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Comparative effectiveness of triple therapy versus dual bronchodilation in COPD

Jaco Voorham, Massimo Corradi, Alberto Papi, Claus F. Vogelmeier, Dave Singh, Leonardo M. Fabbri, Marjan Kerkhof, Janwillem H. Kocks, Victoria Carter, David Price
ERJ Open Research 2019 5: 00106-2019; DOI: 10.1183/23120541.00106-2019
Jaco Voorham
1Observational and Pragmatic Research Institute, Singapore, Singapore
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Massimo Corradi
2Dept of Medicine and Surgery, University Hospital of Parma, Parma, Italy
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Alberto Papi
3Dept of Medical Sciences, University of Ferrara, Ferrara, Italy
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Claus F. Vogelmeier
4Dept of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany
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Dave Singh
5University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK
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Leonardo M. Fabbri
3Dept of Medical Sciences, University of Ferrara, Ferrara, Italy
6COPD Center, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
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Marjan Kerkhof
1Observational and Pragmatic Research Institute, Singapore, Singapore
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Janwillem H. Kocks
1Observational and Pragmatic Research Institute, Singapore, Singapore
7General Practitioners Research Institute, Groningen, The Netherlands
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Victoria Carter
1Observational and Pragmatic Research Institute, Singapore, Singapore
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David Price
1Observational and Pragmatic Research Institute, Singapore, Singapore
8Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
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  • For correspondence: dprice@opri.sg
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  • FIGURE 1
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    FIGURE 1

    Study design. ICS: inhaled corticosteroid; LABA: long-acting inhaled β-agonist; LAMA: long-acting muscarinic antagonist.

  • FIGURE 2
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    FIGURE 2

    Flow diagram of patient selection. CPRD: Clinical Practice Research Datalink; LABA: long-acting inhaled β-agonist; LAMA: long-acting muscarinic antagonist; OPCRD: Optimum Patient Care Research Database.

  • FIGURE 3
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    FIGURE 3

    a) Effect modification by number of exacerbations in the baseline year. b) Effect modification by baseline blood eosinophil count. LAMA: long-acting muscarinic antagonist; LABA: long-acting inhaled β-agonist.

Tables

  • Figures
  • Supplementary Materials
  • TABLE 1

    Study outcomes and definitions

    Primary
    •  1) Time to first exacerbation

    •   Respiratory-related hospital attendance/admission AND/OR

    •   Respiratory-related emergency room attendance AND/OR

    •   Prescription of acute OCS course AND/OR

    •   Antibiotics prescribed with evidence of lower respiratory consultation on the same day

    Secondary
    •  2) Time to first acute respiratory event

    •   Respiratory-related consultation, not for annual monitoring review

    •  3) Time to treatment failure

    •   Prescription of additional chronic therapy (theophylline or other methylxanthines); maintenance OCS; PDE4 inhibitor; macrolides (e.g. azithromycin, erythromycin); mucolytics (e.g. carbocysteine, N-acetylcysteine); LTRA (nedocromil) AND/OR

    •   An exacerbation (as defined above)

    •  4) Time to first acute OCS course

    •  5) Time to first antibiotics prescription with evidence of lower respiratory consultation, to avoid misclassification of antibiotics being prescribed for another reason [18]

    •  Number of occurrences in the first 1-year outcome period of:

    •    6) Exacerbations

    •    7) Acute OCS courses

    •    8) Antibiotic prescriptions with evidence of lower respiratory consultation

    •    9) Acute respiratory events

    •  10) mMRC score within 18 months after index date; ≥2 versus <2

    •  11) Time to first pneumonia diagnosis

    •     Chest radiography AND/OR

    •     Diagnostic code

    OCS: oral corticosteroid; PDE: phosphodiesterase; LTRA: leukotriene receptor antagonist; mMRC: modified Medical Research Council dyspnoea scale.

