Figures
- FIGURE 1
Study design. ICS: inhaled corticosteroid; LABA: long-acting inhaled β-agonist; LAMA: long-acting muscarinic antagonist.
- 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
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
- 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-value SMD Age years 69.2±10.7/70.0 (15.0) 69.4±10.2/69.0 (14.0) 0.672 2.0 ≥40– <60 years 92 (19.7%) 194 (16.4%) 0.278 6.8 ≥60– <80 years 295 (63.3%) 778 (65.9%) ≥80 years 79 (17.0%) 209 (17.7%) Males 233 (50.0%) 603 (51.1%) 0.699 2.1 Index year 2013.2±3.4/2014.0 (5.0) 2012.5±2.9/2013.0 (4.0) <0.001 21.8 BMI n (% nonmissing) 463 (99.4%) 1167 (98.8%) 0.506 7.5 <18.5 kg·m−2 22 (4.8%) 69 (5.9%) ≥18.5– <25 kg·m−2 145 (31.3%) 397 (34.0%) ≥25– <30 kg·m−2 159 (34.3%) 376 (32.2%) ≥30 kg·m−2 137 (29.6%) 325 (27.8%) Current smoker No 256 (54.9%) 653 (55.3%) 0.896 0.7 Yes 210 (45.1%) 528 (44.7%) Asthma diagnosis, ever 38 (8.2%) 153 (13.0%) 0.006 15.7 Charlson Comorbidity Index ≤1 333 (71.5%) 845 (71.5%) 0.999 0.1 2–4 76 (16.3%) 190 (16.1%) 5–9 26 (5.6%) 67 (5.7%) ≥10 31 (6.7%) 79 (6.7%) Blood eosinophil count n (% nonmissing) 391 (83.9%) 983 (83.2%) 0.808 2.2 <0.05×109 cells per L 8 (2.0%) 31 (3.2%) 0.05–0.14×109 cells per L 110 (28.1%) 267 (27.2%) 0.15–0.24×109 cells per L 110 (28.1%) 281 (28.6%) 0.25–0.34×109 cells per L 80 (20.5%) 187 (19.0%) 0.3–0.44×109 cells per L 27 (6.9%) 86 (8.7%) 0.4–0.54×109 cells per L 23 (5.9%) 54 (5.5%) 0.5–0.64×109 cells per L 10 (2.6%) 30 (3.1%) ≥0.65×109 cells per L 23 (5.9%) 47 (4.8%) SABA prescriptions 0 63 (13.5%) 237 (20.1%) 0.021 8.1 1–2 103 (22.1%) 235 (19.9%) 3–5 100 (21.5%) 220 (18.6%) 6–9 108 (23.2%) 241 (20.4%) ≥10 92 (19.7%) 248 (21.0%) Salbutamol-equivalent average daily SABA dose 0 μg 63 (13.5%) 237 (20.1%) 0.033 8.9 1–100 μg 48 (10.3%) 110 (9.3%) 101–200 μg 83 (17.8%) 189 (16.0%) 201–300 μg 58 (12.4%) 110 (9.3%) 301–400 μg 41 (8.8%) 102 (8.6%) >400 μg 173 (37.1%) 433 (36.7%) SAMA prescriptions 0 415 (89.1%) 1044 (88.4%) 0.982 1.6 1 11 (2.4%) 31 (2.6%) 2 7 (1.5%) 19 (1.6%) ≥3 33 (7.1%) 87 (7.4%) LAMA prescriptions 0 139 (29.8%) 343 (29.0%) 0.001 13.9 1–3 89 (19.1%) 213 (18.0%) 4–6 81 (17.4%) 135 (11.4%) 7–9 56 (12.0%) 124 (10.5%) 10–12 63 (13.5%) 216 (18.3%) ≥13 38 (8.2%) 150 (12.7%) Average daily OCS dose <2.5 mg 379 (81.3%) 983 (83.2%) 0.433 1.2 ≥2.5– <5 mg 52 (11.2%) 112 (9.5%) ≥5– <7.5 mg 18 (3.9%) 31 (2.6%) ≥7.5 mg 16 (3.4%) 49 (4.1%) 5 mg 0 (0.0%) 4 (0.3%) 6 mg 1 (0.2%) 2 (0.2%) Acute respiratory events in baseline year# 0 22 (4.7%) 53 (4.5%) 0.797 5.0 1 48 (10.3%) 116 (9.8%) 2 90 (19.3%) 200 (16.9%) 3 96 (20.6%) 256 (21.7%) ≥4 210 (45.1%) 556 (47.1%) Exacerbations in baseline year# 2 287 (61.6%) 698 (59.1%) 0.718 3.4 3 105 (22.5%) 284 (24.0%) 4 34 (7.3%) 101 (8.6%) ≥5 40 (8.6%) 98 (8.3%) Acute OCS courses in baseline year# 0 95 (20.4%) 234 (19.8%) 0.700 1.7 1 117 (25.1%) 328 (27.8%) ≥2 254 (54.5%) 619 (52.4%) Antibiotic courses in baseline year# 0 80 (17.2%) 202 (17.1%) 0.627 2.9 1 115 (24.7%) 296 (25.1%) 2 183 (39.3%) 435 (36.8%) 3 63 (13.5%) 165 (14.0%) 4 13 (2.8%) 55 (4.7%) ≥5 12 (2.6%) 28 (2.4%) GOLD severity (% nonmissing) 373 (80.0%) 957 (81.0%) 0.394 8.0 Mild, FEV1 >80% predicted 44 (11.8%) 105 (11.0%) Moderate, FEV1 50–80% predicted 190 (50.9%) 447 (46.7%) Severe, FEV1 30–50% predicted 94 (25.2%) 281 (29.4%) Very severe, FEV1 <30% predicted 45 (12.1%) 124 (13.0%) GOLD risk group¶ n (% nonmissing) 389 (83.5%) 976 (82.6%) 0.187 7.9 C 236 (60.7%) 554 (56.8%) D 153 (39.3%) 422 (43.2%) mMRC score n (% nonmissing) 389 (83.5%) 976 (82.6%) 0.671 5.7 0, not troubled by breathlessness 37 (9.5%) 98 (10.0%) 1, short of breath 199 (51.2%) 456 (46.7%) 2, slower in walking 96 (24.7%) 266 (27.3%) 3, stopping for breath 49 (12.6%) 131 (13.4%) 4, too breathless to leave the house 8 (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
Improved Unchanged Worsened NNB LAMA/LABA Triple therapy LAMA/LABA Triple therapy LAMA/LABA Triple therapy Exacerbations 225 (73.5%) 651 (78.2%) 41 (13.4%) 96 (11.5%) 40 (13.1%) 85 (10.2%) 21 Acute respiratory events 173 (56.5%) 550 (66.1%) 51 (16.7%) 123 (14.8%) 82 (26.8%) 159 (19.1%) 10 Acute OCS courses 158 (51.6%) 494 (59.4%) 98 (32.0%) 213 (25.6%) 50 (16.3%) 125 (15.0%) 15 Antibiotics courses 193 (63.1%) 523 (62.9%) 72 (23.5%) 218 (26.2%) 41 (13.4%) 91 (10.9%) 134 mMRC score 32 (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 cohort Events per cohort Comparison Cohort Patients Total years Mean±sd years# Events IR per patient-year IR difference (95% CI) IR ratio (95% CI) Exacerbation (primary outcome) TT 1181 1022 0.74±0.88 812 0.794 −0.119 (−0.233– −0.004) 0.870 (0.763–0.994) DB 466 346 0.87±1.04 316 0.913 Acute respiratory event (secondary outcome) TT 1181 592 0.37±0.53 957 1.618 −0.560 (−0.803– −0.316) 0.743 (0.659–0.840) DB 466 172 0.50±0.73 374 2.178 Treatment failure (secondary outcome) TT 1181 867 0.60±0.77 874 1.008 −0.227 (−0.374– −0.080) 0.816 (0.720–0.927) DB 466 278 0.73±0.92 343 1.236 Acute OCS course (secondary outcome) TT 1181 1367 1.02±1.21 683 0.499 −0.058 (−0.134–0.019) 0.896 (0.777–1.037) DB 466 477 1.16±1.28 266 0.557 Antibiotics course (secondary outcome) TT 1181 1341 1.00±1.17 659 0.491 −0.052 (−0.129–0.025) 0.904 (0.781–1.049) DB 466 465 1.14±1.27 253 0.544 Pneumonia diagnosis (secondary outcome) TT 1181 2772 2.24±2.16 62 0.022 −0.003 (−0.014–0.009) 0.899 (0.560–1.480) DB 466 1044 2.35±2.00 26 0.025 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
Outcome Patients Unadjusted Adjusted HR (95% CI) p-value HR (95% CI) p-value First exacerbation 1647 0.90 (0.79–1.02) 0.111 0.87 (0.76–0.99) 0.040 First acute respiratory event 1647 0.79 (0.70–0.88) <0.001* 0.74 (0.66–0.84) <0.001* Treatment failure 1647 0.86 (0.76–0.98) 0.020 0.83 (0.73–0.95) 0.005* First acute OCS course 1647 0.95 (0.82–1.09) 0.437 0.93 (0.80–1.07) 0.298 First antibiotics course 1647 0.91 (0.79–1.04) 0.171 0.89 (0.77–1.04) 0.138 Pneumonia diagnosis 1647 1.26 (0.80–1.98) 0.325 0.71 (0.21–2.38) 0.573 RR (95% CI) p-value RR (95% CI) p-value Exacerbation rate 1138 0.85 (0.73–1.00) 0.056 0.86 (0.73–1.01) 0.068 Acute OCS courses rate 1138 0.83 (0.68–1.01) 0.067 0.80 (0.66–0.98) 0.030 Antibiotics courses rate 1138 0.88 (0.72–1.06) 0.183 0.91 (0.75–1.10) 0.332 Acute respiratory events rate 1138 0.80 (0.70–0.90) <0.001 0.79 (0.70–0.90) <0.001* OR (95% CI) p-value RR (95% CI) p-value mMRC ≥2 885 1.20 (0.86–1.68) 0.293 1.12 (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].
Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material 00106-2019.supp
Supplementary figure 1a 00106-2019.supp_fig1a
Supplementary figure 1b 00106-2019.supp_fig1b
Supplementary figure 1c 00106-2019.supp_fig1c
