Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding
BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.38356.641134.8F (Published 10 March 2005) Cite this as: BMJ 2005;330:568
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Sir,
In their reply to my letter [1], Howden and colleagues [2] spend considerable time indulging in a straw man fallacy. At no time did I say or imply that I interpreted their data as proving that PPIs increase the mortality in patients with bleeding peptic ulcers. However, I still believe that their comment that “… there may have been too few patients in our pooled analysis of mortality to enable us to detect a difference” [3] is curious. At best, it creates unnecessary doubt and, at worst, it raises the spectre of bias. The authors should ask themselves why, after analysing the results of 18 studies with a total of 2,774 patients and producing an odds ratio of 1.11 (CIs 0.79-1.57), they chose to make a comment that suggested that proton pump inhibitors may, after all, reduce mortality.
Howden et al. suggest that I have misinterpreted the statement in their paper that “It is, however, a remarkably consistent observation that such treatment reduces rates of rebleeding and, in general, the need for surgical intervention.” They say that the consistency refers to the subgroup analysis yet, in the context of the statement, there is nothing to indicate that this is the case. It is the responsibility of the authors to ensure that such misinterpretations are avoided and this could have been achieved simply by qualifying the phrase “consistent observation”. They should re-read the final paragraph in the published paper and ask themselves whether or not it might have been made more explicit.
Howden et al. judge the study by Hasselgren et al. [4] to be an outlier and, by referring to the low mortality rate in the placebo group, implicitly raise questions about the validity of its results. Although the selection of the study by Hasselgren et al. for particular scrutiny may be justified on statistical grounds, it may also be viewed as a one-sided reaction to unwelcome results.
Throughout their reply, Howden et al. repeatedly imply that I did not read the complete on-line version of their paper. This is simply untrue. Indeed, it was the contents of Table I – only available on-line – that drew my attention to the possible relevance of the different location of studies included in their meta-analysis.
Howden et al. do not agree with my exclusion of comparative studies between PPIs and H2-receptor antagonists. I focussed on the results the seven placebo-controlled randomised trials because the matter in question is not whether PPIs are superior to H2-receptor antagonists but rather whether PPIs are of benefit to patients with acute peptic ulcer haemorrhage in terms of reducing mortality, re-bleeding or surgery. As it happens, these seven studies also turn out to be the largest in the meta- analysis. Concentrating on the placebo-controlled studies, the striking finding was the difference in the efficacy of PPIs in terms of re-bleeding between the three studies from Europe and the four from Asia. None of the European studies reported any reduction in re-bleeding with PPIs whereas three of the four Asian trials showed benefit. Regardless of the reasons for this discrepancy – and, as outlined in my letter [1], there may be other factors apart from the differences in the populations studied – this finding is crucial to any recommendations regarding the management of patients. Clearly, if we are concerned about the external validity of the data, then we should base recommendations on those studies which recruited patients who most closely reflect the target population. Thus, in the United Kingdom, we should give preference to data from studies performed here and in the rest of Europe. Accordingly, we should conclude that the relevant data do not show that PPIs reduce mortality, re-bleeding or surgery in patients with peptic ulcer haemorrhage.
No doubt, this interpretation of the data will be anathema to the advocates of meta-analysis. But, before they rush to criticise, they may, perhaps, stop and wonder why it is that this methodology may so readily lead to a clash with common sense.
References
[1] Penston J. An alternative interpretation of the data. BMJ. Rapid responses, 14th march 2005.
[2] Howden CW, Leontiadis GI, Sharma VK. An alternative interpretation of the data. BMJ. Rapid responses, 22nd March 2005.
[3] Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta- analysis of proton pump inhibitor therapy in peptic ulcer bleeding. BMJ 2005;330;568-70.
[4] Hasselgren G, Lind T, Lundell L, Aadland E, Efskind P, et al. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicentre study.Scand J Gastroenterol 1997;32;328-33.
Competing interests: None declared
Competing interests: No competing interests
Re: Evidence that omeprazole causes organ dysfunctions?
EDITOR: Many of Dr Fiddian-Green’s provocative comments are unrelated to our work. Objective measures of shock or its metabolic consequences were not available to us from the published trials we reviewed. We will not reiterate here our views on the mortality data - but we invite Dr Fiddian-Green to read our response to Dr Penston. We considered only “all- cause” mortality and agree fully with Dr Fiddian-Green’s presumption that not all the deaths that occur following ulcer bleeding are directly related to the actual bleed. We have made no statement or study of any possible long-term metabolic consequences of PPI therapy. All we would state in mitigation is that these drugs have been intensively and extensively studied and there have been millions of patient-years of exposure. Had some relatively – or extremely – infrequent but unusual adverse event been encountered, it is likely to have been detected even with our admittedly imperfect monitoring systems. We do not recommend the routine use of PPI therapy for patients undergoing general anaesthesia because we are unaware of any evidence from randomised controlled trials to attest to its efficacy, appropriateness or need.
