Figures
- FIGURE 1
Forest plot of benzodiazepine (BDZ)/opioid treatment and hospital admissions.
- FIGURE 2
Forest plot of benzodiazepine (BDZ)/opioid treatment and mortality.
- FIGURE 3
Cumulative incidence function (CIF) plot of benzodiazepine treatment on mortality.
Tables
- TABLE 1
Baseline characteristics according to treatment status of 1603 patients with oxygen-dependent fibrotic interstitial lung disease
BDZs Opioids Unexposed p-value Subjects 196 252 1214 Age at starting LTOT years 77.5±8.2 76.1±8.9 76.3±8.8 0.156 Female 89 (45.4) 123 (48.8) 415 (34.2) <0.001 FEV1 % pred# 66.3±37.3 67.0±39.7 71.6±40.3 0.106 VC % pred# 54.7±34.2 56.2±35.6 60.4±34.7 0.052 FEV1/VC# 0.9±0.3 0.9±0.3 0.8±0.4 0.427 PaO2 breathing air# kPa 6.5±1.0 6.6±1.0 6.6±1.0 0.441 PaCO2 breathing air# kPa 5.3±1.0 5.3±1.0 5.1±0.9 <0.001 PaO2 breathing oxygen# kPa 5.7±0.9 5.7±1.0 5.4±1.0 0.001 Smoking status Never-smoker 61 (31.1) 66 (26.2) 338 (27.8) 0.797 Ex-smoker 1 (1.0) 3 (1.2) 9 (0.7) Ex-/current smoker 105 (53.6) 149 (59.1) 698 (57.5) Missing 30 (15.31) 37 (14.7) 178 (14.7) BMI¶ kg·m−2 <18.5 10 (5.1) 12 (4.8) 35 (2.9) 0.579 18.5–24.9 107 (54.6) 143 (56.8) 707 (58.2) 25–29.9 53 (27.0) 67 (26.6) 314 (25.9) ≥30 26 (13.3) 30 (11.9) 158 (13.0) WHO Performance Status 0–1 76 (38.8) 93 (36.9) 566 (46.6) <0.001 2 54 (27.6) 70 (27.8) 350 (28.8) 3–4 49 (25.0) 60 (23.8) 161 (13.3) Missing 17 (8.7) 29 (11.5) 137 (11.3) Hospitalisations within 4 years before baseline 4 (2–6) 4 (2–6) 2 (1–4) <0.001 Hospitalised days out of the 91 days before baseline 14 (5.5–24) 15 (8–27) 11.5 (4–21) <0.001 Follow-up time hospitalised (follow-up time/hospitalised days) % 7.6 (2.3–20.3) 8.4 (2.6–19.8) 6.2 (2.1–16.8) 0.175 Cardiovascular diseases n 0 45 (23.0) 59 (23.4) 416 (34.3) <0.001 1 3 (1.5) 3 (1.2) 58 (4.8) 2 65 (33.2) 68 (27.0) 300 (24.7) ≥3 83 (42.4) 122 (48.4) 440 (36.2) Comorbidity COPD 50 (25.5) 67 (26.4) 234 (19.3) 0.010 Cancer 81 (41.3) 107 (42.5) 417 (34.4) 0.016 Depression/anxiety 43 (21.9) 33 (13.1) 37 (3.1) <0.001 Diabetes mellitus 44 (22.5) 73 (29.0) 219 (18.0) <0.001 Injury 33 (16.8) 54 (21.4) 154 (12.7) <0.001 Osteoporosis 11 (5.6) 35 (13.9) 47 (3.9) <0.001 Renal failure 18 (9.2) 25 (9.9) 65 (5.4) 0.007 Pulmonary hypertension 12 (6.1) 24 (9.5) 86 (7.1) 0.315 GORD 12 (6.1) 18 (7.1) 37 (3.1) 0.003 BDZs High (>15 mg·day−1 oral oxazepam equivalent) 65 (33.2) 27 (10.7) Low (≤15 mg·day−1 oral oxazepam equivalent) 131 (66.8) 32 (12.7) Opioids High (>30 mg·day−1 oral morphine equivalent) 33 (16.8) 122 (48.4) Low (≤30 mg·day−1 oral morphine equivalent) 27 (13.8) 130 (51.6) Oral corticosteroids 107 (54.6) 135 (53.6) 603 (49.7) 0.284 Azathioprine 8 (4.1) 13 (5.2) 89 (7.3) 0.142 N-acetylcysteine 81 (41.3) 76 (30.2) 372 (30.6) 0.010 Data presented as n, mean±sd, n (%) or median (interquartile range), unless otherwise stated. LTOT: long-term oxygen therapy; FEV1: forced expiratory volume in 1 s; VC: vital capacity; PaO2: arterial oxygen tension; PaCO2: arterial carbon dioxide tension; BMI: body mass index; WHO: World Health Organization; COPD: chronic obstructive pulmonary disease; GORD: gastro-oesophageal reflux disease; BDZ: benzodiazepine. Immunosuppressive drugs (including mycophenolate) used by five patients at baseline. #: summary statistics for imputed data applying Rubin's combination rules: FEV1 % pred (42.4% missing), VC % pred (42.7% missing), FEV1 (38.9% missing), VC (39.2% missing), PaO2 breathing air (22.4% missing), PaCO2 breathing air (22.8% missing) and PaO2 breathing oxygen (15.5% missing); ¶: missing BMI (31.1%) imputed into category 18.5–24.9 kg·m−2. p-value calculated using ANOVA, Kruskal–Wallis or Chi-squared test.