    • TABLE 2

      Patient baseline characterisation, matched

      LAMA/LABA (n=466)Triple therapy (n=1181)p-valueSMD
      Age years69.2±10.7/70.0 (15.0)69.4±10.2/69.0 (14.0)0.6722.0
       ≥40– <60 years92 (19.7%)194 (16.4%)0.2786.8
       ≥60– <80 years295 (63.3%)778 (65.9%)
       ≥80 years79 (17.0%)209 (17.7%)
      Males233 (50.0%)603 (51.1%)0.6992.1
      Index year2013.2±3.4/2014.0 (5.0)2012.5±2.9/2013.0 (4.0)<0.00121.8
      BMI n (% nonmissing)463 (99.4%)1167 (98.8%)0.5067.5
       <18.5 kg·m−222 (4.8%)69 (5.9%)
       ≥18.5– <25 kg·m−2145 (31.3%)397 (34.0%)
       ≥25– <30 kg·m−2159 (34.3%)376 (32.2%)
       ≥30 kg·m−2137 (29.6%)325 (27.8%)
      Current smoker
       No256 (54.9%)653 (55.3%)0.8960.7
       Yes210 (45.1%)528 (44.7%)
      Asthma diagnosis, ever38 (8.2%)153 (13.0%)0.00615.7
      Charlson Comorbidity Index
       ≤1333 (71.5%)845 (71.5%)0.9990.1
       2–476 (16.3%)190 (16.1%)
       5–926 (5.6%)67 (5.7%)
       ≥1031 (6.7%)79 (6.7%)
      Blood eosinophil count n (% nonmissing)391 (83.9%)983 (83.2%)0.8082.2
       <0.05×109 cells per L8 (2.0%)31 (3.2%)
       0.05–0.14×109 cells per L110 (28.1%)267 (27.2%)
       0.15–0.24×109 cells per L110 (28.1%)281 (28.6%)
       0.25–0.34×109 cells per L80 (20.5%)187 (19.0%)
       0.3–0.44×109 cells per L27 (6.9%)86 (8.7%)
       0.4–0.54×109 cells per L23 (5.9%)54 (5.5%)
       0.5–0.64×109 cells per L10 (2.6%)30 (3.1%)
       ≥0.65×109 cells per L23 (5.9%)47 (4.8%)
      SABA prescriptions
       063 (13.5%)237 (20.1%)0.0218.1
       1–2103 (22.1%)235 (19.9%)
       3–5100 (21.5%)220 (18.6%)
       6–9108 (23.2%)241 (20.4%)
       ≥1092 (19.7%)248 (21.0%)
      Salbutamol-equivalent average daily SABA dose
       0 μg63 (13.5%)237 (20.1%)0.0338.9
       1–100 μg48 (10.3%)110 (9.3%)
       101–200 μg83 (17.8%)189 (16.0%)
       201–300 μg58 (12.4%)110 (9.3%)
       301–400 μg41 (8.8%)102 (8.6%)
       >400 μg173 (37.1%)433 (36.7%)
      SAMA prescriptions
       0415 (89.1%)1044 (88.4%)0.9821.6
       111 (2.4%)31 (2.6%)
       27 (1.5%)19 (1.6%)
       ≥333 (7.1%)87 (7.4%)
      LAMA prescriptions
       0139 (29.8%)343 (29.0%)0.00113.9
       1–389 (19.1%)213 (18.0%)
       4–681 (17.4%)135 (11.4%)
       7–956 (12.0%)124 (10.5%)
       10–1263 (13.5%)216 (18.3%)
       ≥1338 (8.2%)150 (12.7%)
      Average daily OCS dose
       <2.5 mg379 (81.3%)983 (83.2%)0.4331.2
       ≥2.5– <5 mg52 (11.2%)112 (9.5%)
       ≥5– <7.5 mg18 (3.9%)31 (2.6%)
       ≥7.5 mg16 (3.4%)49 (4.1%)
       5 mg0 (0.0%)4 (0.3%)
       6 mg1 (0.2%)2 (0.2%)
      Acute respiratory events in baseline year#
       022 (4.7%)53 (4.5%)0.7975.0
       148 (10.3%)116 (9.8%)
       290 (19.3%)200 (16.9%)
       396 (20.6%)256 (21.7%)
       ≥4210 (45.1%)556 (47.1%)
      Exacerbations in baseline year#
       2287 (61.6%)698 (59.1%)0.7183.4
       3105 (22.5%)284 (24.0%)
       434 (7.3%)101 (8.6%)
       ≥540 (8.6%)98 (8.3%)
      Acute OCS courses in baseline year#
       095 (20.4%)234 (19.8%)0.7001.7
       1117 (25.1%)328 (27.8%)
       ≥2254 (54.5%)619 (52.4%)
      Antibiotic courses in baseline year#
       080 (17.2%)202 (17.1%)0.6272.9
       1115 (24.7%)296 (25.1%)
       2183 (39.3%)435 (36.8%)
       363 (13.5%)165 (14.0%)
       413 (2.8%)55 (4.7%)
       ≥512 (2.6%)28 (2.4%)
      GOLD severity (% nonmissing)373 (80.0%)957 (81.0%)0.3948.0
       Mild, FEV1 >80% predicted44 (11.8%)105 (11.0%)
       Moderate, FEV1 50–80% predicted190 (50.9%)447 (46.7%)
       Severe, FEV1 30–50% predicted94 (25.2%)281 (29.4%)
       Very severe, FEV1 <30% predicted45 (12.1%)124 (13.0%)
      GOLD risk group¶ n (% nonmissing)389 (83.5%)976 (82.6%)0.1877.9
       C236 (60.7%)554 (56.8%)
       D153 (39.3%)422 (43.2%)
      mMRC score n (% nonmissing)389 (83.5%)976 (82.6%)0.6715.7
       0, not troubled by breathlessness37 (9.5%)98 (10.0%)
       1, short of breath199 (51.2%)456 (46.7%)
       2, slower in walking96 (24.7%)266 (27.3%)
       3, stopping for breath49 (12.6%)131 (13.4%)
       4, too breathless to leave the house8 (2.1%)25 (2.6%)