Grigoris I Leontiadis, consultant gastroenterologist, Department of Gastroenterology, University Hospital of North Durham, Durham DH1 5TW
Virender K Sharma, associate professor, Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259, USA
Colin W Howden, professor,
Division of Gastroenterology, Northwestern University Feinberg School of
Medicine, Chicago, IL 60611, USA
c-howden@northwestern.edu
Competing interests: As stated in our original publication
Competing interests: No competing interests
RESPONSE: Re: Risk of rebleeding with adherent clot
EDITOR: Dr Ammar says that we mentioned that patients with bleeding peptic ulcers with endoscopic findings of adherent clot have low risk of rebleeding. The exact phrasing we used was: "Endoscopic findings that predict rebleeding, surgical intervention, and death include active arterial bleeding, oozing of blood, or a non-bleeding visible vessel. Patients with an adherent clot in the base of the ulcer are at lower risk." We did not say or mean to imply that they were at "low risk"; they are, however, at "lower" risk compared to patients with arterial bleeding, oozing of blood, or a non-bleeding visible vessel. In any case, this issue is not of critical importance to the aims and results of our review.
Laine provided an editorial to the paper by Jensen and colleagues that Dr Ammar cites (ref #5 in the long version of our paper)1. In that, Dr Laine mentions "The appearance of an ulcer at endoscopy, however, provides important additional prognostic information. Data from older studies in which patients received no endoscopic therapy indicate that surgery for further bleeding was required in 0.5% of patients with clean- based ulcers, 6% of those with flat pigmented spots, 10% of those with clots in the ulcer base, 34% of those with nonbleeding visible vessels, and 35% of those with active bleeding"; and also: "Reported prevalences of clots in patients with bleeding ulcers are widely variable, ranging from 0 to 50%, whereas rebleeding rates also vary markedly, from 8% to 36%."
Grigoris I Leontiadis, consultant gastroenterologist, Department of Gastroenterology, University Hospital of North Durham, Durham DH1 5TW
Virender K Sharma, associate professor, Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259, USA
Colin W Howden, professor, Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA c-howden@northwestern.edu
Competing interests: As per our initial publication
Competing interests: No competing interests
Re: An alternative interpretation of the data
We provided pooled mortality rates for the convenience of readers so that they could form some idea of the average risk of mortality in each intervention group. One should not draw the conclusion that there was a true or meaningful difference in mortality between these two groups just because of a small absolute numerical difference. In fact, this difference of 0.6% represents the absolute risk difference (RD) for mortality. One needs to know the 95% CI and the statistical significance of such a difference. These were not provided for RD in the paper as, in consultation with the Cochrane Collaboration, we had pre-determined to use the odds ratio (OR) as the measure of pooled effect. We can, however, now also provide full information on the RD of 0.006 (95% CI = -0.01 to 0.02; P = 0.55). This is clearly non-significant and should be interpreted as insufficient evidence of any effect (either detrimental or beneficial) of PPIs on mortality. This was the principal conclusion stated in our paper.
Had the RD been non-significantly in favour of PPI treatment, we would still have reached the same conclusion.
There is a clear outlier effect from the study of Hasselgren et al in which the mortality rate was higher in the PPI-treated patients than in those given placebo (6.9% vs. 0.6%)1. We assume that Dr Penston would agree that a mortality of 0.6% among elderly patients with ulcer bleeding (which was the group specifically recruited for that trial) is, to say the least, unexpected – especially as many of the patients with high-risk endoscopic stigmata did not receive endoscopic haemostatic therapy. We invite Dr Penston to view the complete on-line version of our manuscript and consider the sensitivity analyses we conducted around this specific issue. When, by sensitivity analysis, we removed this trial, the pooled mortality rates became 5.0% for PPI and 5.2% for control (RD = 0.002; 95%CI = -0.02 to 0.01; OR = 0.95; 95%CI = 0.66 to 1.36). Again this result is far from significant – in any conventional sense of the word.
