2023
Trends in Upper Gastrointestinal Bleeding in Patients on Primary Prevention Aspirin: A Nationwide Emergency Department Sample Analysis, 2016-2020
Li D, Laine L, Shung D. Trends in Upper Gastrointestinal Bleeding in Patients on Primary Prevention Aspirin: A Nationwide Emergency Department Sample Analysis, 2016-2020. The American Journal Of Medicine 2023, 136: 1179-1186.e1. PMID: 37696350, PMCID: PMC10841721, DOI: 10.1016/j.amjmed.2023.08.010.Peer-Reviewed Original ResearchConceptsUpper gastrointestinal bleedingGastrointestinal bleedingRed blood cell transfusionNationwide Emergency Department SamplePrimary cardiovascular preventionRecent guideline recommendationsBlood cell transfusionProportion of hospitalizationsEmergency Department SampleMedicare reimbursementInternational Statistical ClassificationRelated Health ProblemsCardiovascular preventionCell transfusionOlder patientsHospital admissionCommon etiologyGuideline recommendationsMajor complicationsUlcer diseaseEndoscopic interventionRevision codesAppropriate indicationsRecent guidelinesCardiovascular disease
2022
Deprescription of aspirin for primary prevention is uncommon at discharge in hospitalised patients with gastrointestinal bleeding
Li D, Ong S, Hughes M, Hung K, Agarwal R, Alexis J, Damianos J, Sharma S, Pires J, Nanna M, Laine L. Deprescription of aspirin for primary prevention is uncommon at discharge in hospitalised patients with gastrointestinal bleeding. Alimentary Pharmacology & Therapeutics 2022, 57: 94-102. PMID: 36394111, DOI: 10.1111/apt.17278.Peer-Reviewed Original ResearchConceptsMajor adverse cardiovascular eventsGastrointestinal bleedingPrimary preventionCardiovascular eventsRisk of MACEYale-New Haven HospitalPrimary cardiovascular preventionAdverse cardiovascular eventsKaplan-Meier curvesLong-term outcomesRisk-benefit ratioLog-rank testAspirin 81Hospitalised patientsPrimary endpointSecondary endpointsCardiovascular preventionSubsequent hospitalisationMedian ageDeprescriptionHigh riskAspirinHospitalisationPatientsPreventionAssociation of Antisecretory Drugs with Upper Gastrointestinal Bleeding in Patients Using Oral Anticoagulants: A Systematic Review and Meta-Analysis
Kurlander JE, Barnes GD, Fisher A, Gonzalez JJ, Helminski D, Saini SD, Sengupta N, Yang YX, Scheiman J, Laine L. Association of Antisecretory Drugs with Upper Gastrointestinal Bleeding in Patients Using Oral Anticoagulants: A Systematic Review and Meta-Analysis. The American Journal Of Medicine 2022, 135: 1231-1243.e8. PMID: 35679879, PMCID: PMC10031639, DOI: 10.1016/j.amjmed.2022.05.031.Peer-Reviewed Original ResearchConceptsUpper gastrointestinal bleedingProton pump inhibitorsGastrointestinal bleedingH2-receptor antagonistsObservational studyOral anticoagulantsAntisecretory drugsRelative riskLower riskNonsteroidal anti-inflammatory drug useSystematic reviewAnti-inflammatory drug useOvert upper gastrointestinal bleedingLow statistical heterogeneitySingle observational studyGreater treatment effectRandom-effects modelWeb of ScienceConcomitant aspirinRandomized trialsCochrane LibraryPump inhibitorsBias assessmentStatistical heterogeneityBleeding
2021
Antiplatelet Monotherapy Is Associated with an Increased Risk of Bleeding After Endoscopic Sphincterotomy
Zakko A, Zakko L, Grimshaw AA, Laine L. Antiplatelet Monotherapy Is Associated with an Increased Risk of Bleeding After Endoscopic Sphincterotomy. Digestive Diseases And Sciences 2021, 67: 4161-4169. PMID: 34796411, DOI: 10.1007/s10620-021-07302-w.Peer-Reviewed Original ResearchConceptsEndoscopic retrograde cholangiopancreatographyPost-sphincterotomy bleedingAntiplatelet monotherapyInclusion criteriaRisk of bleedingROBINS-I toolNewcastle-Ottawa ScaleHigh-quality studiesRandom-effects modelBackgroundClinical guidelinesAntithrombotic therapyAdult patientsCohort studyEndoscopic sphincterotomyPrimary outcomeAntiplatelet agentsOvid EmbaseRetrograde cholangiopancreatographyCochrane LibraryOvid MEDLINEMonotherapyMethodological qualityBleedingUnique citationsPatientsGastrointestinal Injury Caused by Aspirin or Clopidogrel Monotherapy Versus Dual Antiplatelet Therapy ∗
