10/15/16. From A to Wheeze Acetaminophen s Role in the Asthma Epidemic. Do you recommend: Acetaminophen? Ibuprofen?

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1 10/15/16 From A to Wheeze Acetaminophen s Role in the Asthma Epidemic Gretchen Dao, PharmD Community Pharmacy PGY1 Resident H-E-B/University of Texas at AusGn October 21, A 7-year-old child on controller therapy for asthma has a temperature of F and a new prescripeon for an anebioec. Her mother tells you that the pediatrician recommended that she should also get something OTC for the fever. Do you recommend: A. Acetaminophen? B. Ibuprofen? 3 Learning ObjecEves n Discuss the role of acetaminophen (APAP) in the asthma epidemic in children n Evaluate safety of other alternagves n Provide appropriate analgesic/angpyregc recommendagons for children with asthma 1

2 Background Asthma 4 Asthma StaEsEcs million physician office visits $50 billion spent per year 1.8 million ED visits 49% of children with asthma missed >1 day of school Data, StaGsGcs, and Surveillance. Center for Disease Control and PrevenGon. (2016) 6 Data, StaGsGcs, and Surveillance. Center for Disease Control and PrevenGon. (2016) 2

3 7 8.4% Data, StaGsGcs, and Surveillance. Center for Disease Control and PrevenGon. (2016) 8 Data, StaGsGcs, and Surveillance. Center for Disease Control and PrevenGon. (2016) What causes asthma? 9 n Environmental triggers n Airway infecgons n GeneGcs n Hygiene Hypothesis??? APAP??? What Is Asthma? U.S. NaGonal Library of Medicine. (2014) 3

4 What is asthma? 10 Image: Haderer & Muller, illustrated for the American College of Chest Physicians. (2016) Pathophysiology 11 COX-2 ê Cell mediated immunity & Delayed hypersensievity Varner AE, Busse WW, Lemanske RF. Ann Allergy Asthma Immunol. (1998) Allergic inflammaeon é APAP and Asthma Three Main QuesGons Does frequent APAP use lead to asthma in children? 2. Does frequent APAP use worsen symptoms in children who already have asthma? 3. Are the alternagves (i.e. ibuprofen) any safer? Litonjua. N Engl J Med. (2016) 4

5 From A to Wheeze ObservaGonal Studies 13 The First Hypothesis: Varner, et al. (1998) 14 NoEced in 1980s: Pediatric aspirin (ASA) use decreased Childhood asthma prevalence increased Hypothesis Decreased use of ASA may be a factor in facilitagng allergic sensigzagon and asthma. Varner AE, Busse WW, Lemanske RF. Ann Allergy Asthma Immunol. 1998;81(4): The First Hypothesis: Varner, et al. (1998) ASA 15 APAP? COX-2 é Cell mediated immunity & Delayed hypersensievity Varner AE, Busse WW, Lemanske RF. Ann Allergy Asthma Immunol. 1998;81(4): Allergic inflammaeon ê 5

6 The First Hypothesis: Varner, et al. (1998) 16 CorrelaEon? Coincidence? Varner AE, Busse WW, Lemanske RF. Ann Allergy Asthma Immunol. 1998;81(4): The First Hypothesis: Varner, et al. (1998) 17 n Conclusion: n EliminaGon of pediatric ASA may be an important contributor n RelaGonship between APAP and asthma is unproven, further invesggagon is needed Varner AE, Busse WW, Lemanske RF. Ann Allergy Asthma Immunol. 1998;81(4): Epidemiological Evidence: Shaheen, et al. (2000) 18 n Background: n Animal studies showed that APAP depletes glutathione (GSH) in lungs n GSH is an angoxidant that may defend against oxidagve stress of asthma inflammagon n Increased GSH levels in airways of adults with asthma Hypothesis Frequent APAP use is associated with asthma. Shaheen, et al. Thorax. 2000;55(4):

7 Epidemiological Evidence: Shaheen, et al. (2000) 19 Design PopulaGon based case-control Survey on frequency of ASA/APAP use in people with asthma vs. without Controlled for confounding risk factors ParEcipants Aged 16-49y Defined asthmagc or non-asthmagc based on screening quesgons N = 1574 (664 cases vs. 910 controls) Shaheen, et al. Thorax. 2000;55(4): Epidemiological Evidence: Shaheen, et al. (2000) 20 Shaheen, et al. Thorax. 2000;55(4): Epidemiological Evidence: Shaheen, et al. (2000) 21 Shaheen, et al. Thorax. 2000;55(4):

