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Drug treatment of non-variceal upper gastrointestinal bleeding
BaillieÁre's Clinical Gastroenterology Vol. 14, No. 3, pp. 357±364, 2000
doi:10.1053/bega.2000.0084, available online at http://www.idealibrary.com on
1 Drug treatment of non-variceal upper gastrointestinal bleeding M. J. S. Langman Professor of Medicine Department of Medicine, University of Birmingham, UK
Despite many clinical investigations, proof is lacking that pharmacological treatments signi®cantly in¯uence the outcome in non-variceal upper gastrointestinal bleeding. Reaching conclusions has been hindered by the small size of many studies in a situation in which a large number of patients must be included if con®dent conclusions are to be reached. In addition, many studies, by comparing two potentially active treatments without a placebo group, have been unable to determine whether an equivalence of the active treatments represents equivalent but active or equivalent but inactive therapy. Key words: peptic ulcer; gastrointestinal bleeding; drug therapy.
The treatment of bleeding peptic ulcer has gone through several phases. It has evolved from an initial belief in gastric rest, to a realization that withholding ¯uid led to circulatory collapse and uraemic death. The succeeding phase of liberal feeding, ¯uid intake and blood transfusion represented, in essence, a laissez-faire approach, acknowledging that medical intervention, except to replace blood lost, did more harm than good. Early diagnosis then enjoyed a vogue, but it was insecurely placed because diagnostic knowledge was unaccompanied by eective means of dierential intervention, the place of surgery being de®ned by the occurrence of severe repeated bleeding rather than by selection according to speci®c risks associated with the ulcer. The development of eective anti-secretory and anti-®brinolytic agents, and the demonstration that potent acid inhibition induced ulcer healing, led to trials of pharmacotherapy in peptic ulcer bleeding in a period overlapping with the introduction of endoscopic treatment. Pharmacotherapy has a logical basis in that acid peptic inhibition, apart from inducing ulcer healing, inhibits ®brinolysis, thus tending to stabilize clotting around bleeding vessels, a process that is enhanced by aminocaproic acid derivatives. To what extent have the logical bases of pharmacological treatment led to real improvements in the management of peptic ulcer bleeding? Many treatment trials have been carried out, followed by the inevitable meta-analyses seeking to establish whether underpowered studies provide common threads suggesting eective therapy against a background of demonstrable ecacy with regard to physical endoscopic therapies. 1521±6918/00/030357+08 $35.00/00
c 2000 Harcourt Publishers Ltd. *
358 M. J. S. Langman
ASSESSING TREATMENT VALUE The indices available to assess the response to therapy include visible re-bleeding, the need for electrophysical endoscopic treatment, the emergency operation rate and the death rates, as well as the intermediate markers of transfusion rate and altered length of hospital stay. To be persuasive, common patterns of, for example, reduced rebleeding, operation rate and death rate are required. In addition, studies of quality should be expected to be randomized and double-blind, with a clearly speci®ed primary end-point and with evident power of discrimination between what is eective and ineective at that end-point. Methods of case selection should be clear, so that the reader can deduce whether a given study suggests that treatment can be shown to work in those selected, or, more importantly, whether it can be shown to work in unselected consecutive cases likely to be similar to those found in ordinary clinical practice. These criteria have, however, seldom been met.1 Meta-analytic techniques should in their turn take account of the problems by examining data sets to determine whether they are likely to be representative of the general run of case series, and by seeking to ®nd sets that have gone unreported. Such sets tend to dier from those published, by negativity of outcome (reporting bias). Data examination for consistency depends on the analysis of variation between series and upon the use of funnel plots that array clinical series according to size. On the hypothesis that unreported sets are often small and apparently lacking in any suggestion of bene®t, such plots can tend to show that smaller reported series are more likely to be in favour of the treatment oered, suggesting a publication bias. In cardiovascular disease and cancer treatment, it is generally accepted that either very large, simple trials or, alternatively, robust aggregations of data from disparate studies are required if reliable conclusions on treatment ecacy are to be drawn. Such studies are generally lacking when examining outcome in bleeding peptic ulcer.
