SUMMARY INTRODUCTION. Accepted for publication 5 August 2003

Transcription

1 Aliment Pharmacol Ther 2003; 18: doi: /j x Three-day intravenous triple therapy is not effective for the eradication of Helicobacter pylori infection in patients with bleeding gastro-duodenal ulcer M. ROMERO-GÓMEZ*, C. MARTÍNEZ-DELGADO, P. HERGUETAà, J.-M. NAVARRO, A. GARRIDO-SERRANO, O. SANTOS** & C. MONTOJO** *Digestive and Hepatology Unit, Hospital Universitario de Valme, Seville, Spain; Research Unit, Hospital Universitario Nuestra Señora de Alarcos, Ciudad Real, Spain; àgastroenterology Department, Hospital Universitario Virgen Macarena, Sevilla, Spain; Digestive Unit, Hospital Costa de Sol, Marbella (Málaga), Spain; Digestive Unit, Hospital Minas de Río Tinto, Huelva, Spain; and **Pharmacy Unit, Hospital Universitario Nuestra Señora de Alarcos, Ciudad Real, Spain Accepted for publication 5 August 2003 SUMMARY Aim: To test the efficacy of an ultra-short intravenous triple therapy against Helicobacter pylori infection in patients with bleeding peptic ulcer against standard oral 1-week triple therapy in a randomised, double-blind prospective trial. Methods: Patients: (n ¼ 75) with haemorrhagic peptic ulcer and H. pylori infection were randomised into: an Intravenous Group to receive omeprazole, clarithromycin and amoxicillin clavulanic acid intravenously b.d. for 3 days followed by 7 days of oral omeprazole plus placebo of clarithromycin and amoxicillin; an Oral Group to receive intravenous omeprazole plus placebo of clarithromycin and amoxicillin clavulanic acid followed by 7 days of oral omeprazole, clarithromycin and amoxicillin b.d. Gastric biopsies were obtained for urease test. A 13 C-urea breath test was performed to check for H. pylori eradication. Results: Intention-to-treat eradication was 50% (19/ 38) in the Intravenous Group and 78% (29/37) in the Oral Group (odds ratio 3.63; 95% confidence interval ; P < 0.01; number needed to treat (NNT) ¼ 4). Per protocol eradication was 50% (14/ 28) in the Intravenous Group and 86% (24/28) in the Oral Group (P < 0.005). There were no statistically significant differences in adverse events between the two treatment groups. Conclusions: An ultra-short, 3-day, intravenous, triple therapy containing omeprazole, clarithromycin and amoxicillin clavulanic acid cannot be recommended as an effective eradication regimen for H. pylori infection related to haemorrhagic gastro-duodenal ulcer. INTRODUCTION Correspondence to: Dr. M. Romero-Gómez, Digestive and Hepatology Unit, Hospital Universitario de Valme, Ctra Cádiz s/n, Sevilla, Spain. mromerog@supercable.es The incidence of peptic ulcer bleeding has been estimated around 50 cases per inhabitants per year. 1, 2 Haemorrhage occurs in > 12% of untreated peptic ulcer patients within 5 years of follow-up postdiagnosis. 3 Helicobacter pylori infection has been detected in the majority of patients with bleeding ulcers, depending on the diagnostic methods used and whether nonsteroid anti-inflammatory drugs (NSAIDs) had been prescribed in the week prior to the haemorrhage. 4 Eradication of the infection results in a lower rate of re-bleeding 5 and better outcomes can be expected compared to maintenance therapy with anti-h2, or noneradication. 6 8 Intravenous administration of proton-pump inhibitors for 3 days can decrease the risk Ó 2003 Blackwell Publishing Ltd 1023

2 1024 M. ROMERO- GÓMEZ et al. of re-bleeding after endoscopy therapy 9 and improve the H. pylori eradication rate when followed by a 1-week oral triple therapy. 10 Lastly, compliance was observed to be the most important factor affecting successful eradication 11 and, although longer treatment schedules can achieve higher eradication rates, the level of compliance is significantly lower. 12 In an open-labelled, pilot study of intravenous administration of a triple therapy schedule combining omeprazole, metronidazole and ampicillin over 3 days, we achieved an eradication rate of > 80%. 