RSS Feeds
-
Letter of reply to all correspondents
Submit responseWe would like to thank all correspondents for their considered comments. Lin, Han, Kaako and Piscoya raised concerns about the use of placebo as a comparator in our study of peptic ulcer bleed patients. When this study was planned, the efficacy of intravenous PPI for treatment of peptic ulcer bleed was still in question and there was no approved comparator treatment. After full discussion of the design with health agencies (FDA and EMEA), it was agreed that the study should be placebo- controlled and this design has resulted in the first approval of intravenous PPI for this indication in a number of countries. Now that the efficacy of intravenous PPI has been accepted by health authorities, we agree in principal with both Lin and Yih that it would be logical to explore different dosages of intravenous therapy and also the possible utility of oral PPI therapy. A comparison of oral with iv therapy may require very many patients, however, even if a non-inferiority design is chosen to demonstrate similar efficacy.
Lin also raised concerns about the low mortality and rebleeding rates observed in our study. Whilst we agree that the study quoted by Lau et al (New Engl J Med 2007;356:1631-40) studied pre-emptive therapy with omeprazole and so had a different design, there was a placebo group, permitting comparison of mortality rates, although we do accept that patients in that study were probably a lower risk group. However, other recent studies in PUB patients have reported similarly low mortality rates (Jensen et al, Am J Gastroenterol 2006;101:1991-1999, and van Rensburg et al, Aliment Pharmacol Ther 2009;29:497-507). We also attempted to provide other explanations in the manuscript for the low mortality rates, such as exclusion of patients with the worst prognosis ie highest ASA scores. Some earlier studies also included more patients who first bled as “inpatients” rather than “outpatients”, making them clinically high- risk patients.
Concerning the low re-bleeding rates observed, there was a strong emphasis on efficient endoscopic treatment in our study, which we consider to be one of its strengths, in that even with such state of the art therapy, profound acid suppression still provided additional benefit. The issue of whether to standardise endoscopic therapy in the study was thoroughly discussed within the steering committee with the view that various endoscopic approaches were used in different centers. We reached a decision deliberately to allow “real world” endoscopic treatment , in order to evaluate the true value of adjuvant esomeprazole therapy in current clinical practice. If one controls too many variables in a study, there may be criticism for making the design remote from reality.
Yih raised an issue concerning the multi-ethnicity in our study. Whilst our study population was largely Caucasian, a sufficient number of Asians were included to permit separate analyses of their data, allowing them to be examined as an “internal control” in the study.
Finally, in response to the comments of Kaako and Dib concerning sponsorship by a pharmaceutical company, there was complete transparency in all interactions between the steering committee and sponsor in this study and even the formation of an “at arms length” Data and Safety Monitoring Board. This was affirmed in Dib’s comment.
Conflict of Interest:
None declared
-
High Dose PPI vs placebo or Low Dose PPI?
Submit responseI read with great interest the article by Sung et al. (1). However, it seems to be no news on the issue that proton pump inhibitors (PPI) are better than placebo in the treatment of ulcer bleeding, this was assessed for over a decade and there are even some studies of cost effectiveness that support this conclusion (2).
There are also some studies that used low dose PPI and found that there are no differences between high or low doses of PPI (3,4,5).
So, maybe the issue should be whether or not is is ethical to continue to use placebo as a control when there is enough evidence that PPI should be used in peptic ulcer bleeding and perhaps the only new studies on this issue should be the ones that compare different doses or the ones that evaluate the cost-effectiveness of these different doses.
References
1. Sung JJ, Barkun A, Kuipers EJ, Mossner J, Jensen DM, et al. Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding: A Randomized Trial. Ann Intern Med Feb 16.2009;150(7):455-64.
2. van Zanten S. Cost-effectivenessof intravenous proton pump inhibitors in high risk bleeders. Can J Gastroenterol 2004;18(2):749-50
3. Udd M, Miettinen P, Palmu A, Heikkinen M, Janatuinen E. et al. Regular-dose versus High-dose Omeprazole in Peptic Ulcer Bleeding. A Prospective Randomized Double-blind Study. Scand J Gastroenterol 2001;12: 1332-8.
4. Hung WK, Li VKM, Chung CK, Ying MWL, Loo CK et al.Randomized trial comparing pantoprazole infusion, bolus and no treatment on gastric pH and recurrent bleeding in peptic ulcers.ANZ J. Surg. 2007; 77: 677–681
5. Andriulli A, Loperfido S, Focareta R, Leo P, Fornari F et al.High-Versus Low-Dose Proton Pump Inhibitors After Endoscopic Hemostasis in Patients With Peptic Ulcer Bleeding: A Multicentre, Randomized Study. Am J Gastroenterol 2008;103:3011–3018
Conflict of Interest:
None declared
-
Low-dose Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding
Submit responseTo the editor:
We read with great interest the excellent paper by Sung JJ and colleagues (1). They concluded that high-dose intravenous esomeprazole given after successful endoscopic therapy to patients with high-risk peptic ulcer bleeding reduced recurrent bleeding at 72 hours and had sustained clinical benefits for up to 30 days.
