Omeprazole provides quicker symptom relief and duodenal ulcer healing than ranitidine

GASTROENTEROLOGY 1990$&276-263

Omeprazole Provides Quicker Symptom Relief and Duodenal Ulcer Healing Than Ranitidine R. D. G. E.

J. MCFARLAND, M. C. BATESON, J. R. B. GREEN, P. O’DONOGHUE, M. W. DRONFIELD, P. W. N. KEELING, J. BURKE, R. J. DICKINSON, D. R. SHREEVE, M. PEERS, and P. D. I. RICHARDSON

Ulster Hospital, Dundonald, Belfast, United Kingdom; General Hospital, Bishop Auckland, United Kingdom: City General Hospital, Stoke-on-Trent, United Kingdom; St. Vincent’s Hospital, Dublin, Ireland; District Hospital, Peterborough, United Kingdom; St. James’ Hospital, Dublin, Ireland; Limerick Regional Hospital, Limerick, Ireland; Hinchingbrooke Hospital, Huntingdon, United Kingdom: North Manchester General Hospital, Manchester, United Kingdom; and Medical Department, Astra Pharmaceuticals Ltd., Kings Langley, United Kingdom

In a double-blind, parallel-group clinical trial in 248 patients with symptomatic duodenal ulcers 197% > 5 mm diameter], 126 were randomized to receive omeprazole 20 mg once daily in the morning and 122 were randomized to receive ranitidine 300 mg once daily at night for 2 wk and if the ulcers were unhealed for a total of 4 wk. When ulcer healing was assessed on an intention-to-treat basis, 79% of those receiving omeprazole had healed ulcers after 2 wk compared with 62% of those receiving ranitidine gain for omeprazole, 18%; (p < 0.005; therapeutic 95% confidence intervals, + 6% to +29%). At 4 wk the figures were 91% (omeprazole) and 80% (ranitidine) (p < 0.05). After 2 wk, 77% of omeprazoletreated and 59% of ranitidine-treated patients were free of ulcer pain (p = 0.005). Assessed by diary cards (successfully completed by 92% of patients), daytime pain resolved more quickly in omeprazole-treated patients than in those receiving ranitidine (p < 0.01). Omeprazole-treated patients took fewer antacids (p < 0.05) over the first 2 wk. Omeprazole, 20 mg each morning, provides more rapid relief of the symptoms of duodenal ulcer and heals a greater proportion of duodenal ulcers within 2 and 4 wk than ranitidine, 300 mg each night.

0

meprazole effectively controls gastric acid secretion (1) by selectively inhibiting the enzyme hydrogen-potassium-stimulated adenosine triphosphatase (H+,K+-ATPase) (Z), the gastric proton pump

in the parietal cells, which controls the final step of gastric acid production. Previous studies (3-5) have revealed higher healing rates for duodenal ulcers in patients receiving omeprazole, 20 mg once daily, than in those receiving ranitidine, 150 mg twice daily. A single nighttime dose of 300 mg ranitidine was shown to be as effective in healing duodenal ulcers (6) as 150 mg twice daily (hid.); this was confirmed in a large trial (594 patients) (71, which also showed equivalence of symptom relief with the 2 regimens. Coupled with convenience for the patient, this has led to increasing use of 300 mg ranitidine each night in the treatment of duodenal ulcers. The present trial was designed to compare omeprazole 20 mg once daily in the morning with ranitidine 300 mg once daily at night in the healing and symptom relief of duodenal ulcers; few data are available on symptom relief, but because both drugs relieve ulcer pain within 2-4 wk in most patients, we used diary cards to obtain a continuous record of pain over the first 2 wk of treatment. Methods Patients Patients were symptomatic duodenal

eligible for the study if they had or pyloric canal ulcer crater verified

Abbreviation used in this paper: H*,K+-ATPase. hydre9enpotassium-stimulated adenosine triphusphatase. 0 1696 by the American Gastreenterelegical Assedation 0016.5065/90/$3.00

