Ng 2012.

Methods	Parallel‐group randomised controlled trial
Participants	Baseline characteristics Number randomised: 313 Number analysed: 311 Esomeprazole Age (years; mean (SD)): 64.3 (13.8) Number of participants at baseline (n): 164 Gender (male/female; n): 126/37 Famotidine Age (years; mean (SD)): 63.1 (13.2) Number of participants at baseline (n): 149 Gender (male/female; n): 107/41 Inclusion criteria Admitted for ACS or acute STEMI Requiring active treatment with aspirin, clopidogrel, and one of enoxaparin or thrombolytics Exclusion criteria Known active peptic ulcer disease GI bleeding within 8 weeks Known iron deficiency anaemia Mechanical ventilation with endotracheal intubation Active cancer Liver cirrhosis End‐stage renal failure Life expectancy < 1 year Known allergy to aspirin, clopidogrel, enoxaparin, famotidine, or esomeprazole Pregnancy Lactation Child‐bearing potential in the absence of contraception Co‐prescription of NSAIDs, corticosteroid, or warfarin Non‐oral feeding Impaired gastrointestinal absorption, for example, vomiting, already treated with a PPI for > 1 day or another clinical trial drug for ulcer disease Vulnerable subjects Age < 18 years Persons related unequally to investigators (students and employees) Mentally or cognitively disabled people Baseline imbalances: The 2 treatment groups were similar with respect to baseline demographic characteristics, history of ulcers, cardiac disease, percutaneous coronary stenting, baseline haemoglobin and serum creatinine levels, and use of enoxaparin or thrombolytics
Interventions	Esomeprazole Dose (total/d): 20 mg Duration of treatment (days): minimum of 4 weeks and maximum of 52 weeks Route: PO Intervention: oral esomeprazole 20 mg (Nexium, AstraZeneca, Södertälje, Sweden) before bedtime, at least 1 hour after dinner Concomitant medications: In patients without prior antiplatelet therapy, the loading dose of aspirin was 300 mg in chewable form, while the loading dose of clopidogrel was 300 mg. Patients were maintained with aspirin 80 to 160 mg daily and clopidogrel 75 mg daily. Patients with implantation of drug‐eluting coronary stents were maintained with aspirin 160 mg daily for 3 months. Enoxaparin was given subcutaneously at a dose of 1 mg/kg twice daily in conjunction with oral aspirin and clopidogrel therapy until clinical stabilisation, for a minimum of at least 2 days. In patients with renal impairment, the frequency of enoxaparin was reduced to 1 mg/kg once daily if the estimated creatinine clearance was below 30 mL/min. Anti‐Xa activity was not monitored. The protocol for administration of thrombolytics was that of the American Heart Association — Guidelines for the Management of Patients with STEMI 2004 Famotidine Dose (total/d): 40mg Duration of treatment (days): minimum of 4 weeks and maximum of 52 weeks Route: PO Intervention: oral famotidine 40 mg (2 tablets of FAMOLTA 20 mg; Jean‐Marie Pharmacal, Hong Kong) before bedtime, at least 1 hour after dinner Concomitant medications: In patients without prior antiplatelet therapy, the loading dose of aspirin was 300 mg in chewable form, while the loading dose of clopidogrel was 300 mg. Patients were maintained with aspirin 80 to 160 mg daily and clopidogrel 75 mg daily. Patients with implantation of drug‐eluting coronary stents were maintained with aspirin 160 mg daily for 3 months. Enoxaparin was given subcutaneously at a dose of 1 mg/kg twice daily in conjunction with oral aspirin and clopidogrel therapy until clinical stabilisation, for a minimum of at least 2 days. In patients with renal impairment, the frequency of enoxaparin was reduced to 1 mg/kg once daily if the estimated creatinine clearance was below 30 mL/min. Anti‐Xa activity was not monitored. The protocol for administration of thrombolytics was that of the American Heart Association — Guidelines for the Management of Patients with STEMI 2004 Adherence to regimen: Compliance was assessed by pill count. Good compliance with study drugs (≥ 90% ): 100% in famotidine group and 98.8% in esomeprazole group Duration of trial: July 2008 to September 2010 Duration of follow‐up: minimum of 4 weeks and maximum of 52 weeks
