Meta-analysis of randomized controlled trials comparing standardclinical doses of omeprazole and lansoprazole in erosive oesophagitis

V. K. SHARMA*, G. I . LEONTIADIS  & C. W. HOWDENà*University of Arkansas for Medical Sciences, Little Rock, AR, USA;  `G. Papanikolaou' Hospital, Thessaloniki, Greece and

àNorthwestern University Medical School, Chicago, IL, USA

Accepted for publication 6 September 2000

INTRODUCTION

Proton pump inhibitors are the drugs of choice for the

treatment of erosive oesophagitis. In comparative

clinical trials and in meta-analyses, they have been

shown to be superior to H2-receptor antagonists in

healing oesophageal erosions and in relieving associated

symptoms.1 For the different classes of antisecretory

drugs, there is a statistically signi®cant linear relation-

ship between suppression of 24-h intragastric acidity

and oesophagitis healing rates.2 In one comparative

pharmacodynamic study, lansoprazole 30 mg o.d. pro-

duced a quantitatively greater degree of suppression of

intragastric acidity than omeprazole 20 mg.3 These

doses of the two drugs are typically used in the

treatment of erosive oesophagitis. Through the meta-

analysis of randomized controlled trials, we wanted to

determine whether the putative superior antisecretory

effect of lansoprazole had been translated into a

demonstrable advantage in healing rates.

MATERIALS AND METHODS

Using the MEDLINE and EMBASE databases, two of the

authors independently performed fully recursive

literature searches for randomized controlled trials

comparing omeprazole and lansoprazole in erosive

oesophagitis. We used `omeprazole', `lansoprazole',

and `oesophagitis' as text words and key words in the

SUMMARY

Background: Omeprazole and lansoprazole are used to

treat erosive oesophagitis in the respective daily doses of

20 and 30 mg.

Aim: To investigate, by meta-analysis, whether treat-

ment with lansoprazole 30 mg increases erosive

oesophagitis healing rates over omeprazole 20 mg.

Methods: We searched for randomized, double-blind

trials comparing omeprazole 20 mg and lansoprazole

30 mg in endoscopically diagnosed erosive oesophagitis.

After assessing for homogeneity, non-heterogeneous

trials were combined and pooled healing rates derived.

We calculated the relative bene®t increase, absolute

bene®t increase and number needed to treat.

Results: Six trials without signi®cant heterogeneity met

predetermined inclusion criteria. By per protocol ana-

lysis, pooled healing rates for omeprazole 20 mg and

lansoprazole 30 mg were, respectively, 74.7% and

77.7% after 4 weeks and 87.0% and 88.7% after

8 weeks. The corresponding ®gures by intention-

to-treat analysis were 70.8% and 72.7% after 4 weeks

and 81.8% and 83.3% after 8 weeks. In each analysis

the absolute bene®t increase for lansoprazole was small

and its 95% con®dence interval encompassed zero.

Conclusion: Lansoprazole 30 mg produces healing rates

in erosive oesophagitis that are not statistically signi®-

cantly different to those of omeprazole 20 mg.

Correspondence to: Dr C. W. Howden, Northwestern University, North-

western Center for Clinical Research, 680 N. Lake Shore Drive, Suite

# 1220, Chicago, IL 60611, USA.E-mail: c-howden@nwu.edu

Aliment Pharmacol Ther 2001; 15: 227±231.

Ó 2001 Blackwell Science Ltd 227

search. We did not con®ne our search to publications in

the English language. We also included abstracts

presented at major meetings. We supplemented the

search by contacting the US manufacturers of ome-

prazole and lansoprazole to determine whether they had

any unpublished data.

For a trial to be included in the meta-analysis, it had to

have compared omeprazole 20 mg o.d. and lansopraz-

ole 30 mg o.d. in the treatment of patients with

endoscopically documented erosive oesophagitis. Con-

trolled trials had to be randomized and double-blinded.

Healing rates, determined by repeat endoscopy, had to

be reported after 4 and/or 8 weeks by per protocol and/

or intention-to-treat analysis. Dual publications were

excluded. If multiple publications of the same data were

retrieved, only the most recent version was included.

Each author reviewed all randomized controlled trials

independently to assess their suitability for inclusion in

the meta-analysis. Disputes concerning trial inclusion

or exclusion were settled by consensus.

We assessed homogeneity among randomized con-

trolled trials according to the Breslow±Day method.4 We

speci®ed the lansoprazole healing rate as the `experi-

mental event rate' and the omeprazole healing rate as

the `control event rate'.5 We calculated the relative

bene®t increase as (experimental event rate±control

event rate)/control event rate, and absolute bene®t

increase as experimental event rate±control event rate.

