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Is overreliance on short-acting β2-agonists associated with health risks in the older asthma population?

Teresa To, Jingqin Zhu, Emilie Terebessy, Kimball Zhang, Andrea S. Gershon, Christopher Licskai
ERJ Open Research 2022 8: 00032-2022; DOI: 10.1183/23120541.00032-2022
Teresa To
1Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
2The Hospital for Sick Children, Toronto, ON, Canada
3ICES, Toronto, ON, Canada
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  • For correspondence: teresa.to@sickkids.ca
Jingqin Zhu
2The Hospital for Sick Children, Toronto, ON, Canada
3ICES, Toronto, ON, Canada
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Emilie Terebessy
2The Hospital for Sick Children, Toronto, ON, Canada
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Kimball Zhang
2The Hospital for Sick Children, Toronto, ON, Canada
3ICES, Toronto, ON, Canada
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Andrea S. Gershon
1Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
2The Hospital for Sick Children, Toronto, ON, Canada
3ICES, Toronto, ON, Canada
4Division of Respirology, Dept of Medicine, University of Toronto, Toronto, ON, Canada
5Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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  • ORCID record for Andrea S. Gershon
Christopher Licskai
6Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
7London Health Sciences, Victoria Hospital, London, ON, Canada
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  • FIGURE 1
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    FIGURE 1

    Forest plot comparing adjusted hazard ratios (AHRs) for all-cause mortality from Cox proportional hazards regression. The Cox proportional hazards regression models were adjusted for the following: age, sex, prevalence of comorbidities, prevalence of asthma exacerbation at baseline as an indicator of severity of asthma, Ontario Marginalization Index (deprivation and dependency), rurality and asthma medication use at baseline. SABA: short-acting β2-agonist; ref: reference.

  • FIGURE 2
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    FIGURE 2

    Forest plot comparing adjusted hazard ratios (AHRs) for severe asthma exacerbations from Cox proportional hazards regression. The Cox proportional hazards regression models were adjusted for the following: age, sex, prevalence of comorbidities, prevalence of asthma exacerbation at baseline as an indicator of severity of asthma, Ontario Marginalization Index (deprivation and dependency), rurality and asthma medication use at baseline. SABA: short-acting β2-agonist; ref: reference.

Tables

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  • TABLE 1

    Characteristics of the study population and baseline medication use by number of short-acting β2-agonist (SABA) canisters (n=59 533)