February 1990

OMEPRAZOLE OR RANITIDINE IN DUODENAL ULCER

by endoscopy not more than 4 days before inclusion in the trial. The principal exclusions were pregnancy, liability to become pregnant, lactation, age 48 or >80 yr, coexisting gastric ulcer with center 23 cm from the pylorus, pyloric stenosis, oesophageal abnormalities, active upper gastrointestinal bleeding, acid-lowering or major gastroduodenal surgery, serious concurrent disease, significant abnormalities in blood tests, use of H, antagonists or other antiulcer drugs (except simple antacids) in the week before endoscopy, use of drugs [e.g., nonsteroidal anti-inflammatory drugs) that might interfere with the study, use of anticoagulants or phenytoin, or potential poor compliance. All patients gave informed consent to participate. The approval of the ethics committee at each hospital was obtained before the entry of patients.

wk. Multivariate (logit) analysis with various prognostic factors was carried out to establish the relative importance of these factors as predictors of ulcer healing. Endoscopic data were available for 97% of randomized patients at 2 wk and 93% at 4 wk. Wilcoxon tests, stratified for pretreatment symptoms, were used to assess the effects of the 2 drugs on the symptoms recorded at clinic visits. The differences between variables recorded on diary cards in the two treatment groups were compared using Kolmogorov-Smirnov tests. Data are presented as means * SD unless stated to the contrary; 95% confidence intervals were calculated for the ulcer healing rates and the difference between healing rates on the z drugs (“therapeutic gain”). p Values ~0.05 are regarded as nonsignificant. The trial was designed to have an 80% power to detect a 20% difference in the ulcer healing rates of omeprazole and ranitidine at p to.05 if 190 patients completed the study. The influence of age and smoking on healing rates with the 2 drugs were prospectively defined subgroup analyses.

Study

Design

The trial was carried out in 15 centers in the United Kingdom and the Republic of Ireland. Patients were randomly assigned, double-blind, to receive omeprazole (Astra Pharmaceuticals Limited, Hertfordshire, England), one ZOmg capsule each morning and one placebo tablet each night, or ranitidine (Glaxo Group Research Limited, Greenford, England), one placebo capsule each morning and one 300-mg tablet each night. The initial treatment was for 2 wk; repeat endoscopy was performed, and if the patient was free of symptoms and the ulcer crater(s) were healed, the trial ended. If the patient had pain or unhealed ulcer crater(s) after z wk. blinded medication continued for an additional 2 wk.

Results Patients

Ulcer

Analyses Ulcer healing is assessed on an intention-to-treat basis. One patient randomized to omeprazole but withdrawn on day 4 because of obstruction of the superior vena cava associated with carcinoma of the lung was omitted from all analyses. x2 tests were used to compare cumulative rates of ulcer healing in the 2 treatment groups after 2 and 4

at Randomization

In terms of demographic data and ulcer history (Table l), the 2 treatment groups were comparable at the time of randomization. Both groups were also comparable in terms of endoscopic findings of ulcer size and number of ulcers (Table 2).

Assessments Endoscopic examination of the esophagus, stomach, and duodenum was performed at entry [no more than 4 days before the first trial drugs were taken), after 2 wk (13-17 days] and, when appropriate, after 4 wk (27-31 days). The location and diameter of all duodenal ulcers were recorded; “healing” was defined as complete reepithelialization of all ulcer craters. Ulcer symptoms were recorded at each clinic visit, as were possible adverse drug experiences [by open questioning). Patients kept daily diary cards recording the presence or absence of day and night ulcer pain and the number of antacid tablets taken. The antacids supplied for use as required between endoscopy and entry to the trial and during the trial were Rennies (Nicholas Laboratories Ltd., Slough, England; 680 mg calcium carbonate plus 80 mg light magnesium carbonate per tablet; the neutralizing capacity of each tablet is 130 ml of 0.1 N HCl).

