Sucralfate

Abstract

Objectives To determine the effectiveness of ranitidine and sucralfate in the prevention of stress ulcer in critical patients and to assess if these treatments affect the risk of nosocomial pneumonia.

Design Published studies retrieved through Medline and other databases. Five meta-analyses evaluated effectiveness ill terms of bleeding rates (A: ranitidine v placebo; B: sucralfate v placebo) and infectious complications in terms of incidence of nosocomial pneumonia (C: ranitidine v placebo; D: sucralfate v placebo; E: ranitidine v sucralfate). Trial quality was determined with an empirical ad hoc procedure.

Main outcome measures Rates of clinically important gastrointestinal bleeding and nosocomial pneumonia (compared between the two study arms and expressed with odds ratios specific for individual studies and meta-analytic summary odds ratios).

Results Meta-analysis A (five studies) comprised 398 patients; meta-analysis C (three studies) comprised 311 patients; meta-analysis D (two studies) comprised 226 patients: and meta-analysis E (eight studies) comprised 1825 patients. Meta-analysis B was not carried out as the literature search selected only one clinical trial. In meta-analysis A ranitidine was found to have the same effectiveness as placebo (odds ratio of bleeding 0.72, 95% confidence interval 0.30 to 1.70, P = 0.46). In placebo controlled studies (meta-analyses C and D) ranitidine and sucralfate had no influence on the incidence of nosocomial pneumonia. In comparison with sucralfate, ranitidine significantly increased the incidence of nosocomial pneumonia (meta-analysis E: 1.35, 1.07 to 1.70, P = 0.012). The mean quality score in the four analyses (on a 0 to 10 scale) ranged from 5.6 in meta-analysis E to 6.6 in meta-analysis A.

Conclusions Ranitidine is ineffective in the prevention of gastrointestinal bleeding in patients in intensive care and might increase the risk of pneumonia. Studies on sucralfate do not provide conclusive results. These findings are based on small numbers of patients, and firm conclusions cannot presently be proposed.

Introduction

Ranitidine and sucralfate are widely used to prevent stress ulcers in patients admitted to intensive care units.[1] A meta-analysis published by Cook et al in 1996 showed that [H.sub.2] receptor antagonists (such as cimetidine and ranitidine together) are more effective than placebo for this clinical indication.[2] With regard to sucralfate, this meta-analysis found a small but significant reduction in overt bleeding but no effect on clinically important events. The meta-analysis did not resolve the question of an increased risk of nosocomial pneumonia related to the use of [H.sub.2] receptor antagonists.

Several arguments emphasise the need for up to date information on this issue. Firstly, ranitidine has become the main [H.sub.2] receptor antagonist used for prophylaxis for stress ulcers, and cimetidine has generally been abandoned[1]; secondly, new findings have been published on effectiveness and complications of ranitidine; and, thirdly, a meta-analytic comparison of ranitidine versus placebo has never been carried out, and, as the comparison of sucralfate and placebo made by Cook et al gave no proof of the effectiveness of this drug, ranitidine and sucralfate might both be ineffective. Another problem is that the most recent randomised studies on this topic did not include a group with no prophylaxis and compared supposedly active treatments with one another.[3 4]

We conducted a literature search to identify randomised trials, and we carried out a meta-analysis to update the results of Cook's study with regard to effectiveness and infectious complications.

Methods

Searching

Our Medline search covered the period from 1966 to 20 June 2000 and was based on four key words (stress, pneumonia, ranitidine, sucralfate) and on the extraction of studies published in English. Randomised studies were identified by using the key words "randomized controlled trial" or "random" according to a validated literature search.[5]

This search was supplemented by examining the Iowa-IDIS system (Iowa Drug Information, Iowa University, United States) from 1966 to December 1999 and Drugdex (CD Rom Drugdex, vol 104, Micromedex, Englewood, Colorado, United States).

Selection

We carried out five meta-analyses that evaluated data on effectiveness in terms of rates of bleeding (meta-analysis A: ranitidine v placebo; meta-analysis B: sucralfate v placebo) and incidence of nosocomial pneumonia (meta-analysis C: ranitidine v placebo; meta-analysis D: sucralfate v placebo; meta-analysis E: ranitidine v sucralfate). Eligible studies were included in meta-analysis A or B if they met the following criteria: patients were admitted to an intensive care unit or were undergoing mechanical ventilation, or both; randomised design; assessment of gastrointestinal bleeding. In meta-analyses C, D, and E the inclusion criterion gastrointestinal bleeding was replaced by the assessment of pneumonia.