INITIAL TRIALS OF ANTI-SECRETORY AGENTS USING H2-ANTAGONISTS Table 1 shows the data from trials conducted up to 15 years ago, on the H2 antagonist treatment of ulcer bleeding arrayed according to the size of the study.2 Power is not only generally lacking, but also severely lacking in individual studies. The ®gures could nevertheless be aggregated to suggest that treatment might be eective but that further investigations would be needed to obtain a con®rmation of this. Plausibility depended upon a demonstration that better results appeared to be obtainable in gastric than duodenal ulcer bleeding, as might be expected if acid inhibition were easier to achieve in the relatively hyposecretory stomach of the gastric ulcer patient. Table 2 compares the contribution of the 13 smallest trials in Table 1a, involving a total of 508 patients, with that of the 13 largest trials, with 2162 patients, in terms of reductions in the re-bleeding, operation and death rates. The smallest trials, although including only one-®fth of the patients, account for most of the modest reduction in rebleeding (suggesting a possible bias) with no dierence in contribution to the just signi®cant reductions in the operation and death rates. Subsequent data have given mixed and indierent support to the thesis that acid inhibition is eective. This might be because treatment is pharmacodynamically
Drug treatment of non-variceal bleeding 359 Table 1. Contributions to overall change in chances of bleeding, operation and death according to series size during treatment in 26 trials of H2-antagonists. Series
No. included
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Total
Bleeding
Operation
Death
19 21 28 29 29 30 37 40 40 48 60 62 65 69 72 88 88 93 100 105 109 113 150 158 213 519
ÿ1.6 1.1 0 ÿ0.6 ÿ1.9 1.4 ÿ1.5 ÿ0.5 0.6 ÿ0.5 ÿ3.3 1.7 ÿ5.4 1.5 0 ÿ0.1 2.9 ÿ3.4 ÿ4.0 0.9 ÿ0.8 ± ± ÿ3.3 0.6 ÿ0.4
± 1.1 ÿ1.5 0 ÿ0.4 ± ± ÿ0.5 0 ÿ0.5 ÿ0.7 2.5 ÿ2.8 ± 0 0.9 2.4 ÿ0.4 ÿ3.5 0.7 ÿ0.7 ÿ0.2 ÿ6.0 ÿ1.8 ÿ2.5 ÿ1.9
± 0.5 0.5 0 ÿ1.9 ± 0.5 1.0 0.8 1.0 0 0.1 ÿ3.2 ± ÿ1.8 ÿ0.1 0.5 ÿ1.5 0 ÿ1.0 0.5 ÿ0.6 ÿ1.5 0.6 0 ÿ7.5
2660
ÿ12.3
ÿ15.8
ÿ13.6
Table 2. Contributions to observed dierence between the observed and expected values of the 13 smallest series. Bleeding
Operation
Death
13 smallest (n 508)
ÿ10.5
ÿ2.8
ÿ1.7
13 largest (n 2152)
ÿ1.8
ÿ13.0
ÿ11.9
ÿ12.3
ÿ15.8
ÿ13.6
Total Typical odds ratio 95% Con®dence interval Statistical signi®cance
0.89 0.73±1.08 Not signi®cant
0.78 0.61±1.00 0.05
0.70 0.50±0.96 0.02
ineective or because, even though it is eective, it does not in¯uence the immediate outcome in gastroduodenal arterial bleeding. Pharmacodynamics An examination of the eects of H2-antagonists on acid secretion have shown that inhibition is most obvious when the natural secretory drive is low, i.e. during fasting and at night. In contrast, acidity, at least when measured as acid concentration, is less aected after meals.
360 M. J. S. Langman
In theory, administering histamine H2-antagonists intravenously might therefore be expected to demand a higher dose and would ideally utilise continuous intravenous administration with intragastric pH monitoring to titrate the dosage against ¯uctuating requirements. Such studies have shown that a continuous infusion of famotidine of the order of 3 mg per hour, about twice the recommended oral dose used in treating gastro-oesophageal re¯ux, can markedly raise acidity in pH terms.3,5±8 The alternative method of obtaining rapid, profound acid secretory inhibition is by the use of a proton pump inhibitor. With the exemplar drug omeprazole, this is not rapidly achievable with oral treatment, full inhibition in this situation taking 48±72 hours to develop. This is because inhibition takes place only when the proton pump is actively working. A bolus intravenous dosage, or preferably a primed infusion of a proton pump inhibitor, is therefore necessary to provide a sustained and consistent inhibition of secretion. In this context, it should be noted that pH is a logarithmic scale, and inhibition to, for example, a pH of 4 implies a thousand-fold reduction in acidity, which will be accompanied by a reduced secretory volume. An initial bolus dosage with 40 mg or probably preferably 80 mg omeprazole, followed by an infusion of 4±8 mg per hour, is most likely to raise the pH above 6.0, but whether such profound secretory inhibition is required clinically in managing patients with haematemesis and melaena is unclear.3,9±11 Later trials of H2-antagonists and proton pump inhibitors These trials have depended almost entirely upon randomized trials of proton pump inhibitors, compared with either a placebo or with H2-antagonists. Placebo-controlled trials are clearly preferable, given the possibility that H2-antagonists might themselves have useful eects, albeit possibly less than those of proton pump inhibitors. The data obtained in placebo-controlled trials have provided mixed and confusing results. In the largest trial, Daneshmend et al12 examined outcome in terms of the death, transfusion, re-bleeding and operation rates in 1147 patients admitted with haematemesis and melaena of all types, treatment being started at admission and consisting of omeprazole 80 mg intravenously as a bolus dose, followed by parenteral doses of 40 mg three times every 8 hours and then 40 mg orally twice daily. Treatment was double blind. There was no signi®cant dierence in the death rate (omeprazole 6.9%, placebo 5.3%) nor in the transfusion need (52% and 53% respectively) or re-bleeding (15% and 18%) or operation rate (11% and 11%). These negative ®ndings contrast with evidence of bene®t in trials in Denmark, Sweden and India. All these trials were smaller, and the bene®t was apparently greatest in the smallest. In Denmark13, 274 patients were randomly assigned to intravenous omeprazole 80 mg as a bolus dose, then 8 mg per hour for 72 hours and subsequently oral treatment 20 mg daily. The primary ecacy measure was the worst, ranking on a scale death 5, surgery 4, additional endoscopic treatment 3, more than 3 units of blood 2, and 1±3 units of blood 1. Bene®t (P 0.004) was found on this composite scale as a primary variable, and 91% of the omeprazole-treated group did not die, did not need surgery and did not need additional endoscopic treatment, compared with 80% of those receiving placebo. The second, Swedish, study involved 330 patients aged 60 and over who were allocated to a virtually identical regimen or placebo.14 The overall outcome was signi®cantly improved (P 0.017), as were the secondary variables of a reduced operation rate (P 0.003) and the degree (P 0.004) and duration (P 0.003) of bleeding. In the ®rst of these two studies, the mortality rate did not dier between omeprazole and
