Web site designed and maintained by Chris Cairns  © SICS EBM Group 2004                                  

Sucralfate versus Ranitidine - The definitive study

Citation/s:A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. NEJM 1998; 338:791-7. Deborah Cook et al for the Canadian Critical Care Trials Group

Lead author's name and fax: Dr Deborah Cook. Department of Medicine, St Joseph's Hospital

Three-part Clinical Question: Is Ranitidine superior to Sucralfate in the prophylaxis of upper GI haemorrhage in patients requiring ventilation and if so does it lead to an increased rate of ventilator-associated pneumonia. Although the incidence of GI haemorrhage in intensive care is low there has, for many years, been a heated debate between thoughs that favour ranitidine or sucralfate for its prophylaxis. Respiratory failure and coagulopathy are strong risk factors for clinically important GI haemorrhage. Both regimens are superior to placebo. The exponents of sucralfate have argued that ranitidine administration leads to lowering of gastric pH and hence an increased risk of ventilator associated pneumonia. Most of the trials to date have suffered from poor design. These flaws were highlighted in a meta-analysis by Cook et al (JAMA 1996;275:308-14) the conclusion of which was that there was a need for a large well conducted RCT to settle the argument once and for all. This trial sets out to fulfil this need.

Search Terms: RCT, Gastrointestinal haemorrhage, ranitidine, sucralfate

The Study: Double-blinded concealed randomised controlled trial with intention-to-treat.

The Study Patients: October 1992 to May 1996 all patients admitted to the 16 participating intensive care units were screened for eligibility to enter the trial. All patients expected to be ventilated for at least 48 hours were eligible. Exclusion criteria were a diagnosis of All patients followed up until they died or were discharged from ICU. GI bleeding or pneumonia on admission, gastrectomy, a prognosis considered to be hopeless, previous randomization to this or any other trial, or receipt of two or more previous doses of open-label prophylactic therapy. In this study of the 7986 patients admitted during the trial period 6786 were excluded. Over 90% of the scheduled drug doses were administered in both groups. Similar numbers in the ranitidine and sucralfate groups (14 & 16 respectively) received an additional drug as prophylaxis outside the study protocol. Enteral feeding was started a median of three days after admission to the ICU. Definition of Gastrointestinal bleeding All patients were monitored for clinical signs of overt bleeding, including haematemesis, NG aspirate containing blood or coffee ground material, malena or pr bleeding. Clinically important bleeding was defined as overt bleeding plus of the following, in the absence of another cause: (1) a spontaneous drop of 20mmHg or more in the systolic or diastolic blood pressure within 24hrs of a gastrointestinal haemorrhage, (2) an increase in the pulse rate of more than 20bpm and an decrease in the SBP of more than 10mmHg on the patient assuming an upright position, (3) a decrease in Hb of a least 2g/dl in 24hrs and the transfusion of 2 units of packed red cells within 24hrs after bleeding, (4) failure of the Hb conc. to increase after transfusion by at least the number of units transfused minus 2. Ventilator-associated Pneumonia definitions Pneumonia suspected on clinical grounds if new radiographic infiltrate had persisted for at least 48 hours plus at least 2 of the following; (1) temperature >38.5 or <35, (2) WCC >10,000 or < 3,000 (3) purulent sputum, (4) isolation of pathogenic bacteria from an endotracheal aspirate. Patients suspected of pneumonia on clinical grounds underwent BAL or protected brush-catheter sampling. An pneumonia-adjudication committee would then examine all the evidence and use internationally recognised criteria to determine whether the pneumonia was ventilator-associated in origin (modified Centres for Disease Control and Prevention, Clinical Pulmonary Infection Score, Memphis Ventilator-associated Pneumonia Consensus Conference for VAP.

Control group (N = 604; 604 analysed): Sucralfate 1g six hourly via a gastric tube. Ranitidine placebo.

Experimental group (N = 596; 596 analysed): Ranitidine as an intravenous bolus as per the following regimen; 50mg eight hourly for creatinine clearance greater than 50ml/hr; 50 mg 12 hourly if creatinine clearance 25 to 50ml/hr; 50mg every 24 hours if creatinine clearance less than 25ml/min; if on dialysis then 50mg bd. Sucralfate placebo.

The Evidence:

Outcome	Time to Outcome	CER Sucralfate	EER Ranitidine	RRR	ARR	NNT
Gastrointestinal Bleeding	ICU stay	0.038	0.017	55%	0.021	48
	95% Confidence Intervals:			7% to 100%	0.003 to 0.039	25 to 391
Ventilator-Associated pneumonia	ICU stay	0.162	0.191	-18%	-0.029	-34
	95% Confidence Intervals:			-45% to 9%	-0.072 to 0.014	NNT = 71 to INF; NNH = 14 to INF
Death	ICU stay	0.228	0.235	-3%	-0.007	-143
	95% Confidence Intervals:			-24% to 18%	-0.055 to 0.041	NNT = 25 to INF; NNH = 18 to INF

EBM assessment of the paper

1) Do the methods allow accurate testing of the hypothesis? Yes
2) Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes
3) Are conclusions valid in light of the results? Yes - Ranitidine is superior to sucralfate in prophylaxis against GI bleeding in high risk critical care patients. (ventilated and/or coagulopathy). There is a trend towards a higher rate of VAP when ranitidine is used but this is not significant.
4) Did results get omitted, and why? No
5) Did they suggest areas of further research? No
6) Did they make any recommendations based on the results and were they appropriate? Yes - ranitidine should be used for gastric prophylaxis in high risk critical care patients
7) Is the study relevant to my clinical practice? Yes
8) What level of evidence does this study represent? - 1⁺⁺
9) What grade of recommendation can I make on this result alone? - A
10) What grade of recommendation can I make when this study is considered along with other available evidence? - A
11) Should I change my practice because of these results? - Yes
12) Should I audit my current practice because of these results? - Yes

Comments

A well conducted, large, multi-centre, randomized, double blind trial which gives a definitive answer to a question which has been debated foe many years. Ranitidine, when compared to sucralfate, significantly reduced the incidence of clinically significant bleeding. There was no significant difference in mortality or the rate of VAP (although there was a trend suggesting lower rates in the sucralfate group). It would have been interesting to have a third patient group given no prophylactic medication but enterally fed.

Appraised by: Dr Chris Cairns. Spr in Intensive Care. Royal Infirmary of Edinburgh; Wednesday, March 13, 2002
Email: Chris.Cairns@btinternet.com
Kill or Update By: March 2005

Printer-friendly format