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, yearCountrySettingStudy designAimDefinition of long-term useRationale
Haastrup et al, 20185DenmarkN/AReviewOverview of side effects of long-term PPI use>2 weeksEarlier studies showing no important side effects if used ≤2 weeks
Revaiah et al, 201820IndiaSecondary sectorSingle-centre, cross-sectionalRisk of small bacterial overgrowth in PPI users>3 monthsNo
Torvinen-Kiiskinen et al, 201821FinlandPrimary sectorCase–controlRisk of hip fractures among community-dwelling residents with Alzheimer’s≥1 yearNo
Biyik et al, 201722TurkeyOutpatient gastroenterology clinicCohort studyRisk of hypomagnesaemia in PPI users≥6 monthsNo
Takahari et al, 201723JapanSecondary sectorCross-sectionalFrequency of gastric cobblestone-like lesions in PPI users undergoing endoscopy≥6 monthsNo
Lochhead et al, 201724USANurses’ health studyCross-sectionalAssociation between PPI use and cognitive function≥2 yearsNo
Kearns et al, 201725UKPrimary sectorCase–controlAssociation between PPI use and pancreatic cancer>2 yearsAvoiding reverse causation
Targownik et al, 201726CanadaGeneral populationCross-sectionalAssociation between PPI use and bone structure≥5 yearsNo
Bahtiri et al, 201727TurkeyGeneral populationCohortRisk of hypomagnesaemia12 monthsNo
Huang et al, 201628TaiwanGeneral populationCohortAssociation between PPI use and risk of spontaneous bacterial peritonitis in patients with decompensated liver cirrhosis>180 daysNo
Takeda et al, 201529JapanOutpatientsCross-sectionalPrevalence of hypomagnesaemia>1 yearNo
Lundell et al, 201514N/ASystematic reviewSystematic reviewEffects of PPI on serum gastrin levels and gastric histology>48 monthsFDA requesting 3-year safety data from manufacturers
Song et al, 201430Cochrane reviewN/ASystematic reviewRisk of gastric pre-malignant lesions in PPI users≥6 monthsNo
Lewis et al, 201431AustraliaGeneral populationCohortPPIs and risk of falls and fractures in elderly women≥1 yearNo
Helgadóttir, 201432IcelandSecondary sectorCross-sectionalSerum gastrin levels in PPI users≥2 yearsNo
Bektas et al, 201233TurkeySecondary sectorCross-sectionalECL hyperplasia in PPI users≥6 monthsNo
Pregun et al, 201134HungarySecondary sectorCohortEffect of PPI on serum chromogranin-A and gastrin levels>6 monthsNo
Sarzynski et al, 201135USAPrimary sectorRetrospective cohortAssociation between PPI use and iron-deficiency anaemia>1 yearNo
Fujimoto and Hongo, 201136JapanMulticentreCohortEfficacy and safety of 104 weeks treatment with rabeprazole104 weeksNo
Lombardo et al, 201037ItalySecondary sectorCohortIncidence of small intestinal bacterial overgrowth among PPI users>2 monthsNo
Yoshikawa et al, 200938JapanSecondary sectorCase–controlBody mass index changes during PPI therapy in patients with GORD>10 monthsNo
Ally et al, 200939USAOutpatient clinicRetrospectiveRisk of fundic gastric polyps in PPI users>48 monthsNo
Van Soest et al, 200840The NetherlandsGeneral practiceCase–controlRisk of colorectal cancer among PPI users>365 days within 5 yearsNo
Hashimoto et al, 200741JapanSecondary sectorClinical trialPPI-induced tolerance to histamine-2-receptor antagonists>4 weeksNo
Yang et al, 200742UKGeneral practiceCase–controlRisk of colorectal cancer among PPI users≥5 years cumulative useThe definition is argued to be able to demonstrate an accelerative effect on the transformation from adenomas to carcinomas
Robertson et al, 200743DenmarkPopulation basedCase–controlRisk of colorectal cancer among PPI users>7 yearsThe definition is argued to be able to demonstrate an accelerative effect on the transformation from adenomas to carcinomas
Jalving et al, 200644The NetherlandsSecondary sectorCross-sectionalRisk of fundic gastric polyps in PPI users≥1 yearsNo
Hritz et al, 200545HungarySecondary sectorClinical trialEffect of PPI on gastric cell proliferation6 monthsNo
ClinicalTrials.govAustriaSecondary sectorClinical trialIntestinal microbiota in PPI users≥6 monthsNo
Studies of treatment effects of long-term PPI use (n=13)
Kiso et al, 201746JapanOutpatient clinicCross-sectionalEndoscopic findings in patients undergoing gastric screening>8 weeksNo
Funaki et al, 201747JapanOutpatient clinicCross-sectionalEfficacy of PPI in patients with NERD with and without irritable bowel syndrome>6 monthsROME III criteria for functional disorders (duration >6 months)
