Vascular Overviews Group Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials Vascular Overviews Group 15-March-2018

PRISMA Diagram 32826 articles identified 10260 through MEDLINE search 22555 through EMBASE search 11 through manual search 8155 duplicates removed 24671 identified for screening 22035 excluded on the basis of title and abstract 2636 full-text articles assessed for eligibility 1286 articles (including 1286 trials) excluded, plus an additional 17 trials reported in articles that also contained an eligible trial. These 1303 trials were excluded for the following primary reasons: - 229 trials not randomised - 92 trials too short (<2 weeks for prevention or healing trials) - 411 unsuitable or confounded comparison - 508 different-dose or within-class comparison - 20 trials of children (<18 years) - 13 trials in critical care settings - 10 review articles - 5 ongoing trials - 4 variceal indication - 11 articles unobtainable* 1350 eligible articles, including 1212 eligible trials† *Full-text copies of these articles were unobtainable from all available sources including the British Library. †Some trials were published in more than one article (and, conversely, a few articles reported results from more than one trial).

Gastroprotectant vs control Gastroprotectant vs gastroprotectant** Availability of data for measuring the effects of gastroprotectants   Prevention Trials Healing Trials Acute Bleeding Trials Trials (%) Participants (%) Gastroprotectant vs control Endoscopic ulcer* 162 (28) 31580 (29) 207 (89) 22086 (92) - Symptomatic ulcer* 73 (13) 21505 (19) Mortality+ 185 (32) 57472 (52) 43 (18) 6243 (26) 31 (86) 7596 (97) Further bleeding, endoscopy, surgery or transfusion 33 (92) 7662 (98) Bleeds, perforations or obstructions 115 (20) 41764 (38) No data available for any of the above outcomes 259 (45) 33122 (30) 18 (8) 1250 (5) 2 (6) 106 (1) Total 580 110626 233 24033 36 7826 Gastroprotectant vs gastroprotectant** 22 (14) 5781 (18) 150 (90) 25494 (90) 15 (9) 3199 (10) 61 (38) 10716 (33) 68 (41) 11739 (41) 16 (89) 3478 (96) 17 (94) 3518 (97) 41 (26) 8065 (24) 74 (46) 16813 (51) 14 (8) 2661 (9) 1 (6) 122 (3) 160 32959 167 28306 18 3640 * Duodenal, gastric or any (i.e, not subdivided). ** Only comparisons between two different class of gastroprotectants were included for analysis. + Cause-specific or total (i.e, all-cause) mortality. Trials with no events reported in both arms contributed to this table. In addition, there were 29 trials in which the number randomised was not reported.

Prevention trials - effects of gastroprotectants on endoscopic ulcers 0.1 0.25 0.5 1 2 Prevention trials - effects of gastroprotectants on endoscopic ulcers No. Events/Patients (%) Allocated GPT control Odds Ratio (95 or 99% CI) Less likely with GPT More likely Any PPI 29 314/6541 (4.8%) 937/4912 (19.1%) 0.20 (0.17 - 0.23) P A 22 228/3427 (6.7%) 435/2532 (17.2%) 0.26 (0.20 - 0.32) H2RA 105 1347/8074 (16.7%) 2298/6187 (37.1%) 0.32 (0.28 - 0.35) Any GPT 152 1889/18042 (10.5%) 3502/13255 (26.4%) 0.27 (0.25 - 0.29) p<0.0001 (Heterogeneity c = 39.5, p<0.0001) Duodenal 59/3846 (1.5%) 286/3042 (9.4%) 0.14 (0.10 - 0.19) PA 17 96/3187 (3.0%) 132/2324 (5.7%) 0.41 (0.28 - 0.61) 81 1008/6939 (14.5%) 1709/5083 (33.6%) 0.29 (0.26 - 0.34) 116 1163/13972 (8.3%) 2085/10073 (20.7%) 0.27 (0.25 - 0.30) 39.0, p<0.0001) Gastric 19 212/4150 (5.1%) 501/3356 (14.9%) 0.26 (0.21 - 0.32) 127/3323 (3.8%) 310/2440 (12.7%) 0.22 (0.16 - 0.29) 39 327/3857 (8.5%) 572/2845 (20.1%) 0.39 (0.32 - 0.48) 74 666/11330 (5.9%) 1257/8277 (15.2%) 0.30 (0.27 - 0.33) 25.0, p<0.0001) 99% or 95% CI c c