279

tients pared

Healing

After 2 wk of treatment, 79% (99/1X) of pareceiving omeprazole had healed ulcers comwith 61% (75/122)of those receiving ranitidine

Table 1. Patient Characteristics Randomization

Omeprazole group (n = 126)

Variable Sex (M:F) Age (18-64

at the Time of

91:35 yr: 65-80

yr]”

Mean * SD (yr) Height [cm) Weight (kg) Smokers ( yes:no) Duration of ulcer symptoms [yr] Median Duration of current episode (wk) Median Number of episodes in past yr Median Intermittent symptoms”

114:12

77:45 106:16

46 + 14

169 + 9 72 f 13 63:63 7.6

Ranitidine group (n = 122)

+ 6.4

46 + 15 168

+ 10

71

L 13

71:51 7.2

t 9.7

5

9.9 *

3 11.5

7.9

* 6.7

6 2.5

k 2.4

6 3.8

+ 6.6

1 44

1 41

There are no significant differences behveen the treatment groups for any of these variables. “Number of patients.

280 MCFARLAND ET AL.

Table 2.

GASTROENTEROLOGY

Endoscopic Findings at the Time of Entry to the Trial

Finding

Omeprazolegroup

Ranitidinegroup

[n = 128)

(n = 122)

96 20 5 5

100 14 1 7

3

5

98

95

25

19 3 9*5 8

Number of ulcers 1 3 3 >3 Size of ulcers ~5 mm 5-10 mm 11-20 mm 220 mm Size (mm diameter)

Median

Vol. 98, No. 2

Table 3. Prognostic Factors for Duodenal Ulcer Healing [Logit Analysis] Partial X2

Factor

df

v value”

2wk

0 9*4 8

Figures show number of patients in each category. The size is the diameter of the sole or largest [“index”] ulcer. Ninety-seven percent of patients had ulcers r5 mm in diameter.

(p < 0.005; therapeutic gain, 18%; 95% confidence interval, +6% to +29%) (Figure 1). After 4 wk, the cumulative healing rates were 91% (114/125) (omeprazole) and 80% (97/122) (ranitidine) (p < 0.05; therapeuticgain, 12%; 95% confidence interval, -13% to +l?O%].

Ulcer Healing-Prognostic

Factors

Treatmen* Smoking Complete model” 4wk Treatmentb Smoking Complete model”

8.13 9.68

1

0.004

0.64

1 2

0.002 0.73

4.34

1

0.04

5.18 1.10

1

0.02

2

0.58

See text for factors that a preliminary model showed to have no influence on ulcer healing. “A low p value (~0.05) for an individual factor indicates a significant prognostic effect. bOmeprazole v. ranitidine. “A high p value (>O.l) indicates a good model fit.

Ulcer Healing-Subgroup

Subgroup analyses were carried out for smoking and size of ulcer at randomization; both showed a consistently greater proportion of omeprazole-treated patients than ranitidine-treated patients with healed ulcers after 2 and 4 wk (Table 4). With only 28 patients aged >65 yr, subgroup analysis for this group was considered inappropriate. Symptom Relief-Clinic

Multivariate analysis (logit model) was used to assess the influence, if any, of a series of factors on ulcer healing rates. There was no evidence that gender, age, or number or size of ulcers influenced the likelihood of ulcers healing within 2 or 4 wk. In a final logit model, only smoking and treatment (omeprazole favoring healing over ranitidine) had strong prognostic effects on ulcer healing (Table 3).

Analyses

Visits

At entry, all patients reported ulcer symptoms: after 2 wk of treatment, i’7% of those who had received omeprazole reported no ulcer symptoms compared with 59% of those treated with ranitidine (p < 0.01). On a cumulative basis, after 4 wk, 89% and 85% respectively (NS) were asymptomatic (Figure 2). At entry, 109 of 118 (92%) patients who would receive omeprazole and 105 of 115 (91%) who would receive ranitidine for whom data are available reported daytime epigastric pain: after 2 wk of treatment, 95 patients (81%) in the omeprazole group and 73 patients (63%) in the ranitidine group (p < 0.01) were free of pain (Figure 3). At entry, 69% of the patients in the omeprazole

% patients with healed ulcers

Table 4. Duodenal

Ulcer Healing in Subgroups of Patients Ulcer healing rates

Number of patients Subgroup 2 weeks

4 weeks

Figure 1. Duodenal ulcer healing rates after 2 and 4 wk of treatment with either omeprazole, 20 mg o.m. [w), or ranitidine, 300 mg nocte (0) Small bars show 95% confidence intervals. The differences are significant after both 2 (p c 0.01) and 4 (p c 0.05) wk.