Drug treatment of non-variceal bleeding 361
placebo, while in the second it was higher in those receiving omeprazole (6.9% compared with a very low rate of 0.6% on placebo). The fourth trial15, on 220 ulcer patients with stigmata of recent bleeding in India, used oral omeprazole 40 mg twice daily for 5 days or placebo. The re-bleeding, operation and transfusion rates diered markedly (re-bleeding 10.9% and 36.4% respectively, operative rate 7.3% and 23.6%, and transfusion rate 29.1% and 70.1%). These trials are dicult to reconcile. The Swedish and Danish studies used marginally more eective anti-secretory regimens than did the UK study. Composite outcomes diered signi®cantly and favoured omeprazole-takers in the Scandinavian studies, but with no evidence of an eect on the death rate. In contrast, the Indian study used an oral regimen that would be expected to be slowly eective compared with parenteral drug, but it had the most favourable results on active agent. The dierence in transfusion rate is striking despite a similar initial haemoglobin level of 9.8 and 9.6 g/dl in the omeprazole and placebo recipients respectively. By examining the published data, we can calculate what proportion of blood transfusions were carried out because of recurrent bleeding and therefore what proportion must have related to initial haemodynamic needs or prior anaemia. In omeprazoletakers, 13.6% of patients were noted to have continued, spurting or recurrent bleeding, but the overall transfusion rate was 29.1%. We can deduce, therefore, that 15.5% received transfusion for clinical stabilization rather than because of recurrent bleeding. In contrast, 39% of placebo-takers showed recurrent bleeding of all types, yet 70.1% were transfused; 31.1% can thus be deduced to have received blood for stabilization. These data suggest a marked imbalance in the need for initial transfusion despite an apparently similar initial haemoglobin level. The authors suggest that the parietal cell mass in Indian patients is relatively low and thus explains the ecacy of oral treatment, although the other main factor to consider is access to active proton pumps, which is much more ecient with intravenous drugs. Other studies using proton pump inhibition are relatively unhelpful because active comparators, usually ranitidine, were employed. The number treated was usually small, and no consistent treatment eects were noted.16±23 A further large placebo-controlled study24 was carried out with the H2-antagonist famotidine in patients with endoscopically demonstrated gastric and duodenal ulcers thought to be likely to re-bleed (with oozing, black slough, fresh clot attached or a visible vessel). Four hundred and ninety-seven patients received famotidine 10 mg intravenously as a bolus and then at a rate of 3.2 mg per hour, 508 receiving an identicallooking placebo. The treatment groups were well matched, but the outcome did not dier materially, the death rates being 6.2% and 5.0% respectively, the re-bleeding rates 23.9% and 25.5%, and the operation rates 15.5% and 17.1%. The treatment regimen was tested for anti-secretory ecacy before the trial and raised the pH to above 6.0. The overall conclusion from these studies probably has to be that if anti-secretory treatment with histamine H2-antagonists or omeprazole is useful, the bene®ts are marginal.
SOMATOSTATIN AND ITS ANALOGUES The outcomes of trials employing somatostatin more or less parallel those from trials using H2-antagonists or omeprazole.25±29 Small studies have shown promise; larger ones have not indicated bene®t, although some have suggested a change in indicators
362 M. J. S. Langman
such as the transfusion rate. The bases for suggesting bene®t have included a reduction in gastrin, gastric acid and pepsin secretion, as well as splanchnic blood ¯ow. A large trial using the natural hormone and conducted in 630 patients admitted with haematemesis and melaena of all causes showed no favourable trend in death rate (somatostatin 9.8%, placebo 7.9%), an almost identical operation rate (somatostatin 35%, placebo 34%) but less re-bleeding (somatostatin 70%, placebo 89%; although the dierence was not signi®cant). It could be argued that infusions of the natural hormone with its very short half-life would not give eective secretory control. However, another reasonably large trial26 conducted in 273 patients using a long-acting analogue has also a negative result. Trials have generally been of small size. No other trial has included 100 patients, and there is trend towards positive trials being relatively small.26 HAEMOSTASIS BY PHARMACOLOGICAL METHODS OTHER THAN ACID INHIBITION If haemorrhage is to be stemmed, we have to promote clotting in bleeding vessels and/or vascular contraction. A direct attack on the bleeding vessels by endoscopic methods such as sclerosing injections and heater probes has been successful, but this has the practical disadvantage that individual endoscopic intervention is required. Patient management would be much