On-Line Supplement Risks of pneumonia in asthmatic patients taking inhaled corticosteroids Paul M. O Byrne, Soren Pedersen, Lars-Göran Carlsson, Finn Radner,Anders Thorén Stefan Peterson, Pierre Ernst, Samy Suissa.
Additional Analysis As a complementary analysis the overall relative risk (RR) using a Mantel Haenszel (MH) approach stratified by study and adjusted for treatment exposure was calculated. This provided the pooled MH RR and 95% confidence intervals (CI) for pneumonia AE and SAE. For the visual assessment of the risk over all individual studies, a descriptive 95% credibility interval for the RR was provided using the method of Barker and Cadwell (1) with an uninformative uniform prior; the median of the posterior distribution was used to provide a point estimate for the RR, allowing presentation of studies with no event. These Bayesian risk estimates and credibility intervals are presented in forest plots, together with the pooled MH RR and its 95% CI for pneumonia AE and SAE. Reference (1) Barker L, Cadwell BL. An analysis of eight 95 per cent confidence intervals for a ratio of Poisson parameters when events are rare. Stat Med 2008; 27:4030-7.
Table E1 Double-blind placebo-controlled trials included in the primary analysis Studycode Duration Age min Age max exposure (1000 treatment years) ICS Non-ICS ICS Non-ICS daily delivered doses of budesonide* (μg) Comparison Budesonide pmdi trials 04-2180 3 months 18 72 86 57 29 0.02 0.01 0.01 320 BUD CFC vs PLA 04-2182 3 months 6 18 59 30 29 0.01 0.01 0.01 320 BUD CFC vs PLA Budesonide Turbuhaler trials 04-2184 12 months 19 62 37 19 18 0.03 0.02 0.02 320 BUD TBH vs PLA 04-2205 12 months 18 68 74 38 36 0.06 0.03 0.03 320 BUD TBH vs PLA 04-2291 3 months 12 70 324 245 79 0.07 0.05 0.02 1280 BUD TBH vs PLA 04-3020 3 months 18 70 472 380 92 0.09 0.08 0.01 160;320;640;1280 BUD TBH vs PLA 04-3021 3 months 19 70 273 184 89 0.06 0.04 0.02 160;320 BUD TBH vs PLA 04-3023 3 months 6 18 404 301 103 0.08 0.06 0.02 160;320;640 BUD TBH vs PLA 04-3049 3 months 16 66 260 172 88 0.06 0.04 0.02 160;640 BUD TBH vs PLA 04-3078 4 months 18 52 31 16 15 0.01 0.00 0.00 640 BUD TBH vs PLA vs Sodium cromoglicate (N=15, excluded) 04-3083 3 months 18 70 286 227 59 0.06 0.05 0.01 160 BUD TBH vs PLA 04-3084 3 months 7 16 162 122 40 0.04 0.03 0.01 80;160 BUD TBH vs PLA SD-004-0009 4 months 18 70 309 205 104 0.09 0.07 0.03 160;320 BUD TBH vs PLA SD-004-0111** 12 months of 36 months 4 66 7221 3630 3591 6.47 3.28 3.19 320 (children 160) BUD TBH vs PLA on top of regular asthma treatment SD-004-0278 3 months 18 70 177 90 87 0.04 0.02 0.02 320 BUD TBH vs PLA SD-004-0279 3 months 18 70 184 93 91 0.03 0.02 0.01 160 BUD TBH vs PLA SD-004-0280 3 months 6 17 274 183 91 0.05 0.04 0.02 160;320 BUD TBH vs PLA SD-004-0620 3 months 18 80 621 497 124 0.12 0.10 0.02 160;640 BUD TBH vs PLA SD-004-0726 3 months 6 17 516 410 106 0.11 0.09 0.02 160;640 BUD TBH vs PLA