Data extraction and assessment of quality of trials

Data were extracted with a structured form. We assessed methodological quality by evaluating five items for each trial (patient selection, patient characteristics, randomisation, blinding, definition of bleeding or of pneumonia).[2] Methodological quality was graded for each of the five items on a scale of 0, 1, or 2 (maximum score = 10).

Data synthesis

Assessment of clinical heterogeneity was focused in particular on a comparison of the definitions of bleeding and pneumonia across the trials. Qualitative information is given in the longer version of this paper on the BMJ's website. The odds ratio was used as the principal measure for comparing the treatment effect within each trial. The calculations of summary odds ratios presented here were based on a random effect model.[6 7] Odds ratios based on a fixed effect model are given on the BMJ's website.[6] Heterogeneity was assessed as previously described.[6]

Results

Effectiveness of ranitidine v placebo (meta-analysis A)--We identified five trials,[8-12] with a mean (SD) quality score of 6.6 (0.9). With respect to the end point of clinically important bleeding, this meta-analysis (table 1) failed to show any significant benefit of ranitidine (summary odds ratio 0.95, 0.37 to 2.43, P = 0.92; [chi square] for heterogeneity 6.8, df 4, P = 0.15).

Table 1 Meta-analysis A: rates of gastrointestinal bleeding in patients treated with ranitidine or placebo (five randomised studies)

Effectiveness of sucralfate v placebo (meta-analysis B)--We found only one trial[8] that met the inclusion criteria and so no meta-analysis was carried out. The quality score of this trial was 7.0. The bleeding rate in the sucralfate group was 4% (1/24) and 3% (1/30) in the placebo group (1.26, 0.12 to 12.9, P = 0.70).

Incidence of pneumonia with ranitidine v placebo (meta-analysis C)--Our third meta-analysis included three randomised studies[9 10 12] that compared the incidence of pneumonia between ranitidine and placebo The mean (SD) quality score for these trials was 6.0 (1.0). The analysis of these three trials (table 2) found no significant difference in the rate of pneumonia with ranitidine and placebo (summary odds ratio 1.10, 0.45 to 2.66, P = 0.84; [chi square] for heterogeneity 4.38, df 2, P = 0.11).

Table 2 Meta-analysis C: rates of nosocomial pneumonia in patients treated with ranitidine or placebo (three randomised studies)

Incidence of pneumonia with sucralfate v placebo (meta-analysis D)--Our fourth meta-analysis included two randomised studies[13 14] that compared the incidence of pneumonia between sucralfate and placebo The quality score for these trials was 5 and 7, respectively. There was no significant difference in the rate of pneumonia with sucralfate and placebo (summary odds ratio 2.11, 0.79 to 5.64, P=0.14; [chi square] for heterogeneity 0.30, df 1, P = 0.58) (table 3).

Table 3 Meta-analysis D: rates of nosocomial pneumonia in patients treated with sucralfate or placebo (two randomised studies)

Incidence of pneumonia with ranitidine v sucralfate (meta-analysis E)--Our fifth meta-analysis included eight randomised studies[3 15-22] that compared the incidence of pneumonia with ranitidine and sucralfate. The quality score for these trials was 5.6 (2.3). The analysis of these eight trials (table 4) showed a significantly increased risk of pneumonia with ranitidine compared with sucralfate (summary odds ratio 1.51, 1.00 to 2.29, P = 0.05; [chi square] for heterogeneity 12.9, df 7, P = 0.08).

Table 4 Meta-analysis E: rates of nosocomial pneumonia in patients treated with ranitidine or sucralfate (eight randomised studies)

Discussion

Our overview of the controlled trials of ranitidine or sucralfate compared with placebo provides a picture of poor effectiveness. The single trial available on sucralfate[8] does not allow any conclusion to be drawn; the trials on ranitidine[8-12] show no difference compared with placebo.