Outcomes	Outcomes sought in review and reported in trial Gastrointestinal bleeding classified as Overt bleeding of gastroduodenal origin (confirmed by means of upper gastrointestinal endoscopy) defined as haematemesis, melena, or both, with a non‐malignant ulcer or bleeding erosions found on endoscopy or at surgery Overt upper gastrointestinal bleeding of unknown origin defined as haematemesis, melena, or both, without endoscopy performed or Occult gastrointestinal bleeding (confirmed by upper gastrointestinal endoscopy) defined as a decrease of ≥ 2 g/dL in the haemoglobin level, with a non‐malignant ulcer or > 5 erosions found on endoscopy All‐cause mortality in the hospital Adverse events Outcomes sought in review but not reported in trial VAP Duration of ICU stay Duration of intubation Blood transfusions Outcomes reported in trial, but not used in review Time to composite outcome
Notes	Setting: acute medical wards, cardiac care unit, and intensive care unit, Department of Medicine and Geriatric, Ruttonjee Hospital, Hong Kong Sponsorship source: Cardiac Research Fund, Ruttonjee Hospital Conflict of interest: Quote: "Potential competing interests: None" Ethics approval: Quote: "The study protocol was approved by the Ethics Committee of the Hong Kong East Cluster" Informed consent: Quote: "All patients gave their written, informed consent" Clinical trials registration: This study was registered at http://www.clinicaltrials.gov (Identifier NCT00683111) Sample size calculation: Yes, described under statistical analysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Ward clerks at the four acute medical wards, the cardiac ward, and the intensive care ward generated 50 treatment codes labelled A and 50 codes labelled B. These were sealed in identical, blinded envelopes that were shuffled randomly"
Allocation concealment (selection bias)	Low risk	Quote: "Ward clerks at the four acute medical wards, the cardiac ward, and the intensive care ward generated 50 treatment codes labelled A and 50 codes labelled B. These were sealed in identical, blinded envelopes that were shuffled randomly. Th e investigators drew a blinded envelope randomly, and the pharmacist dispensed the repackaged medi‐ cation. The investigators and patients were blinded to the treatment‐group assignments"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The investigators drew a blinded envelope randomly, and the pharmacist dispensed the repackaged medication. The investigators and patients were blinded to the treatment‐group assignments. The treatment codes were released aft er approval of the completion of the study by the Ethics Committee"
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: "overt bleeding of gastroduodenal origin (confirmed by means of upper endoscopy), overt upper GIB of unknown origin, bleeding of occult gastrointestinal origin (confirmed by means of upper gastrointestinal endoscopy), obstruction, or perforation" Comment: objective criteria for the measurement of GI bleeding reported
Blinding (detection bias) Nosocomial pneumonia	Unclear risk	Comment: Study did not address this outcome
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Quote: "The investigators drew a blinded envelope randomly, and the pharmacist dispensed the repackaged medication. The investigators and patients were blinded to the treatment‐group assignments. The treatment codes were released after approval of the completion of the study by the Ethics Committee"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "No patients were lost to follow‐up. Premature termination occurred in 34 (20.9%) and 31 (20.9%) patients in the esomeprazole and famotidine groups, respectively. No patient in the esomeprazole group and three (2.1%) patients in the famotidine group refused to continue the study. In the famotidine group, one patient with significant dyspepsia withdrew consent, while the remaining two patients did not give specific reasons" Comment: Flow chart of participant flow is included, and no incomplete reporting of outcome data is suspected
Selective reporting (reporting bias)	Low risk	Comment: All outcomes that are listed in the Methods section are also reported in the Results section
Other bias	Low risk	Comment: no other sources of bias suspected