Proton pump inhibitor for non-erosive reflux disease: A meta-analysis

Table 1 Details of these studies n (%)

First author	Country	Year	Study design	Arms of treatment	Age (yr)	Gender (M/F)	n	BMI	Helicobacter pylori infection	Hiatal hernia	Smokers	Alcohol users	Therapeutic duration	Adverse events	Effective
Talley	United	2002	RCT	Esomeprazole 20 mg	48.0	135/158	293	-	90	89	-	-	6 mo	5	101 (34.6)
et al[23]	Kingdom			Esomeprazole 40 mg	48.4	135/147	282	-	101	92	-	-		6	84 (29.7)
				placebo	48.2	58/88	146	-	57	39	-	-		2	30 (17.8)
Juul-Hansen	Norway	2009	RCT	Lansoprazole 15 mg	47.5	11/21	32	26.4	6	10	8	-	6 mo	2	28 (87.5)
et al[24]				Ranitidine 75 mg	48.0	12/19	31	25.2	6	6	8	-		4	14 (45.2)
Kinoshita	Japan	2011	RCT	Rabeprazole 5 mg	46.3	38/55	93	22.4	35	-	-	-	4 wk	32	36 (35.0)
et al[25]				Rabeprazole 10 mg	46.8	50/51	101	23.2	42	-	-	-		37	44 (44.0)
				placebo	49.7	40/51	91	23.2	44	-	-	-		32	19 (21.0)
Kobeissy	Lebanon	2012	RCT	Rabeprazole 20 mg	45.4	16/28	44	-	-	-	-	-	4 wk	-	20 (45.5)
et al[26]				Ranitidine 300 mg	45.1	16/23	39	-	-	-	-	-		-	17 (43.6)
Talley	Australia	2001	RCT	Esomeprazole 20 mg	49.0	94/76	170	-	64	65	-	-	6 mo	11	146 (85.0)
et al[27]				placebo	49.0	98/74	172	-	57	75	-	-		13	83 (48.0)
Fass	United States	2009	RCT	Dexlansoprazole 30 mg	47.6	84/231	315	29.0	95	-	72	162	4 wk	6	173 (54.9)
et al[28]				Dexlansoprazole 60 mg	47.5	106/209	315	29.6	90	-	57	181		8	157 (50.0)
				placebo	47.6	84/233	317	29.1	89	-	52	182		1	59 (18.5)
Fujiwara	Japan	2005	RCT	Omeprazole 20 mg	55.0	20/30	50	22.8	22	14	6	18	4 wk	-	43 (86.0)
et al[29]				Famotidine 20 mg	56.6	23/25	48	22.2	22	11	11	17		-	36 (75.0)
Nakamura	Japan	2010	RCT	Omeprazole 20 mg	51.4	8/9	17	-	5	9	-	-	8 wk	0	13 (75.0)
et al[30]				Roxitidine 75 mg	48.6	9/7	16	-	7	8	-	-		0	11 (70.6)
Miner	United States	2002	RCT	Rabeprazole 10 mg	44.4	28/37	65	30.9	17	-	22	29	4 wk	14	19 (29.3)
et al[31]				Rabeprazole 20 mg	45.5	25/33	68	30.3	24	-	21	26		17	19 (28.3)
				placebo	46.1	24/26	70	30.2	28	-	22	30		18	2 (3.4)
Armstrong	Canada	2001	RCT	Pantoprazole 40 mg	47.1	57/49	106	-	16	-	66	71	4 wk	32	41 (52.8)
et al[32]				Nizatidine 150 mg	47.6	51/51	102	-	20	-	64	67		39	33 (42.9)
Lind	Sweden	1999	RCT	Omeprazole 10 mg	52.0	53/86	139	-	-	76	24	88	4 wk	-	116 (83.5)
et al[33]				Omeprazole 20 mg	51.0	65/77	142	-	-	72	43	85		-	99 (69.7)
				placebo	48.0	61/82	143	-	-	74	57	97		-	80 (55.9)
Richter	United States	2000	RCT	Lansoprazole 15 mg	44.9	115/161	276	-	66	-	75	132	8 wk	-	37 (13.4)
et al[34]				Lansoprazole 30 mg	45.1	122/155	277	-	66	-	88	129		-	97 (35.0)
				Ranitidine 150 mg	45.2	108/170	278	-	63	-	69	126		-	64 (23.0)
				placebo	46.3	30/37	67	-	9	-	19	35		-	10 (14.7)
Bytzer	Denmark	2004	RCT	Rabeprazole 10 mg	47.0	123/156	279	26.0	100	-	-	-	6 mo	113	241 (86.4)
et al[12]				placebo	48.0	57/82	139	27.0	52	-	-	-		47	94 (67.6)
Kahrilas	United States	2009	RCT	Rabeprazole 20 mg	43.1	40/89	129	29.3	42	-	35	58	4 wk	-	42 (32.4)
et al[35]				placebo	44.0	45/87	132	30.0	40	-	36	51		-	5 (3.8)
Lind	Sweden	1997	RCT	Omeprazole 10 mg	49.0	89/110	199	-	-	-	60	133	4 wk	6	98 (49.2)
et al[33]				Omeprazole 20 mg	50.0	66/139	205	-	-	-	46	121		11	125 (61.0)
				placebo	51.0	51/54	105	-	-	-	22	64		7	25 (23.8)
Uemura	Japan	2008	RCT	Omeprazole 10 mg	44.4	47/49	96	-	37	5	-	-	4 wk	12	44 (45.8)
et al[36]				Omeprazole 20 mg	43.8	53/40	93	-	49	9	-	-		22	43 (46.2)
				placebo	42.4	53/49	92	-	32	2	-	-		17	22 (23.9)
Talley	Australia	2002	RCT	Pantoprazole 20 mg	53.0	78/76	154	28.9	-	-	65	28	6 mo	86	109 (71.0)
et al[27]				Ranitidine 150 mg	52.0	83/70	153	28.4	-	-	61	30		83	86 (56.0)