Table E1 Double-blind placebo-controlled trials included in the primary analysis Studycode Duration Age min Age max exposure (1000 treatment years) ICS Non-ICS ICS Non-ICS daily delivered doses of budesonide* (μg) Comparison Budesonide nebulizing suspension trials 04-3069*** 3 months 4 8 218 160 58 0.05 0.03 0.01 250,500;1000 BUD NEB vs PLA 04-3072 3 months 4 9 178 134 44 0.04 0.03 0.01 500;1000;2000 BUD NEB vs PLA 04-3100*** 3 months 4 9 271 212 59 0.05 0.04 0.01 250,500;1000 BUD NEB vs PLA Budesonide/formoterol pmdi trials SD-039-0716 3 months 6 89 511 257 254 0.10 0.05 0.04 320/18; 320 SD-039-0717 3 months 8 87 596 348 248 0.11 0.07 0.04 640/18; 640; 640+18 SD-039-0726 3 months 16 79 751 598 153 0.17 0.14 0.03 160/9; 320 Formoterol Turbuhaler trials SD-037-0345 12 months 12 76 698 459 239 0.60 0.39 0.21 160 plus 9; 160 vs FORM TBH (18μg) vs PLA BUD/FORM HFA vs [BUD HFA plus FORM TBH]vs BUD HFA vs FORM TBH (18μg) vs PLA vs PLA BUD TBH vs [BUD TBH plus FORM TBH] vs PLA 14993 9067 5926 8.62 4.80 3.82 *Delivered doses of 80, 160, 320, 640 or 1280 µg correspond to metered doses of 100, 200, 400, 800 and 1600 µg of budesonide ** Only data from the first 12 months have been included in the analysis *** Patients aged 3 years and younger have been removed from the dataset and have thus not been counted
Table E2 Double-blind controlled trials included in the supplementary analysis Studycode Duration Age min Age max Budeso nide Comparat or exposure (1000 treatment years) Budesoni de Compara tor daily delivered doses of budesonide (μg) Comparison Budesonide pmdi trials 04-2180 3 months 18 72 86 57 29 0.02 0.01 0.01 320 BUD CFC vs PLA 04-2182 3 months 6 18 59 30 29 0.01 0.01 0.01 320 BUD CFC vs PLA Budesonide Turbuhaler trials 04-2184 12 months 19 62 37 19 18 0.03 0.02 0.02 320 BUD TBH vs PLA 04-2205 12 months 18 68 74 38 36 0.06 0.03 0.03 320 BUD TBH vs PLA 04-2291 3 months 12 70 324 245 79 0.07 0.05 0.02 1280 BUD TBH vs PLA 04-2292 3 months 12 70 257 257 0 0.06 0.06 0 320 BUD TBH vs BUD TBH 04-3000 4 months 18 68 158 158 0 0.05 0.05 0 320 vs 640 BUD TBH vs BUD TBH 04-3020 3 months 18 70 472 380 92 0.09 0.08 0.01 160;320;640;1280 BUD TBH vs PLA 04-3021 3 months 19 70 273 184 89 0.06 0.04 0.02 160;320 BUD TBH vs PLA 04-3023 3 months 6 18 404 301 103 0.08 0.06 0.02 160;320;640 BUD TBH vs PLA 04-3049 3 months 16 66 260 172 88 0.06 0.04 0.02 160;640 BUD TBH vs PLA 04-3064 12 months 7 11 91 46 45 0.04 0.04 0.07 320 04-3066 6 months (of 18 months) 5 10 178 117 64 0.06 0.06 0 dose titration 04-3078 4 months 18 52 46 16 30 0.01 0.00 0.00 640 BUD TBH vs Sodium cromoglicate BUD TBH dose titration (openlabel vs Sodium cromoglicate N=64) BUD TBH vs PLA (N=15) (vs Sodium cromoglicate N=15) 04-3083 3 months 18 70 286 227 59 0.06 0.05 0.01 160 BUD TBH vs PLA 04-3084 3 months 7 16 162 122 40 0.04 0.03 0.01 80;160 BUD TBH vs PLA 04-3085 3 months 5 13 206 206 0 0.05 0.05 0 160;320 BUD TBH vs BUD TBH BN-00P-0070 3 months 18 70 197 96 101 0.04 0.02 0.02 640 BUD TBH vs FLUT SD-004-0009 4 months 18 70 309 205 104 0.09 0.07 0.03 160;320 BUD TBH vs PLA