Bittl JA, Laine L. Gastrointestinal Injury Caused by Aspirin or Clopidogrel Monotherapy Versus Dual Antiplatelet Therapy ∗. Journal Of The American College Of Cardiology 2021, 79: 129-131. PMID: 34752903, DOI: 10.1016/j.jacc.2021.10.027.Commentaries, Editorials and Letters
2016
Efficacy and Safety of Proton-Pump Inhibitors in High-Risk Cardiovascular Subsets of the COGENT Trial
Vaduganathan M, Cannon CP, Cryer BL, Liu Y, Hsieh WH, Doros G, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Bhatt DL, Investigators C. Efficacy and Safety of Proton-Pump Inhibitors in High-Risk Cardiovascular Subsets of the COGENT Trial. The American Journal Of Medicine 2016, 129: 1002-1005. PMID: 27143321, DOI: 10.1016/j.amjmed.2016.03.042.Peer-Reviewed Original ResearchConceptsDual antiplatelet therapyProton pump inhibitorsAcute coronary syndromePercutaneous coronary interventionCardiovascular eventsCoronary syndromeCoronary interventionGastrointestinal eventsPercutaneous coronary intervention-treated patientsSafety of PPIsUnadjusted Cox proportional hazards modelCox proportional hazards modelDays of randomizationMajor cardiovascular eventsComposite cardiovascular eventsSubset of patientsSafety of omeprazoleProportional hazards modelGastroprotective strategiesMedian followPPI therapyAntiplatelet therapyFrequent indicationHazards modelPatientsProton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy
Vaduganathan M, Bhatt DL, Cryer BL, Liu Y, Hsieh WH, Doros G, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Cannon CP, Investigators C. Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy. Journal Of The American College Of Cardiology 2016, 67: 1661-1671. PMID: 27012778, DOI: 10.1016/j.jacc.2015.12.068.Peer-Reviewed Original ResearchMeSH KeywordsAgedAspirinClopidogrelDose-Response Relationship, DrugDrug Therapy, CombinationDyspepsiaFemaleGastrointestinal HemorrhageHumansIntestinal ObstructionIntestinal PerforationMaleMiddle AgedMyocardial InfarctionMyocardial RevascularizationOmeprazolePainPeptic UlcerPlatelet Aggregation InhibitorsProspective StudiesProton Pump InhibitorsStrokeTiclopidineConceptsDual antiplatelet therapyLow-dose aspirinProton pump inhibitorsMajor adverse cardiac eventsAdverse cardiac eventsPPI therapyAntiplatelet therapyAspirin usersGastrointestinal eventsCardiac eventsGI eventsMeier estimatesArtery diseaseCardiovascular endpointsLow-dose aspirin usersPrimary cardiovascular endpointUpper GI eventsHigh-dose aspirinPeripheral artery diseasePercutaneous coronary interventionCoronary artery diseaseHigh rateAspirin groupBlinded gastroenterologistsAspirin dose
2015
The effects of proton pump inhibition on patient‐reported severity of dyspepsia when receiving dual anti‐platelet therapy with clopidogrel and low‐dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial
Vardi M, Cryer BL, Cohen M, Lanas A, Schnitzer TJ, Lapuerta P, Goldsmith MA, Laine L, Doros G, Liu Y, McIntosh AI, Cannon CP, Bhatt DL. The effects of proton pump inhibition on patient‐reported severity of dyspepsia when receiving dual anti‐platelet therapy with clopidogrel and low‐dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial. Alimentary Pharmacology & Therapeutics 2015, 42: 365-374. PMID: 26032114, PMCID: PMC4494867, DOI: 10.1111/apt.13260.Peer-Reviewed Original ResearchConceptsDual anti-platelet therapyAnti-platelet therapyGastrointestinal Event TrialLow-dose aspirinNonpain symptomsEvents trialPatient-reported outcome dataPercent of patientsPatient-reported symptomsPatient-reported outcomesPatient-reported severityOmeprazole groupProphylactic omeprazoleCardiovascular safetyGastrointestinal bleedingPain intensityClinical eventsOmeprazole useClinical significanceOutcome dataAssessment QuestionnaireClopidogrelDyspepsiaTherapyPatients
2014
NSAID-Associated Gastrointestinal Bleeding: Assessing the Role of Concomitant Medications
Laine L. NSAID-Associated Gastrointestinal Bleeding: Assessing the Role of Concomitant Medications. Gastroenterology 2014, 147: 730-733. PMID: 25167988, DOI: 10.1053/j.gastro.2014.08.021.Commentaries, Editorials and Letters
2013
Gastroprotection in Low-Dose Aspirin Users for Primary and Secondary Prevention of ACS: Results of a Cost-Effectiveness Analysis Including Compliance