Ulcer size t8 mm r8 mm Smoking Yes No

0

R

54

71 61 63

0, omeprazole; R, ranitidine.

2wk

4wk

0

R

0

R

56

74%

67%

85%

84%

66

83%

56%

94%

77%

71 51

73% 86%

52% 75%

87% 94%

75 % 88%

OMEPRAZOLE

February 1990

100

OR RANITIDINE

IN DUODENAL

ULCER

281

100

80 % patients with symptoms

% of patients

50

60 40

20

C 4 weeks

2 weeks

Randomization

0

Figure 2. Proportion of patients in each treatment group with epigastric pain at the time of randomization and after 2 and 4 wk of treatment with omeprazofe, 20 mg o.m. (0), or ranitidine, 200 mg nocte (Rj The difference after 2 wk is significant (p < 0.01). E, Mild; R, moderate; W,severe.

07 overall

symptoms

07

07

Daytime epigsstric pain

Nocturnal epigsstric pain

07

Weeks

Figure 2. Proportions of patients in each treatment group with duodenal ulcers and symptoms associated with ulceratfon. Data elicited by physicians at clinic visits. l, Omeprazole; n, ranitidine.

group and 70% in the ranitidine group reported nighttime epigastric pain; after z wk of treatment, the figures were 13% and 19% (NS], respectively. Heartburn was reported by 39Yo of omeprazole-treated of ranitidine-treated patients at patients and 45% entry: after 2 wk, these proportions had decreased to 3% and 12Yc, respectively (p < 0.05). So few (~5%) patients reported nausea, vomiting, hematemesis, or melena after 2 wk that statistical analysis of these symptoms would not be meaningful.

Symptom Relief-

Diary Cards

Diary cards were used to obtain continuous information on daytime and nighttime pain (presence or absence) and antacid consumption from day 2 (the first trial day on which all patients took both the morning capsule and the evening tablet) to day 13, inclusive. Data were obtained for 113 patients in the omeprazole group and 102 in the ranitidine group (90% and 84% of randomized patients; 95% and 87% of those for whom data are available at 2-wk clinic visits). Figure 4 shows the prevalence of daytime and nighttime pain over the first 2 wk of treatment, Enhanced pain relief with omeprazole is associated with lower use of antacids [Figure 5); the mean consumption of antacids was 6.9 tablets per patient over days 2-13, inclusive, in the omeprazole group and 9.1 tablets per patient in the ranitidine group. The cumulative numbers of antacid tablets taken from day 2 were 722 in the omeprazole group and 868 (20% more) in the ranitidine group (p < 0.01; Figure 5). The proportion of patients who were asymptomatic and abstained

Ulcer Healing With Symptom Relief After 2 wk, 67% of omeprazole-treated patients were free of symptoms and had healed ulcers, compared with 40% of ranitidine-treated patients (p < 0.01). The proportions with healed ulcers but residual symptoms were 13% of omeprazole-treated patients and 23% of ranitidine-treated patients; 10% and 19%, respectively, had relief of symptoms but unhealed ulcers, and 10% and 18% had symptoms and unhealed ulcers. % patients with

pain

50-

DAY (~~0.05)

0

NIGHT

40% patients wtthpain \

30.

0 \

20. _

Figure 4. Proportion of patients in each treatment group recordfng the presence of daytime and nighttime pain on diary cards. l, Omeprazole; n, ranitidine.

??I?+[[

10

O+

2

3

4

5

6

7

8 Day

9

10

11

12 13

14

O*

2

3

4

5

6

7

8 Day

9

10

11 12

13

14

282

MCFARLAND

GASTROENTEROLOGY

ET AL.

Table 5. Adverse

1000 Cumulative antacid consumption

System

(tablets)

5oo

I ‘2

I

I

3 4

ti

In

8

8

8

11

8

1

5 6 7 6 9 10 11 12 13 14

Day Figure 5. Cumulative consumption of antacids by duodenal ulcer patients receiving omeprazole (0) or ranitidine (0) once daily (p < 0.01).

from taking antacids, i.e., in whom symptoms had resolved, was higher in the omeprazole group than the ranitidine group (p -C0.05; Figure 6).