The number needed to treat was calculated as the

inverse of the absolute bene®t increase.5 In this context,

the number needed to treat represents the additional

number of patients who would require to be treated

with lansoprazole rather than omeprazole to heal

erosive oesophagitis. These values were determined for

individual trials and for the pooled data, according to

the established methods described elsewhere.5, 6 The

95% con®dence interval (CI) for the absolute bene®t

increase was calculated for each trial and for the pooled

data. The upper and lower limits of the 95% CI for the

number needed to treat were de®ned, respectively, as

the inverses of the lower and upper limits of the 95% CI

of the absolute bene®t increase. When the 95% CI of the

absolute bene®t increase encompassed zero, the number

needed to treat, corresponding to the lower limit of the

95% CI on the absolute bene®t increase, was expressed

in the form of a number needed to harm.5 Otherwise, a

negative value would have been generated which, for a

number needed to treat, would be an arguably non-

sensical result, as discussed elsewhere.7

We also determined pooled Mantel±Haenszel odds

ratios (ORM-H) for the probability of healing on lansop-

razole rather than on omeprazole for the pooled per

protocol and intention-to-treat data after 4 and 8 weeks

of treatment.

RESULTS

We initially identi®ed nine randomized controlled

trials.8±16 We excluded one because it had not been

conducted according to a double-blind design.14

Another was excluded because it reported healing rates

after 3 weeks rather than 4 or 8 weeks.15 We excluded

a third because it compared lansoprazole 30 mg with

omeprazole 40 mg.16 Of the six trials remaining, there

was complete agreement among the authors regarding

their suitability for inclusion.8±13 All were published in

the English language except for one, which was

published in French.12 Five randomized controlled trials

had been performed in Western Europe;8, 9, 11±13 the

sixth in the United States.10 Four were available as full

peer-reviewed publications;9±12 two as abstracts

only.8, 13

Per protocol analysis

Four randomized controlled trials reported the results of

a per protocol analysis after 4 weeks; the details are

listed in Table 1.9±12 Since there was no signi®cant

heterogeneity among these randomized controlled trials

(P � 0.89), they were pooled. Pooled healing rates were

77.7% and 74.7% for lansoprazole 30 mg and ome-

prazole 20 mg, respectively. The relative bene®t

increase was 4.1% and the absolute bene®t increase

was 3.1% (95% CI: ± 1.1±7.3). Figure 1 displays the

absolute bene®t increase and 95% CI for individual

Table 1. Summary results for four randomized controlled trials

reporting per protocol analyses at 4 weeks' treatment

Lansoprazole 30 mg Omeprazole 20 mg

Reference n

Healing

rate (%) n

Healing

rate (%)

Hatlebakk9 86 66.3 85 63.5

Castell10 396 83.3 411 82.0

Mee11 233 70.0 240 63.3

Petite12 53 88.7 53 86.8

Pooled 768 77.7 789 74.7

228 V. K. SHARMA et al.

Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 227±231

trials and the pooled data. The number needed to treat

was 32.4 (95% CI: 13.7 to number needed to harm

87.4). The pooled ORM-H for endoscopic healing on

lansoprazole rather than omeprazole was 1.19 (95% CI:

0.94±1.50).

Four randomized controlled trials had reported healing

rates by per protocol analysis after 8 weeks; details are

listed in Table 2.9±11, 13 There was no signi®cant

heterogeneity among the randomized controlled trials

(P � 0.66), which were therefore pooled. Pooled heal-

ing rates were 88.7% for lansoprazole 30 mg and

87.0% for omeprazole 20 mg. The relative bene®t

increase was 2.0% and the absolute bene®t increase

was 1.7% (95% CI: ± 1.5±5). Figure 2 displays the

absolute bene®t increase and 95% CI for individual

trials and the pooled data. The number needed to treat

was 57.5 (95% CI: 20 to number needed to harm 65.5).

The pooled ORM-H for endoscopic healing on lansopraz-

ole rather than omeprazole was 1.18 (95% CI: 0.87±

1.61).

Intention-to-treat analysis

Five randomized controlled trials reported the results of

intention-to-treat analyses after 4 weeks of treatment.8±12

Details are listed in Table 3. There was no signi®cant

heterogeneity among these randomized controlled trials

(P � 0.36). Pooled healing rates on lansoprazole 30 mg

and omeprazole 20 mg were, respectively, 72.7% and

70.8%. The relative bene®t increase was 2.8% and the

absolute bene®t increase was 2.0% (95% CI: ± 2.0±6.0).

Figure 3 displays the absolute bene®t increase and 95%

CI for individual trials and the pooled data. The number

needed to treat was 50.7 (95% CI: 16.7 to number

needed to harm 49.3). The pooled ORM-H for endoscopic

healing on lansoprazole rather than omeprazole was

1.11 (95% CI: 0.90±1.35).