Since studies have shown that antacid might improve outcomes in patients with peptic ulcer bleeding (2), one issue that need to be raised was whether it was ethical to treat these patients with placebo. We strongly suggest that the authors should further investigate whether high- dose intravenous esomeprazole prevents recurrent peptic ulcer bleeding better than low-dose intravenous esomeprazole, instead of placebo.
References:
1 Sung JJ, Barkun A, Kuipers EJ, Mossner J, Jensen DM, Stuart R, et al. Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding: A Randomized Trial. Ann Intern Med Feb 16.2009;150(7):455-64.
2 Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med. 2000;343:310-6.
Conflict of Interest:
None declared
-
Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding: A Randomized Trial
Submit responseI read with interest about your trial to evaluate the role of intravenous esomeprazole to prevent peptic ulcer re-bleeding. I agree that there are only a few studies that did not show significant difference of proton-pump inhibitors use in the treatment of peptic ulcer disease. For instance, Villanueva's study (1) suggested that omeprazole does not improve the efficacy of ranitidine after endoscopic injection therapy in patients with an active arterial bleeding ulcer. Also Daneshmend's study (2) concluded that there is no justification to the routine use of acid inhibiting drugs in the management of haematemesis and melaena.
However, looking at the whole picture is crucial to evaluate that effect. Multiple studies have shown significant effect of PPI in the treatment of acute bleeding ulcer (3, 4, 5).
Furthermore, two metanalysis of the related studies showed positive benificial effect. Gisbert's metanalysis (6) suggested that PPI are more effective than H2 blocker in preventing persistent or recurrent bleeding from peptic ulcer. Leontiadis GI et al (7) metaanalysis suggests that treatment with PPI reduces the risk of rebleeding and the requirement for surgery after ulcer bleeding.
With these thoughts in mind, that may raise the question about the ethical issue of using placebo instead of PPI which showed efficacy in the treatment of acute GI bleed as suggested above.
Another point we should keep in the back of our minds is the conflict of interest from conducting that large multicenter study which was funded by a pharmaceutical company.
Anyhow, this study provides further evidence to support the use of high-dose intravenous esomeprazole as adjuvant therapy to endoscopic therapy in the western white population.
References:
(1) Omeprazole versus ranitidine as adjunct therapy to endoscopic injection in actively bleeding ulcers: a prospective and randomized study. Villanueva C et al. Endoscopy 1995 May; 27(4):308-12
(2) Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. Daneshmend TK et al. BMJ 1992 Jan 18;304(6820):143-7
(3) A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Lin HJ et al. Arch Intern Med 1998 Jan 12;158(1):54-8
(4) A comparison of omeprazole and placebo for bleeding peptic ulcer. Khuroo MS et al. N Engl J Med 1997 Apr 10;336(15):1054-8
(5) Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomized double-blind placebo-controlled multicentre study. Schaffalitzky de Muckadell OB et al. Scand J Gastroenterol 1997 Apr;32(4):320-7.
(6) Proton pump inhibitors versus H2-antagonists: a meta-analysis of their efficacy in treating bleeding peptic ulcer Gisbert JP. Aliment Pharmacol Ther 2001 Jul;15(7):917-26.
(7) Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding. Leontiadis GI et al. BMJ 2005 Mar 12;330(7491):568. Epub 2005 Jan 31
Conflict of Interest:
None declared
-
On Trying to be Objective
Submit responseEven though conflicts of interest are made very clear in this paper (as it should always), we must keep in mind that when research is funded by the pharmaceutical industry and/ or employees are involved, it is more likely to encounter with favourable outcomes than otherwise (1).
References
1) Tungaraza T, Poole R. Influence of drug company authorship and sponsorship on drug trial outcomes. Br J Psychiatry, 2007;191:82-3.
Conflict of Interest:
None declared
-
Proton Pump Inhibitor in Bleeding Peptic Ulcers
Submit responseWe would like to comment on the article by Sung et al.(1), which reaffirmed the clinical effectiveness of infusional esomeprazole as an adjuvant pharmacotherapy for high-risk bleeding peptic ulcers.
First, it is extraordinary that the rebleeding rate and mortality rate in the placebo recipients were 13.6% and 2.1%, noticeably lower than most previous reports. A recent Cochrane meta-analysis revealed a rebleeding rate of 19.2% and a mortality rate of 4.9% in the bleeding ulcer patients receiving placebo(2). Unfortunately, the authors did not explain the discrepancy regarding recurrent bleeding, and their explanation for mortality was confusing. They argued that the lower-than- expected mortality rate was similar to those reported most recently by Lau and colleagues(3)." However, the Lau study aimed to explore the effect of preemptive proton pump inhibitor (PPI) before endoscopy and therefore comprised heterogeneous bleeders. We do not understand why this study could be comparable to the Lau study, in which only 60% of the participants bled from peptic ulcers; moreover, most of them (even the preemptive placebo group) did not have high-risk stigmata.
