Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors

Figures & data

Table 1 Included studies of gastro-protection

Study	Comparisons		NSAID	Number	Mean age	Primary or secondary	Follow-up times (months)
	Intervention	Comparator
Misoprostol
Graham^Citation30	misoprostol 400 μg/day misoprostol 800 μg/day	placebo	ibuprofen, piroxicam, naproxen	421	59	primary	1, 2, 3
Agrawal^Citation21	misoprostol 800 μg/day	placebo	various	356	60	primary	3
Chandrasekaran^Citation26	misoprostol 600 μg/day	placebo	various	90	39	primary	1
Saggioro^Citation39	misoprostol 800 μg/day	placebo	various	166	56	primary	1
Bolten^Citation24	misoprostol 400–600 μg/day	placebo	diclofenac	361	60	primary	1
Verdickt^Citation42	misoprostol 400–600 μg/day	placebo	diclofenac	339	53	primary	3
Melo^Citation14	misoprostol 400 μg/day + diclofenac	placebo + piroxicam	piroxicam	643	60	primary	1
Graham^Citation31	misoprostol 800	placebo	various	643	59	primary	3
Henriksson^Citation34	misoprostol 600 μg/day	placebo	naproxen, ibuprofen, aspirin	40	60	primary	1
Roth^Citation38	misoprostol 800	placebo	ibuprofen	113	53 and 60	primary	3
Delmas^Citation28	misoprostol 400 μg/day misoprostol 800 μg/day	placebo	various	256	54	primary	1
Elliott^Citation29	misoprostol 600–800 μg/day	placebo	various	83	65	primary	3, 6, 12
Agrawal^Citation22	misoprostol 400–600 μg/day	placebo	diclofenac	384	57	secondary	3, 6, 12
Raskin^Citation36	misoprostol 400 μg/day misoprostol 600 μg/day misoprostol 800 μg/day	placebo	various	1618	58	primary	3
Silverstein^Citation40	misoprostol 800 μg/day	placebo	various	8843	68	primary	24
Bocanegra^Citation23	misoprostol 200 μg bid misoprostol 200 μg tid	placebo	diclofenac	481	62	primary	1
Chan^Citation25	misoprostol 200 bid	nabumetone	naproxen	90	74	secondary	6
H2 antagonists
Berkowitz^Citation43	ranitidine 150 mg bid	placebo	aspirin	50	28.5	primary	1
Roth^Citation140	cimetidine 400 mg/day	placebo	various	26	nd	primary	10
Ehsanullah^Citation44	ranitidine 150 mg bid	placebo	various	297	57	primary	1, 2
Robinson^Citation46	ranitidine 150 mg bid	placebo	various	144	48	primary	1, 2
Swift^Citation50	ranitidine 150 mg bid	placebo	various	24	56.5	primary	4
Robinson^Citation45	ranitidine 150 mg/day	placebo		227	54.2	primary	1
Levine^Citation49	nizatidine 150 mg bid	placebo		496	56.9	primary	3
Simon^Citation51	nizatidine 150 mg/day	nizatidine 150 mg bid		237	58	secondary	3, 6
Taha^Citation47	famotidine 20 mg/day famotidine 40 mg/day	placebo	various	285	53.4	primary	1, 3, 6
Wolde^Citation53	ranitidine 300 bid	placebo		30	67 ranitidine, 58 placebo	secondary	12
Van Groenendael^Citation48	ranitidine 150 mg bid (Grp B)	placebo	various	36	52	primary	1
Hudson^Citation52	famotidine 40 mg bid	placebo	various	78	58	secondary	1, 3, 6
Proton pump inhibitors
Cullen^Citation55	omeprazole 20 mg/day	placebo		168		primary	6
Ekstrom^Citation56	omeprazole 20 mg/day	placebo	Various	177	58	primary	3
Hawkey^Citation85	misoprostol 400 μg/day omeprazole 20 mg/day	placebo	diclofenac, ketoprofen, naproxen	725	58	secondary	6
Bianchi Porro^Citation54	pantoprazole 40 mg/day	placebo	various	104	58	primary	3
Lai^Citation57	lansoprazole 30 mg	placebo	naproxen	43	69	secondary	2
Head to head comparisons
Valentini^Citation41	misoprostol 400 ranitidine 150 mg bid		diclofenac	61	59.2	44%	n/a
Raskin^Citation37	misoprostol 800 μg/day	ranitidine 150 mg bid	various	538	61	primary	2
Hawkey^Citation85	misoprostol 400 μg/day omeprazole 20 mg/day	placebo	diclofenac, ketoprofen, naproxen	725	58	secondary	6
Yeomans^Citation58	omeprazole 20 mg/day	ranitidine 150 mg bid	diclofenac, indomethacin, naproxen	425	56	30%	1, 2
Jensen^Citation35	misoprostol 200 μg qid	omeprazole 20 mg bid	various	46	n/a	secondary	6
Graham^Citation32	misoprostol 800 μg lansoprazole 15 mg lansoprazole 30 mg	placebo	various	537	60	secondary	3
Stupnicki^Citation13	misoprostol 400 μg/day	pantoprazole 40 mg/day	diclofenac	515	55	primary	1