8 Epidemiological Evidence: Shaheen, et al. (2000) 22 n Conclusion: n Frequent (daily/weekly) APAP use, possibly overuse, posigvely associated with asthma n Dose-related response - causal? n Unlikely that relagonship is auributable to higher prevalence of co-morbidity n ASA avoidance can only explain part of the associagon, not all Shaheen, et al. Thorax. 2000;55(4): An Ecological Look: Newson, et al. (2000) 23 So far: n Varner: êasa à éapap à éasthma? n Shaheen: frequent APAP çè asthma? Hypothesis Countries with higher nagonal APAP sales are associated with higher asthma symptom prevalence. Newson, et al. Eur Respir J. 2000;16(5): An Ecological Look: Newson, et al. (2000) 24 Design Linear regression analysis: InternaGonal symptom-prevalence data NaGonal per-capita APAP sales ParEcipants Aged 6-7y, 13-14y N =? (22 countries) Newson, et al. Eur Respir J. 2000;16(5):

9 An Ecological Look: Newson, et al. (2000) 25 Newson, et al. Eur Respir J. 2000;16(5): An Ecological Look: Newson, et al. (2000) 26 English-speaking countries Newson, et al. Eur Respir J. 2000;16(5): An Ecological Look: Newson, et al. (2000) 27 n Anglophone effect n English-speaking Western countries tend to have: n Highest prevalence of asthma symptoms n Highest APAP sales n Post hoc analysis: n All associagons between APAP and asthma symptoms à abolished or non-significant Newson, et al. Eur Respir J. 2000;16(5):

10 An Ecological Look: Newson, et al. (2000) 28 n Conclusion: n NaGonal APAP sales posigvely associated with prevalence of asthma symptoms n Anglophone effect n Likely due to confounder strongly associated with English-speaking countries n Warrants further invesggagon Newson, et al. Eur Respir J. 2000;16(5): LimitaEons to ObservaEonal 30 Studies n Weak strength of evidence n Confounding by indicagon n Causal associagon is difficult to determine n Exposure data not linked to individuals Pu_ng It All Together Meta-Analysis 31 10

11 Meta-Analysis: Garcia-Marcos, et al. (2011) 32 n 41 sub-studies n Infants, children, adults, pregnant women n Longitudinal, cross-secgonal n Pooled OR = 1.48 n no macer what type of study, age, or Eme of exposure, there is always a posieve associaeon between exposure and respiratory symptoms Garcia-Marcos L, Sanchez-Solis M, Perez-Fernandez V. Curr Opin Allergy Clin Immunol. 2011;11(3): Meta-Analysis: Garcia-Marcos, et al. (2011) 33 Garcia-Marcos L, Sanchez-Solis M, Perez-Fernandez V. Curr Opin Allergy Clin Immunol. 2011;11(3): What About AlternaEves? APAP vs. Ibuprofen 34 11

12 First Randomized Controlled Trial: 35 Lesko, et al. (2002) Hypothesis Short-term use of ibuprofen increases asthma morbidity in children Design Randomized, double-blind, APAP-controlled Measured hospitalizagon and outpagent visits for asthma Lesko, et al. Pediatrics. 2002;109(2):E20. First Randomized Controlled Trial: 36 Lesko, et al. (2002) ParEcipants Aged 6m-12y with asthma and fever N = 1879 IntervenEon APAP 12 mg/kg, ibuprofen 5 mg/ kg, ibuprofen 10 mg/kg Followed x 4 weeks Lesko, et al. Pediatrics. 2002;109(2):E20. First Randomized Controlled Trial: 37 Lesko, et al. (2002) Results No difference in hospitalizagon rates OutpaGent visits significantly lower in ibuprofen group Lesko, et al. Pediatrics. 2002;109(2):E20. 12