Table E2 Double-blind controlled trials included in the supplementary analysis Studycode Duration Age min SD-004-0024 SD-004-0111 4 months (of 17 months) 12 months of 36 months Age max Budeso nide Comparat or exposure (1000 treatment years) Budesoni de Compara tor daily delivered doses of budesonide (μg) Comparison 18 67 61 61 0 0.02 0.02 0 1280;2560 BUD TBH vs BUD_TBH 4 66 7221 3630 3591 6.47 3.28 3.19 320 (children 160) BUD TBH vs PLA on top of regular asthma treatment SD-004-0210 3 months 18 74 589 589 0 0.13 0.13 0 160;960 BUD TBH vs BUD TBH SD-004-0278 3 months 18 70 177 90 87 0.04 0.02 0.02 320 BUD TBH vs PLA SD-004-0279 3 months 18 70 184 93 91 0.03 0.02 0.01 160 BUD TBH vs PLA SD-004-0280 3 months 6 17 274 183 91 0.05 0.04 0.02 160;320 BUD TBH vs PLA SD-004-0620 3 months 18 80 621 497 124 0.12 0.10 0.02 160;640 BUD TBH vs PLA SD-004-0726 3 months 6 17 516 410 106 0.11 0.09 0.02 160;640 BUD TBH vs PLA Budesonide nebulizing suspension trials 04-3069 3 months 4 8 218 160 58 0.05 0.03 0.01 250,500;1000 BUD NEB vs PLA 04-3072 3 months 4 9 178 134 44 0.04 0.03 0.01 500;1000;2000 BUD NEB vs PLA 04-3100 3 months 4 9 271 212 59 0.05 0.04 0.01 250,500;1000 BUD NEB vs PLA SD-004-0764 3 months 12 77 767 767 0 0.15 0.15 0 Budesonide/formoterol pmdi trials D5896C00001 SD-039-0681 3 months 3 months 12 79 618 618 0 0.13 0.13 0 500;1000;2000; 4000;640 160/9;320/9; 320/18; 320 11 79 679 679 0 0.15 0.15 0 640/18 vs 640 SD-039-0682 3 months 6 11 622 622 0 0.14 0.14 0 320/18 vs 320 SD-039-0716 3 months 6 89 511 257 254 0.10 0.05 0.04 320/18; 320 SD-039-0717 3 months 8 87 596 348 248 0.11 0.07 0.04 640/18; 640; 640+18 BUD NEB vs PBUD TBH BUD/FORM HFA vs BUD/FORM TBH vs BUD CFC BUD/FORM HFA vs BUD/FORM TBH vs BUD CFC vs FORM TBH (18μg) vs PLA BUD/FORM HFA vs [BUD HFA plus FORM TBH]vs BUD HFA vs FORM TBH (18μg) vs PLA
Table E2 Double-blind controlled trials included in the supplementary analysis Studycode Duration Age min Age max Budeso nide Comparat or exposure (1000 treatment years) Budesoni de Compara tor daily delivered doses of budesonide (μg) SD-039-0718 3 months 6 15 411 273 138 0.08 0.05 0.03 160/18;160 Comparison vs FORM TBH SD-039-0725 3 months 6 15 521 521 0 0.12 0.12 0 160/18;160/9, 160 SD-039-0726 3 months 16 79 751 598 153 0.17 0.14 0.03 160/9; 320 SD-039-0728 12 months 12 81 708 708 0 0.63 0.63 0 Budesonide/formoterol Turbuhaler trials 640/18; 1280/36;1280 D5890C00002 6 months 12 80 2304 1151 1153 1.09 0.55 0.54 640/18 vs PLA BUD/FORM TBH vs FLUT/SALM SD-039-0348 3 months 18 78 467 467 0 0.10 0.10 0 160/9 vs 320 BUD/FORM TBH vs BUD TBH SD-039-0349 3 months 18 78 362 362 0 0.08 0.08 0 640/18 vs 640 BUD/FORM TBH vs BUD