Prevention trials - effects of gastroprotectants on symptomatic ulcers 0.1 0.25 0.5 1 2 Prevention trials - effects of gastroprotectants on symptomatic ulcers No. Events/Patients (%) Allocated GPT control Odds Ratio (95 or 99% CI) Less likely with GPT More likely Any PPI 8 28/2585 (1.1%) 152/2587 (5.9%) 0.15 (0.09 - 0.23) PA 4 14/4619 (0.3%) 41/4673 (0.9%) 0.38 (0.18 - 0.79) H2RA 39 481/2653 (18.1%) 943/2184 (43.2%) 0.27 (0.23 - 0.32) Any GPT 51 523/9857 (5.3%) 1136/9444 (12.0%) 0.25 (0.22 - 0.29) p<0.0001 (Heterogeneity = 12.7, p=0.0018) Duodenal 1/60 (1.7%) 44/63 (69.8%) 0.05 (0.02 - 0.15) 7/4404 (0.2%) 14/4439 (0.3%) 0.52 (0.15 - 1.75) 29 404/2204 (18.3%) 786/1734 (45.3%) 0.26 (0.21 - 0.31) 31 412/6668 (6.2%) 844/6236 (13.5%) 0.25 (0.21 - 0.28) 19.6, p<0.0001) Gastric - 7/4444 (0.2%) 17/4482 (0.4%) 0.44 (0.14 - 1.38) 6 64/228 (28.1%) 97/224 (43.3%) 0.48 (0.28 - 0.83) 71/4672 (1.5%) 114/4706 (2.4%) 0.47 (0.32 - 0.69) 0.0, p=0.85) 99% or 95% CI c c c

0.1 0.5 1 2.5 Prevention trials - effects of gastroprotectants on ulcer complications and all-cause mortality No. Events/Patients (%) Allocated GPT control Odds Ratio (95 or 99% CI) Less likely with GPT More likely Bleeds PPI 18 14/5910 (0.2%) 88/4937 (1.8%) 0.21 (0.12 - 0.36) PA 3 33/4464 (0.7%) 53/4489 (1.2%) 0.63 (0.35 - 1.12) H2RA 29 43/3631 (1.2%) 84/2779 (3.0%) 0.49 (0.30 - 0.80) Any GPT 49 90/14139 (0.6%) 221/12130 (1.8%) 0.40 (0.32 - 0.50) p<0.0001 (Heterogeneity 2 = 15.3, p=0.0005) Perforations 1/1917 (0.1%) 2/981 (0.2%) 0.31 (0.01 - 13.74) 1/4700 (0.0%) 8/4594 (0.2%) 0.19 (0.03 - 1.37) 0/49 (0.0%) 1/50 (2.0%) 5 2/6666 (0.0%) 10/5470 (0.2%) 0.21 (0.06 - 0.81) p=0.0089 0.2, p=0.92) Obstructions 1/1938 (0.1%) 1/1935 (0.1%) 0/4404 (0.0%) 3/4439 (0.1%) 0.14 (0.00 - 5.20) 3/394 (0.8%) 6/404 (1.5%) 0.52 (0.07 - 3.68) 4 4/6736 (0.1%) 10/6778 (0.1%) 0.43 (0.13 - 1.42) p=0.12 1.4, p=0.49) All-cause mortality 37/7471 (0.5%) 31/5352 (0.6%) 1.01 (0.50 - 2.05) 17/4853 (0.4%) 20/4752 (0.4%) 0.81 (0.32 - 2.00) 420/3520 (11.9%) 445/2959 (15.0%) 0.83 (0.61 - 1.13) 51 474/15844 (3.0%) 496/13063 (3.8%) 0.85 (0.69 - 1.04) p=0.11 0.5, p=0.77) 99% or 95% CI c c c c

ulcers, bleeds and all-cause mortality, subdivided by use of NSAIDs 0.1 0.25 0.5 1 2.5 Prevention trials - effects of gastroprotectants on endoscopic and symptomatic ulcers, bleeds and all-cause mortality, subdivided by use of NSAIDs No. tNSAID/ COXIB/ aspirin use Events/Patients (%) Allocated GPT control Odds Ratio (95 or 99% CI) Less likely with GPT More likely Any endoscopic ulcer NSAID use 51 660/11409 (5.8%) 1220/8068 (15.1%) 0.27 (0.24 - 0.31) No NSAID use 34 397/2089 (19.0%) 784/1674 (46.8%) 0.26 (0.21 - 0.32) T otal 85 1057/13498 (7.8%) 2004/9742 (20.6%) 0.27 (0.25 - 0.29) p<0.0001 (Heterogeneity 2 = 0.2, p=0.62) Any symptomatic ulcer 9 23/6871 (0.3%) 95/6917 (1.4%) 0.28 (0.17 - 0.46) 17 162/1369 (11.8%) 449/1127 (39.8%) 0.21 (0.16 - 0.27) 26 185/8240 (2.2%) 544/8044 (6.8%) 0.22 (0.18 - 0.26) 2.0, p=0.16) Bleeds 21 50/11706 (0.4%) 146/10106 (1.4%) 0.35 (0.24 - 0.52) 10 8/648 (1.2%) 24/555 (4.3%) 0.28 (0.10 - 0.79) 31 58/12354 (0.5%) 170/10661 (1.6%) 0.34 (0.26 - 0.45) 0.3, p=0.56) All-cause mortality 38/11944 (0.3%) 34/9826 (0.3%) 0.95 (0.50 - 1.81) 5 5/466 (1.1%) 2/462 (0.4%) 2.34 (0.25 - 21.96) 22 43/12410 (0.3%) 36/10288 (0.3%) 1.03 (0.64 - 1.65) p=0.90 1.3, p=0.25) 99% or 95% CI c c c c

