Table 1.

Methodologic Characteristics of Included Studies

Study	Lanas 201516	Lee 202117	Lin 201122	Maruyama 201825	Moayyedi 201918	Ray 201624	Ray 201823
Primary study design	Case-control study with prospective case ascertainment	Retrospective cohort study	Retrospective, population-based, nested case-control study	Retrospective cohort study	3 × 2 partial factorial double-blind trial, with simultaneous randomization to 1 of 3 antithrombotic drug regimens, and to PPI vs placebo	Retrospective cohort study	Retrospective cohort study
Anticoagulants	Not stated	Warfarin, rivaroxaban, dabigatran, apixaban, edoxaban; DOACs included both regular and reduced dosing	Warfarin	Dabigatran, rivaroxaban, or apixaban	Group 1: rivaroxaban 2.5 mg twice daily with aspirin 100 mg/d Group2: rivaroxaban 5 mg twice daily*	Warfarin	Apixaban, dabigatran, rivaroxaban, warfarin
Antisecretory agent	Any PPI	Any prescription PPI	Current use of any PPI (initiated at least 1 month before index date) Current use of any H2RA (initiated at least 1 month before index date)	Any PPI	Pantoprazole 40 mg/d	Any prescription PPI	Any prescription PPI
Comparator	No PPI	No PPI	No PPI (in prior year); no H2RA (in prior year)	No PPI	Placebo	No PPI	No PPI
Country, time period	Spain, 2009 to mid- 2013	Korea, with patients initiating anticoagulant between January 2010 and April 2018	UK, January 1, 2000 to December 31, 2007	Japan, prescribed anticoagulant between April 2011 and November 2015	580 centers in 33 countries, randomization March 2013 through May 2016	United States, Tennessee Medicaid 1996–2011 and 5% national Medicare Sample 2011–2013	United States, January 1, 2011 to September 30, 2015
Source population	A network of general hospitals integrated within the Spanish Association of Gastroenterology and the Biomedical Investigation Network Center of hepatic and digestive diseases	Korean Health Insurance Review and Assessment database, which includes the entire South Korean population	THIN database: UK primary care record database with >3 million patients	Single institution	—	Patients receiving Tennessee Medicaid and the 5% National Medicare Sample	Medicare beneficiaries
Inclusion and exclusion criteria	Inclusion: Age 20–90 years  Exclusion: liver disease, coagulation disorders or malignancy within the previous 5 years; bleeding caused by gastroesophageal or intestinal varices, GI cancer, Mallory-Weiss lesions, associated coagulopathy, and esophagitis; patients with unreliable sources of information; patients refusing participation; patients with inhospital bleeding.	Inclusion: Atrial fibrillation, initiated oral anticoagulant between January 2010 and April 2018, with a prior history of upper GI bleeding before oral anticoagulant initiation  Exclusion: Patients prescribed an oral anticoagulant within 1 year before the study period (January 2009-December 2009), patients <20 years old, diagnosis of valvular atrial fibrillation, pulmonary embolism, deep vein thrombosis, end-stage renal disease, or joint replacement	Inclusion: Age 40–84 years, enrolled with primary care provider for 2 years, prescription data for 1 year  Exclusion for source population: Diagnosis of cancer, esophageal varices, Mallory-Weiss disease, alcohol abuse, liver disease, or coagulopathy For cases, no exclusion criteria could be met in the 2 months after the recorded upper GI bleed, and no discharge from the hospital in the month prior to the upper GI bleed	Inclusion: Age ≥18 years, prescribed anticoagulant for nonvalvular atrial fibrillation  Exclusion: None stated.	Inclusion: Stable atherosclerotic cardiovascular or peripheral arterial disease with no clinical need for PPI. Patients with coronary artery disease <65 years old additionally required to have arterial disease involving 2 vascular beds or 2 additional risk factors.  Exclusions: high risk of bleeding from any site, severe heart failure, significant renal impairment, need for dual antiplatelet or anticoagulant therapy, known hypersensitivity to any of the study drugs.	Inclusion: Age ≥30 years, first prescription for warfarin filled during study period, complete demographic information, full pharmacy benefits, ≥1 outpatient visit and ≥1 filled prescription in past year  Exclusion: Prescription of oral anticoagulant in preceding year, end-stage renal disease, serious GI illness predisposing to bleeding, or bleeding-related hospitalization in past year.	Inclusion: Age ≥30 years, initiated oral anticoagulant during study period, complete demographic information in Medicare files, full pharmacy benefits, ≥1 outpatient visit and ≥1 filled prescription in past year.  Exclusion: Prescription of oral anticoagulant in preceding year, end-stage renal disease, serious GI illness predisposing to bleeding, or bleeding-related hospitalization in past year.
Entire study sample analyzed versus subset who were anticoagulated	Subset	Entire study sample	Subset	Entire study sample	Subset	Entire study sample	Entire study sample
Case definition for upper gastrointestinal bleeding	Hospitalization for GI bleeding (hematemesis, melena, hematochezia, or red blood per rectum). Classified as upper GI bleeding if witnessed hematemesis by hospital staff or either blood in the stomach or a lesion with stigmata of bleeding at upper endoscopy.	Occurrence of an ICD-10 code for upper GI bleeding during an admission that lasted at least 3 days.	Bleeding in stomach or duodenum	Overt “actionable” bleeding, defined as Bleeding Academic Research Consortium (BARC) types 2–5. Anatomic sites considered upper GI bleeding not stated.	Two definitions were examined:†  a: Overt bleeding of gastroduodenal origin (hematemesis or melena) with actively bleeding gastroduodenal lesion (peptic ulcer or neoplasia) confirmed by endoscopy or radiography  b: Overt upper gastrointestinal bleeding of unknown origin (hematemesis with or without melena thought to be related to upper gastrointestinal tract)	Hospitalization for upper gastrointestinal bleeding that was potentially preventable by PPI, including bleeding related to esophagitis, peptic ulcer disease, and gastritis.	Hospitalization for upper gastrointestinal bleeding that was potentially preventable by PPI, including bleeding related to esophagitis, peptic ulcer disease, and gastritis.
Newcastle Ottawa Scale for observational studies†
Selection, max 4	4	4	4	1	n/a	4	4
Comparability, max 2	2	2	2	2		2	2
Exposure (for case-control studies)/Outcome (for cohort studies), max 3	2	3	3	1		3	3
Cochrane Risk of Bias for RCTs (max 6)	—	—	—	—	Low risk of bias in all 6 categories	—	—

DOAC = direct-acting oral anticoagulant; GI = gastrointestinal; H2RA = histamine-2 receptor antagonist; PPI = proton pump inhibitor; RCT = randomized controlled trial.

^*Participants were also randomized to an aspirin-only group; however, this arm of the trial did not meet the inclusion criteria for the systematic review so data are not presented.

^†The trial’s primary efficacy outcome was defined as a composite of upper GI clinical events, which also included occult bleeding (drop in the hemoglobin of ≥2 g/dL), symptomatic gastroduodenal ulcers with at least 3 days of gastrointestinal pain, or ≥5 gastroduodenal erosions (confirmed by endoscopy) with at least 3 days of GI pain, upper GI obstruction, or perforation. Data are presented here only for the 2 components of the composite endpoint that included upper GI bleeding.