Table 1

Overview of the included studies

Definition based on time (n=51)
Studies of side effects related to long-term PPI use (n=29)
Author, year	Country	Setting	Study design	Aim	Definition of long-term use	Rationale
Haastrup et al, 20185	Denmark	N/A	Review	Overview of side effects of long-term PPI use	>2 weeks	Earlier studies showing no important side effects if used ≤2 weeks
Revaiah et al, 201820	India	Secondary sector	Single-centre, cross-sectional	Risk of small bacterial overgrowth in PPI users	>3 months	No
Torvinen-Kiiskinen et al, 201821	Finland	Primary sector	Case–control	Risk of hip fractures among community-dwelling residents with Alzheimer’s	≥1 year	No
Biyik et al, 201722	Turkey	Outpatient gastroenterology clinic	Cohort study	Risk of hypomagnesaemia in PPI users	≥6 months	No
Takahari et al, 201723	Japan	Secondary sector	Cross-sectional	Frequency of gastric cobblestone-like lesions in PPI users undergoing endoscopy	≥6 months	No
Lochhead et al, 201724	USA	Nurses’ health study	Cross-sectional	Association between PPI use and cognitive function	≥2 years	No
Kearns et al, 201725	UK	Primary sector	Case–control	Association between PPI use and pancreatic cancer	>2 years	Avoiding reverse causation
Targownik et al, 201726	Canada	General population	Cross-sectional	Association between PPI use and bone structure	≥5 years	No
Bahtiri et al, 201727	Turkey	General population	Cohort	Risk of hypomagnesaemia	12 months	No
Huang et al, 201628	Taiwan	General population	Cohort	Association between PPI use and risk of spontaneous bacterial peritonitis in patients with decompensated liver cirrhosis	>180 days	No
Takeda et al, 201529	Japan	Outpatients	Cross-sectional	Prevalence of hypomagnesaemia	>1 year	No
Lundell et al, 201514	N/A	Systematic review	Systematic review	Effects of PPI on serum gastrin levels and gastric histology	>48 months	FDA requesting 3-year safety data from manufacturers
Song et al, 201430	Cochrane review	N/A	Systematic review	Risk of gastric pre-malignant lesions in PPI users	≥6 months	No
Lewis et al, 201431	Australia	General population	Cohort	PPIs and risk of falls and fractures in elderly women	≥1 year	No
Helgadóttir, 201432	Iceland	Secondary sector	Cross-sectional	Serum gastrin levels in PPI users	≥2 years	No
Bektas et al, 201233	Turkey	Secondary sector	Cross-sectional	ECL hyperplasia in PPI users	≥6 months	No
Pregun et al, 201134	Hungary	Secondary sector	Cohort	Effect of PPI on serum chromogranin-A and gastrin levels	>6 months	No
Sarzynski et al, 201135	USA	Primary sector	Retrospective cohort	Association between PPI use and iron-deficiency anaemia	>1 year	No
Fujimoto and Hongo, 201136	Japan	Multicentre	Cohort	Efficacy and safety of 104 weeks treatment with rabeprazole	104 weeks	No
Lombardo et al, 201037	Italy	Secondary sector	Cohort	Incidence of small intestinal bacterial overgrowth among PPI users	>2 months	No
Yoshikawa et al, 200938	Japan	Secondary sector	Case–control	Body mass index changes during PPI therapy in patients with GORD	>10 months	No
Ally et al, 200939	USA	Outpatient clinic	Retrospective	Risk of fundic gastric polyps in PPI users	>48 months	No
Van Soest et al, 200840	The Netherlands	General practice	Case–control	Risk of colorectal cancer among PPI users	>365 days within 5 years	No
Hashimoto et al, 200741	Japan	Secondary sector	Clinical trial	PPI-induced tolerance to histamine-2-receptor antagonists	>4 weeks	No
Yang et al, 200742	UK	General practice	Case–control	Risk of colorectal cancer among PPI users	≥5 years cumulative use	The definition is argued to be able to demonstrate an accelerative effect on the transformation from adenomas to carcinomas
Robertson et al, 200743	Denmark	Population based	Case–control	Risk of colorectal cancer among PPI users	>7 years	The definition is argued to be able to demonstrate an accelerative effect on the transformation from adenomas to carcinomas
Jalving et al, 200644	The Netherlands	Secondary sector	Cross-sectional	Risk of fundic gastric polyps in PPI users	≥1 years	No
Hritz et al, 200545	Hungary	Secondary sector	Clinical trial	Effect of PPI on gastric cell proliferation	6 months	No
ClinicalTrials.gov	Austria	Secondary sector	Clinical trial	Intestinal microbiota in PPI users	≥6 months	No
Studies of treatment effects of long-term PPI use (n=13)
Kiso et al, 201746	Japan	Outpatient clinic	Cross-sectional	Endoscopic findings in patients undergoing gastric screening	>8 weeks	No
Funaki et al, 201747	Japan	Outpatient clinic	Cross-sectional	Efficacy of PPI in patients with NERD with and without irritable bowel syndrome	>6 months	ROME III criteria for functional disorders (duration >6 months)