Central nervous Endrocrine Respiratory Circulatory Gastrointestinal Urinary Musculoskeletal Skin Infection Other Total

Events

Durine

Trial Period,

Omeprazole group [n = 125)

Vol. 98, No. 2

by System Ranitidine group (n = 122)

5

6

0 1

1 lb

0

3(lb) 7 2 3 2 0

4 0

2 0 2 1 16

in 13 patients

0 25

in 20 patients

“One extra patient was randomized but excluded from all analyses [see text]. bClassified as serious adverse events.

showed no changes in the numbers of patients with values outside the reference ranges in either treatment group.

Safety No patients were withdrawn

because of worsening of ulcer symptoms. In addition to the patient randomized to omeprazole who was excluded from all analyses, 2 patients were withdrawn from omeprazole treatment (disliked capsules; lower respiratory tract infection] and 7 from ranitidine treatment (1myocardial infarction and ventricular fibrillation: 1 death from aggravated chronic obstructive airway disease [day 251; 1 skin rash: 1 urticaria; 1 pyloric outlet obstruction: 1 pyloric stenosis: 1 coexistent GU). Eight other patients (4 in each group) were lost to follow-up, and 7 patients (2 in the omeprazole group) were withdrawn because of noncompliance with the protocol, making a total of 9 withdrawals in the omeprazole group and 16 in the ranitidine group. A summary of possible adverse events is given in Table 5. Analysis of blood samples taken at the start and end of treatment

% of patients painfree and taking no antacids

:1l 2

3

4

5

6

7

a

9

10

ii

12

13

14

Day

Figure 6. Proportion of patients who hecame free of pain and did not take antacid tablets l, Omeprazole; W,ranitidine; p 10.05.

Discussion This study compared omeprazole with ranitidine in the relief of the symptoms of duodenal ulcer, as well as in the healing of macroscopic lesions. We chose the dose of ranitidine (300 mg nocte) that is becoming most commonly used internationally and a dose of omeprazole (20 mg o.m.) that previous studies have shown to be effective (34 but that does not cause complete 24-h suppression of gastric acid secretion (Ml. The diary card data show that over the first 2 wk of treatment, daytime epigastric pain resolved more quickly in patients taking omeprazole than in those taking ranitidine; moreover, those taking omeprazole took fewer antacids than those taking ranitidine. The reliability of these data is supported both by the high completion rate for the diary cards (>90% of those attending the 2-wk clinic visit) and by the concordance of the symptoms assessed at the 2-wk clinic visit: like the diary cards, this assessment showed a significant advantage for omeprazole. Although both drugs alleviated the symptoms of duodenal ulcers in the majority of patients, omeprazole was consistently more effective after the 2- and 4-wk treatment periods used in this study (Figures 3 and 4). After 2 wk, about twice as many patients in the ranitidine group as in the omeprazole group still had unhealed ulcers and complained of symptoms. This study supports the view that nighttime epigastric pain is not as common as daytime pain in duodenal ulcer patients and resolves quickly (9). The importance of daytime control of intragastric acidity is shown by the lower daytime pain experienced by patients receiving omeprazole compared with those receiving ranitidine.

February 1990

In this study, the ulcer healing rates were high; on an intention-to-treat analysis, about 80% of patients’ duodenal ulcers healed with omeprazole after 2 wk of treatment. On all indexes measured in this study (which met the recruitment target that had been defined prospectively on a statistical basis], omeprazole, 20 mg o.m., provided accelerated relief of symptoms and duodenal ulcer healing compared with ranitidine, 300 mg nocte. This advantage held true for all subgroups of patients analyzed (Table 4); although the results of such subgroup analyses are to be treated with caution, the therapeutic gain (healing rate of omeprazole minus that of ranitidine) of 18% overall after 2 wk was greater for patients with large ulcers and smokers than for patients with small ulcers and nonsmokers. This suggests that omeprazole heals ulcers of all sizes, including those in which there may be other factors that complicate healing. Moreover, there was better correlation between healing of the ulcer and relief of symptoms in the omeprazole group; roughly twice as many patients treated with ranitidine had either healed ulcers but persisting symptoms or relief of symptoms but unhealed ulcers compared with patients treated with omeprazole. It is probable that the consistently enhanced rates of duodenal ulcer healing and symptom relief with omeprazole (two thirds of patients achieved both in 2 wk) are associated with its greater efficacy than H,receptor antagonists in the control of intragastric acidity (10). In this study, its selectivity is reflected in tolerability that is as good as ranitidine. References 1. Lind T, Cederberg