RCT: Randomized controlled trials; M: Male; F: Female; BMI: Body mass index.

Table 2 Results of univariate meta-regression analysis exploring factors influencing efficacy and adverse rate of proton pump inhibitor for non-erosive reflux disease

Factors	Efficacy		Adverse rate
	Coefficient	P value	Coefficient	P value
Age	0.0177315	0.170	0.0075041	0.665
Gender	-0.2213605	0.186	0.0209630	0.894
BMI	-0.0127987	0.484	-0.0044024	0.808
n	-0.0005643	0.154	-0.0001338	0.733
Helicobacter pylori infection	-0.6007750	0.217	0.1326016	0.736
Hiatal hernia	0.9702707	0.030	-0.4392244	0.081
Smoking	-0.2591453	0.528	0.5030517	0.245
Drinking	0.3296374	0.303	-0.6776039	0.053
Therapeutic duration	0.0008200	0.857	-0.0015192	0.722
Dose	-0.0026090	0.414	0.0003684	0.897

BMI: Body mass index.

Table 3 Quality of outcomes according to Grade system

Outcome	Study design	Risk of bias	Inconsistecy	Indirectness	Imprecision	Publication bias	Quality of evidence
PPI vs H2RA on the rate of symptomatic relief	RCT	Serious1	No	No	No	Serious4	Low
Long-duration subgroup	RCT	Serious2	No	No	No	Serious4	Low
Short-duration subgroup	RCT	Serious2	No	No	No	Serious4	Low
High-dose subgroup	RCT	Serious2	No	No	No	Serious4	Low
Lose-dose subgroup	RCT	Serious2	No	No	No	Serious4	Low
PPI vs placebo on the rate of symptomatic relief	RCT	No	Series3	No	No	No	Moderate
Long-duration subgroup	RCT	No	Series3	No	No	No	Moderate
Short-duration subgroup	RCT	No	No	No	No	No	High
High-dose subgroup	RCT	No	No	No	No	No	High
Lose-dose subgroup	RCT	No	Series3	No	No	No	Moderate
PPI vs H2RA on the rate of adverse events	RCT	Serious2	No	No	No	Serious4	Low
PPI vs placebo on the rate of adverse events	RCT	No	Series3	No	No	No	Moderate
Long-duration subgroup	RCT	No	No	No	No	No	High
Short-duration subgroup	RCT	No	Series3	No	No	No	Moderate
High-dose subgroup	RCT	No	Series3	No	No	No	Moderate
Lose-dose subgroup	RCT	No	No	No	No	No	High
Overall efficacy of PPI against NERD	RCT	Serious1	Series3	No	No	No	Low
Long-duration subgroup	RCT	Serious2	Series3	No	No	No	Low
Short-duration subgroup	RCT	Serious2	No	No	No	No	Moderate
High-dose subgroup	RCT	Serious2	Series3	No	No	No	Low
Lose-dose subgroup	RCT	Serious2	No	No	No	No	Moderate
Overall safety of PPI against NERD	RCT	Serious2	Series3	No	No	Serious4	Low
Long-duration subgroup	RCT	Serious2	Series3	No	No	Serious4	Low
Short-duration subgroup	RCT	No	No	No	No	Serious4	High
High-dose subgroup	RCT	No	Series3	No	No	Serious4	Moderate
Lose-dose subgroup	RCT	Serious2	No	No	No	Serious4	Moderate

¹Allocation concealment and blind method were not offered which resulted in very serious bias;

²Allocation concealment and blind method were not offered which resulted in very serious bias mild bias;

³The assessing standard of outcomes maybe contribute to the heterogeneity;

⁴Publication bias may be existed. RCT: Randomized controlled trials; NERD: Non-erosive reflux disease; PPI: Proton pump inhibitor; H₂RA: H₂ receptor antagonists.