Healing trials - effects of gastroprotectants on ulcer healing 0.5 1 2 5 Healing trials - effects of gastroprotectants on ulcer healing No. Events/Patients (%) Allocated GPT control Odds Ratio (95 or 99% CI) Less likely with GPT More likely Endoscopic ulcer healing PPI 24 1650/1925 (85.7%) 650/1033 (62.9%) 5.22 (4.00 - 6.80) PA 37 1501/2452 (61.2%) 751/1729 (43.4%) 2.27 (1.91 - 2.70) H2RA 148 5714/7533 (75.9%) 2676/5670 (47.2%) 3.80 (3.44 - 4.20) Any GPT 207 8865/11910 (74.4%) 4050/8373 (48.4%) 3.49 (3.28 - 3.72) p<0.0001 (Heterogeneity = 62.0, p<0.0001) Endoscopic duodenal ulcer healing 17 950/1095 (86.8%) 426/672 (63.4%) 5.91 (4.20 - 8.33) 19 866/1458 (59.4%) 382/953 (40.1%) 2.21 (1.77 - 2.77) 97 3924/5154 (76.1%) 1786/3929 (45.5%) 4.09 (3.63 - 4.61) 131 5740/7707 (74.5%) 2567/5495 (46.7%) 3.73 (3.45 - 4.03) 53.4, p<0.0001) Endoscopic gastric ulcer healing 4 648/774 (83.7%) 179/306 (58.5%) 4.47 (2.87 - 6.97) 16 435/698 (62.3%) 252/577 (43.7%) 2.60 (1.87 - 3.61) 45 1306/1675 (78.0%) 773/1421 (54.4%) 3.05 (2.47 - 3.76) 65 2389/3147 (75.9%) 1204/2304 (52.3%) 3.09 (2.73 - 3.50) 6.9, p=0.0325) 99% or 95% CI c c c

Acute UGI bleeding treatment trials - effects of gastroprotectants on 0.25 0.5 1 2 Acute UGI bleeding treatment trials - effects of gastroprotectants on further bleeding, need for blood transfusion and endoscopic interventions No. Events/Patients (%) Allocated GPT control Odds Ratio (95 or 99% CI) Less likely with GPT More likely Further bleeding PPI 12 192/2234 (8.6%) 311/2198 (14.1%) 0.57 (0.44 - 0.73) H2RA 18 320/1487 (21.5%) 376/1478 (25.4%) 0.79 (0.63 - 1.00) Any GPT 30 512/3721 (13.8%) 687/3676 (18.7%) 0.68 (0.60 - 0.78) p<0.0001 (Heterogeneity = 6.5, p=0.0107) Blood transfusion 5 449/974 (46.1%) 542/967 (56.0%) 0.67 (0.52 - 0.85) 266/434 (61.3%) 259/426 (60.8%) 1.01 (0.70 - 1.48) 10 715/1408 (50.8%) 801/1393 (57.5%) 0.75 (0.65 - 0.88) p=0.0003 6.2, p=0.0130) Endoscopic interventions 8 140/1890 (7.4%) 234/1906 (12.3%) 0.56 (0.42 - 0.75) - 0.56 (0.45 - 0.70) 99% or 95% CI c c

Acute UGI bleeding treatment trials - effects of gastroprotectants on 0.25 0.5 1 2 Acute UGI bleeding treatment trials - effects of gastroprotectants on surgery and all-cause mortality No. Events/Patients (%) Allocated GPT control Odds Ratio (95 or 99% CI) Less likely with GPT More likely Surgery PPI 12 120/2234 (5.4%) 187/2198 (8.5%) 0.62 (0.45 - 0.84) H2RA 15 197/1331 (14.8%) 239/1349 (17.7%) 0.81 (0.61 - 1.07) An y GPT 27 317/3565 (8.9%) 426/3547 (12.0%) 0.72 (0.61 - 0.84) p<0.0001 (Heterogeneity = 2.9, p=0.09) All-cause mortality 84/2234 (3.8%) 86/2198 (3.9%) 0.98 (0.64 - 1.48) 17 95/1526 (6.2%) 113/1525 (7.4%) 0.83 (0.57 - 1.22) 29 179/3760 (4.8%) 199/3723 (5.3%) 0.90 (0.72 - 1.11) p=0.31 0.5, p=0.46) 99% or 95% CI c c