Furthermore, the non-significant trend in favour of control treatment was clearly not robust to the exclusion of the trial with the most extreme results; in fact the "non-significant trend" can easily be inverted in favour of PPI treatment. Mortality has been surprisingly difficult for us to study because, compared to re-bleeding, it was a relatively uncommon event. We feel justified in stating that “… there may have been too few patients in our pooled analysis of mortality data to enable us to detect a difference” because there were only 71 deaths among 1371 patients on PPI treatment in the pooled mortality analysis, and 65 out of 1403 patients on control treatment. It is hardly surprising that these pooled rates are not robust to sensitivity analysis.
In the complete on-line version of the meta-analysis, we carefully identified those RCTs that were placebo-controlled and those that compared a PPI with an H2-receptor antagonist (H2RA). In one of the pre-specified sub-group analyses, we found essentially the same overall conclusions from the placebo-controlled and the H2RA-controlled trials. We do not, therefore, accept Dr Penston’s imputation that valid conclusions can be drawn only from placebo-controlled trials. However, if he wishes to do so, he will find essentially the same conclusions as from our full analysis.
Dr Penston attempts to support his arguments by “vote counting”: simply adding up the numbers of “positive” and “negative” studies for individual end-points of interest. Such a simplistic approach cannot take account of the relative sample sizes and methodological quality scores of the individual trials and is best avoided lest unsupportable conclusions are prematurely drawn.
Dr Penston also questions our comments on the consistency of our findings. In this, it must be made clear that we did not use consistency to refer to results of individual trials, but rather to the pooled results of the various pre-determined sub-group analyses regarding re-bleeding and surgical intervention rates. (Indeed, had the results of individual RCTs all been consistent with each other, there would have been no need for a systematic review and meta-analysis.) We invite Dr Penston to examine Table 3 in the on-line version of our paper. We should state that such a table was – for the purposes of space – omitted from the print version of the paper but is freely available on-line. In each of these sub-group analyses, the findings were highly consistent – that is that PPI therapy did not influence all-cause mortality but did reduce re-bleeding and usually reduced surgery.
Dr Penston also questions our impartiality. As required by the British Medical Journal and the Cochrane Collaboration (and as we would anyway have insisted upon), we provided a full and detailed summary of our relationships with those pharmaceutical companies marketing PPIs. We believe in the principle of full disclosure and will leave it up to the readership of the BMJ to decide if our judgement has been in any way impaired by these relationships. It is our collective and sincere belief that it has not. Furthermore, this was not a concern voiced by the editorial staff of the BMJ or by its expert external reviewer. Nor was this concern expressed by any of the four international experts who acted as reviewers of our manuscript for the Cochrane Collaboration.
Dr Penston’s closing paragraphs contains errors of perception, errors of fact and differences of opinion and interpretation. First, and as we have extensively reviewed above, we have never attempted to promote the notion that PPIs improve survival from ulcer bleeding. Second, we believe that there is evidence for reduced rates of re-bleeding and surgical intervention resulting from PPI therapy for ulcer bleeding in European trials. However, the magnitude effect is noticeably greater in Asian trials. A post hoc analysis comparing results of trials conducted in Asia and elsewhere is currently in press elsewhere and was presented in 2004 at Digestive Diseases Week in New Orleans 2. Lastly – and something that we can hopefully agree upon as a difference of opinion or emphasis – we do not agree that there is no role for IV PPI therapy for patients with recently bleeding peptic ulcers. For those patients who receive endoscopic haemostatic therapy for ulcer bleeding, there is compelling evidence that such therapy reduces the re-bleeding risk. Although, the individual trials administered IV PPI therapy for 72 hours, it is our practice to switch patients to oral PPI therapy sooner than that if they are clinically stable and can take oral medication. We agree with Dr Penston’s impression that IV PPI therapy may have been over-used in certain circumstances. We cannot make any concluding statements about the value – or lack thereof – of administering IV PPI therapy before diagnostic endoscopy in patients with upper gastrointestinal tract bleeding since our review focused only on patients with endoscopically-confirmed bleeding ulcer.
Grigoris I Leontiadis, consultant gastroenterologist, Department of Gastroenterology, University Hospital of North Durham, Durham DH1 5TW
Virender K Sharma, associate professor, Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259, USA
Colin W Howden, professor, Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA c-howden@northwestern.edu
References
1. Hasselgren G, Lind T, Lundell L, Aadland E, Efskind P, Falk A, et al. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicenter study. Scand J Gastroenterol 1997;32: 328-33.