simpli®ed by the introduction of pharmacological treatment that would reduce or stem haemorrhage but be independent of a knowledge of the site or nature of the bleeding lesion. Since gastric juice has ®brinolytic properties, there is a case for using inhibitors, provided they are safe and in particular do not predispose to thrombosis in sites where it is not wanted. Tranexamic acid has been subjected to testing on several occasions.30±34 Undesirable pro-thrombotic properties in areas outside the gastrointestinal tract have not proved clinically problematic, although the database obtained in patients with bleeding peptic ulcers is limited. The particular reason for requiring evidence of safety in gastrointestinal use is that gastrointestinal bleeding is generally associated with a raised circulatory platelet count. Whether this enhances pro-thrombotic tendencies is unclear, but it is reasonable to require data showing that the chance of thrombosis in sites outside the stomach is not enhanced. By the same token, evidence of ecacy is also limited. Meta-analysis35 has suggested that the use of tranexamic acid is bene®cial, but the data are heavily weighted by one trial indicating a signi®cantly reduced risk of death, albeit without the expected commensurate eects on the risk of re-bleeding.33 CONCLUSION There is a lack of clear and consistent evidence that anti-secretory or anti-®brinolytic treatment is clinically bene®cial in peptic ulcer bleeding. Smaller trials have indicated bene®t more often than larger ones, suggesting a publication bias, and in addition by the use of clinical indicators as surrogates for important outcomes. Much eort has been devoted to devising drug regimens that guarantee anacidity, but without generating clear and unequivocal evidence that such powerful measures are bene®cial. Many trials have used potentially active comparators, but they often suer from the defects of small size and a lack of clear, prede®ned outcome measures, as well as failing
Drug treatment of non-variceal bleeding 363
to produce evidence of clinically important changes in outcome. Although it is quite probable that the use of anti-secretory drugs modestly reduces the re-bleeding rate, the eect on clinical outcome is less clear. The case for increasingly powerful clinical regimens in this context has not been made. Anti-®brinolytics may be as eective, or more so, but they have been less well tested, and the outcome of meta-analysis is heavily skewed by a single relatively large trial. The mortality rate has been unaected, although it is noteworthy in this context that the death rate in the larger reported trials has been relatively low. In the UK, the death rate seen in the larger trials has been about half that found in a recent general survey of the outcome of peptic ulcer bleeding.36 This may mean that patients whose disease is likely to have a poor outlook have tended to be missed, or excluded, from those studies. The consequences are twofold: ®rst, the power of studies to ®nd a real dierence in outcome is, if present, reduced, and second, doubts are raised about the generalizability of any conclusions based on the trial data. Taken overall, there is indierent support for the use of pharmacological treatment in managing peptic ulcer or other types of non-variceal upper gastrointestinal bleeding.
REFERENCES 1. Langman MJS. Upper gastrointestinal bleeding: the trials of trials. Gut 1985; 26: 217±220. 2. Collins R & Langman M. Treatment with histamine H2 antagonists in acute upper gastrointestinal haemorrhage. New England Journal of Medicine 1985; 313: 660±666. 3. Reynolds JR, Walt RP, Clark AG et al. Intragastric pH monitoring in acute upper gastrointestinal bleeding and the eects of intravenous cimetidine and ranitidine. Alimentary Pharmacology and Therapeutics 1987; 1: 23±30. 4. Walt RP, Reynolds JR, Langman MJS et al. Intravenous omeprazole rapidly raises intragastric pH. Gut 1985; 26: 902±906. 5. Labenz J, Peitz U, Leusing C et al. Ecacy of primed infusions of high dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut 1997; 40: 36±41. 6. Merki HS, Witzel L, Kaufman D et al. Continuous infusions of famotidine maintain high intragastric pH in duodenal ulcer. Gut 1988; 29: 453±457. 7. Fullarton GM, MacDonald AM, Mann SG & McColl KEL. Controlled study of the eects of intravenous famotidine on intragastric pH in bleeding peptic ulcers. Alimentary Pharmacology and Therapeutics 1991; 5: 77±84. 8. De Graef J & Woussen-Colle MC. In¯uence of the stimulation state of the parietal cells on the inhibitory eect of omeprazole on gastric acid secretion in dogs. Gastroenterology 1986; 91: 333±337. 9. Lind T, Moore M & Olbe L. Intravenous omeprazole eect on 24 hour intragastric pH in duodenal ulcer patients. Digestion 1986; 34: 7486. 10. Killerich S, Rannem T & Elsborg L. Eect of intravenous infusion of omeprazole and ranitidine on twenty-four hour intragastric pH in patients with a history of duodenal ulcer. Digestion 1995; 56: 25±30. 11. Labenz J, Peitz U, Leusing C et al. Ecacy of primed infusions with high dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut 1997; 40: 36±41. 12. Daneshmend TK, Hawkey CJ, Langman MJS et al. Omeprazole versus placebo for acute upper gastrointestinal bleeding: randomised double blind controlled trial. British Medical Journal 1992; 304: 143±147. 13. de Muckadell OBS, Havelund T, Harlind S et al. Eect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomised double blind placebo controlled multicentre study. Scandinavian Journal of Gastroenterology 1997; 32: 320±327. 14. Hasselgren G, Lind T, Lundell L et al. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Scandinavian Journal of Gastroenterology 1997; 32: 328±333. 15. Khuroo MS, Yattoo GN, Javid G et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. New England Journal of Medicine 1997; 336: 1054±1058.