- TABLE 2
Exposure to benzodiazepines (BDZs) and opioids in 1603 patients with fibrotic interstitial lung disease
BDZs Opioids Exposed at baseline Total 196 252 Low dose 131 (66.8) 130 (51.6) High dose 65 (33.2) 122 (48.4) Dose at baseline DDD·day−1 0.2 (0.1–0.4) 0.3 (0.1–0.5) Exposed at baseline but unexposed during follow-up 51 (26.0) 77 (30.6) Exposure during follow-up % of time 83 (0–100) 63 (0–100) Medication-naive (unexposed) in preceding 12 months# 55 (29.3) 59 (25.0) Not exposed at baseline Total 1407 1351 Unexposed at baseline but exposed during follow-up 429 (30.5) 401 (29.7) Dose during follow-up DDD·day−1 0.0 (0.0–0.0) 0.0 (0.0–0.0) Exposure during follow-up % of time 0 (0–16) 0 (0–10) Medication-naive (unexposed) in preceding 12 months# 1199 (92.7) 1034 (83.1) Data are presented as n, n (%) or median (interquartile range). DDD: defined daily dose. #: among patients with at least 12 months of medication exposure data (n=1481).
- TABLE 3
Benzodiazepines (BDZs) and opioids and adjusted hazard ratio of admission to hospital and mortality in 1603 patients with oxygen-dependent fibrotic interstitial lung disease
Adjusted HR (95% CI)# Admission Mortality BDZs Untreated 1 1 Low dose 1.19 (0.95–1.49) 1.13 (0.92–1.38) High dose 1.27 (0.92–1.73) 1.46 (1.08–1.97) Opioids Untreated 1 1 Low dose 1.21 (0.96–1.52) 1.22 (0.99–1.50) High dose 1.08 (0.86–1.35) 1.11 (0.89–1.39) Covariates Age years 0.98 (0.98–0.99) 1.02 (1.01–1.03) Male 1.05 (0.93–1.19) 1.41 (1.24–1.60) VC % pred 1.00 (1.00–1.00) 1.00 (1.00–1.00) FEV1/VC 1.07 (0.94–1.22) 0.99 (0.89–1.11) PaO2 breathing air 1.00 (0.93–1.07) 1.00 (0.94–1.07) PaCO2 breathing air 0.95 (0.84–1.07) 0.89 (0.79–1.00) PaO2 breathing oxygen 0.99 (0.88–1.10) 0.99 (0.89–1.11) BMI kg·m−2 <18.5 1 1 18.5–24.9 1.26 (0.86–1.85) 0.72 (0.52–0.99) 25–29.9 1.30 (0.87–1.92) 0.70 (0.50–0.97) ≥30 1.28 (0.85–1.93) 0.54 (0.38–0.77) WHO Performance Status 0–1 1 1 2 1.09 (0.95–1.25) 1.48 (1.29–1.70) 3–4 0.78 (0.63–0.96) 2.00 (1.67–2.38) Missing 1.04 (0.86–1.26) 1.49 (1.22–1.81) Cardiovascular diseases n 0 1 1 1 1.11 (0.85–1.47) 1.03 (0.76–1.41) 2 1.05 (0.90–1.22) 0.99 (0.85–1.16) ≥3 1.04 (0.89–1.21) 1.05 (0.90–1.23) Comorbidity Cancer 1.15 (1.02–1.30) 0.85 (0.75–0.96) Depression/anxiety 0.79 (0.60–1.05) 1.08 (0.82–1.41) Diabetes mellitus 0.95 (0.82–1.10) 1.04 (0.90–1.20) Injury 1.05 (0.90–1.24) 1.10 (0.93–1.29) Osteoporosis 1.03 (0.80–1.33) 0.83 (0.64–1.09) Renal failure 0.83 (0.61–1.13) 1.50 (1.19–1.90) Pulmonary hypertension 0.88 (0.68–1.14) 1.10 (0.86–1.41) GORD 1.15 (0.85–1.56) 0.85 (0.62–1.17) Hospitalisations within 4 years before baseline 1.05 (1.02–1.07) 0.99 (0.97–1.01) Hospitalised days within the 91 days before baseline 1.00 (1.00–1.01) 1.00 (1.00–1.01) VC: vital capacity; FEV1: forced expiratory volume in 1 s; PaO2: arterial oxygen tension; PaCO2: arterial carbon dioxide tension; BMI: body mass index; WHO: World Health Organization; GORD: gastro-oesophageal reflux disease. #: model adjusted for all variables in the table as well as smoking status, and use of corticosteroids, azathioprine and N-acetylcysteine.
Supplementary Material
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Supplementary tables: sensitivity analyses ERJ-01278-2018_Supplement
