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The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports

Miriam Bennett, Catherina L. Chang, Michael Tatley, Ruth Savage, Robert J. Hancox
ERJ Open Research 2021 7: 00801-2020; DOI: 10.1183/23120541.00801-2020
Miriam Bennett
1Respiratory Research Unit, Dept of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand
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  • ORCID record for Miriam Bennett
  • For correspondence: miriam.bennett@nhs.net
Catherina L. Chang
1Respiratory Research Unit, Dept of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand
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Michael Tatley
2New Zealand Pharmacovigilance Centre, Division of Health Sciences, University of Otago, Dunedin, New Zealand
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Ruth Savage
2New Zealand Pharmacovigilance Centre, Division of Health Sciences, University of Otago, Dunedin, New Zealand
3Dept of General Practice, University of Otago, Christchurch, New Zealand
4Uppsala Monitoring Centre, Uppsala, Sweden
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Robert J. Hancox
1Respiratory Research Unit, Dept of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand
5Dept of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
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  • ORCID record for Robert J. Hancox
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  • FIGURE 1
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    FIGURE 1

    Pictorial representation of β-adrenoceptor activity in the presence of background catecholamines, β-agonists and β-blockers. ISA: intrinsic sympathomimetic activity.

  • FIGURE 2
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    FIGURE 2

    PRISMA flow diagram of articles considered in the literature review.

Tables

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  • TABLE 1

    Commonly used β-blockers and their relative β-adrenoceptor selectivity and partial agonist and inverse agonist properties

    Cardioselective β1-blockers (relative selectivity of β1 versus β2)Nonselective β-blockers (relative selectivity of β1 versus β2)
    Partial agonist/ISAAcebutolol (2.4#)
    Practolol (>14.1#)
    Labetalol (2.5#)
    Alprenolol (16.2#)
    Inverse agonistMetoprolol (2.3#, 6.0¶)
    Atenolol (4.7#, 5.7¶)
    Bisoprolol (13.5#, 19.6¶)
    Nebivolol (40.6¶)
    Carvedilol (4.5#)
    Propranolol (8.3#)
    Sotalol (12.0#)
    Nadolol (23.4#)
    Timolol (25.7#)

    A relative selectivity ratio of 1 demonstrated equal activity at both β1- and β2-adrenoceptors. ISA: intrinsic sympathomimetic activity. #: according to Baker [26] using cell lines expressing human adrenoceptors; ¶: according to Ladage et al. [49] in their review figure.

    • TABLE 2

      Summary studies included in review

      Type of studyPublications found in the search and considered in the review
      Meta-analysis or systematic review4 (3 meta-analyses, 1 systematic review)
      Randomised controlled trial53 (765 participants in total of which 682 people with asthma and 83 with reversible airways disease)
      Non-randomised trial31 (106 915 participants in total of which 63 763 were asthma alone, 43 152 were asthma or COPD)
      Literature review12 (9 asthma, 1 obstructive lung disease, 1 reversible airways disease and 1 on adverse reactions to β-blockers)
      Other27 (8 case reports, 7 murine models, 7 guinea pig models, 4 opinion articles, 1 questionnaire)

      Studies that could be allocated to two categories are included in the highest tier (for example, meta-analysis above non-randomised trial).

      • TABLE 3

        Summary of VigiBase total and fatal reports for cardioselective β1-blockers with asthma or bronchospasm as reported suspected adverse reactions from start to December 2019

        Cardioselective β1-blockersReactions coded as asthmaReactions coded as bronchospasm
        TotalOf which were fatalTotalOf which were fatal
        Metoprolol28643226
        Atenolol14113853
        Bisoprolol9501081
        Nebivolol290320
        Betaxolol180860
        Acebutolol51300
        Celiprolol60411
        Landiolol1000
        Esmolol10111
        Esatenolol1000
      • TABLE 4

        VigiBase data: clinical details of all five reported fatalities with cardioselective β1-blocker use in patients with an adverse drug reaction of asthma or bronchospasm who had evidence of pre-existing asthma

        ReportYearCardioselective β1-blockersReported adverse drug reactions
        NameDoseDurationIndication
        11985MetoprololNot stated1.1 yearsNot statedAsthma (general anaesthetic medications listed)
        22017Metoprolol100 mg by mouth once dailyNot statedHypertensionAsthma, sepsis, pneumonia, emphysema, decreased immune response, renal cancer
        32018Acebutolol600 mg by mouth once dailyNot statedNot statedAsthma, acute MI, cardiogenic shock, metastatic renal cancer
        42009Atenolol50 mg once dailyNot statedNot statedBronchospasm, acute MI, cardiac failure, aspiration, sudden cardiac death
        52019AtenololNot stated11 yearsHypertensionAsthma, viral pneumonia (immunosuppressant medicines listed)

        MI: myocardial infarction.

        Supplementary Materials

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          Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

          Supplementary material 00801-2020.SUPPLEMENT

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        The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports
        Miriam Bennett, Catherina L. Chang, Michael Tatley, Ruth Savage, Robert J. Hancox
        ERJ Open Research Jan 2021, 7 (1) 00801-2020; DOI: 10.1183/23120541.00801-2020

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        The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports
        Miriam Bennett, Catherina L. Chang, Michael Tatley, Ruth Savage, Robert J. Hancox
        ERJ Open Research Jan 2021, 7 (1) 00801-2020; DOI: 10.1183/23120541.00801-2020
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