Hatlebakk et al, 201648	Europe (several countries)	Secondary sector	RCT	Comparing anti-reflux surgery with PPI treatment in patients with chronic GERD	5 years	No
Yoon et al, 201449	South Korea	HP-positive patients	RCT	Eradication rates with different durations of pretreatment with PPI	≥56 days	No
Poh et al, 201117	USA	Outpatient clinic	RCT	Comparing stimulus response functions to acid in users and non-users of PPI undergoing acute stress	8 weeks	No
Labenz et al, 200950	Sweden	Secondary sector	RCT	Predictors of symptom resolution in patients with GERD during maintenance PPI therapy	>6 months	Maintenance phase after healed oesophagitis
Sugano et al, 201351	Japan	Outpatient clinic	Clinical trial	Gastroprotective effect of omeprazole	1 year	No
Fujimoto and Hongo, 201052	Japan	Secondary sector	Cohort	Relapse of GERD during long-term PPI therapy	104 weeks	No
Kandil et al, 201015	Egypt	Outpatient clinic	Cohort	Effect of exogenous melatonin in patients with GERD	4 and 8 weeks	No
Mason et al, 200853	UK	General practice	RCT	Effect of HP eradication in long-term users of PPI	A repeat prescription for PPI begun at least 12 months ago	Previous article by Hungin et al54
Raghunath et al, 200955	UK	Primary care	Cross-sectional	Symptoms in patients on long-term PPI therapy	A repeat prescription for PPI begun at least 12 months ago	Previous article by Hungin et al54
Usai et al, 200816	Italy	Secondary sector	Cohort	Recurrence of reflux symptoms in patients with coeliac disease with NERD	>8 weeks	No
Frazzoni et al, 200756	Italy	Secondary sector	Cohort	Efficacy of long-term PPI on intraoesophageal acid suppression	2 years of continuous use	No
Studies of deprescribing long-term PPI (n=6)
Pezeshkian and Conway, 201857	USA	N/A	Review	Guidance on deprescribing PPI in older adults	>12 weeks	Approved duration of treatment
Boghossian et al, 201758	Cochrane review	N/A	Systematic review	Effects of deprescribing PPI in adults	≥28 days	No
Walsh et al, 201659	Canada	General practice	Cross-sectional	Deprescribing	≥8 weeks	Guideline recommending reassessment of PPIs after 8 weeks
Van der Velden et al, 201360	The Netherlands	Primary care	RCT	Deprescribing	≥1 year	No
Bjornsson et al, 200661	Sweden	Secondary sector	Clinical trial	Discontinuation	>8 weeks	No
Krol et al, 200462	The Netherlands	General practice	RCT	Discontinuation	≥12 weeks	No
Pharmacoepidemiological studies of long-term PPI use (n=3)
Othman et al, 201663	UK	General population	Cohort	Prevalence and pattern of PPI prescribing	≥1 year continuous use	No
Lødrup et al, 201464	Denmark	General population	Survey	Use of PPIs	≥120 days the past year	No
Haroon et al, 201365	Ireland	Secondary sector	Survey	Reasons for treatment	2 years	No
Definition based on quantity of PPI (n=10)
Studies of side effects related to long-term PPI use (n=6)
Imfeld et al, 201866	UK	General population	Case–control	Risk of dementia	≥100 prescriptions	No
Shao et al, 201867	Taiwan	General population	Case–control	Risk of hepatocellular carcinoma	>28 DDDs	No
Sieczkowska et al, 201868	Poland	Outpatient clinic and general practice	Cohort	Risk of small intestinal bacterial overgrowth	PPI for at least 75% of the time during the previous 3 months at a minimum dose of 20 mg per day	No
Chien et al, 201669	Taiwan	General population	Case–control	Risk of periampullar cancer	>180 DDDs	No
Clooney et al, 201670	Canada	General population	Cross-sectional	Gut microbiome in long-term PPI users	>180 tablets each year in a 5-year period	No
Den Elzen et al, 200871	The Netherlands	General population	Cross-sectional	Risk of vitamin B₁₂ deficiency	>810 DDDs in 3 years	No
Studies of deprescribing long-term PPI (n=2)
Reimer and Bytzer, 201072	Denmark	Primary care	Cross-sectional	Discontinuation in symptomatically treated patients	120 tablets of any PPI in the previous 12 months	No
Clinicaltrials.gov	USA	Primary care	Clinical trial	Evaluation of a deprescribing programme	90-day prescription within 120 days	No
Pharmacoepidemiological studies of long-term PPI use (n=2)
Wallerstedt et al, 20174	Sweden	General population	Cross-sectional	Prevalence of PPI use among residents ≥65 years	Filled prescriptions for PPI covering ≥75% of the year	No
Haastrup et al, 20162	Denmark	General population	Cohort	Predictors of incident long-term use among first-time users	>60 DDDs within 6 months	Definition used in other studies

DDDs, defined daily doses; ECL, enterochromaffin-like; FDA, Food and Drug Administration; GERD, gastro-oesophageal reflux disease; HP, Helicobacter pylori; N/A, not available; NERD, non-erosive reflux disease; PPI, proton pump inhibitor; RCT, randomised controlled trial.