TBH SD-039-0353 3 months 4 17 286 286 0 0.06 0.06 0 320/18 vs 320 BUD/FORM TBH vs BUD TBH SD-039-0618 3 months 17 75 344 168 176 0.08 0.04 0.04 320/9 BUD/FORM TBH vs FLUT SD-039-0665 3 months 18 80 616 616 0 0.13 0.13 0 160/9 vs 160 BUD/FORM TBH vs BUD TBH SD-039-0666 3 months 18 78 523 523 0 0.11 0.11 0 320/9 vs 320 BUD/FORM TBH vs BUD TBH SD-039-0667 6 months 11 79 696 696 0 0.33 0.33 0 SD-039-0668 12 months 11 80 1890 1890 0 1.69 1.69 0 SD-039-0673 12 months 4 79 2753 2753 0 2.48 2.48 0 SD-039-0686 7 months 12 85 160/9 (SMART) vs 320 320/9 (SMART) vs 640 160/9 (SMART) vs 160/9 vs 640 658 434 224 0.34 0.22 0.12 640/18; ind dose BUD/FORM TBH vs BUD TBH BUD/FORM TBH vs BUD TBH BUD/FORM TBH vs BUD TBH BUD/FORM TBH vs FLUT/SALM SD-039-0688 3 months 4 11 630 630 0 0.14 0.14 0 320/18 vs 320 BUD/FORM TBH vs BUD TBH SD-039-0689 6 months 12 79 456 456 0 0.20 0.20 0 1280/36;1280 BUD/FORM TBH vs BUD TBH SD-039-0714 3 months 11 17 270 270 0 0.06 0.06 0 320/9 vs 320
Table E2 Double-blind controlled trials included in the supplementary analysis Studycode Duration Age min Age max SD-039-0734 12 months 12 89 SD-039-0735 6 months 11 83 Formoterol Turbuhaler trials Budeso nide Comparat or exposure (1000 treatment years) Budesoni de Compara tor 3382 3382 0 3.14 3.14 0 3321 2202 1119 1.50 0.99 0.51 37-3018 12 months 17 70 853 853 0 0.72 0.72 0 daily delivered doses of budesonide (μg) 320/9 (SMART) vs 320/9 320/9 (SMART) vs 640/18 160+ 18; 160; 640+18; 640 37-3041 12 months 19 69 60 60 0 0.05 0.05 0 160+ 18; 640 SD-037-0345 12 months 11 82 1970 1731 239 1.76 1.55 0.21 160+ 9; 160 RofleponideTurbuhaler trials Comparison BUD/FORM TBH vs BUD/FORM TBH BUD/FORM TBH vs BUD/FORM TBH vs FLUT/SALM BUD TBH vs [BUD TBH plus FORM TBH] BUD TBH vs [BUD TBH plus FORM TBH] BUD TBH vs [BUD TBH plus FORM TBH] vs PLA SD-050-0437 3 months 18 70 472 240 232 0.10 0.05 0.05 160;960 Rofleponide TBH vs BUD TBH 42686 33496 9190 24.0 18.9 5.2
Table E3 Reporting of pneumonia as AE and SAE in the double-blind controlled trials included in the supplementary analysis Subgroup on budesonide Exposure on budesonide in TTY (%) of patients reporting pneumonia AEs on budesonide (%) of patients reporting pneumonia SAEs on budesonide All trials excluding START 29886 15.6 202 (0.68%) 49 (0.16%) START alone 3630 3.3 33 (0.91%) 8 (0.22%) Patients aged 4-11years 4818 2.2 54 (1.12%) 11 (0.23%) Patients aged 12-78 years 28678 16.7 181 (0.63%) 46 (0.16%) All trials 33496 18.9 235 (0.70%) 57 (0.17%)