364 M. J. S. Langman 16. Brunner G & Chang J. Intravenous therapy with high doses of ranitidine and omeprazole in critically ill patients with bleeding peptic ulceration of the upper gastro-intestinal tract: an open randomised controlled trial. Digestion 1990; 45: 217±225. 17. Cardi M, Muttilo IA, Amadori L et al. Intravenous omeprazole versus ranitidine in the treatment of haemorrhagic duodenal ulcer: a prospective randomised study. Annales de Chirurgie 1997; 51: 136±139. 18. Goletti O, Sidoti F, Lippolis PV et al. Omeprazole versus ranitidine plus somatostatin in the treatment of severe gastroduodenal bleeding: a prospective, randomised controlled trial. Italian Journal of Gastroenterology 1994; 26: 72±74. 19. Lanas A, Artal A, Blas J et al. Eect of parenteral omeprazole and ranitidine on gastric pH and the outcome of bleeding peptic ulcer. Journal of Clinical Gastroenterology 1995; 21: 103±106. 20. Mohammed SA & Al Karawi MA. Omeprazole versus histamine H2 receptor antagonists in the treatment of acute upper non-variceal bleeding. Hepatogastroenterology 1996; 43: 863±865. 21. Peres Flores R, Garcia Molinero MJ, Herrero Quiros C et al. The treatment of upper digestive haemorrhage of peptic origin: intravenous ranitidine versus intravenous omeprazole. Revista Espanola de Enfermedades Digestivas 1994; 86: 637±641. 22. Prassler R, Hendrich H, Barnet J et al. Do proton pump inhibitors after endoscopic control of acute ulcer haemorrhage have an advantage of H2 receptor antagonists? Zeitschrift fuÈr Gastroenterologie 1995; 24: 431±434. 23. Villanueva C, Balanzo J, Torras X et al. Omeprazole versus ranitidine as adjunct therapy to endoscopic injection in actively bleeding ulcers: a prospective and randomised study. Endoscopy 1995; 27: 308±312. 24. Walt RP, Cottrell J, Mann SG et al. Continuous intravenous famotidine for haemorrhage from peptic ulcer. Lancet 1992; 340: 1058±1062. 25. Basile M, Celi S & Parisi A. Somatostatin in the treatment of severe upper gastro-intestinal bleeding of peptic origin. Italian Journal of Surgical Science 1984; 14: 31±35. 26. Chrisiansen J, Ottenjann R & von Arx F. Placebo controlled trial with the somatostatin analogue SMS 201-995 in peptic ulcer bleeding. Gastroenterology 1989; 97: 568±574. 27. Magnusson I, Ihre T, Johansson C et al. Randomised double blind trial of somatostatin in the treatment of massive upper gastro-intestinal haemorrhage. Gut 1985; 26: 221±226. 28. Somerville KW, Henry DA, Davies JG et al. Somatostatin in treatment of haematemesis and melaena. Lancet 1985; 1: 130±132. 29. Torres AJ, Landa I, Hernandez F et al. Somatostatin in the treatment of severe upper gastrointestinal bleeding: a multicentre controlled trial. British Journal of Surgery 1986; 73: 786±789. 30. Cormack F, Chakrabarti RR, Jouhar AJ & Fearnley GR. Tranexamic acid in upper gastrointestinal haemorrhage. Lancet 1973; 1: 1207±1208. 31. Biggs JC, Hugh TB & Dodds AJ. Tranexamic acid and upper gastrointestinal haemorrhage ± a double blind trial. Gut 1976; 17: 729±734. 32. Engqvist A, Brostrom O & Feilitzen F. Tranexamic acid in massive haemorrhage from the upper gastrointestinal tract ± a double blind study. Scandinavian Journal of Gastroenterology 1979; 14: 839±844. 33. Barer D, Ogilivie A, Henry D et al. Cimetidine and tranexamic acid in the treatment of acute upper gastrointestinal tract bleeding. New England Journal of Medicine 1983; 308: 1571±1575. 34. von Holstein CC, Eriksson SBS & Kallen R. Tranexamic acid as an aid to reducing blood transfusion requirements in gastric and duodenal bleeding. British Medical Journal 1987; 294: 7±10. 35. Henry DA & O'Connell DL. Eects of ®brinolytic inhibitors on mortality from upper gastrointestinal haemorrhage. British Medical Journal 1989; 298: 1142±1146. 36. Rockall TA, Logan RFA, Devlin HB et al. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. British Medical Journal 1995; 311: 222±226.
doi:10.1053/bega.2000.0084, available online at http://www.idealibrary.com on
1 Drug treatment of non-variceal upper gastrointestinal bleeding M. J. S. Langman Professor of Medicine Department of Medicine, University of Birmingham, UK
Despite many clinical investigations, proof is lacking that pharmacological treatments signi®cantly in¯uence the outcome in non-variceal upper gastrointestinal bleeding. Reaching conclusions has been hindered by the small size of many studies in a situation in which a large number of patients must be included if con®dent conclusions are to be reached. In addition, many studies, by comparing two potentially active treatments without a placebo group, have been unable to determine whether an equivalence of the active treatments represents equivalent but active or equivalent but inactive therapy. Key words: peptic ulcer; gastrointestinal bleeding; drug therapy.