    CovariatesNumber of SABA canistersTotalp-value#
    01–23–5≥6
    Subjects n33 33217 7365332313359 533
    Participant factors
     Sex n (%)
      Female21 898 (65.7)12 561 (70.8)3645 (68.4)1982 (63.3)40 086 (67.3)<0.001
      Male11 434 (34.3)5175 (29.2)1687 (31.6)1151 (36.7)19 447 (32.7)
     Age at index date years
      Mean±sd69.80±6.1269.55±5.8269.38±6.0869.35±6.2669.67±6.04<0.001
      Median (IQR)67.00 (65.00–73.00)67.00 (65.00–72.00)66.00 (65.00–72.00)66.00 (65.00–72.00)67.00 (65.00–72.00)<0.001
     Age group at index
     date years, n (%)
      65–6921 254 (63.8)11 551 (65.1)3536 (66.3)2080 (66.4)38 421 (64.5)<0.001
      70–745533 (16.6)3044 (17.2)841 (15.8)476 (15.2)9894 (16.6)
      75–793415 (10.2)1727 (9.7)498 (9.3)300 (9.6)5940 (10.0)
      80–893130 (9.4)1414 (8.0)457 (8.6)277 (8.8)5278 (8.9)
     Age at asthma
     prevalence
     years
      Mean±sd59.73±9.7459.40±9.5959.98±10.4759.62±10.8559.64±9.83<0.001
      Median (IQR)59.00 (52.00–66.00)59.00 (52.00–66.00)60.00 (51.00–67.00)59.00 (50.00–67.00)59.00 (52.00–66.00)0.004
     Years of asthma at index
     date
      Mean±sd10.03±6.6110.12±6.859.32±7.079.60±7.099.97±6.76<0.001
      Median (IQR)10.63 (4.14–15.16)10.68 (3.65–15.53)9.78 (1.72–14.99)10.19 (2.25–14.95)10.57 (3.68–15.23)<0.001
    Baseline asthma medication use, n (%)
     No asthma medication20 672 (62.0)0 (0.0)0 (0.0)0 (0.0)20 672 (34.7)<0.001
     ICS only or ICS-LABA11 653 (35.0)3988 (22.5)1742 (32.7)1134 (36.2)18 517 (31.1)
     SABA only0 (0.0)6292 (35.5)1100 (20.6)491 (15.7)7883 (13.2)
     Other asthma
     medication
    1007 (3.0)7456 (42.0)2490 (46.7)1508 (48.1)12 461 (20.9)
    Socio-demographic factors
     Neighbourhood income
     quintile, n (%)
      1 (lowest)5639 (16.9)2972 (16.8)1051 (19.7)704 (22.5)10 366 (17.4)<0.001
      26648 (19.9)3562 (20.1)1133 (21.2)726 (23.2)12 069 (20.3)
      36445 (19.3)3563 (20.1)1073 (20.1)642 (20.5)11 723 (19.7)
      46911 (20.7)3763 (21.2)1048 (19.7)522 (16.7)12 244 (20.6)
      5 (highest)7604 (22.8)3843 (21.7)1010 (18.9)527 (16.8)12 984 (21.8)
      Missing85 (0.3)33 (0.2)17 (0.3)12 (0.4)147 (0.2)
    Ontario Marginalization Indices (lowest quintile is the least marginalised)
     Deprivation quintile,
     n (%)
      1 (least)6953 (20.9)3735 (21.1)1000 (18.8)516 (16.5)12 204 (20.5)<0.001
      26752 (20.3)3517 (19.8)978 (18.3)505 (16.1)11 752 (19.7)
      36606 (19.8)3506 (19.8)989 (18.5)616 (19.7)11 717 (19.7)
      46652 (20.0)3532 (19.9)1190 (22.3)710 (22.7)12 084 (20.3)
      5 (most)6185 (18.6)3354 (18.9)1135 (21.3)766 (24.4)11 440 (19.2)
      Missing184 (0.6)92 (0.5)40 (0.8)20 (0.6)336 (0.6)
     Dependency quintile,
     n (%)
      1 (least)5449 (16.3)3186 (18.0)1044 (19.6)678 (21.6)10 357 (17.4)<0.001
      25981 (17.9)3322 (18.7)1040 (19.5)620 (19.8)10 963 (18.4)
      36142 (18.4)3236 (18.2)971 (18.2)611 (19.5)10 960 (18.4)
      46528 (19.6)3326 (18.8)937 (17.6)512 (16.3)11 303 (19.0)
      5 (most)9048 (27.1)4574 (25.8)1300 (24.4)692 (22.1)15 614 (26.2)
      Missing184 (0.6)92 (0.5)40 (0.8)20 (0.6)336 (0.6)
     Ethnic concentration
     quintile, n (%)
      1 (least)5161 (15.5)2846 (16.0)830 (15.6)461 (14.7)9298 (15.6)<0.001
      25325 (16.0)2928 (16.5)856 (16.1)418 (13.3)9527 (16.0)
      36005 (18.0)3135 (17.7)848 (15.9)455 (14.5)10 443 (17.5)
      47207 (21.6)3567 (20.1)960 (18.0)560 (17.9)12 294 (20.7)
      5 (most)9450 (28.4)5168 (29.1)1798 (33.7)1219 (38.9)17 635 (29.6)
      Missing184 (0.6)92 (0.5)40 (0.8)20 (0.6)336 (0.6)
     Instability quintile, n (%)
      1 (least)6470 (19.4)3689 (20.8)1129 (21.2)712 (22.7)12 000 (20.2)<0.001
      26539 (19.6)3512 (19.8)949 (17.8)516 (16.5)11 516 (19.3)
      36224 (18.7)3264 (18.4)975 (18.3)560 (17.9)11 023 (18.5)
      46045 (18.1)3188 (18.0)1017 (19.1)535 (17.1)10 785 (18.1)
      5 (most)7870 (23.6)3991 (22.5)1222 (22.9)790 (25.2)13 873 (23.3)
      Missing184 (0.6)92 (0.5)40 (0.8)20 (0.6)336 (0.6)
     Rural residence, n (%)3046 (9.1)1738 (9.8)545 (10.2)307 (9.8)5636 (9.5)0.015
     Follow-up years
      Mean±sd8.82±3.258.82±3.179.07±3.359.01±3.588.85±3.25<0.001
      Median (IQR)8.50 (6.41–11.59)8.47 (6.41–11.55)8.75 (6.65–12.17)8.81 (6.56–12.34)8.53 (6.43–11.66)<0.001
     Number of comorbidities,
     n (%)
      07732 (23.2)4029 (22.7)1206 (22.6)626 (20.0)13 593 (22.8)0.001
      112 762 (38.3)6940 (39.1)2053 (38.5)1240 (39.6)22 995 (38.6)
      28260 (24.8)4407 (24.8)1396 (26.2)831 (26.5)14 894 (25.0)
      ≥34578 (13.7)2360 (13.3)677 (12.7)436 (13.9)8051 (13.5)
    Outcomes
     Deaths, n (%)4487 (13.5)1942 (10.9)703 (13.2)552 (17.6)7684 (12.9)<0.001
     Severe asthma
    exacerbation, n (%)
    446 (1.3)642 (3.6)343 (6.4)295 (9.4)1726 (2.9)<0.001

    SABA: short-acting β2-agonist; IQR: interquartile range; ICS: inhaled corticosteroid; ICS-LABA: ICS long-acting β2-agonist. #: p-values were calculated using Chi-squared statistics for categorical variables and ANOVA for numerical variables.