Hatlebakk et al, 201648Europe (several countries)Secondary sectorRCTComparing anti-reflux surgery with PPI treatment in patients with chronic GERD5 yearsNo
Yoon et al, 201449South KoreaHP-positive patientsRCTEradication rates with different durations of pretreatment with PPI≥56 daysNo
Poh et al, 201117USAOutpatient clinicRCTComparing stimulus response functions to acid in users and non-users of PPI undergoing acute stress8 weeksNo
Labenz et al, 200950SwedenSecondary sectorRCTPredictors of symptom resolution in patients with GERD during maintenance PPI therapy>6 monthsMaintenance phase after healed oesophagitis
Sugano et al, 201351JapanOutpatient clinicClinical trialGastroprotective effect of omeprazole1 yearNo
Fujimoto and Hongo, 201052JapanSecondary sectorCohortRelapse of GERD during long-term PPI therapy104 weeksNo
Kandil et al, 201015EgyptOutpatient clinicCohortEffect of exogenous melatonin in patients with GERD4 and 8 weeksNo
Mason et al, 200853UKGeneral practiceRCTEffect of HP eradication in long-term users of PPIA repeat prescription for PPI begun at least 12 months agoPrevious article by Hungin et al54
Raghunath et al, 200955UKPrimary careCross-sectionalSymptoms in patients on long-term PPI therapyA repeat prescription for PPI begun at least 12 months agoPrevious article by Hungin et al54
Usai et al, 200816ItalySecondary sectorCohortRecurrence of reflux symptoms in patients with coeliac disease with NERD>8 weeksNo
Frazzoni et al, 200756ItalySecondary sectorCohortEfficacy of long-term PPI on intraoesophageal acid suppression2 years of continuous useNo
Studies of deprescribing long-term PPI (n=6)
Pezeshkian and Conway, 201857USAN/AReviewGuidance on deprescribing PPI in older adults>12 weeksApproved duration of treatment
Boghossian et al, 201758Cochrane reviewN/ASystematic reviewEffects of deprescribing PPI in adults≥28 daysNo
Walsh et al, 201659CanadaGeneral practiceCross-sectionalDeprescribing≥8 weeksGuideline recommending reassessment of PPIs after 8 weeks
Van der Velden et al, 201360The NetherlandsPrimary careRCTDeprescribing≥1 yearNo
Bjornsson et al, 200661SwedenSecondary sectorClinical trialDiscontinuation>8 weeksNo
Krol et al, 200462The NetherlandsGeneral practiceRCTDiscontinuation≥12 weeksNo
Pharmacoepidemiological studies of long-term PPI use (n=3)
Othman et al, 201663UKGeneral populationCohortPrevalence and pattern of PPI prescribing≥1 year continuous useNo
Lødrup et al, 201464DenmarkGeneral populationSurveyUse of PPIs≥120 days the past yearNo
Haroon et al, 201365IrelandSecondary sectorSurveyReasons for treatment2 yearsNo
Definition based on quantity of PPI (n=10)
Studies of side effects related to long-term PPI use (n=6)
Imfeld et al, 201866UKGeneral populationCase–controlRisk of dementia≥100 prescriptionsNo
Shao et al, 201867TaiwanGeneral populationCase–controlRisk of hepatocellular carcinoma>28 DDDsNo
Sieczkowska et al, 201868PolandOutpatient clinic and general practiceCohortRisk of small intestinal bacterial overgrowthPPI for at least 75% of the time during the previous 3 months at a minimum dose of 20 mg per dayNo
Chien et al, 201669TaiwanGeneral populationCase–controlRisk of periampullar cancer>180 DDDsNo
Clooney et al, 201670CanadaGeneral populationCross-sectionalGut microbiome in long-term PPI users>180 tablets each year in a 5-year periodNo
Den Elzen et al, 200871The NetherlandsGeneral populationCross-sectionalRisk of vitamin B12 deficiency>810 DDDs in 3 yearsNo
Studies of deprescribing long-term PPI (n=2)
Reimer and Bytzer, 201072DenmarkPrimary careCross-sectionalDiscontinuation in symptomatically treated patients120 tablets of any PPI in the previous 12 monthsNo
Clinicaltrials.govUSAPrimary careClinical trialEvaluation of a deprescribing programme90-day prescription within 120 daysNo
Pharmacoepidemiological studies of long-term PPI use (n=2)
Wallerstedt et al, 20174SwedenGeneral populationCross-sectionalPrevalence of PPI use among residents ≥65 yearsFilled prescriptions for PPI covering ≥75% of the yearNo
Haastrup et al, 20162DenmarkGeneral populationCohortPredictors of incident long-term use among first-time users>60 DDDs within 6 monthsDefinition 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.