Figure 1 Misoprostol vs placebo for the prevention of gastric ulcers – efficacy by dose.

Figure 2 Misoprostol vs placebo – drop-outs due to side-effects by dose.

Figure 3 H2RAs compared to placebo for the prevention of gastric ulcer. Analysis by dose in studies of 12 weeks or longer duration.

Figure 4 H2RAs compared to placebo for the prevention of duodenal ulcer. Analysis by dose in studies of 12 weeks or longer duration.

Figure 5 Proton pump inhibitors compared to placebo for the prevention of gastric ulcer in studies of 8 weeks or longer duration.

Figure 6 Proton pump inhibitors compared to placebo for the prevention of duodenal ulcer in studies of 8 weeks or longer duration.

Table 2 COX-2 included studies

Endpoint	Study	Comparisons		Number of patients	Mean age	Arthritis type	Follow-up
		Intervention	Comparator
Endoscopic ulcer	Celecoxib
	Emery^Citation70	200 mg bid	diclofenac 75 mg bid	655	55	RA	24 weeks
	FDA, 021	50 mg bid, 100 mg bid, 200 mg bid	naproxen 500 mg bid; placebo	1,108	unk	OA	2, 6, 12 weeks
	FDA, 071	200 mg bid	diclofenac 75 mg bid; ibuprofen 800 mg tid	1,097	unk	OA and RA	4, 8, 12 weeks
	Goldstein^Citation69	200 mg bid	naproxen 500 mg bid	537	57	OA and RA	4, 8, 12 weeks
	Simon^Citation71	100 mg bid, 200 mg bid, 400 mg bid	naproxen 500 mg bid; placebo	1,149	54	RA	2, 6, 12 weeks
	Rofecoxib
	Hawkey^Citation73	25 mg/day, 50 mg day	ibuprofen 800 mg tid	775	62	OA	6 weeks, 3, 6 months
	Hawkey^Citation74	50 mg/day	naproxen 500 mg bid; placebo	660	51.7	RA	3, 6, 9, 12 weeks
	Laine^Citation72	25 mg/day, 50 mg/day	ibuprofen 800 mg tid	742	62	OA	6 weeks, 3, 6 months
	Etoricoxib
	Hunt^Citation78 – multiple	120 mg/day	ibuprofen 800 mg tid	680	62	OA	3, 6, 9, 12 weeks
	Hunt^Citation79 – naproxen	120 mg/day	naproxen 500 mg bid; placebo	742	54	OA and RA	3, 6, 9, 12 weeks
	Valdecoxib
	FDA 047	20 mg bid, 40 mg bid	naproxen 500 mg bid	1,217	56	OA and RA	26 weeks
	FDA 063	10 mg/day, 20 mg/day	diclofenac 75 mg bid	784	unk	OA	1, 2, 4, 6 weeks
	Kivitz^Citation80	5 mg/day, 10 mg/day, 20 mg/day	naproxen 500 mg tid; placebo	1,019	60	OA	2, 6, 12 weeks
	Sikes^Citation76	10 mg/day, 20 mg/day	ibuprofen 800 mg tid; diclofenac 75 mg bid; placebo	1,052	60	OA	2, 6, 12 weeks
	Lumiracoxib
	Hawkey^Citation74,Citation113	lumiracoxib 200 mg/day, 400 mg/day; celecoxib 200 mg/day	ibuprofen 800 mg tid	1,042	58.7	OA	4, 8, 13 weeks
	Kivitz^Citation81	lumiracoxib 400 mg/day, 800 mg/day; celecoxib 200 mg bid	ibuprofen 800 mg tid	893	51.7	RA	8, 13 weeks
Clinical ulcer complications	Celecoxib
	Goldstein^Citation92 combined analysis study	25 mg bid to 400 mg bid	naproxen 500 mg bid; diclofenac 75 mg bid; ibuprofen 800 mg tid; placebo	11,008	59	OA and RA	2 to 24 weeks
	Silverstein^Citation82	400 mg bid	diclofenac 75 mg bid; iboprofen 800 mg tid	8,059	60	OA and RA	4, 13, 26 weeks (1 year FDA)
	Singh^Citation91 Success-1	100 mg bid, 200 mg bid	naproxen 500 mg bid	13,274	62	OA	6, 12 weeks