Table E4 Reporting of pneumonia AEs in trials comparing high-dose and low-dose budesonide Studycode on HIGH BUD on LOW BUD Exposure on HIGH BUD (TTY) Exposure on LOW BUD (TTY) (%) of patients reporting pneumonia AEs HIGH BUD LOW BUD HR (95% CI) Rate per TTY (%) of patients reporting pneumonia AEs 04-3000 79 79 0.02 0.02 0 0.0% 0.0 0 0.0% 0.0 04-3020 196 184 0.04 0.04 0 0.0% 0.0 0 0.0% 0.0 04-3021 91 93 0.02 0.02 0 0.0% 0.0 0 0.0% 0.0 04-3023 99 202 0.02 0.04 0 0.0% 0.0 0 0.0% 0.0 04-3049 87 85 0.02 0.02 1 1.1% 51.2 0 0.0% 0.0 04-3069 59 101 0.01 0.02 0 0.0% 0.0 0 0.0% 0.0 04-3072 87 47 0.02 0.01 0 0.0% 0.0 0 0.0% 0.0 04-3100 104 108 0.02 0.02 1 1.0% 48.2 2 1.9% 91.2 37-3018 429 424 0.37 0.35 1 0.2% 2.7 2 0.5% 5.6 37-3041 31 29 0.03 0.03 1 3.2% 34.8 1 3.4% 38.9 SD-004-0210 294 295 0.06 0.06 2 0.7% 31.0 0 0.0% 0.0 SD-004-0764 616 151 0.12 0.03 1 0.2% 8.5 0 0.0% 0.0 SD-039-0673 818 788 0.73 0.70 8 1.0% 10.9 7 0.9% 10.0 SD-050-0437 121 119 0.03 0.03 0 0.0% 0.0 4 3.4% 158.2 All trials 3111 2705 1.51 1.39 15 0.6% 9.9 16 0.6% 11.5 0.88 (0.43;1.78) Rate per TTY
Studycode Reporting of pneumonia SAEs in trials comparing high-dose and low-dose budesonide on HIGH BUD on LOW BUD reporting pneumonia SAEs HIGH BUD LOW BUD 04-3000 79 79 0 0 04-3020 196 184 0 0 04-3021 91 93 0 0 04-3023 99 202 0 0 04-3049 87 85 1 0 04-3069 59 101 0 0 04-3072 87 47 0 0 04-3100 104 108 0 1 37-3018 429 424 0 0 37-3041 31 29 0 0 SD-004-0210 294 295 0 0 SD-004-0764 616 151 0 0 SD-039-0673 818 788 1 0 SD-050-0437 121 119 0 0 reporting pneumonia SAEs All trials 3111 2705 2 0.06% 1 0.04%
Table E5 Reporting of pneumonia AEs in trials comparing budesonide and fluticasone Studycode on BUD on FLUT Exposure on BUD (TTY) Exposure on FLUT (TTY) (%) of patients reporting pneumonia AEs BUD FLUT HR (95% CI) Rate per TTY (%) of patients reporting pneumonia AEs BN-00P-0070 96 101 0.02 0.02 0 0.0% 0.0 0 0.0% 0.0 D5890C00002 1151 1153 0.55 0.54 9 0.8% 16.4 7 0.6% 12.9 SD-039-0618 168 176 0.04 0.04 1 0.6% 26.5 0 0.0% 0.0 SD-039-0686 434 224 0.22 0.12 10 2.3% 44.6 6 2.7% 50.7 SD-039-0735 2202 1119 0.99 0.51 13 0.6% 13.1 8 0.7% 15.8 All trials 4051 2773 1.82 1.23 33 0.81% 18.1 21 0.76% 17.1 1.01 (0.58;1.75) Rate per TTY Studycode Reporting of pneumonia SAEs in trials comparing budesonide and fluticasone on BUD on FLUT (%) of patients reporting pneumonia SAEs BUD FLUT (%) of patients reporting pneumonia SAEs BN-00P-0070 96 101 0 0.0% 0 0.0% D5890C00002 1151 1153 2 0.17% 2 0.17% SD-039-0618 168 176 0 0.0% 0 0.0% SD-039-0686 434 224 1 0.23% 0 0.0% SD-039-0735 2202 1119 5 0.22% 3 0.27% All trials 4051 2773 8 0.20% 5 0.18%
Table E6 Statistical analysis of time to first pneumonia, sex and race as separate factors Variable Contrast Event/N Ratio 95% C.I. P-value Factor test Sex F vs M 101/15089 vs 134/18407 1.071 0.825 1.391 0.6070 0.6070 Race 0.7940 Black vs Cauc 2/899 vs 175/23681 0.457 0.113 1.843 0.2709 Oriental vs Cauc 34/3602 vs 175/23681 1.103 0.764 1.593 0.6013 Other* vs Cauc 11/1788 vs 175/23681 0.899 0.488 1.653 0.7311 Missing **vs Cauc 13/3526 vs 175/23681 0.971 0.547 1.724 0.9199 * Other race than caucasian, black or oriental ** Note that a total of 3526 patients were classified with a missing code. The latter group was mainly from older studies where the race had not been collected.