13 As such, a triple therapy using a proton-pump inhibitor combined with two antibiotics administered intravenously for 3 days appears to be successful in eradicating H. pylori infection, in improving compliance and decreasing the re-bleeding rate in patients with bleeding peptic ulcers. Hypotheses and objectives We hypothesized that, in patients with digestive haemorrhagia and bleeding gastro-duodenal ulcers, the percentage eradication resulting from a short 3-day intravenous therapy would be similar to (or better than) the standard 7-day oral antibiotic therapy. Also, we assessed the patients tolerance of the 3-day infusion. We present here a randomised, multicentre, doubleblind, placebo-controlled trial comparing a 3-day intravenous schedule of omeprazole, clarithromycin and amoxicillin clavulanic acid vs. the standard schedule of 1-week orally administered omeprazole plus clarithromycin and amoxicillin for the eradication of H. pylori infection in patients suffering from bleeding gastroduodenal ulcers. Patients and methods Seventy-five consecutive patients from eight hospitals in Southern Spain who were suffering from an upper digestive tract haemorrhage as a result of peptic ulcers and H. pylori infection were enrolled. All the patients provided written informed consent to participate in the study. The protocol was approved by the Ethical Committees of the participating hospitals. The study was performed between April 2000 and January Patients excluded were those who were taking antibiotics in the month prior to the study, who had a history of allergy to penicillin, were under 18 years of age, showed clinical evidence of cardiovascular disease, or had respiratory, kidney or liver dysfunction. Seventy-five patients were enrolled, of whom 38 were assigned to the Intravenous Group and 37 to the Oral Group. Prescription NSAID drugs were being taken in the previous week by 18 patients and were discontinued in all patients on presentation with gastrointestinal haemorrhage. Gastric ulcer was diagnosed in 19, duodenal in 54 and double lesion in two patients. There were 62 males and 13 females in the study. The level of bleeding was assessed using the Forrest classification. 14 Briefly, Forrest I for active bleeding (Forrest Ia, active arterial bleeding; Forrest Ib, sheet bleeding), Forrest II for stigmata of recent bleeding (Forrest IIa, visible vessel; Forrest IIb, adherent clot and Forrest IIc, flat clot) and Forrest III when no stigmata of haemorrhage was observed. Endoscopy of the ulcer indicated bleeding status on the Forrest scale of Ia in four, Ib in seven, IIa in eight, IIb in 16 and III in 40 patients. There were 19 patients who received endoscopy therapy. A diagnostic baseline oral endoscopy was performed, and biopsy samples of corpus and antrum were obtained for the urease test (Jatrox-test, Rohm-Pharma GmbH, Weiterstadt, Germany). In the hours following the endoscopy, patients were randomised (Figure 1) to the Intravenous Group to receive intravenously omeprazole (40 mg) + clarithromycin (500 mg) + amoxicillin clavulanic acid (1000/ 200 mg) b.d. for 3 days followed by 1-week treatment with orally administered omeprazole (20 mg) + placebo instead of clarithromycin and amoxicillin clavulanic acid. The alternative treatment (the Oral Group) consisted of intravenous omeprazole (40 mg) b.d. + intravenous placebo of clarithromycin and amoxicillin clavulanic acid followed by 1-week of orally administered omeprazole (20 mg) + clarithromycin (500 mg) + amoxicillin (1000 mg) b.d. All patients continued receiving 20 mg of omeprazole every day for 3 weeks. Randomisation was performed using C4-S.P.D. software distributed by Glaxo-Wellcome using blocks of 16 cases. The randomisation list was prepared in the Investigation Unit and sent to the Pharmacy Service of the Hospital de Alarcos, where the drug placebo medications were made up centrally. The randomisation sequence was known only to this service, and none of the other investigators was aware of the treatment assignment. Clarithromycin and amoxicillin clavulanic acid and placebo were re-encapsulated using a Strocar machine

