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Helicobacter pylori and peptic-ulcer disease
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Helicobacter pylori and peptic-ulcer disease Sir—Jia-Qing Huang and colleagues report on the role of Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) in peptic ulcer disease (Jan 5, p 14).1 We believe their conclusion that H pylori raises ulcer risk in patients using these drugs is erroneous and arises by selection. Their conclusions on the prevalence of endoscopically detected ulcers are based on four or five studies selected from 16 that met their inclusion criteria. Although they state reasons for excluding reports, six of those not selected do not support their findings. Furthermore, the conclusions of other well designed studies addressing this question, which did not meet their inclusion criteria, differ from their own. Moreover, in the selected studies, no control who had an ulcer was negative for H pylori and NSAID use. This zero rate required statistical modelling by adding a constant pseudo count. Therefore, data calculated by comparison are distorted pseudo estimates. Clinical trials, which provide a far larger, more rigorous, controlled, prospective data source were not analysed. In such studies, results have shown effects that range from increased risk of ulceration in H pylori-positive patients taking NSAIDs2 to no effect and greater effectiveness of acidsuppression,2 and overall do not support Huang and colleagues’ conclusions. Selection bias may also exist in the analysis of ulcer bleeding. A large study that was not analysed shows an opposite effect to that of Huang and colleagues.3 Again, clinical trials in which clinically important ulcer complications were the primary endpoint do not support a role for H pylori,4 whereas a significant reduction in such events, in patients on NSAIDs or rofecoxib in endoscopic studies, has been reported.5 If these papers had been included, no additive risk between H pylori and NSAIDs on ulcer bleeding would have been evident. The aims and methods of the included studies are heterogeneous, which makes it debatable whether
meta-analysis, defined as combined analysis of similar studies to produce a unifying conclusion, is an appropriate statistical tool. For reasons that are unclear, the primary conclusion of the nine studies of ulcer bleeding differ from Huang and colleagues’ conclusions (reduced ulceration in two, reduced gastric ulceration in one, no effect in four, enhanced ulcer risk in one, and lowered subgroup risk in one).2 Prescribers need to know what to do when an NSAID user presents with a clinical event such as a bleeding peptic ulcer. Trial data show that 18·8% of such patients will have a further ulcer bleeding episode if they have H pylori eradication and continue taking an NSAID, compared with 4·4% if they continue taking NSAIDs and a protective proton-pump inhibitor and do not have H pylori eradication. Since there are no data, prescribers can make their own decisions about giving H pylori eradication as well as protonpump inhibitor, but should bear in mind that H pylori eradication will reduce the effectiveness of proton pump inhibitors at lowering the concentration of intragastric acid by a hundred-fold.2 *J R Boulton-Jones, C J Hawkey Division of Gastroenterology, Queens Medical Centre, Nottingham, NG7 2UH, UK (e-mail: [email protected]) 1
2
3
4
5
Huang J-Q, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in pepticulcer disease: a meta analysis. Lancet 2002; 359: 14–22. Hawkey CJ. Helicobacter pylori, NSAIDS and cognitive dissonance. Aliment Pharmacol Ther 1999; 13: 695–702. Stack WA, Atherton JC, Hawkey GM, Logan RFA, Hawkey CJ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther 2002; 16: 497–506. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–28. Hawkey CJ, Laine L, Harper SE, et al. Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials. Aliment Pharmacol Ther 2001; 15: 1593–601.
THE LANCET • Vol 359 • June 1, 2002 • www.thelancet.com
Sir—Jia-Qing Huang and colleagues1 and Francis Chan and colleagues (Jan 5, p 9),2 with an accompanying Jan 5 Commentary from Roy Pounder,3 discuss the role of H pylori and NSAIDs in peptic-ulcer disease, and the need for bacterial eradication before NSAID treatment is started. In Chan and colleagues’ report and in virtually all the studies reviewed by Huang and colleagues, the patients enrolled were assessed by non-invasive tests for H pylori status (serology, urea breath test, or both). In addition to possible false-positive and falsenegative results, especially in patients taking antisecretive drugs, as Pounder notes, these non-invasive tests give us no data about the status of gastroduodenal mucosa. When we are starting a study of the role of H pylori and NSAIDs, we know exactly the time at which NSAID treatment begins, but we do not know for how long the bacterial infection persists, which gastric areas are colonised, and how serious the damage due to the infection is. We have shown that H pylori and NSAIDs are independent causal factors of peptic ulceration and that different NSAIDs have minimum inhibitory concentrations that may be active in vivo against H pylori.4 From a pathophysiological point of view, it seems obvious that a chemical attack by NSAIDs should quickly increase the damage of a mucosa already seriously damaged by a long-term bacterial infection.5 By contrast, gastroduodenal colonisation by H pylori may be inhibited by the presence of large areas of epithelial erosion due to NSAIDs and by the direct activity of the drugs. Until endoscopy-based studies with histological assessment of seriate biopsy samples are done, we believe that available data do not permit definitive conclusions. Michele Caselli, *Vittorio Alvisi School of Gastroenterology, University of Ferrara, 46 Via Borsari, 44100 Ferrara, Italy (e-mail: [email protected]) 1
Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in
1943