      Data are presented as mean±sd/median (interquartile range) unless otherwise stated. LAMA: long-acting muscarinic antagonist; LABA: long-acting inhaled β-agonist; SMD: standardised mean difference; IQR: interquartile range; BMI: body mass index; SABA: short-acting inhaled β-agonist; SAMA: short-acting muscarinic antagonist; LAMA: long-acting muscarinic antagonist; OCS: oral corticosteroid; GOLD: Global Initiative for Chronic Obstructive Lung Disease; FEV1: forced expiratory volume in 1 s; mMRC: modified Medical Research Council dyspnoea scale. #includes the index date; ¶: symptom and risk based. p-values are for the Kruskal–Wallis equality-of-populations rank test or Pearson's Chi-squared test of independent categories, where appropriate.

      • TABLE 3

        Number of patients improving or worsening from baseline to the first outcome year, matched

        ImprovedUnchangedWorsenedNNB
        LAMA/LABATriple therapyLAMA/LABATriple therapyLAMA/LABATriple therapy
        Exacerbations225 (73.5%)651 (78.2%)41 (13.4%)96 (11.5%)40 (13.1%)85 (10.2%)21
        Acute respiratory events173 (56.5%)550 (66.1%)51 (16.7%)123 (14.8%)82 (26.8%)159 (19.1%)10
        Acute OCS courses158 (51.6%)494 (59.4%)98 (32.0%)213 (25.6%)50 (16.3%)125 (15.0%)15
        Antibiotics courses193 (63.1%)523 (62.9%)72 (23.5%)218 (26.2%)41 (13.4%)91 (10.9%)134
        mMRC score32 (16.7%)32 (6.1%)101 (52.6%)264 (50.2%)59 (30.7%)163 (31.0%)

        LAMA: long-acting muscarinic antagonist; LABA: long-acting inhaled β-agonist; NNB: number needed for one patient to benefit from triple therapy [21]; OCS: oral corticosteroid; mMRC: modified Medical Research Council dyspnoea scale.