3 ERADICATION OF H. PYLORI INFECTION IN ULCER PATIENTS 1025 Figure 1. Protocolscheme showing treatment-group assignment. (Strocar, Valencia, Spain). Intravenous medication was prepared at each hospital and administered in opaque bags (Baxter, Barcelona, Spain). All drugs were provided prepackaged to the patients, physicians and nurses, all of whom were blind as to the nature of the contents. The administration of the predetermined treatment regimen depended on the time and hospital where the patient was recruited. A breath test 15 (Helicobacter Test INFAI, Institut für biomedizinische Analytik & NMR, Bochum, Germany) to test for eradication was performed 45 days after inclusion into the study. The test was conducted according to instructions established by the European standard method for the urea breath test. This involved measuring the 13 C concentrations in exhaled air preand 30 min post-administration of 75 mg of 13 C-labelled urea. An increase > 5/1000 was considered positive. Adverse events were monitored at all outpatient visits. Leukopenia was considered when lower than 4.2 K/lL, thrombocytopenia when lower than 142 K/lL and renal impairment when creatinine was higher than 1.3 mg/dl. Estimation of sample size Sample size estimation was based on the assumption that intravenous or oral triple therapy would achieve a similar eradication rate and, should there be differences, these would be detected if > 5%. The estimated sample size was 120 patients with a type I error of 0.05 and type II of 0.2 (Fisher s exact test, two-sided). 16 The inverse sine transformation was used when comparing proportions that could affect > 80% of the sample, as expected in eradication regimens. For sample size calculation, we estimated an eradication rate of efficacy for the Group of 86% and 91% for the Oral Group. The protocol allowed for an interim analysis of efficacy. Statistical analysis All data analysis was carried out according to a preestablished analysis plan. An interim analysis of the data from 75 patients provided clear evidence of significant differences between both treatment arms, and the trial was discontinued to preclude patients in the ultra-short intravenous treatment arm being disadvantaged. Intention-to-treat analysis included all 75 randomised cases and a per protocol analysis included 56 patients following the exclusion of major violations (six patients did not return for the urea breath test and, in one case a major violation was detected, which was a previous treatment with clarithromycin). Also, five patients did not complete the therapy because of adverse events, and seven patients were noncompliant in that at least three doses were not taken. All data were analysed using SPSS 11.0 for Windows (Chicago, IL). Comparisons between paired groups were made using the Mann Whitney U-test or Student s t-test for continuous variables, and the v-square or Fisher s exact probability test for categorical data. All values are presented as means ± standard deviation (s.d.). A probability value of P < 0.05 was considered statistically significant. Backward logistic regression was applied to calculate the odds ratio (OR) and the 95% confidence interval (95% CI) for each comparison. The number needed to treat (NNT) was also calculated.

4 1026 M. ROMERO- GÓMEZ et al. Characteristic Intravenous Group (n ¼ 38) Oral Group (n ¼ 37) P-value Age 53.5 (14) 49.4 (15) Haemoglobin (g/dl) 11.6 (2.3) 10.9 (2.6) Urea (mg/dl) 74.5 (34) 63.3 (27) Creatinine (mg/dl) baseline 0.95 (0.2) 0.93 (0.2) Gender: Males; n (%) 30 (78.9%) 32 (86.5%) NSAID use 12 (31.6%) 6 (16.2%) Duodenal ulcer 28 (73.7%) 26 (70.3Æ%) Table 1. Demographic, biochemical and haematological features of the patients randomised to the two treatment groups Mean (s.d.). NSAIDs, nonsteroid anti-inflammatory drugs. RESULTS The characteristics of the patients are summarised in Table 1. There were no differences between the groups with respect age, gender, urea and haemoglobin levels, ulcer sites, previous NSAID consumption and active bleeding. In the intention-to-treat analysis, eradication was achieved in 19 patients (50%) out of 38 cases in the Intravenous Group compared to 29 of 37 patients (78.4%) in Oral Group [v-squared test ¼ 6.55; P ¼ 0.01; OR 3.63; 95% CI , NNT 4; 95% CI 3 13)]. In the per-protocol analysis, the eradication rate was 50% (14 of 28 patients) in the Intravenous Group and 85.7% (24 of 28 patients) in Oral Group (v-squared test ¼ 8.18; P ¼ 0.004; OR 6.0; 95% CI ; NNT 3; 95% CI 2 8) (Table 2). Patients (n ¼ 57) without previous NSAIDs were analysed separately, and the intention-to-treat response was 53.8% (14 of 26 patients) in the Intravenous Group compared to 80.6% (25 of 31 patients) in the Oral Group (v-squared test ¼ 4.7; P ¼ 0.03; OR 