	Zhao^Citation89	50 mg bid, 100 mg bid, 200 mg bid	naproxen 500 mg bid: placebo	1,004	62.2	OA	2, 6, 12 weeks
	Rofecoxib
	Bombardier^Citation83	50 mg/day	naproxen 500 mg bid	8,076	58	RA	4, 8, 12 months
	Geusens^Citation90	25 mg/day, 50 mg/day	naproxen 500 mg bid; placebo	1,023	53.6	RA	2, 4, 8, 12 weeks
	Langman^Citation66 combined analysis study	25 mg/day, 50 mg/day	ibuprofen 800 mg tid; diclofenac 50 mg tid; nabumetone 1,500 mg/day	5,435	63	OA	6 weeks, 4, 6, 12, 24 months
	Lisse^Citation88	25 mg/day	naproxen 500 mg bid	5,597	63	OA	3, 6, 9, 12 weeks
	Saag^Citation101	12.5 mg/day, 25 mg/day	ibuprofen 800 mg tid	736	61	OA	2, 4, 6 weeks
	Saag^Citation101	12.5 mg/day, 25 mg/day	diclofenac 50 mg tid	693	62	OA	up to 1 year
	Etoricoxib
	Leung^Citation87	60 mg/day	naproxen 500 mg bid; placebo	501	63	OA	2, 4, 8, 12 weeks
	Ramey^Citation68 combined analysis study	5 to 120 mg/day	diclofenac 150 mg/day; naproxen 1000 mg/day; ibuprofen 2400 mg/day	5,441	56.7	OA and RA	up to 190 weeks
	Laine^Citation116 MEDAL	60 or 90 mg/day	diclofenac 150 mg/day	34 701	63	OA and RA	up to 36 months
	Valdecoxib
	Goldstein^Citation92 combined analysis study	5 to 80 mg/day	naproxen 500 mg bid; diclofenac 75 mg bid; ibuprofen 800 mg tid; placebo	7,445	58.1	OA and RA	up to 26 weeks
	Lumiracoxib
	Schnitzer^Citation86 TARGET	400 mg/day	naproxen 500 mg bid; ibuprofen 800 mg tid	18,244	63.5	OA	4, 13, 20, 26, 39, 52 weeks
	COX-2 and PPI
	Chan^Citation118	celecoxib 200 mg bid	diclofenac 75 mg + omeprazole 20 mg	287	67	OA and RA	24 weeks
	Lai^Citation119	celecoxib 200 mg daily	naproxen 250 mg tid + lansoprosol 30 mg	142	57	OA and RA	24 weeks
	Chan^Citation120	celecoxib 200 mg bid	celecoxib 200 mg bid; esomeprazole 20 mg bid	271	71	OA and RA	52 weeks
Tolerability	Celecoxib
	Bensen^Citation95	50 mg bid, 100 mg bid, 200 mg bid	naproxen 500 mg bid; placebo	1,003	62	OA	2, 6, 12 weeks
	Geba^Citation102	celecoxib 200 mg/day; rofecoxib 12.5 mg/day, 25 mg/day	acetaminophen 4000 mg/day	382	63	OA	2, 4, 6 weeks
	Kivitz^Citation122	100 mg/day, 200 mg/day, 400 mg/day	naproxen 500 mg bid; placebo	1,061	62.6	OA	2, 6, 12 weeks
	McKenna^Citation104	100 mg bid	diclofenac 50 mg tid; placebo	600	62	OA	2, 6 weeks
	McKenna^Citation105	celecoxib 200 mg/day; rofecoxib 25 mg/day	placebo	182	62	OA	3, 6 weeks
	Whelton^Citation103	celecoxib 200 mg/day; rofecoxib 25 mg/day	none	811	74	OA	1, 2, 6 weeks
	Williams^Citation94	200 mg/day	placebo	686	63	OA	2, 6 weeks
	Williams^Citation142	100 mg bid, 200 mg/day	placebo	718	61.5	OA	2, 6 weeks
	Rofecoxib
	Cannon^Citation98	12.5 mg/day 25 mg/day	diclofenac 50 mg tid	784	64	OA	up to 1 year
	Day^Citation97	12.5 mg/day, 25 mg/day	ibuprofen 800 mg tid	809	64	OA	2, 4, 6 weeks
	Ehrich^Citation99	25 to 125 mg/day	placebo	219	64	OA	1, 2, 4, 6 weeks
	Myllykangas^Citation121	12.5 mg/day	naproxen 500 mg bid	944	61.6	OA	2, 4, 6 weeks