    • TABLE 2

      All-cause mortality hazard ratios (HRs) from Cox proportional hazard regressions (n=59 533)

      Unadjusted HR
      (95% CI)
      p-valueAHR
      (95% CI)
      p-value
      Exposure
       SABA canisters per year
        01.23 (1.16–1.29)<0.00011.07 (0.98–1.17)0.15
        1–21.00(Reference)1.00(Reference)
        3–51.14 (1.05–1.25)0.001.11 (1.02–1.22)0.02
        ≥61.52 (1.38–1.67)<0.00011.56 (1.41–1.71)<0.0001
      Covariate
       Deprivation quintile
        1 (least)1.00(Reference)1.00(Reference)
        21.09 (1.01–1.17)0.021.03 (0.95–1.11)0.47
        31.12 (1.04–1.21)0.001.00 (0.93–1.08)0.97
        41.21 (1.13–1.3)<0.00011.03 (0.96–1.11)0.44
        5 (most)1.33 (1.23–1.42)<0.00011.11 (1.04–1.19)0.00
       Dependency quintile
        1 (least)1.00(Reference)1.00(Reference)
        21.10 (1.01–1.20)0.021.03 (0.95–1.12)0.52
        31.15 (1.06–1.25)0.001.08 (0.99–1.17)0.07
        41.30 (1.20–1.41)<0.00011.16 (1.07–1.26)0.00
        5 (most)1.67 (1.56–1.8)<0.00011.25 (1.16–1.34)<0.0001
       Age group at index date1.17 (1.16–1.17)<0.00011.16 (1.16–1.17)<0.0001
       Male sex (reference=female)1.09 (1.04–1.14)0.001.30 (1.24–1.36)<0.0001
       Rural residence
       (reference=urban)
      1.05 (0.97–1.13)0.241.19 (1.10–1.28)<0.0001
       ICS only or ICS-LABA1.00(Reference)1.00(Reference)
       No asthma medication1.43 (1.35–1.51)<0.00011.26 (1.18–1.34)<0.0001
       SABA only1.29 (1.20–1.39)<0.00011.19 (1.08–1.31)0.00
       Other asthma medication1.26 (1.19–1.35)<0.00011.16 (1.07–1.26)0.00
       Asthma exacerbation in
       baseline period
      0.90 (0.69–1.16)0.401.08 (0.83–1.39)0.58
      Number of comorbidities
        01.00(Reference)1.00(Reference)
        11.63 (1.51–1.76)<0.00011.25 (1.15–1.34)<0.0001
        22.54 (2.36–2.75)<0.00011.66 (1.54–1.79)<0.0001
        ≥33.75 (3.46–4.06)<0.00012.13 (1.96–2.31)<0.0001

      AHR: adjusted hazard ratio; SABA: short-acting β2-agonist; ICS: inhaled corticosteroid; ICS-LABA: ICS long-acting β2-agonist.

      • TABLE 3

        Severe asthma exacerbation hazard ratios (HRs) from Cox proportional hazard regressions (n=59 533)

        Unadjusted HR
        (95% CI)
        p-valueAHR
        (95% CI)
        p-value
        Exposure
        SABA canisters per year
          00.38 (0.34–0.43)<0.00010.64 (0.56–0.75)<0.0001
          1–21.00(Reference)1.00(Reference)
          3–51.73 (1.52–1.97)<0.00011.59 (1.4–1.82)<0.0001
          ≥62.50 (2.17–2.87)<0.00012.26 (1.96–2.60)<0.0001
        Covariate
        Deprivation quintile
          1 (least)1.00(Reference)1.00(Reference)
          21.07 (0.91–1.25)0.43351.05 (0.89–1.23)0.5702
          31.21 (1.03–1.41)0.01851.14 (0.97–1.33)0.1055
          41.32 (1.14–1.54)0.00031.23 (1.05–1.43)0.0089
          5 (most)1.51 (1.30–1.76)<0.00011.42 (1.22–1.65)<0.0001
         Dependency quintile
          1 (least)1.00(Reference)1.00(Reference)
          20.82 (0.70–0.96)0.01350.84 (0.71–0.98)0.0305
          30.99 (0.85–1.15)0.84071.01 (0.87–1.18)0.911
          40.93 (0.8–1.09)0.35960.95 (0.82–1.12)0.558
          5 (most)0.89 (0.77–1.02)0.09580.90 (0.78–1.05)0.179
         Age group at index date0.98 (0.97–0.99)<0.00010.98 (0.97–0.99)<0.0001
         Male sex (reference=female)0.67 (0.60–0.75)<0.00010.69 (0.62–0.77)<0.0001
         Rural residence
         (reference=urban)
        1.67 (1.47–1.91)<0.00011.73 (1.51–1.98)<0.0001
         Number of comorbidities
          01.00(Reference)1.00(Reference)
          11.01 (0.89–1.14)0.89020.98 (0.86–1.11)0.7211
          21.05 (0.91–1.20)0.52191.03 (0.90–1.19)0.637
          ≥30.91 (0.77–1.07)0.25660.97 (0.82–1.15)0.7115