13 First Randomized Controlled Trial: Lesko, et al. (2002) ASA 38 APAP? COX-2 Ibu é Cell mediated immunity & Delayed hypersensievity Allergic inflammaeon ê ê First Randomized Controlled Trial: 39 Lesko, et al. (2002) n Conclusion: n Compared to APAP, ibuprofen has lower risk of asthma morbidity n Due to no placebo-control, cannot determine whether difference is due to APAP increasing risk or ibuprofen decreasing risk Lesko, et al. Pediatrics. 2002;109(2):E20. AVICA Trial Sheehan, et al. (2016) 40 Hypothesis Asthma morbidity is higher in APAP vs. ibuprofen in children with mild persistent asthma Design MulGcenter, prospecgve, double-blind, parallel-group 48 weeks, measured exacerbagon frequencies Sheehan, et al. N Engl J Med. 2016;375(7):

14 AVICA Trial Sheehan, et al. (2016) 41 ParEcipants Aged 1-5y with mild persistent asthma N = 300 IntervenEon APAP 15 mg/kg q6h prn Ibuprofen 9.4 mg/kg q6h prn Sheehan, et al. N Engl J Med. 2016;375(7): AVICA Trial Sheehan, et al. (2016) 42 Results No significant difference in exacerbagon rates between groups Sheehan, et al. N Engl J Med. 2016;375(7): AVICA Trial Sheehan, et al. (2016) 43 n Conclusion: n No significant difference does not necessarily mean that they are equal (RR CI = ) n Results may not be generalizable to: n Higher severity of asthma n Non-adherent children n Due to no placebo-control, cannot exclude possibility that both ibuprofen and APAP may be associated Sheehan, et al. N Engl J Med. 2016;375(7):

15 10/15/16 What Do You Think? RevisiGng the PaGent Case A 7-year-old child on controller therapy for asthma has a temperature of F and a new prescripeon for an anebioec. Her mother tells you that the pediatrician recommended that she should also get something OTC for the fever. Do you recommend: A. Acetaminophen? B. Ibuprofen? Reviewer s Thoughts 46 15

16 Evidence Checklist 47 q Exposure precedes onset of disease q Plausible biological mechanism q Consistency across different study sewngs q Temporal relagonship to exposure q IdenGficaGon of dose-response effect q Specificity to causagve agent with no convincing alternagve explanagon q Reversibility of the causal effect Weatherall, et al. Clin Exp Allergy. 2015;45(1): Conclusion 48 n MulGple observagonal studies suggest: n Dose-related relagonship between APAP use (possibly APAP overuse) and asthma n Plausible mechanism(s) n ExisGng RCTs suggest: n Ibuprofen is not necessarily a beuer alternagve n More RCTs needed to strengthen evidence n Lacking data on reversibility of effect Acknowledgements 49 n Dr. Nathan Pope n H-E-B/UT Residents & Preceptors Evaluator: Prof. Marcia Kiger 16

17 Bibliography 50 n Data, StaGsGcs, and Surveillance. Center for Disease Control and PrevenGon. hups:// Published September 8, Accessed October 3, n Garcia-Marcos L, Sanchez-Solis M, Perez-Fernandez V. Early exposure to acetaminophen and allergic disorders. Curr Opin Allergy Clin Immunol. 2011;11(3): n Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity ayer the short-term use of ibuprofen in children. Pediatrics. 2002;109(2):E20. n Litonjua AA. Acetaminophen and Asthma--A Small Sigh of Relief?. N Engl J Med. 2016;375(7): n Newson RB, Shaheen SO, Chinn S, Burney PG. Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J. 2000;16(5): Bibliography 51 n Shaheen SO, Sterne JA, Songhurst CE, Burney PG. Frequent paracetamol use and asthma in adults. Thorax. 2000;55(4): n Sheehan WJ, Mauger DT, Paul IM, et al. Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma. N Engl J Med. 2016;375(7): n Varner AE, Busse WW, Lemanske RF. Hypothesis: decreased use of pediatric aspirin has contributed to the increasing prevalence of childhood asthma. Ann Allergy Asthma Immunol. 1998;81(4): n Weatherall M, Ioannides S, Braithwaite I, Beasley R. The associagon between paracetamol use and asthma: causagon or coincidence?. Clin Exp Allergy. 2015;45(1): n What Is Asthma? U.S. NaGonal Library of Medicine. hups:// Published August 4, Accessed October 3, From A to Wheeze Acetaminophen s Role in the Asthma Epidemic Gretchen Dao, PharmD Community Pharmacy PGY1 Resident H-E-B/University of Texas at AusGn October 21,