	Schnitzer^Citation100	5 to 50 mg/day	placebo	658	55	RA	2, 4, 8 weeks
	Truitt^Citation96	12.5 mg/day, 25 mg/day	nabumetone 1500 mg/day; placebo	341	83	OA	1, 2, 4, 6 weeks
	Etoricoxib
	Collantes^Citation110	90 mg/day	naproxen 500 mg bid; placebo	891	52	RA	2, 4, 8, 12 weeks
	Gottesdiener^Citation108	Part 1: 5 to 90 mg/day Part 2: 30 mg/day, 60 mg/day 90 mg/day	Part 1: placebo Part 2: diclofenac 50 mg tid	617	60	OA	1, 2, 4, 6, 8, 14 weeks
	Matsumoto^Citation111	90 mg/day	naproxen 500 mg bid; placebo	816	56	RA	2, 4, 8, 12 weeks
	Wiesenhutter^Citation123	30 mg/day	ibuprofen 2400 mg/day; placebo	258	61.3	OA	1, 2, 4, 6 weeks
	Zacher^Citation109	60 mg/day	diclofenac 50 mg tid	516	63	OA	2, 4, 6, 8 weeks
	Valdecoxib
	Bensen^Citation107	10 mg/day, 20 mg/day, 40 mg/day	naproxen 500 mg bid; placebo	1,090	55	RA	4, 8, 12 months
	FDA 061	10 mg/day, 20 mg/day, 40 mg/day	naproxen 500 mg bid; placebo	1,093	57	RA	12 weeks
	Makarowski^Citation106	5 mg/day, 10 mg/day	naproxen 500 mg bid; placebo	513	68	OA	3 weeks
	Pavelka^Citation77	20 mg/day, 40 mg/day	diclofenac 75 mg bid	722	56	RA	2, 6, 8, 12, 18, 26 weeks
	Lumiracoxib
	Geusens^Citation124	200 mg/day, 400 mg/day	naproxen 500 mg bid	1,124	71	RA	2, 4, 13, 20, 26 weeks
	Grifka^Citation125	200 mg/day, 400 mg/day	placebo	594	61.9	OA	2, 4, 6 weeks
	Lehmann^Citation126	100 mg/day, 100 mg/day with 200 mg loading dose for first 2 weeks; celecoxib 200 mg/day	placebo	1,684	62.4	OA	2, 4, 8, 13 weeks
	Schnitzer^Citation86	50 mg bid, 100 mg bid, 200 mg bid, 400 mg bid	diclofenac 400 mg bid; placebo	583	60.3	OA	4 weeks
	Schnitzer^Citation86	50 mg bid, 100 mg bid, 200 mg bid, 400 mg bid	diclofenac 400 mg bid; placebo	569	54.4	RA	2, 6, 12 weeks
	Tannenbaum^Citation141	lumiracoxib 200 mg/day, 400 mg/day; celecoxib 200 mg/day	placebo	1,702	64.3	OA	2, 4, 8, 13 weeks

Abbreviations: unk, unknown; OA, osteoarthritis; PPI, protein pump inhibitors; RA, rheumatoid arthritis.

Figure 7 COX-2 vs tNSAID for endoscopic ulcers with any COX-2 dose.

Figure 8 Gastroduodenal ulcers analysed by individual COX-2 inhibitor compared to tNSAIDs.

Figure 9 POBs (perforation, obstruction or bleeding) with COX-2s vs tNSAIDs.

Figure 10 PUBs (POBs [perforation, obstruction or bleeding] or symptomatic ulcer) with COX-2s vs tNSAIDs.

Figure 11 Clinical ulcers (PUBs [perforation, obstruction, bleeding or the presence of a symptomatic ulcer]) with COX-2 + ASA vs tNSAID + ASA.

Note: This is a non-randomized comparison.

Figure 12 Clinical ulcers (PUBs [perforation, obstruction, bleeding or the presence of a symptomatic ulcer]) with COX-2 + ASA vs COX-2 alone.

Note: This is a non-randomized comparison.

Figure 13 Clinical ulcers (PUBs [perforation, obstruction, bleeding or the presence of a symptomatic ulcer]) with tNSAID + ASA vs tNSAID alone.

Note: This is a non-randomized comparison.

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