        AHR: adjusted hazard ratio; SABA: short-acting β2-agonist.

        • TABLE 4

          Summary of findings from other published studies

          CountryAuthors [ref.]Published yearJournalYear of dataStudy populationStudy size Findings
          SABA overuse prevalence (%)All-cause mortality#Asthma exacerbation#
          FranceRaherison-Semjen et al. [21]2018Eur Respir J2018Aged ≥18 years with an asthma diagnosisn=15 58728.30Not reportedNot reported
          PolandKupczyk et al. [22]2019Eur Respir J2018Aged 18–64 years with an asthma diagnosisn=91 67329–37Not reportedNot reported
          GermanyWorth et al. [19]2021Respir Res2017–2018Aged ≥12 years with an asthma diagnosis in the Disease Analyser database (IQVIA)n=15 64036Not reportedNot reported
          UKBloom et al. [9]2020Adv Ther2007–2017Aged ≥12 years with an asthma diagnosisn=574 91338Not available (due to small numbers)1–2 canisters: 1.20 (1.16–1.24)
          3–5 canisters:
          1.24 (1.20–1.28)
          ItalyDi Marco et al. [8]2021Adv Ther2015–2018Aged ≥12 years with an asthma diagnosisn=22 1029Not reportedCompared to <3 canisters/year:
          ≥3 canisters:
          1.27 (1.21–1.33)
          SwedenNwaru et al. [7]2020Eur Respir J2006–2016Aged 12–45 years in the nationwide longitudinal cohort, those who collected medication for COPDn=365 32430Compared to <3 canisters/year:
          3–5 canisters:
          1.26 (1.14–1.39)
          6–10 canisters
          1.67 (1.49–1.87)
          ≥11 canisters:
          2.35 (2.02–2.72)
          Compared to <3 canisters/year:
          3–5 canisters:
          1.26 (1.24–1.28)
          6–10 canisters:
          1.44 (1.41–1.46)
          ≥11 canisters:
          1.77 (1.72–1.83)
          TaiwanWang et al. [23]2021NPJ Prim Care Resp Med2001–2015Aged 12–100 years with asthma who enrolled in the Taiwanese pay-for-performance asthma programmen=218 03916Compared to no ICS and <3 canisters/year:
          3–6 canisters:
          1.17 (1.09–1.25)
          ≥7 canisters:
          2.01 (1.89–2.13)
          Compared to no ICS and <3 canisters/year:
          3–6 canisters:
          2.43 (2.36–2.50)
          ≥7 canisters:
          4.94 (4.79–5.09)
          CanadaTo et al.
          (current study)
          2022ERJ Open Res2006–2020Aged 65–99 years with prevalent asthma in the OASISn=59 53314Compared to 1–2 canisters/year:
          3–5 canisters:
          1.11 (1.02–1.22)
          ≥6 canisters:
          1.56 (1.41–1.71)
          Compared to 1–2 canisters/year:
          3–5 canisters:
          1.59 (1.40–1.82)
          ≥6 canisters:
          2.26 (1.96–2.60)

          SABA: short-term β2-agonist; ICS: inhaled corticosteroid; OASIS: Ontario Asthma Surveillance System. #: all-cause mortality and asthma exacerbation data presented as hazard ratio (95% CI).

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          Is overreliance on short-acting β2-agonists associated with health risks in the older asthma population?
          Teresa To, Jingqin Zhu, Emilie Terebessy, Kimball Zhang, Andrea S. Gershon, Christopher Licskai
          ERJ Open Research Jan 2022, 8 (1) 00032-2022; DOI: 10.1183/23120541.00032-2022

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          Is overreliance on short-acting β2-agonists associated with health risks in the older asthma population?
          Teresa To, Jingqin Zhu, Emilie Terebessy, Kimball Zhang, Andrea S. Gershon, Christopher Licskai
          ERJ Open Research Jan 2022, 8 (1) 00032-2022; DOI: 10.1183/23120541.00032-2022
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