The treatment of bleeding peptic ulcer has gone through several phases. It has evolved from an initial belief in gastric rest, to a realization that withholding ¯uid led to circulatory collapse and uraemic death. The succeeding phase of liberal feeding, ¯uid intake and blood transfusion represented, in essence, a laissez-faire approach, acknowledging that medical intervention, except to replace blood lost, did more harm than good. Early diagnosis then enjoyed a vogue, but it was insecurely placed because diagnostic knowledge was unaccompanied by eective means of dierential intervention, the place of surgery being de®ned by the occurrence of severe repeated bleeding rather than by selection according to speci®c risks associated with the ulcer. The development of eective anti-secretory and anti-®brinolytic agents, and the demonstration that potent acid inhibition induced ulcer healing, led to trials of pharmacotherapy in peptic ulcer bleeding in a period overlapping with the introduction of endoscopic treatment. Pharmacotherapy has a logical basis in that acid peptic inhibition, apart from inducing ulcer healing, inhibits ®brinolysis, thus tending to stabilize clotting around bleeding vessels, a process that is enhanced by aminocaproic acid derivatives. To what extent have the logical bases of pharmacological treatment led to real improvements in the management of peptic ulcer bleeding? Many treatment trials have been carried out, followed by the inevitable meta-analyses seeking to establish whether underpowered studies provide common threads suggesting eective therapy against a background of demonstrable ecacy with regard to physical endoscopic therapies. 1521±6918/00/030357+08 $35.00/00
c 2000 Harcourt Publishers Ltd. *
358 M. J. S. Langman
ASSESSING TREATMENT VALUE The indices available to assess the response to therapy include visible re-bleeding, the need for electrophysical endoscopic treatment, the emergency operation rate and the death rates, as well as the intermediate markers of transfusion rate and altered length of hospital stay. To be persuasive, common patterns of, for example, reduced rebleeding, operation rate and death rate are required. In addition, studies of quality should be expected to be randomized and double-blind, with a clearly speci®ed primary end-point and with evident power of discrimination between what is eective and ineective at that end-point. Methods of case selection should be clear, so that the reader can deduce whether a given study suggests that treatment can be shown to work in those selected, or, more importantly, whether it can be shown to work in unselected consecutive cases likely to be similar to those found in ordinary clinical practice. These criteria have, however, seldom been met.1 Meta-analytic techniques should in their turn take account of the problems by examining data sets to determine whether they are likely to be representative of the general run of case series, and by seeking to ®nd sets that have gone unreported. Such sets tend to dier from those published, by negativity of outcome (reporting bias). Data examination for consistency depends on the analysis of variation between series and upon the use of funnel plots that array clinical series according to size. On the hypothesis that unreported sets are often small and apparently lacking in any suggestion of bene®t, such plots can tend to show that smaller reported series are more likely to be in favour of the treatment oered, suggesting a publication bias. In cardiovascular disease and cancer treatment, it is generally accepted that either very large, simple trials or, alternatively, robust aggregations of data from disparate studies are required if reliable conclusions on treatment ecacy are to be drawn. Such studies are generally lacking when examining outcome in bleeding peptic ulcer.
INITIAL TRIALS OF ANTI-SECRETORY AGENTS USING H2-ANTAGONISTS Table 1 shows the data from trials conducted up to 15 years ago, on the H2 antagonist treatment of ulcer bleeding arrayed according to the size of the study.2 Power is not only generally lacking, but also severely lacking in individual studies. The ®gures could nevertheless be aggregated to suggest that treatment might be eective but that further investigations would be needed to obtain a con®rmation of this. Plausibility depended upon a demonstration that better results appeared to be obtainable in gastric than duodenal ulcer bleeding, as might be expected if acid inhibition were easier to achieve in the relatively hyposecretory stomach of the gastric ulcer patient. Table 2 compares the contribution of the 13 smallest trials in Table 1a, involving a total of 508 patients, with that of the 13 largest trials, with 2162 patients, in terms of reductions in the re-bleeding, operation and death rates. The smallest trials, although including only one-®fth of the patients, account for most of the modest reduction in rebleeding (suggesting a possible bias) with no dierence in contribution to the just signi®cant reductions in the operation and death rates. Subsequent data have given mixed and indierent support to the thesis that acid inhibition is eective. This might be because treatment is pharmacodynamically
Drug treatment of non-variceal bleeding 359 Table 1. Contributions to overall change in chances of bleeding, operation and death according to series size during treatment in 26 trials of H2-antagonists. Series
No. included
A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Total
Bleeding
Operation
Death
19 21 28 29 29 30 37 40 40 48 60 62 65 69 72 88 88 93 100 105 109 113 150 158 213 519
ÿ1.6 1.1 0 ÿ0.6 ÿ1.9 1.4 ÿ1.5 ÿ0.5 0.6 ÿ0.5 ÿ3.3 1.7 ÿ5.4 1.5 0 ÿ0.1 2.9 ÿ3.4 ÿ4.0 0.9 ÿ0.8 ± ± ÿ3.3 0.6 ÿ0.4
± 1.1 ÿ1.5 0 ÿ0.4 ± ± ÿ0.5 0 ÿ0.5 ÿ0.7 2.5 ÿ2.8 ± 0 0.9 2.4 ÿ0.4 ÿ3.5 0.7 ÿ0.7 ÿ0.2 ÿ6.0 ÿ1.8 ÿ2.5 ÿ1.9
± 0.5 0.5 0 ÿ1.9 ± 0.5 1.0 0.8 1.0 0 0.1 ÿ3.2 ± ÿ1.8 ÿ0.1 0.5 ÿ1.5 0 ÿ1.0 0.5 ÿ0.6 ÿ1.5 0.6 0 ÿ7.5
2660
ÿ12.3
ÿ15.8
ÿ13.6
Table 2. Contributions to observed dierence between the observed and expected values of the 13 smallest series. Bleeding
Operation
Death
13 smallest (n 508)
ÿ10.5
ÿ2.8
ÿ1.7
13 largest (n 2152)
ÿ1.8
ÿ13.0
ÿ11.9
ÿ12.3
ÿ15.8
ÿ13.6
Total Typical odds ratio 95% Con®dence interval Statistical signi®cance
0.89 0.73±1.08 Not signi®cant
0.78 0.61±1.00 0.05
0.70 0.50±0.96 0.02
ineective or because, even though it is eective, it does not in¯uence the immediate outcome in gastroduodenal arterial bleeding. Pharmacodynamics An examination of the eects of H2-antagonists on acid secretion have shown that inhibition is most obvious when the natural secretory drive is low, i.e. during fasting and at night. In contrast, acidity, at least when measured as acid concentration, is less aected after meals.