        • TABLE 4

          Unadjusted incidence rate (IR) ratios for time-to-event outcomes, by matched treatment cohort

          Patients and follow-up years per cohortEvents per cohortComparison
          CohortPatientsTotal yearsMean±sd years#EventsIR per patient-yearIR difference (95% CI)IR ratio (95% CI)
          Exacerbation (primary outcome)TT118110220.74±0.888120.794−0.119 (−0.233– −0.004)0.870 (0.763–0.994)
          DB4663460.87±1.043160.913
          Acute respiratory event (secondary outcome)TT11815920.37±0.539571.618−0.560 (−0.803– −0.316)0.743 (0.659–0.840)
          DB4661720.50±0.733742.178
          Treatment failure (secondary outcome)TT11818670.60±0.778741.008−0.227 (−0.374– −0.080)0.816 (0.720–0.927)
          DB4662780.73±0.923431.236
          Acute OCS course (secondary outcome)TT118113671.02±1.216830.499−0.058 (−0.134–0.019)0.896 (0.777–1.037)
          DB4664771.16±1.282660.557
          Antibiotics course (secondary outcome)TT118113411.00±1.176590.491−0.052 (−0.129–0.025)0.904 (0.781–1.049)
          DB4664651.14±1.272530.544
          Pneumonia diagnosis (secondary outcome)TT118127722.24±2.16620.022−0.003 (−0.014–0.009)0.899 (0.560–1.480)
          DB46610442.35±2.00260.025

          OCS: oral corticosteroid; TT: triple therapy; DB: dual bronchodilation with long-acting muscarinic antagonist/long-acting inhaled β-agonist. #: mean follow-up time in years available.

          • TABLE 5

            Unadjusted and adjusted effects of triple therapy compared with dual bronchodilation (baseline) on outcomes of interest during the outcome period

            OutcomePatientsUnadjustedAdjusted
            HR (95% CI)p-valueHR (95% CI)p-value
            First exacerbation16470.90 (0.79–1.02)0.1110.87 (0.76–0.99)0.040
            First acute respiratory event16470.79 (0.70–0.88)<0.001*0.74 (0.66–0.84)<0.001*
            Treatment failure16470.86 (0.76–0.98)0.0200.83 (0.73–0.95)0.005*
            First acute OCS course16470.95 (0.82–1.09)0.4370.93 (0.80–1.07)0.298
            First antibiotics course16470.91 (0.79–1.04)0.1710.89 (0.77–1.04)0.138
            Pneumonia diagnosis16471.26 (0.80–1.98)0.3250.71 (0.21–2.38)0.573
            RR (95% CI)p-valueRR (95% CI)p-value
            Exacerbation rate11380.85 (0.73–1.00)0.0560.86 (0.73–1.01)0.068
            Acute OCS courses rate11380.83 (0.68–1.01)0.0670.80 (0.66–0.98)0.030
            Antibiotics courses rate11380.88 (0.72–1.06)0.1830.91 (0.75–1.10)0.332
            Acute respiratory events rate11380.80 (0.70–0.90)<0.0010.79 (0.70–0.90)<0.001*
            OR (95% CI)p-valueRR (95% CI)p-value
            mMRC ≥28851.20 (0.86–1.68)0.2931.12 (0.76–1.66)0.566

            HR: hazard ratio; OCS: oral corticosteroid; mMRC: modified Medical Research Council dyspnoea scale; RR: rate ratio. *: p<0.05 after controlling for 10 statistical tests for secondary outcomes performed following Holm's method [22].

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              Supplementary figure 1a 00106-2019.supp_fig1a

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            Comparative effectiveness of triple therapy versus dual bronchodilation in COPD
            Jaco Voorham, Massimo Corradi, Alberto Papi, Claus F. Vogelmeier, Dave Singh, Leonardo M. Fabbri, Marjan Kerkhof, Janwillem H. Kocks, Victoria Carter, David Price
            ERJ Open Research Jul 2019, 5 (3) 00106-2019; DOI: 10.1183/23120541.00106-2019

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            Comparative effectiveness of triple therapy versus dual bronchodilation in COPD
            Jaco Voorham, Massimo Corradi, Alberto Papi, Claus F. Vogelmeier, Dave Singh, Leonardo M. Fabbri, Marjan Kerkhof, Janwillem H. Kocks, Victoria Carter, David Price
            ERJ Open Research Jul 2019, 5 (3) 00106-2019; DOI: 10.1183/23120541.00106-2019
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