3.57; 95% CI ; NNT 4; 95% CI 2 33). Also, per-protocol analysis showed an eradication rate of 55% (11 of 20 patients) in the Intravenous Group compared to 83.3% (20 of 24 patients) in the Oral Group (v-squared test ¼ 4.21; P ¼ 0.04; OR 4.1; 95% CI ; NNT 4; 95% CI 2 53) (Table 3). In multivariate analysis using backward logistic linear regression, treatment type (OR ¼ 4.88; 95% CI ; P ¼ 0.007) but not previous NSAID use (P ¼ 0.953) was the independent variable associated with eradication of H. pylori infection. Adverse events and re-bleeding rate The most frequent adverse event reported was phlebitis; seven patients in the Intravenous Group vs. two in the N Eradication rates Intravenous group Oral group OR (95% CI) NNT (95% CI) Table 2. Intention-to-treat (ITT) and per protocol (PP) eradication rates in the 2 treatment groups ITT 75 19/38 (50%) 29/37 (78.4%) 3.6 ( ) 4 (3 13) PP 56 14/28 (50%) 24/28 (85.7%) 6 (1.6 21) 3 (2 8) OR, odds ratio; 95% CI: 95% confidence interval. N Eradication rate Intravenous group Oral group OR (95% CI) NNT (95% CI) ITT 57 14/26 (53.8%) 25/31 (80.3%) 3.57 ( ) 4 (2 33) PP 44 11/20 (55%) 20/24 (83.3%) 4.1 ( ) 4 (2 53) Table 3. Intention-to-treat (ITT) and per-protocol (PP) eradication rates in the patients with bleeding ulcer and without previous NSAID use, randomised to the two treatment groups OR, odds ratio; 95% CI: 95% confidence interval. NNT, number needed to treat.

5 ERADICATION OF H. PYLORI INFECTION IN ULCER PATIENTS 1027 Table 4. Adverse events reported in the patients in the two groups Adverse event Oral Group (Fisher two-tailed test; P ¼ 0.083) (Table 4). Haemorrhagic relapse occurred in five patients; three in the Intravenous Group and two in the Oral Group (P ¼ N.S.). No patients required surgical intervention. DISCUSSION Intravenous group (n ¼ 38) Oral Group (n ¼ 37) P-value Phlebitis 7 (18.4%) 2 (5.4%) Leukopenia 2 (5.2%) 0 (0%) N.S. Thrombocytopenia 1 (2.6%) 0 (0%) N.S. Diarrhoea 2 (5.2%) 1 (2.7%) N.S. Renal impairment 2 (5.2%) 0 (0%) N.S. Dysgeusia 0 (0%) 1 (2.7%) N.S. Headache 0 (0%) 1 (2.7%) N.S. Nausea 0 (0%) 1 (2.7%) N.S. Bacteriuria 0 (0%) 1 (2.7%) N.S. N.S., not statistically significant. An ultra-short 3-day intravenous regimen achieved eradication in approximately half the patients in this randomised study, and, as such, this schedule would not be recommendable as an effective eradication regimen in patients with haemorrhage associated with gastro-duodenal ulcer and H. pylori infection. These results are not in agreement with previous, open-label, studies that found eradication rates > 80%; 13, 17 the main difference, apart from the current study being a randomised controlled trial, was the use of metronidazole instead of clarithromycin. Administering metronidazole intravenously achieves higher concentrations in gastric juices than in serum. 18 Also, omeprazole increases the area-under-the curve of metronidazole in gastric juice but does not affect the concentrations of the drug in serum. Hence, metronidazole offers considerable pharmaco-dynamic advantages when used intravenously. Indeed, oral ultra-short regimens appear to be effective only when metronidazole has been included in triple or quadruple combination therapies Although the 3-day intravenous regimen has been found to be less than successful in the eradication of H. pylori, this does not necessarily mean that other regimens may not be more effective. The ideal combination of intravenously administered drugs remains unknown. For example, intravenous administration of antibiotics such as metronidazole and macrolides (erythromycin) induce gastric secretion, but ampicillin 22 and amoxicillin 23 do not, even following omeprazole pre-treatment. Conversely, orally administered 1-week triple therapy commencing after 3 days of intravenous omeprazole achieves expected successful eradication rates. 10 Trials evaluating the efficacy of intravenous administrations of drugs for the eradication of the H. pylori infection are scarce, and their results are very inconsistent. A pilot trial found that administering imipenem and omeprazole intravenously for 2 days did not succeed in eradicating the H. pylori infection. 24 Administering amoxicillin intravenously for 1 or 3 days together with omeprazole taken orally for 2 weeks did not succeed in eradicating H. pylori. 