2. GI Leontiadis, L McIntyre, VK Sharma, CW Howden. Influence of geographical location of randomized controlled trials on effectiveness of PPI treatment in ulcer bleeding: A post hoc analysis of a Cochrane Collaboration systematic review. Gastroenterology 2004, 126: A-192.
Competing interests: As stated in our initial publication
Competing interests: No competing interests
This is a important study because it illustrates the pitfalls in failing to include an objective metabolic measure of shock, the most relevant variable, in the analysis of the data.
The authors concluded that, "Proton pump inhibitor treatment had no significant effect on mortality (odds ratio 1.11, 95% confidence interval 0.79 to 1.57; number needed to treat (NNT) incalculable) but reduced rebleeding (0.46, 0.33 to 0.64; NNT 12) and surgery (0.59, 0.46 to 0.76; NNT 20)" (1). They added that, "Results were similar when the meta- analysis was restricted to the 10 trials with the highest methodological quality:". Yet as James Penston oberved in his rapid rsponse, "there was a non-significant increase in mortality in patients receiving proton pump inhibitors compared with controls (5.2% v 4.6%)". Might we be looking at two opposing effects, a beneficial effect on bleeding and need for surgery to stop it and an adverse effect upon the ability to withstand the bleeding and/or surgery?
A case has been made for proton pump inhibitors having a mitochondrial effect in all cells, one that impairs their cytpoprotctive response to acute reductive stress such as that likely to be imposed by haemorrhage (2). The fear is that in so doing it may increase the risk of developing organ dysfunctions and death from them. Even in the absence of acute reductive stress proton pump inhibitors have caused organ injury, microscopic colitis and interstitial nephritis. If proton pump inhibitors can cause organ dysfunctions in patients exposed to acute reductive stress the anaesthetic practice of administering proton pump inhibitors before elective surgery to reduce the risk of aspiration pneumonia (3) could be having a similar effect.
The problem is that organ dysfunctions and deaths can occur so long after the intitiating event (4) that they are often considered unrelated events and can be omitted from analyses of outcome even after surgery. A myocardial infarct if often interpeted as an unavoidable act of God. Deaths occurring mor than 30 days later are also often considered unrelated events. They may not be. Consider fractured hips.
There is a significant difference in mortality between patients having surgery within 24 hours of admission (20%) and those having surgery beyond 24 hours of admission (50%). Even when only the healthy subgroup of ASA I and II patients were considered, the relative risk of death was 4.5 times greater if surgery occurred after 24 hours from admission. More importantly the attrition continues threafter, the overall mortality at 1 year being 14%, at 2 years 26%, and at 3 years 33% (5). The same trend almost certainly occurs in the case of bleeding ulcers. A much longer view is required in measuring outcomes from therapeutic interventions for acute events.
Proton pump inhibitors are most likely to cause organ dysfunctions in those who have developed severe acute reductive stress. The very likely inclusion of a majority of patients who did not, in the studies included in this meta-analysis, might have concealed a real effect. The increase in mortality from 4.6% to 5.2% might be real and better defined by stratifying patients by the severity of their shock and/or number of units of blood they received. In the absence of measurements of gastric intramucosal pH shock is unlikely to be accurately defined especially in its degree and duration (6,7).
The real concern might be for the long term administration of proton pump inhibitors. Might it increase the risk of organ dyfunctions and death in all acute illnesses, including all accidents, acute cardiovascular events, and systemic infections? Might the hypothetical risk of proton pump inhibitors even be cummulative? What of the potential for the adverse effect being additive with those of other drugs and also causing chronic organ dyfunctions (8)?
These pressing questions are never going to be answered by The Adverse Event Reporting System (AERS) designed to support the FDA's post- marketing safety surveillance program for all approved drug and therapeutic biologic products (9).
1. Grigoris I Leontiadis, Virender K Sharma, and Colin W Howden Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding BMJ 2005; 330: 568
2. Microscopic colitis: the tip of an omeprazole iceberg? Richard G Fiddian-Green eCMAJ, 25 Nov 2004 eLetter re: Sandra Dial Clostridium difficile colitis: A marker for ischemic colitis? CMAJ 2004; 171: 1326-1327
3. Memis D, Turan A, Karamanlioglu B, Saral P, Ture M, Pamukcu Z. The effect of intravenous pantoprazole and ranitidine for improving preoperative gastric fluid properties in adults undergoing elective surgery. Anesth Analg. 2003 Nov;97(5):1360-3.