Design of new trials

Authoritative recommendations suggest the use of ranitidine for prophylaxis for stress ulcers,[23] but our results indicate that some points of consensus need to be revised. For example, recent randomised studies on prophylaxis for stress ulcers[3 4] have invariably compared (unproved) active treatments with one another but no longer use a placebo group.

New large scale randomised trials seem to be the only way to resolve this issue. New trials, however, may raise the ethical question of which treatment is appropriate for the control group. One possibility is to give cimetidine to the control group because cimetidine has been shown to be possibly effective,[2] but this would mean reusing a drug that has largely been abandoned. Another possibility is to conduct new large scale controlled trials of ranitidine compared with placebo, but the use of placebo can be questionable from an ethical point of view. A third solution could be to design new randomised trials according to a strategy of early treatment of stress ulcer with or without prophylaxis. In this latter case, after randomisation to prophylaxis or placebo the patients could be subjected to intensive gastrointestinal monitoring (for example, by examining nasogastric aspirate at short intervals) and at the first signs of bleeding their participation in the trial could be stopped with immediate initiation of an aggressive antisecretory treatment. A drawback of this third solution is that the clinical weight of the end point of early bleeding is less than that of the end point of clinically important bleeding.

Effect on pneumonia

The results of three meta-analyses that evaluated pneumonia were contradictory in some respects. The statistical power of these comparisons was better for meta-analysis E (1825 patients) than for meta-analysis C (311 patients); this could in part explain the higher incidence of pneumonia with ranitidine compared with sucralfate but not compared with placebo.

The main conclusion is that there are insufficient data on effectiveness to be able to conclude anything one way or the other. This can be an important argument for further trials.

What is already known on this topic

Ranitidine and sucralfate are widely used to prevent gastrointestinal bleeding in patients in intensive care

Several recommendations suggest this form of prophylaxis, but both the Food and Drug Administration and European Medicines Evaluation Agency have not given their approval

What this study adds

This analysis showed that ranitidine and sucralfate do not prevent gastrointestinal bleeding in patients in intensive care

Ranitidine can increase the risk of nosocomial pneumonia under certain circumstances

These findings are based on small numbers of patients and so firm conclusions cannot presently be proposed

Current recommendations on prophylaxis for stress ulcers should be revised according to these results

We thank Dr Enrico Tendi, head of the pharmaceutical service of the Careggi hospital, for stimulating the discussion on this topic.

Contributors: AM had the original idea for the present study, set up the project, designed the protocol, organised searches, supervised data extraction, supervised cross checking and validation work, assessed methodological quality of the trials, carried out statistical calculations, and discussed analysis and subsequent results. ST had the original idea for the present study, set up the project, designed the protocol, organised searches, checked accuracy of data extraction, supervised cross checking and validation work, carried out statistical calculations, and discussed analysis and subsequent results. MV was involved in the original project, helped to devise protocol, organised searches, extracted data from the studies, assessed methodological quality of the trials, arranged statistical input, collaborated in analyses, and discussed analysis and subsequent results. MG was involved in the original project, helped to devise protocol and organise searches, assessed methodological quality of the trials, collaborated in analyses, and discussed analysis and subsequent results. AC was involved in the original project, helped to devise protocol and organise searches, supervised data extraction, collaborated in analyses, and discussed analysis and subsequent results. The paper was written jointly by AM and ST. AM is guarantor.

Funding: None.

Competing interests: On other occasions, our group has received support from GlaxoWellcome (Italy) in the following terms: AM has received funds for a member of his staff (MV) working on a pharmacoeconomic project on colon cancer; ST has been reimbursed for attending three symposiums; MV received financial support for the colon cancer project and a fee for consulting about remifentanil; AC has received a fee for speaking and a fee for organising an educational seminar.

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(Accepted 1 August 2000)

Laboratorio SIFO di Farmacoeconomia, Centro Informazione Farmaci, Servizio Farmaceutico, Azienda Ospedaliera Careggi, 50134 Florence, Italy

A Messori coordinator

S Trippoli coordinator

M Vaiani research fellow

Unita' di Terapia Intensiva Respiratoria, Azienda Ospedaliera Careggi

M Gorini staff physician

A Corrado head

Correspondence to: A Messori md3439@mclink.it

BMJ 2000;321:1103-6

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