Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

Please visit the new Evidence Based Journal Club Reviews

Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials

Messori A, Trippoli S, Vaiani M, Gorini M, Corrado A.

Br Med J. 2000;321:1103-1106. [abstract] [full-text]

Reviewed by Steven Cray, Birmingham Children's Hospital, UK

Review posted May 30, 2001

---

I. Are the results of the study valid?

A. Primary questions:

1. Did the overview address a focused clinical question?

The objective of this meta-analysis was to determine the effectiveness of ranitidine and sucralfate in the prophylaxis of stress ulceration in critically ill patients and to assess whether these treatments affect the risk of nosocomial pneumonia. The authors carried out five meta-analyses to evaluate effectiveness in 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).

The authors' intention was to update a previous meta-analysis by Cook et al (1) which showed a reduction in clinically important gastrointestinal bleeding with histamine2-receptor antagonists (ranitidine and cimetidine). The data were insufficient to determine the net effect of sucralfate or to resolve the issue of nosocomial pneumonia.

2. Were the criteria used to select articles for inclusion appropriate?

The authors 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 data of infectious complications in terms of incidence of nosocomial pneumonia (meta-analysis C: ranitidine v placebo; meta-analysis D: sucralfate v placebo; meta-analysis E: ranitidine v sucralfate). The authors investigated the issue of effectiveness only in studies with a control group that received no prophylaxis, while the issue of infectious complications was also assessed from comparative trials of ranitidine versus 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. Studies were excluded in which gastrointestinal bleeding did not meet the definition of "clinically important bleeding" according to Cook et al. (See footnote). In meta-analyses C, D, and E the inclusion criterion gastrointestinal bleeding was replaced by the assessment of pneumonia. The criteria for the diagnosis of pneumonia were not precisely defined.

B. Secondary questions:

3. Is it unlikely that important, relevant studies were missed?

The authors only included English language studies Ð a quick search of Medline reveals potentially relevant studies in Spanish and German. Also they do not indicate that they sought to identify unpublished studies of potential relevance.

Summary of studies selected for meta-analyses:

Meta-analysis	Number of studies selected	Number of patients included	Mean quality score (max 10)
A: bleeding (ranitidine v placebo)	5	398	6.6
B: bleeding (sucralfate v placebo)	1	54	7.0
C: pneumonia (ranitidine v placebo)	3	311	6.0
D: pneumonia (sucralfate v placebo)	2	226	6.0
E: pneumonia (ranitidine v sucralfate)	8	1825	5.6

4. Was the validity of the included studies appraised?

Methodological quality was evaluated for each of five items (patient selection, patient characteristics, randomisation, blinding, definition of bleeding or of pneumonia) on a scale of 0, 1 or 2 (maximum score 10). Three observers independently assessed quality. See table above for scores.

5. Were assessments of studies reproducible?

Data extraction was performed by one reviewer using a structured form and checked for accuracy by a second reviewer. Differences were resolved by consensus. It is not stated that any method of blinding was used during the data extraction process or to what extent there was disagreement between reviewers.

6. Were the results similar from study to study?

The majority of the studies included were inconclusive (i.e. the 95% confidence interval for odds ratio includes 1). Tests for heterogeneity yielded non-significant P values suggesting that the variation between the results of these studies was not greater than would be expected by chance if the true effect size were the same in each trial. The greatest degree of variability in results between studies was in meta-analysis E (rates of nosocomial pneumonia in patients treated with ranitidine or sucralfate).

II. What are the results?

1. What are the overall results of the review?

Neither ranitidine nor sucralfate reduced the incidence of significant gastrointestinal bleeding. Compared with placebo, ranitidine or sucralfate did not alter the incidence of nosocomial pneumonia. Compared to sucralfate, ranitidine was associated with an increased risk of nosocomial pneumonia (odds ratio 1.35, 95% CI 1.07, 1.70, p = 0.012)

Summary of results of meta-analyses:

Meta-analysis	Odds ratio	95% confidence interval
A: bleeding (ranitidine v placebo)	0.72	0.30 to 1.70
B: bleeding (sucralfate v placebo)	(1.26)	(0.12 to 12.9)*
C: pneumonia (ranitidine v placebo)	0.98	0.56 to 2.66
D: pneumonia (sucralfate v placebo)	2.21	0.86 to 5.65
E: pneumonia (ranitidine v sucralfate)	1.35	1.07 to 1.70

* single study only included Ð meta-analysis not performed

2. How precise were the results?

Comparing ranitidine with sucralfate, the 95% CI for nosocomial pneumonia was 1.07 to 1.70. The interpretation of this is that those patients with nosocomial pneumonia were between 1.07 and 1.70 times as likely to have received ranitidine than sucralfate.

III. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

No studies in children were included.

2. Were all clinically important outcomes considered?

The meta-analysis focussed on clinically important bleeding and nosocomial pneumonia (not precisely defined). Other outcomes such as mortality or length of stay in ICU or hospital were not considered.

3. Are the benefits worth the harms and costs?

No. On the basis of this meta-analysis neither ranitidine nor sucralfate alter the rate of significant gastrointestinal bleeding in critically ill patients and ranitidine may be associated with an increased risk of nosocomial pneumonia. However, there no paediatric studies were included and there are some potential methodological flaws. We can only conclude that more studies are needed, particularly in children.

Footnotes

1. Definition of clinically important bleeding (from Cook et al. (1)): Overt bleeding accompanied by: (a) a decrease in blood pressure of 20 mm Hg within 24 hours of bleeding, (b) a decrease in blood pressure of 10 mm Hg and an increase in heart rate of 20 beats per minute on orthostatic change, or (c) a decrease in haemoglobin of 20 g/L and transfusion of 2 units of blood within 24 hours or as gastric bleeding requiring surgery.

References:

1. Cook DJ, Reeve BK, Guyatt GH, Heyland DK, Griffith LE, Buckingham L, et al. Stress ulcer prophylaxis in critically ill patients: resolving discordant meta-analyses. JAMA 1996; 275: 308-314. [abstract]

Comments

Back to the EB Journal Club Index