4. Associations between intramucosal acidosis in the gut and organ failure. Crit Care Med. 1993 Feb;21(2 Suppl):S103-7.
5. Hamlet WP, Lieberman JR, Freedman EL, Dorey FJ, Fletcher A, Johnson EE. Influence of health status and the timing of surgery on mortality in hip fracture patients. Am J Orthop. 1997 Sep;26(9):621-7.
6. Hamilton-Davies C, Mythen MG, Salmon JB, Jacobson D, Shukla A, Webb AR. Comparison of commonly used clinical indicators of hypovolaemia with gastrointestinal tonometry. Intensive Care Med. 1997 Mar;23(3):276-81.
7. Fiddian-Green RG, Haglund U, Gutierrez G, Shoemaker WC. Goals for the resuscitation of shock. Crit Care Med. 1993 Feb;21(2 Suppl):S25-31.
8. Iatrogenic diseases with a common cause? Richard G Fiddian-Green (25 October 2002) eLetter re: Edward H Wagner and Trish Groves Care for chronic diseases BMJ 2002; 325: 913-914
9. Adverse Event Reporting System. www.fda.gov/cder/aers/default.htm
Competing interests: Patents issued in my name
Competing interests: No competing interests
Sir,
The conclusion of the meta-analysis by Leontiadis et al. [1] that proton pump inhibitors are of benefit in the acute management of peptic ulcer haemorrhage is clearly open to question.
In terms of mortality, none of the 18 studies included in the analysis of the primary end-point reported any significant reduction in the death from bleeding peptic ulcers with proton pump inhibitors. Indeed, there was a non-significant increase in mortality in patients receiving proton pump inhibitors compared with controls (5.2% v 4.6%). Given this, it is difficult to understand why the authors felt obliged to comment that “… there may have been too few patients in our pooled analysis of mortality data to enable us to detect a difference” which, in the context of the discussion section, must be taken to imply a difference in favour of proton pump inhibitors. With regard to the secondary end-points, only four of 19 studies reported a reduction in re-bleeding and only two of 17 showed a statistically significant reduction in surgery. It is extraordinary, therefore, that the authors stated that “It is, however, a remarkably consistent observation that such treatment reduces the rates of rebleeding and, in general, the need for surgical intervention”. Where, one may ask, is the consistency? And where is the impartiality? Surely authors with such close links to the pharmaceutical industry should make more of an effort to dispel any suggestion of bias in the interpretation of the data.
Of the 21 studies included in the meta-analysis, only seven were placebo-controlled [2-8]; these were the largest trials and, unlike some of the remainder, all were double-blind. The three largest studies were from Europe: none demonstrated any reduction in either mortality or re- bleeding; only one reported a reduction in surgery and in this study the upper 95% confidence interval was close to one. [2-4] The four other placebo-controlled trials were carried out in Asia: again, none reported any reduction in mortality; three showed a statistically significant decrease in re-bleeding while only one reported a reduction in surgery. [5 -8] Are these differences accounted for by variations in response to proton pump inhibitors in different populations or do they reflect other differences in the design, performance or analysis of trials? Furthermore, should these differences be taken into account when considering the external validity of the data?
The meta-analysis by Leontiadis et al. once again draws attention to the limitations of this methodology. The studies analysed were heterogeneous in terms of the patients recruited, the drugs used, the routes of administration and the controls. It is not surprising, therefore, that differences in outcome were observed between different studies, leading to confusion and uncertainty. Yet, when the forest plots are cleared away and the fog of statistics is dispersed, there are some useful conclusions to be gleaned from the data set provided in this study. Firstly, proton pump inhibitors do not reduce mortality from peptic ulcer haemorrhage. Secondly, in European populations, there is no evidence that these drugs reduce the rate of re-bleeding or surgery. And finally, given the absence of any therapeutic benefit in favour of parenteral over oral administration and accepting the failure to reduce mortality, re-bleeding or surgery, there can surely be no justification for the current fashion for intravenous proton pump inhibitors in the management of patients with peptic ulcer haemorrhage.
In one respect, the study by Leontiadis et al. leaves the management of peptic ulcer haemorrhage unchanged. Patients with bleeding ulcers will, of course, continue to receive proton pump inhibitors and, as before, these drugs will be prescribed to promote healing. But the notion that these drugs improve survival or reduce the risk of re-bleeding or surgery – at least in European populations – is without foundation and, hence, the emergency care of patients with bleeding peptic ulcers should no longer include intravenous proton pump inhibitors.
References
[1] Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta- analysis of proton pump inhibitor therapy in peptic ulcer bleeding. BMJ 2005;330;568-70.