Second, this study did not standardize endoscopic therapy and failed to provide sufficient information to ensure that the results were unbiased. The categorization of epinephrine injection, thermocoagulation, and hemoclipping in the same group was inappropriate, inasmuch as the hemostatic effect of epinephrine injection was inferior to that of the other two modalities. In fact, optimal hemostasis can be achieved by thermocoagulation or hemoclipping alone, but not by injection therapy alone. Furthermore, with 764 patients from 91 centers, on average fewer than 10 patients were managed in the same hospital. Because endoscopic therapy depends on the operator's skill, we wonder how the investigators adjusted for probable technical variance across these institutions.
Third, we think this study missed an opportunity to achieve a greater impact on current practice, in that placebo was chosen as the comparative drug. The efficacy of infusional PPI in bleeding peptic ulcers was already demonstrated in our study a decade ago(4), and had been supported by compelling evidence by the time the present study was initiated. In a meta -analysis study published in May 2005, Leontiadis et al.(5) already concluded PPI reduced recurrent peptic ulcer bleeding in both Western and Asian trials, notwithstanding a quantitatively (not qualitatively) greater effect in Asian patients. In our opinion, this study should have adopted another PPI, a different dosage, or oral administration as the comparator.
References:
1. Sung JJ, Barkun A, Kuipers EJ, Mossner J, Jensen DM, Stuart R, et al. Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding: A Randomized Trial. Ann Intern Med Feb 16. 2009;150(7) [epub ahead of print]
2. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta-analysis of randomized controlled trials. Mayo Clin Proc 2007;82:286-96.
3. Lau JY, Leung WK, Wu JC, Chan FK, Wong VW, Chiu PW, et al. Omeprazole before endoscopy in patients with gastrointestinal bleeding. N Engl J Med 2007;356:1631-40.
4. Lin HJ, Lo WC, Lee FY, Perng CL, Tseng GY. A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med 1998;158:54-8.
5. Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta-analysis: enhanced efficacy of proton-pump inhibitor therapy for peptic ulcer bleeding in Asia--a post hoc analysis from the Cochrane Collaboration. Aliment Pharmacol Ther 2005;21:1055-61.
Conflict of Interest:
None declared
-
PPI therapy for acute bleeding:missed opportunities and deja-vu all over again.
Submit responseThe authors(1) conclude that this is the first international trial supporting the efficacy of high dose intravenous (iv) proton pump inhibitor (PPI) therapy in patients with acute peptic ulcer bleeding in Caucasians. We have several concerns with this statement. First, initially the authors’ intent was to study a multiethnic population which would have been enlightening as trials to this date have only focused on Asian and Non-Asian populations. However as stated before this trial was primarily comprised of Caucasians. We believe that this population has been studied numerous times before (13 trials in 3219 patients) (2) and this trial adds little to existing evidence.
Second, in the Cochrane review (2) that the authors quote, the issue of high dose versus low dose is addressed and their conclusions were that there does not seem to be an advantage of higher doses of PPI based on indirect comparisons. Third and most important, this trial does not address the issue of oral versus IV PPI therapy. Again in the Cochrane review (2) there was no association of PPI route with treatment effect based on indirect comparisons. In addition a recent head to head randomized controlled trial (RCT) (3) found oral omeprazole as effective as iv omeprazole in patients with acute peptic ulcer bleed in terms of mortality, re-bleeding and surgery. We acknowledge that indirect comparisons and one small RCTs do not provide sufficient evidence for the equivalent effectiveness of oral therapy. We do believe that this raises an important signal and that there is a need for more RCTs comparing oral to iv therapy. In order to justify the authors’ conclusions the study should have compared high dose PPI with low dose PPI rather than placebo. In terms of missed opportunities this trial should have included an oral PPI therapy treatment arm to fill in the clinically important gaps in existing evidence.
References
1. Sung JJY, Barkun A, Kuipers EJ et al. Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding: A Randomized TrialAnn Intern Med Feb 16. 2009;150(7)
2.Leontiadis G I, Sharma V K, Howden C W. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD002094. DOI: 10.1002/14651858.CD002094.pub3.
3.Yilmaz S, Bayan K, Tuzun Y et al. A head to head comparison of oral versus intravenous omeprazole for patients with bleeding peptic ulcers with a clean base, flat spots and adherent clots. World Journal of Gastroenterology 2006;12(48):7837-43
Conflict of Interest:
None declared