Therapy A Comparison of Sucralfate and Ranitidine for the Prevention of Upper Gastrointestinal Bleeding in Patients requiring Mechanical Ventilation
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Summary
Posted By:	Dr. Helen Bunting
E-Mail:	HelenBunting@hotmail.com
Posted Date:	23Apr2001
Title:	A Comparison of Sucralfate and Ranitidine for the Prevention of Upper Gastrointestinal Bleeding in Patients requiring Mechanical Ventilation
Authors:	Cook, Deborah; Guyatt, Gordon; Marshall, John et al.
Reference:	NEJM 1998;338:791-797
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	BACKGROUND: Critically ill patients who require mechanical ventilation are at increased risk for gastrointestinal bleeding from stress ulcers. There are conflicting data on the effect of histamine H2-receptor antagonists and the cytoprotective agent sucralfate on rates of gastrointestinal bleeding, ventilator-associated pneumonia, and mortality. METHODS: In a multicenter, randomized, blinded, placebo-controlled trial, we compared sucralfate with the H2-receptor antagonist ranitidine for the prevention of upper gastrointestinal bleeding in 1200 patients who required mechanical ventilation. Patients received either nasogastric sucralfate suspension (1 g every six hours) and an intravenous placebo or intravenous ranitidine (50 mg every eight hours) and a nasogastric placebo. RESULTS: The patients in the two groups had similar base-line characteristics. Clinically important gastrointestinal bleeding developed in 10 of 596 (1.7 percent) of the patients receiving ranitidine, as compared with 23 of 604 (3.8 percent) of those receiving sucralfate (relative risk, 0.44; 95 percent confidence interval, 0.21 to 0.92; P=0.02). In the ranitidine group, 114 of 596 patients (19.1 percent) had ventilator-associated pneumonia, as compared with 98 of 604 (16.2 percent) in the sucralfate group (relative risk, 1.18; 95 percent confidence interval, 0.92 to 1.51; P=0.19). There was no significant difference between the groups in mortality in the intensive care unit (ICU) (23.5 percent in the ranitidine group and 22.9 percent in the sucralfate group) or the duration of the stay in the ICU (median, nine days in both groups). CONCLUSIONS: Among critically ill patients requiring mechanical ventilation, those receiving ranitidine had a significantly lower rate of clinically important gastrointestinal bleeding than those treated with sucralfate. There were no significant differences in the rates of ventilator-associated pneumonia, the duration of the stay in the ICU, or mortality.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes.The study was "block randomized", with stratification according to center, by means of a computer-generated random-number table prepared at the McMaster University Methods Center, and was managed by the study pharmacist at each site who administered the coded drugs.All care givers and other research personnel were unaware of the randomization schedule and the block size.Concealment was achieved.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes.All patients were accounted for.Protocol violations are described and are similar in the two groups.
2b. Were patients analyzed in the groups to which they were randomized?
	Yes.All patients were analyzed in the groups to which they were randomly assigned according to the intention-to-treat principle.An efficacy analysis was not performed (it was not required).
3. Were patients, health workers, and study personnel blind to treatment?
	Yes.The use of double placebo resulted in blinding of the patients, research nurses, ICU care givers, radiologists, outcome adjudicators and all investigators. The study statistician was also blinded.Clinicians did not monitor gastric PH.
4. Were the groups similar at the start of the trial?
	Yes.Demographic and baseline physiological characteristics, illness severity scores and reasons for admission to the ICU were similar in the two groups.
5. Aside from the experimental intervention, were the groups treated equally?
	The protocol shows that there were no planned differences.Information regarding unplanned differences is not provided. The authors do not report supportive care or use of co-interventions. It may have been helpful to have information on issues such as respiratory care, use of antibiotics and more detailed information on feeding protocols.
What are the Results?
1. How large was the treatment effect?
	a) Gastrointestinal bleeding. Ranitidine = 1.7%, Sucralfate = 3.8%, ARR = 2.1% 95%CI = 0.29 - 3.97% (ranitidine v sucralfate), Relative risk = 0.44 95%CI = 0.21 - 0.92 p = 0.02 (ranitidine v sucralfate). Subgroup analysis of patients with gastric, duodenal or oesophageal ulcers or erosions. Ranitidine = 0.7%, Sucralfate = 1.7%, ARR = 1% (ranitidine v sucralfate), Relative risk = 0.41 95%CI = 0.13 - 1.29 p = 0.22 (ranitidine v sucralfate). b) Pneumonia. Ranitidine = 19.1%, Sucralfate = 16.2%, ARR = 2.9% 95%CI = -1.4% - +7.2% (sucralfate v ranitidine), Relative risk = 1.18 95%CI = 0.92 - 1.51 p = 0.19 (ranitidine v sucralfate). NB power of study = 75%. c) Duration of ICU stay (days)- Median (IQ range). Ranitidine = 9 (5 - 15), Sucralfate = 9 (5 - 17). d) Duration of intubation (days) - Median (IQ range). Ranitidine = 7 (4-13), Sucralfate = 8 (4 - 15). e) Mortality. Ranitidine = 23.5%, Sucralfate = 22.8%, Relative risk = 1.03 95%CI = 0.84 - 1.26 p = 0.79 (ranitidine v sucralfate).
2. How precise was the estimate of the treatment effect?
	The 95%CIs and P values are listed above.The power calculations were based on the figures for pneumonia rather than on the figures for bleeding. The authors felt that pneumonia is an important side effect of gastric PH altering therapy and that previous trials did not examine this issue as rigorously as gastrointestinal bleeding.Based on published data the authors anticipated a 25% incidence of pneumonia and identified a 25% reduction in the risk of pneumonia as clinically important. This led to the calculation of a sample size of 1200 patients, necessary to give the study 75%power to detect such a difference.In this study the relative risk suggests a trend toward a lower incidence of pneumonia among patients receiving sucralfate.We can be only 75% certain that sucralfate does not result in a 25% reduction in the incidence of pneumonia.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	The incidences of gastointestinal bleeding and pneumonia, the effects of treatment on these complications and the level of care provided to these patients in the Canadian setting are probably transportable to most 'westernized' ICU's. This RCT and recent meta-analyses (see review in meta-analysis section) should be assessed to determine their relative merits in your setting.
2. Were all clinically important outcomes considered?
	The incidences of gastointestinal bleeding and nosocomial pneumonia, duration of ICU stay, duration of intubation and mortality in ICU were considered.Durations of intubation and ICU stay were used to reflect severity of illness and cost of ICU care. They are dependent on the criteria for extubation and for discharge from ICU being appropriate.The cost implications are not reported in the study but are addressed in the discussion. They will vary among health care organizations.
3. Are the likely treatment benefits worth the potential harms and costs?
	An economic analysis for an individual organization, together with the implications of published data, should form the basis for a balanced decision. An evidence-based recommendation, which is the building block for an evidence-based guideline, that summarizes this topic can be found in the EBR section.
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