[2] Daneshmend TK, Hawkey CJ, Langman MJ, Logan RF, Long RG. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. BMJ 1992;304;143-7.
[3] Hasselgren G, Lind T, Lundell L, Aadland E, Efskind P, et al. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicentre study.Scand J Gastroenterol 1997;32;328-33.
[4] Schaffalitsky de Muckadell OB, Havelund T, Harling H, Boesby S, et al. Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomised double-blind placebo-controlled multicentre study. Scand J Gastroenterol 1997;32;320-7.
[5] Khuroo MS, Yattoo GN, Javid G, Khan BA, Shah AA, et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med 1997;336;1054-58.
[6] Lau JYW, Sung JJY, Lee KKC, Yung M, Wong SKH, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000;343;310-6.
[7] Javid G, Masoodi I, Zargar S, Khan BA, Yatoo GN, et al. Omeprazole as adjuvant therapy to endsocopic combination sclerotherapy for treating bleeding peptic ulcer. Am J Med 2001;111;280-4.
[8] Kaviani MJ, Hashemi MR, Kazemifar AR, Roozitalab S, et al. Aliment Pharmacol Ther 2003;17;211-6.
Competing interests: None declared
Competing interests: No competing interests
Dr Howden and his colleagues mentioned in their systematic review (1) that patients with bleeding peptic ulcers with endoscopic findings of adherent clot has low risk of rebleeding, however the risk of rebleeding in the reference mentioned in their systematic review (2) was 35.3% for medically treated patients versus 0% endoscopically treated patients (P = 0.011). In a another RCT (3) which compared endoscopic treatment versus medical therapy for patients with adherent clot , the risk of rebleeding was 34.1 % for patients who received medical treatment versus 4.8% in the endoscopic treatment arm , which again you cannot consider it as low risk for rebleeding .
Hussam Ammar MD Missouri , USA
1-Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding .Grigoris I Leontiadis, Virender K Sharma, Colin W Howden
2-Jensen DM, Kovacs TO, Jutabha R, Machicado GA, Gralnek IM, Savides TJ, Smith J, Jensen ME, Alofaituli G, Gornbein J. Gastroenterology. 2002 Aug;123(2):407-13.
3-Bleau, BL, Gostout, CJ, Sherman, KE, et al. Recurrent bleeding from peptic ulcer associated with adherent clot: A randomized study comparing endoscopic treatment with medical therapy. Gastrointest Endosc 2002; 56(1): 1-6
Competing interests: None declared
Competing interests: No competing interests
Re: Re: Evidence that omperazole causes organ dysfunctions?
In replying to my eLetter the authors state, "All we would state in mitigation [of my concerns about shock being inadequately managed and proton pump inhibitors possibly causing organ dysfunctions] is that these drugs have been intensively and extensively studied and there have been millions of patient-years of exposure".
May I draw their attention to the Finnish epidemiological data published in 2002 showing the changes in peptic ulcer disease that have occurred in the 10 years since the introduction of histamine-2-receptor antagonists and proton-pump inhibitors (1). Although the number of elective operations for ulcer disease fell a dramatic 89% overall annual admission rate from ulcer disease increased 79%, the number of emergency operations for performation and bleeding increased 44%, the overall mortality increased 31%, and that from perforations and haemorrhage increased 74%.
Although the blame for these alarming trends cannot be laid at the door of the proton-pump inhibitors per se the data are a serious indictment of "modern" medical management in general certainly in Finland. Part of the problem might be that therapeutic attentions have been focused upon treating mutiple effects without fully apprciating or knowing how the treatments are impacting upon them(2,3,4).
1. Paimela H, Paimela L, Myllykangas-Luosujarvi R, Kivilaakso E. Current features of peptic ulcer disease in Finland: incidence of surgery, hospital admissions and mortality for the disease during the past twenty- five years. Scand J Gastroenterol. 2002 Apr;37(4):399-403.
2. R G Fiddian-Green Diagnostic endoscopy: does it help? Gut 2004;53:913
3. Fiddian-Green RG. Is peptic ulceration a hormonal disease? Lancet. 1977 Jan 8;1(8002):74-7.
4. Tovey FI, Hobsley M, Kaushik SP, Pandey R, Kurian G, Singh K, Sood A, Jehangir E. Duodenal gastric metaplasia and Helicobacter pylori infection in high and low duodenal ulcer-prevalent areas in India. J Gastroenterol Hepatol. 2004 May;19(5):497-505.
Competing interests: None declared
Competing interests: No competing interests