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Helicobacter pylori and peptic-ulcer disease Sir—Jia-Qing Huang and colleagues report on the role of Helicobacter pylori and non-steroidal anti-inflammatory drugs (NSAIDs) in peptic ulcer disease (Jan 5, p 14).1 We believe their conclusion that H pylori raises ulcer risk in patients using these drugs is erroneous and arises by selection. Their conclusions on the prevalence of endoscopically detected ulcers are based on four or five studies selected from 16 that met their inclusion criteria. Although they state reasons for excluding reports, six of those not selected do not support their findings. Furthermore, the conclusions of other well designed studies addressing this question, which did not meet their inclusion criteria, differ from their own. Moreover, in the selected studies, no control who had an ulcer was negative for H pylori and NSAID use. This zero rate required statistical modelling by adding a constant pseudo count. Therefore, data calculated by comparison are distorted pseudo estimates. Clinical trials, which provide a far larger, more rigorous, controlled, prospective data source were not analysed. In such studies, results have shown effects that range from increased risk of ulceration in H pylori-positive patients taking NSAIDs2 to no effect and greater effectiveness of acidsuppression,2 and overall do not support Huang and colleagues’ conclusions. Selection bias may also exist in the analysis of ulcer bleeding. A large study that was not analysed shows an opposite effect to that of Huang and colleagues.3 Again, clinical trials in which clinically important ulcer complications were the primary endpoint do not support a role for H pylori,4 whereas a significant reduction in such events, in patients on NSAIDs or rofecoxib in endoscopic studies, has been reported.5 If these papers had been included, no additive risk between H pylori and NSAIDs on ulcer bleeding would have been evident. The aims and methods of the included studies are heterogeneous, which makes it debatable whether
meta-analysis, defined as combined analysis of similar studies to produce a unifying conclusion, is an appropriate statistical tool. For reasons that are unclear, the primary conclusion of the nine studies of ulcer bleeding differ from Huang and colleagues’ conclusions (reduced ulceration in two, reduced gastric ulceration in one, no effect in four, enhanced ulcer risk in one, and lowered subgroup risk in one).2 Prescribers need to know what to do when an NSAID user presents with a clinical event such as a bleeding peptic ulcer. Trial data show that 18·8% of such patients will have a further ulcer bleeding episode if they have H pylori eradication and continue taking an NSAID, compared with 4·4% if they continue taking NSAIDs and a protective proton-pump inhibitor and do not have H pylori eradication. Since there are no data, prescribers can make their own decisions about giving H pylori eradication as well as protonpump inhibitor, but should bear in mind that H pylori eradication will reduce the effectiveness of proton pump inhibitors at lowering the concentration of intragastric acid by a hundred-fold.2 *J R Boulton-Jones, C J Hawkey Division of Gastroenterology, Queens Medical Centre, Nottingham, NG7 2UH, UK (e-mail: [email protected]) 1
2
3
4
5
Huang J-Q, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in pepticulcer disease: a meta analysis. Lancet 2002; 359: 14–22. Hawkey CJ. Helicobacter pylori, NSAIDS and cognitive dissonance. Aliment Pharmacol Ther 1999; 13: 695–702. Stack WA, Atherton JC, Hawkey GM, Logan RFA, Hawkey CJ. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther 2002; 16: 497–506. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–28. Hawkey CJ, Laine L, Harper SE, et al. Influence of risk factors on endoscopic and clinical ulcers in patients taking rofecoxib or ibuprofen in two randomized controlled trials. Aliment Pharmacol Ther 2001; 15: 1593–601.
THE LANCET • Vol 359 • June 1, 2002 • www.thelancet.com
Sir—Jia-Qing Huang and colleagues1 and Francis Chan and colleagues (Jan 5, p 9),2 with an accompanying Jan 5 Commentary from Roy Pounder,3 discuss the role of H pylori and NSAIDs in peptic-ulcer disease, and the need for bacterial eradication before NSAID treatment is started. In Chan and colleagues’ report and in virtually all the studies reviewed by Huang and colleagues, the patients enrolled were assessed by non-invasive tests for H pylori status (serology, urea breath test, or both). In addition to possible false-positive and falsenegative results, especially in patients taking antisecretive drugs, as Pounder notes, these non-invasive tests give us no data about the status of gastroduodenal mucosa. When we are starting a study of the role of H pylori and NSAIDs, we know exactly the time at which NSAID treatment begins, but we do not know for how long the bacterial infection persists, which gastric areas are colonised, and how serious the damage due to the infection is. We have shown that H pylori and NSAIDs are independent causal factors of peptic ulceration and that different NSAIDs have minimum inhibitory concentrations that may be active in vivo against H pylori.4 From a pathophysiological point of view, it seems obvious that a chemical attack by NSAIDs should quickly increase the damage of a mucosa already seriously damaged by a long-term bacterial infection.5 By contrast, gastroduodenal colonisation by H pylori may be inhibited by the presence of large areas of epithelial erosion due to NSAIDs and by the direct activity of the drugs. Until endoscopy-based studies with histological assessment of seriate biopsy samples are done, we believe that available data do not permit definitive conclusions. Michele Caselli, *Vittorio Alvisi School of Gastroenterology, University of Ferrara, 46 Via Borsari, 44100 Ferrara, Italy (e-mail: [email protected]) 1
Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and nonsteroidal anti-inflammatory drugs in
1943
For personal use. Only reproduce with permission from The Lancet Publishing Group.