25 However, if amoxicillin is administered intravenously for 2 weeks together with oral omeprazole, an eradication rate similar to that achieved with a conventional oral treatment can be obtained. 26 Therefore, administering antibiotics intravenously does not create any additional benefit compared to the standard treatment. Nevertheless, an initial treatment given for 3 days consisting of a dual intravenous therapy followed by an oral treatment achieves excellent eradication rates of close to 100%. 27 Lastly, to exclude prior NSAID intake being a confounding variable, a subanalysis was performed and the differences observed between the oral and intravenous regimens remained as for the analysis of the overall group. Previous NSAID intake was also excluded as an independent variable in the multivariate analysis. We conclude that in patients with a peptic bleeding ulcer, other ultra-short eradication regimens need to be explored since the combination of omeprazole with clarithromycin and amoxicillin clavulanic acid appears not to achieve effective eradication rates. ACKNOWLEDGEMENTS This manuscript is dedicated to the memory of Dr Gonzalo Miño Fungarolas, the sponsor of this study as President of the Sociedad Andaluza de Patología Digestiva, who died on 11 February He is remembered for his enthusiastic commitment, his help and encouragement in addition to his expertise. He will be sorely missed. We thank Dr Lorenzo Garcia Ponte of ABBOTT Laboratories,S.A. for his contribution to the design of the study, financial support in meeting the costs of the patients insurance and for providing oral

6 1028 M. ROMERO- GÓMEZ et al. clarithromycin. Thanks also to Cantabria, S.A. for providing omeprazol; Smith-Kline-Beecham for amoxicillin clavulanic acid; Salvat, S.A for amoxicillin; and Nuclear Ibérica S.A, for the urea breath test. We thank Dr Javier Elviro, Dr Jesús Fernández-Sanz and all of the Administration Team of the Hospital de Alarcos for making the facilities available for the conduct this study. APPENDIX Participating Centres and the Principal Investigators belonging to the Andaluz group for the study of intravenous H. pylori eradication therapy were as follows: Hospital Universitario de Valme, Sevilla; Manuel Romero-Gómez, Raquel Corpas, Lourdes Grande, Maria Miguel Del Corral; Hospital Universitario Virgen Macarena, Sevilla; Pedro Hergueta, María Dolores Guerrero- Aznar; Hospital Costa del Sol, Marbella (Málaga); Jose María Navarro, José Ramón Prado; Hospital Minas de Riotinto, Huelva; Antonio Garrido-Serrano, Esperanza Quintero; Hospital Universitario Reina Sofía, Córdoba; Carmen Gálvez, Manuel Cárdenas; Hospital Juan Ramón Jiménez, Huelva; Manuel Ramos, Salvador Gruntzmancher; Hospital Universitario Virgen del Rocío, Sevilla; José Luis Márquez, María Angeles Pizarro, Trinidad Desongles; Hospital de Alarcos, Ciudad Real; Cristóbal Martínez-Delgado, Otilia Santos, Cristóbal Montojo, Pedro Carpintero. 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7 ERADICATION OF H. PYLORI INFECTION IN ULCER PATIENTS Van Zanten SJ, Goldie J, Hollingsworth J, Silletti C, Richardson H, Hunt RH. Secretion of intravenous administered antibiotics in gastric juice: implications for management of Helicobacter pylori. J Clin Pathol 1992; 45: Ortiz RA, Calafatti SA, Corazzi A, et al. Amoxicillin and ampicillin are not transferred to gastric juice irrespective of Helicobacter pylori status or acid blockade by omeprazole. Aliment Pharmacol Ther 2002; 16: Sung JJ, Chung SC, Hosking SW, et al. Mucosal pharmacokinetics and pilot study of short course of parenteral imipenem in the eradication of Helicobacter pylori. J Gastroenterol Hepatol 1995; 10: Adamek RJ, Opferkuch W, Wegener M. Short-term omeprazole oral/amoxicillin intravenous therapy for Helicobacter pylori eradication. A lack of therapeutic effect. Am J Gastroenterol 1994; 89: Adamek RJ, Wegener M, Labenz J, Freitag M, Opferkuch W, Röld GH. Medium-term results of oral and intravenous omeprazole/amoxicillin Helicobacter pylori eradication therapy. Asm J Gastroenterol 1994; 89: Adamek RJ, Wegener M. Combined intravenous and oral omeprazole/amoxicillin therapy in patients with Helicobacter pylori-positive acute peptic ulcer bleeding. Am J Gastroenterol 1993; 88: 1980.