Five randomized controlled trials reported intention-

to-treat analyses after 8 weeks; the results are summarized

in Table 4.8±11, 13 There was no signi®cant hetero-

geneity among these randomized controlled trials

Table 2. Summary results for four randomized controlled trials

reporting per protocol analyses at 8 weeks' treatment

Lansoprazole 30 mg Omeprazole 20 mg

Reference n

Healing

rate (%) n

Healing

rate (%)

Hatlebakk9 92 84.8 88 85.2

Castell10 395 90.9 407 90.9

Mee11 225 86.7 229 81.7

Pilotto13 43 88.4 53 83.0

Pooled 755 88.7 777 87.0

Table 3. Summary results for ®ve randomized controlled trials

reporting intention-to-treat analyses at 4 weeks' treatment

Lansoprazole 30 mg Omeprazole 20 mg

Reference n

Healing

rate (%) n

Healing

rate (%)

Corallo8 75 85.5 69 84.1

Hatlebakk9 113 62.8 112 65.2

Castell10 421 79.6 431 79.6

Mee11 300 62.0 304 56.6

Petite12 58 81.0 62 74.2

Pooled 968 72.7 978 70.8

Figure 1. Per protocol analysis at 4 weeks. Figure 2. Per protocol analysis at 8 weeks.

PROTON PUMP INHIBITOR META-ANALYSIS 229

Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 227±231

(P � 0.85), which were therefore pooled. The pooled

healing rates were 83.3% for lansoprazole 30 mg and

81.8% for omeprazole 20 mg. The relative bene®t

increase was 1.8% and the absolute bene®t increase

was 1.5% (95% CI: ±1.9±4.9). Figure 4 displays the

absolute bene®t increase and 95% CI for individual

trials and the pooled data. The number needed to treat

was 67.6 (95% CI: 20.5 to number needed to harm

52.3). The pooled ORM-H for endoscopic healing on

lansoprazole rather than omeprazole was 1.11 (95% CI:

0.87±1.41).

DISCUSSION

We were unable to demonstrate a statistically signi®-

cant advantage to lansoprazole 30 mg o.d. over ome-

prazole 20 mg o.d. in healing erosive oesophagitis. By

both per protocol and intention-to-treat analysis, there

was a numerically small advantage to lansoprazole over

omeprazole in terms of pooled healing rates after 4 and

8 weeks of treatment. However, in each analysis, the

95% CI for the absolute bene®t increase encompassed

zero (Figures 1±4). Similarly, the pooled ORM-H for each

analysis was in favour of lansoprazole, although the

95% CI always encompassed unity, making these

statistically non-signi®cant.

No therapeutic bene®t of lansoprazole over omepraz-

ole, in the doses speci®ed, has been found in this

meta-analysis. Any superior antisecretory effect of lansop-

razole 30 mg over omeprazole 20 mg has not therefore

been translated into a statistically signi®cant advantage

in terms of oesophagitis healing rates. However, some

randomized controlled trials included in this meta-

analysis reported more rapid symptom relief on lansop-

razole 30 mg than on omeprazole 20 mg.10, 11 Whilst

the greater antisecretory effect of lansoprazole is not

large enough to affect oesophagitis healing rates, it may

accelerate symptom relief during the ®rst few days of

treatment. Omeprazole has relatively low bioavailability

in the ®rst few days of administration and may take up

to 5 days to achieve a pharmacodynamic steady

state.17±20 It then exerts enough antisecretory effect to

maintain intragastric pH above 4 for a suf®cient period

of time to heal oesophageal erosions, just as effectively

as lansoprazole.2

Until recently, no proton pump inhibitor had been

shown to be statistically signi®cantly superior to

omeprazole in healing erosive oesophagitis. However,

esomeprazole 40 mg is more effective in controlling

intra-oesophageal acid exposure than omeprazole

20 mg.21 Furthermore, this dose of omeprazole1 has

achieved signi®cantly higher healing rates than ome-

prazole 20 mg in two separate multicentre randomized

Table 4. Summary results for ®ve randomized controlled trials

reporting intention-to-treat analyses at 8 weeks' treatment

Lansoprazole 30 mg Omeprazole 20 mg

Reference n

Healing

rate (%) n

Healing

rate (%)

Corallo8 76 88.2 69 88.4

Hatlebakk9 112 84.8 111 86.5

Castell10 421 87.2 431 87.0

Mee11 300 75.3 304 71.1

Pilotto13 43 88.4 53 83.0

Pooled 952 83.3 968 81.8

Figure 3. Intention-to-treat analysis at 4 weeks. Figure 4. Intention-to-treat analysis at 8 weeks.

230 V. K. SHARMA et al.

Ó 2001 Blackwell Science Ltd, Aliment Pharmacol Ther 15, 227±231

controlled trials conducted in the United States.22, 23

Thus, a substantial and sustained increase in antisecre-

tory effect from a proton pump inhibitor may be

associated with an additional improvement in oesoph-

agitis healing rates. The difference in antisecretory

potency between lansoprazole 30 mg and omeprazole

20 mg has presumably not been of suf®cient magnitude

to achieve this.

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