360 M. J. S. Langman
In theory, administering histamine H2-antagonists intravenously might therefore be expected to demand a higher dose and would ideally utilise continuous intravenous administration with intragastric pH monitoring to titrate the dosage against ¯uctuating requirements. Such studies have shown that a continuous infusion of famotidine of the order of 3 mg per hour, about twice the recommended oral dose used in treating gastro-oesophageal re¯ux, can markedly raise acidity in pH terms.3,5±8 The alternative method of obtaining rapid, profound acid secretory inhibition is by the use of a proton pump inhibitor. With the exemplar drug omeprazole, this is not rapidly achievable with oral treatment, full inhibition in this situation taking 48±72 hours to develop. This is because inhibition takes place only when the proton pump is actively working. A bolus intravenous dosage, or preferably a primed infusion of a proton pump inhibitor, is therefore necessary to provide a sustained and consistent inhibition of secretion. In this context, it should be noted that pH is a logarithmic scale, and inhibition to, for example, a pH of 4 implies a thousand-fold reduction in acidity, which will be accompanied by a reduced secretory volume. An initial bolus dosage with 40 mg or probably preferably 80 mg omeprazole, followed by an infusion of 4±8 mg per hour, is most likely to raise the pH above 6.0, but whether such profound secretory inhibition is required clinically in managing patients with haematemesis and melaena is unclear.3,9±11 Later trials of H2-antagonists and proton pump inhibitors These trials have depended almost entirely upon randomized trials of proton pump inhibitors, compared with either a placebo or with H2-antagonists. Placebo-controlled trials are clearly preferable, given the possibility that H2-antagonists might themselves have useful eects, albeit possibly less than those of proton pump inhibitors. The data obtained in placebo-controlled trials have provided mixed and confusing results. In the largest trial, Daneshmend et al12 examined outcome in terms of the death, transfusion, re-bleeding and operation rates in 1147 patients admitted with haematemesis and melaena of all types, treatment being started at admission and consisting of omeprazole 80 mg intravenously as a bolus dose, followed by parenteral doses of 40 mg three times every 8 hours and then 40 mg orally twice daily. Treatment was double blind. There was no signi®cant dierence in the death rate (omeprazole 6.9%, placebo 5.3%) nor in the transfusion need (52% and 53% respectively) or re-bleeding (15% and 18%) or operation rate (11% and 11%). These negative ®ndings contrast with evidence of bene®t in trials in Denmark, Sweden and India. All these trials were smaller, and the bene®t was apparently greatest in the smallest. In Denmark13, 274 patients were randomly assigned to intravenous omeprazole 80 mg as a bolus dose, then 8 mg per hour for 72 hours and subsequently oral treatment 20 mg daily. The primary ecacy measure was the worst, ranking on a scale death 5, surgery 4, additional endoscopic treatment 3, more than 3 units of blood 2, and 1±3 units of blood 1. Bene®t (P 0.004) was found on this composite scale as a primary variable, and 91% of the omeprazole-treated group did not die, did not need surgery and did not need additional endoscopic treatment, compared with 80% of those receiving placebo. The second, Swedish, study involved 330 patients aged 60 and over who were allocated to a virtually identical regimen or placebo.14 The overall outcome was signi®cantly improved (P 0.017), as were the secondary variables of a reduced operation rate (P 0.003) and the degree (P 0.004) and duration (P 0.003) of bleeding. In the ®rst of these two studies, the mortality rate did not dier between omeprazole and
Drug treatment of non-variceal bleeding 361
placebo, while in the second it was higher in those receiving omeprazole (6.9% compared with a very low rate of 0.6% on placebo). The fourth trial15, on 220 ulcer patients with stigmata of recent bleeding in India, used oral omeprazole 40 mg twice daily for 5 days or placebo. The re-bleeding, operation and transfusion rates diered markedly (re-bleeding 10.9% and 36.4% respectively, operative rate 7.3% and 23.6%, and transfusion rate 29.1% and 70.1%). These trials are dicult to reconcile. The Swedish and Danish studies used marginally more eective anti-secretory regimens than did the UK study. Composite outcomes diered signi®cantly and favoured omeprazole-takers in the Scandinavian studies, but with no evidence of an eect on the death rate. In contrast, the Indian study used an oral regimen that would be expected to be slowly eective compared with parenteral drug, but it had the most favourable results on active agent. The dierence in transfusion rate is striking despite a similar initial haemoglobin level of 9.8 and 9.6 g/dl in the omeprazole and placebo recipients respectively. By examining the published data, we can calculate what proportion of blood transfusions were carried out because of recurrent bleeding and therefore what proportion must have related to initial haemodynamic needs or prior anaemia. In omeprazoletakers, 13.6% of patients were noted to have continued, spurting or recurrent bleeding, but the overall transfusion rate was 29.1%. We can deduce, therefore, that 15.5% received transfusion for clinical stabilization rather than because of recurrent bleeding. In contrast, 39% of placebo-takers showed recurrent bleeding of all types, yet 70.1% were transfused; 31.1% can thus be deduced to have received blood for stabilization. These data suggest a marked imbalance in the need for initial transfusion despite an apparently similar initial haemoglobin level. The authors suggest that the parietal cell mass in Indian patients is relatively low and thus explains the ecacy of oral treatment, although the other main factor to consider is access to active proton pumps, which is much more ecient with intravenous drugs. Other studies using proton pump inhibition are relatively unhelpful because active comparators, usually ranitidine, were employed. The number treated was usually small, and no consistent treatment eects were noted.16±23 A further large placebo-controlled study24 was carried out with the H2-antagonist famotidine in patients with endoscopically demonstrated gastric and duodenal ulcers thought to be likely to re-bleed (with oozing, black slough, fresh clot attached or a visible vessel). Four hundred and ninety-seven patients received famotidine 10 mg intravenously as a bolus and then at a rate of 3.2 mg per hour, 508 receiving an identicallooking placebo. The treatment groups were well matched, but the outcome did not dier materially, the death rates being 6.2% and 5.0% respectively, the re-bleeding rates 23.9% and 25.5%, and the operation rates 15.5% and 17.1%. The treatment regimen was tested for anti-secretory ecacy before the trial and raised the pH to above 6.0. The overall conclusion from these studies probably has to be that if anti-secretory treatment with histamine H2-antagonists or omeprazole is useful, the bene®ts are marginal.
