - Asthma catastrophic events - CV adverse events Shrewsbury S, Pyke S, Britton M. BMJ 2000;320:1368-73. Fish JE, Israel E, Murray JJ, et al. Chest 2001;120:423-30. 8

LABA-Associated Pulmonary Concerns (asthma-related intubations and deaths) LABA alone or in combination with ICS versus placebo: LABA with/without ICS versus placebo LABA +ICS versus ICS alone Total 9 The American Journal of Medicine (2010) 123, 322-328

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LABA-Associated CV Concerns LABA alone or in combination with ICS versus placebo: Salpeter SR, Ormiston TM, Salpeter EE. Chest 2004;125:2309-21 11

Biological Background; LABA Cardiovascular Concerns LABA Increase heart rate Hypokalaemia Cardiac Arrhythmia Heart attack and death Johnston SL, Edwards MR. Thorax 2009;64:739-41. 12

Leukotriene Receptor Antagonists (LTRA) Add-on Concens An effective asthma treatment compared with placebo and ICS alone Favored safety profile Possible role in secondary prevention of cardiovascular diseases. Understudied in older adults Bozek A, Warkocka-Szoltysek B, Filipowska-Gronska A, et al. J Asthma 2012;49:530-4. Joos S, Miksch A, Szecsenyi J, et al. Thorax 2008;63:453-62. Ingelsson E, Yin L, Back M. J Allergy Clin Immunol 2012;129:702-7 e2. 13

Biological Background; LTRA Cardio- Protective Effect Leukotrienes Anti- Leukotrienes cysteinyl- leukotriene type 1 receptors Inflammation Atherosclerotic lesions Vasoconstriction Back M. Cardiovasc Drugs Ther 2009;23:41-8. 14

Head to Head Comparisons in Adult Based Research (<65 years old) Asthma outcomes are better with ICS+LABA compared to ICS+LTRA; less asthma exacerbations and better pulmonary function CV outcomes were not compared. Fish JE, Israel E, Murray JJ, et al. Chest 2001;120:423-30. Lee TA, Chang CL, Stephenson JJ, et al. Curr Med Res Opin 2010;26:2851-60. Tan H, Sarawate C, Singer J, et al. Mayo Clin Proc 2009;84:675-84. 15

Head to Head Comparisons in Older Adult Based Research (>=65 years old) Altawalbeh SM, Thorpe CT, Zgibor JC, Kane-Gill S, Kang Y, Thorpe JM.J Am Geriatr Soc. 2016 Aug;64(8):1592-600. 16

In Older Adults Increased CV LABA add-on exacerbations Asthma exacerbations LTRA add-on Increased 17

Objectives: To estimate and compare quality-adjusted survival and costs associated with ICS+LABA and ICS+LTRA treatments in an older adults with asthma. Guide clinical decisions in older adults by combining effectiveness, CV safety and costs in a single analysis. 18

Methods: A Markov model was developed to estimate and compare the incremental costs and quality-adjusted life expectancy. We simulated a cohort of older adults, 66 years of age or older, who were treated for their persistent asthma by ICS+LABA treatment, ICS+LTRA treatment, or ICS (as a reference group). 19

Reasons for using Models in Health Care: The purpose of a decision model is to estimate the effects of various choices Choice 1 Set of Downstream consequences Choice 2 Set of Downstream consequences 20

Fig. 1. Markov model structure. Patients transitioned through five clinical health states: healthy without any exacerbation (well), post asthma exacerbation, post-CV exacerbation, post-asthma/CV exacerbation, and dead. In each cycle, patients could survive or die from experiencing asthma or CV events. 21

Parameters 22

Event Probabilities Data: Fee for Service (FFS) Medicare data files (2009-2010). Study design: Retrospective cohort design. Logistic regression models were used to obtain the adjusted probabilities of asthma and CV hospitalizations by treatment groups. Adjusting for patient ages , race/ethnicity, geographic regions ,gender, enrollment in the low-income subsidy, disability, asthma duration since the first diagnosis in medicare data, preexisting cardiovascular diseases, number of comorbid conditions, and for differing lengths of follow-up time across patient. 23

Results: 24

Base case results 25

One-Way Sensitivity Analyses Thresholds Analyses 26

Probabilistic Sensitivity Analysis Fig. 2. Probabilistic sensitivity analysis results. The CE acceptability curve shows probabilities of treatments being cost-effective. CE, cost-effectiveness 27

Major Findings The cost-effectiveness of ICS+LABA treatment is economically unfavorable in older adults when compared with LTRA as add- on treatment. The extra CV risks associated with LABA treatment compared with LTRA treatment largely offset its superiority in controlling asthma and improving survival, and increase the costs incurred by patients and society. 28

Clinical Implications Important step on the personalized medicine way Clinical provider should consider the risk- benefit ratio when prescribing LABA for elderly 29

In Hospital Death Rates Among Elderly; Age: 65-84 Asthma 0.73% Cardiac dysrhythmias 1.01% Congestive heart failure 3.11% Acute myocardial infarction 6.15% Acute cerebrovascular disease 8.97% HCUPnet 2010 30

Future Directions Subgroup analysis to personalize asthma treatments; Maximize the Benefit/ Risk Ratio Find subgroups in older adults who have the highest CV risks from LABA treatment. 31

Acknowledgement Kenneth J. Smith, MD, MS Section of Decision Sciences and Clinical Systems Modeling, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Joshua M. Thorpe, Ph.D., M.P.H Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. Carolyn T. Thorpe, PhD, MPH Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA. 32

Thank you 33