C, Ekenved G, Haghmd U, Olbe L. Effect of omeprazole-a gastric proton pump inhibitor-on pentagastrin stimulated acid secretion in man. Gut 1983;24:270-6. 2. Fellenius E, Berglindh T, Sachs G, Olbe L, Elander B, Sjbstrand S-E, Wallmark B. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+,K+)ATPase. Nature 1981; 290:X9-61.

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OR RANITIDINE IN DUODENAL ULCER

283

3. Bardhan KD. Bianchi Porro G, Bose K, Daly M, Hinchcliffe RFC, Jonsson E. Lazzaroni M, Naesdal J, Rikner L, Walan A. A comparison of two different doses of omeprazole versus ranitidine in treatment of duodenal ulcers. J Clin Gastroenterol 1986;8:408-13. 4. Barbara L, Blasi A, Cheli R, Corinaldesi R, Dobrilla G, Francavilla A, Rinetti M, Vezzaldini P, Abbiati R, Gradnik R, Ciancamerla G. Chilovi F, Felder M. Ingrosso M, Mangiameli A, Paternico A, Sivelli R, Tomassetti P, Labo G. Omeprazole vs. ranitidine in the short-term treatment of duodenal ulcer: an Italian multicenter study. Hepatogastroenterology 1987;34:22932. 5. Classen M, Dammann H-G, Domschke W, Huttenmann W, Londong W, Rehner M, Simon B, Witzel L, Berger J. Omeprazole heals duodenal, but not gastric ulcers more rapidly than ranitidine. Hepatogastroenterology 1985;32:243-5. 6. Ireland A, Colin-Jones DG, Gear P, Golding PL, Ramage JK, Williams JG, Leicester RJ, Smith CL, Ross G, Barnforth J, Degara CJ, Gledhill T, Hunt RH. Ranitidine 150 mg twice daily vs 300 mg nightly in treatment of duodenal ulcers. Lancet 1984;2:274-6. 7 Lee FI, Reed PI, Crowe JP, McIsaac RL, Wood JR. Acute treatment of duodenal ulcer: a multicentre study to compare ranitidine 156 mg twice daily with ranitidine 300 mg once at night. Gut 1986;27:1091-5. 8. Sharma BK, Walt RP, Pounder RE, Gomes MdeFA, Wood EC, Logan RH. Optimal dose of oral omeprazole for maximal 24 hour decrease of intragastric acidity. Gut 1984;25:945-64. 9. Sharma MP. Choudhari G. Nocturnal pain and duodenal ulcer. Br J Clin Pratt 1988;42:198-9. 10. Hunt RH, Howden CW, Jones DB, Burget DW, Kerr GD. The correlation between acid suppression and peptic ulcer healing. Stand J Gastroenteroll986;21(Suppll25]:22-9.

Received December 19,1988. Accepted July 11,1989. Address requests for reprints to: P. D. I. Richardson, Ph.D., Head of Clinical Research, Astra Pharmaceuticals Limited, Home Park Estate, Kings Langley, Hertfordshire WD4 8DH, England. The ACCORD trial Investigators [and number of patients entered): R. J. McFarland (44); M. C. Bateson (38); J. R. B. Green (24); D. P. O’Donoghue (22); M. W. Dronfield (20); P. W. Keeling (26): G. J. Burke (16); R. J. Dickinson (13); D. R. Shreeve (13); C. L. Corbett, Worksop (81;A. R. Tanner, Stockton (8); M. J. Fairman, Boston (7): M. H. Gleeson, JerseyC.1. (7); R. W. Crofton, Carluke (6); J. R. Bennett, Hull (4). The authors thank Eva Hammarstrom and Alison Scrimgeour for statistical analysis and Pam Soan for preparation of the manuscript.