SOMATOSTATIN AND ITS ANALOGUES The outcomes of trials employing somatostatin more or less parallel those from trials using H2-antagonists or omeprazole.25±29 Small studies have shown promise; larger ones have not indicated bene®t, although some have suggested a change in indicators
362 M. J. S. Langman
such as the transfusion rate. The bases for suggesting bene®t have included a reduction in gastrin, gastric acid and pepsin secretion, as well as splanchnic blood ¯ow. A large trial using the natural hormone and conducted in 630 patients admitted with haematemesis and melaena of all causes showed no favourable trend in death rate (somatostatin 9.8%, placebo 7.9%), an almost identical operation rate (somatostatin 35%, placebo 34%) but less re-bleeding (somatostatin 70%, placebo 89%; although the dierence was not signi®cant). It could be argued that infusions of the natural hormone with its very short half-life would not give eective secretory control. However, another reasonably large trial26 conducted in 273 patients using a long-acting analogue has also a negative result. Trials have generally been of small size. No other trial has included 100 patients, and there is trend towards positive trials being relatively small.26 HAEMOSTASIS BY PHARMACOLOGICAL METHODS OTHER THAN ACID INHIBITION If haemorrhage is to be stemmed, we have to promote clotting in bleeding vessels and/or vascular contraction. A direct attack on the bleeding vessels by endoscopic methods such as sclerosing injections and heater probes has been successful, but this has the practical disadvantage that individual endoscopic intervention is required. Patient management would be much simpli®ed by the introduction of pharmacological treatment that would reduce or stem haemorrhage but be independent of a knowledge of the site or nature of the bleeding lesion. Since gastric juice has ®brinolytic properties, there is a case for using inhibitors, provided they are safe and in particular do not predispose to thrombosis in sites where it is not wanted. Tranexamic acid has been subjected to testing on several occasions.30±34 Undesirable pro-thrombotic properties in areas outside the gastrointestinal tract have not proved clinically problematic, although the database obtained in patients with bleeding peptic ulcers is limited. The particular reason for requiring evidence of safety in gastrointestinal use is that gastrointestinal bleeding is generally associated with a raised circulatory platelet count. Whether this enhances pro-thrombotic tendencies is unclear, but it is reasonable to require data showing that the chance of thrombosis in sites outside the stomach is not enhanced. By the same token, evidence of ecacy is also limited. Meta-analysis35 has suggested that the use of tranexamic acid is bene®cial, but the data are heavily weighted by one trial indicating a signi®cantly reduced risk of death, albeit without the expected commensurate eects on the risk of re-bleeding.33 CONCLUSION There is a lack of clear and consistent evidence that anti-secretory or anti-®brinolytic treatment is clinically bene®cial in peptic ulcer bleeding. Smaller trials have indicated bene®t more often than larger ones, suggesting a publication bias, and in addition by the use of clinical indicators as surrogates for important outcomes. Much eort has been devoted to devising drug regimens that guarantee anacidity, but without generating clear and unequivocal evidence that such powerful measures are bene®cial. Many trials have used potentially active comparators, but they often suer from the defects of small size and a lack of clear, prede®ned outcome measures, as well as failing
Drug treatment of non-variceal bleeding 363
to produce evidence of clinically important changes in outcome. Although it is quite probable that the use of anti-secretory drugs modestly reduces the re-bleeding rate, the eect on clinical outcome is less clear. The case for increasingly powerful clinical regimens in this context has not been made. Anti-®brinolytics may be as eective, or more so, but they have been less well tested, and the outcome of meta-analysis is heavily skewed by a single relatively large trial. The mortality rate has been unaected, although it is noteworthy in this context that the death rate in the larger reported trials has been relatively low. In the UK, the death rate seen in the larger trials has been about half that found in a recent general survey of the outcome of peptic ulcer bleeding.36 This may mean that patients whose disease is likely to have a poor outlook have tended to be missed, or excluded, from those studies. The consequences are twofold: ®rst, the power of studies to ®nd a real dierence in outcome is, if present, reduced, and second, doubts are raised about the generalizability of any conclusions based on the trial data. Taken overall, there is indierent support for the use of pharmacological treatment in managing peptic ulcer or other types of non-variceal upper gastrointestinal bleeding.
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