de Groot NL, van Haalen HG, Spiegel BM, Laine L, Lanas A, Focks JJ, Siersema PD, van Oijen MG. Gastroprotection in Low-Dose Aspirin Users for Primary and Secondary Prevention of ACS: Results of a Cost-Effectiveness Analysis Including Compliance. Cardiovascular Drugs And Therapy 2013, 27: 341-357. PMID: 23417566, DOI: 10.1007/s10557-013-6448-y.Peer-Reviewed Original ResearchMeSH KeywordsAcute Coronary SyndromeAspirinCost-Benefit AnalysisDrug Therapy, CombinationGastrointestinal HemorrhageHealth Care CostsHumansMaleMiddle AgedModels, TheoreticalPatient CompliancePlatelet Aggregation InhibitorsPrimary PreventionProton Pump InhibitorsQuality-Adjusted Life YearsSecondary PreventionConceptsAcute coronary syndromeProton pump inhibitorsUpper GI bleedingSecondary preventionGI bleedingASA monotherapyPPI complianceElevated riskLow-dose ASA usersLow-dose aspirin usersUpper GI side effectsGI side effectsUpper gastrointestinal complicationsCombination of ASABase-case patientProbabilistic sensitivity analysesCost-effectiveness analysisASA usersGastrointestinal complicationsGastroprotective strategiesAspirin usersCoronary syndromePPI useACS eventCase patients
2010
ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use
Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, Scheiman J, Sperling LS, Tomaselli GF. ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use. The American Journal Of Gastroenterology 2010, 105: 2533. PMID: 21131924, DOI: 10.1038/ajg.2010.445.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsAnti-Inflammatory Agents, Non-SteroidalAryl Hydrocarbon HydroxylasesAspirinCardiovascular DiseasesClopidogrelCytochrome P-450 CYP2C19Drug InteractionsDrug Therapy, CombinationGastrointestinal HemorrhageHistamine H2 AntagonistsHumansPiperazinesPlatelet Aggregation InhibitorsPrasugrel HydrochlorideProton Pump InhibitorsPurinergic P2Y Receptor AntagonistsRisk FactorsThienopyridinesThiophenesTiclopidineACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use
Members W, Abraham N, Hlatky M, Antman E, Bhatt D, Bjorkman D, Clark C, Furberg C, Johnson D, Kahi C, Laine L, Mahaffey K, Quigley E, Scheiman J, Sperling L, Tomaselli G. ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use. Circulation 2010, 122: 2619-2633. PMID: 21060077, DOI: 10.1161/cir.0b013e318202f701.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsAnti-Inflammatory Agents, Non-SteroidalAryl Hydrocarbon HydroxylasesAspirinCardiovascular DiseasesClopidogrelCytochrome P-450 CYP2C19Drug InteractionsDrug Therapy, CombinationGastrointestinal HemorrhageHistamine H2 AntagonistsHumansPiperazinesPlatelet Aggregation InhibitorsPrasugrel HydrochlorideProton Pump InhibitorsPurinergic P2Y Receptor AntagonistsRisk FactorsThienopyridinesThiophenesTiclopidineClopidogrel with or without Omeprazole in Coronary Artery Disease
Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP. Clopidogrel with or without Omeprazole in Coronary Artery Disease. New England Journal Of Medicine 2010, 363: 1909-1917. PMID: 20925534, DOI: 10.1056/nejmoa1007964.Peer-Reviewed Original ResearchConceptsProton pump inhibitorsDual antiplatelet therapyUpper gastrointestinal bleedingAntiplatelet therapyCardiovascular eventsGastrointestinal bleedingOvert upper gastrointestinal bleedingPrimary cardiovascular end pointEnd pointEvent ratesEfficacy of clopidogrelSymptomatic gastroduodenal ulcersCardiovascular end pointsComposite of deathNonfatal myocardial infarctionSerious adverse eventsCoronary artery diseaseHigh-risk subgroupsRisk of diarrheaCardiovascular causesGastrointestinal complicationsGastrointestinal eventsOccult bleedingAntithrombotic therapyAdverse events
2007
Evaluation of Proton Pump Inhibitor Use in Patients With Acute Coronary Syndromes Based on Risk Factors for Gastrointestinal Bleed
Schreiner GC, Laine L, Murphy SA, Cannon CP. Evaluation of Proton Pump Inhibitor Use in Patients With Acute Coronary Syndromes Based on Risk Factors for Gastrointestinal Bleed. Critical Pathways In Cardiology A Journal Of Evidence-Based Medicine 2007, 6: 169-172. PMID: 18091407, DOI: 10.1097/hpc.0b013e318159921e.Peer-Reviewed Original ResearchConceptsUse of PPIsAcute coronary syndromeProton pump inhibitorsGI risk factorsRisk factorsCoronary syndromeHigh GI risk patientsProton pump inhibitor useNonsteroidal anti-inflammatory agentsInfection Therapy-ThrombolysisLong-term bleedingPrior GI eventsDual antiplatelet therapyUse of anticoagulantsAnti-inflammatory agentsAtorvastatin EvaluationAntiplatelet therapyGastrointestinal bleedGastrointestinal bleedingGI bleedingGI eventsInhibitor useRisk patientsTrials databasesPump inhibitorsAssessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison
Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP, Committee F. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. The Lancet 2007, 369: 465-473. PMID: 17292766, DOI: 10.1016/s0140-6736(07)60234-7.Peer-Reviewed Original ResearchMeSH KeywordsAgedAnti-Inflammatory Agents, Non-SteroidalArthritisArthritis, RheumatoidAspirinCyclooxygenase 2 InhibitorsCyclooxygenase InhibitorsDiclofenacEtoricoxibFemaleGastrointestinal DiseasesGastrointestinal HemorrhageHumansMaleMiddle AgedOsteoarthritisPeptic UlcerPlatelet Aggregation InhibitorsProton Pump InhibitorsPyridinesSulfonesConceptsProton pump inhibitorsNon-steroidal anti-inflammatory drugsUpper gastrointestinal safetyLow-dose aspirinClinical eventsGastrointestinal safetyRheumatoid arthritisUncomplicated eventsTraditional non-steroidal anti-inflammatory drugsConcomitant proton pump inhibitorsLow-dose aspirin useCOX-2 selective inhibitorsTraditional NSAID diclofenacAnti-inflammatory drugsStandard clinical practiceSelective inhibitorGastrointestinal eventsMultinational EtoricoxibAspirin useGastrointestinal outcomesTreat analysisProtective therapyPump inhibitorsCyclo-oxygenaseNSAID diclofenac
2006
Review article: gastrointestinal bleeding with low‐dose aspirin – what's the risk?
LAINE L. Review article: gastrointestinal bleeding with low‐dose aspirin – what's the risk? Alimentary Pharmacology & Therapeutics 2006, 24: 897-908. PMID: 16948802, DOI: 10.1111/j.1365-2036.2006.03077.x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsLow-dose aspirinGastrointestinal bleedingPlacebo-controlled trialRelative riskNon-aspirin non-steroidal anti-inflammatory drugsLarge Danish cohort studyRandomized placebo-controlled trialNon-steroidal anti-inflammatory drugsAbsolute annual incidenceDanish cohort studyMajor gastrointestinal bleedingUpper gastrointestinal bleedingEnteric-coated aspirinAbsolute rate increaseAnti-inflammatory drugsEndoscopic trialsCorticosteroid useAnticoagulant therapyCardiovascular benefitsCohort studyAnnual incidenceVascular protectionClinical eventsUlcer incidenceOdds ratioSystematic Review and Meta-analysis of Adverse Events of Low-dose Aspirin and Clopidogrel in Randomized Controlled Trials
McQuaid KR, Laine L. Systematic Review and Meta-analysis of Adverse Events of Low-dose Aspirin and Clopidogrel in Randomized Controlled Trials. The American Journal Of Medicine 2006, 119: 624-638. PMID: 16887404, DOI: 10.1016/j.amjmed.2005.10.039.Peer-Reviewed Original ResearchConceptsLow-dose aspirinAspirin/clopidogrelMajor GI bleedingMajor bleedingGI bleedingAdverse eventsIntracranial bleedingRelative riskSystematic reviewMajor bleeding episodesMajor gastrointestinal bleedingRelevant adverse eventsRisk of GIAbsolute risk increaseRandomized Controlled TrialsDay aspirinMajor GIBleeding episodesCardiovascular prophylaxisGastrointestinal bleedingAntiplatelet agentsControlled TrialsWeighted incidenceAbsolute riskClopidogrelClinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program: Cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis
Cannon CP, Curtis SP, Bolognese JA, Laine L, Committee F. Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program: Cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis. American Heart Journal 2006, 152: 237-245. PMID: 16875903, DOI: 10.1016/j.ahj.2006.05.024.Peer-Reviewed Original ResearchMeSH KeywordsAnti-Inflammatory Agents, Non-SteroidalArthritis, RheumatoidAspirinCyclooxygenase InhibitorsDiclofenacDouble-Blind MethodEtoricoxibFemaleHumansMaleMiddle AgedMulticenter Studies as TopicOsteoarthritisPatient SelectionPyridinesRandomized Controlled Trials as TopicResearch DesignRisk AssessmentSulfonesTreatment OutcomeConceptsNonsteroidal anti-inflammatory drugsAnnual event rateThrombotic cardiovascular eventsRheumatoid arthritisCardiovascular eventsEvent ratesHazard ratioTraditional nonsteroidal anti-inflammatory drugsCyclooxygenase-2 selective inhibitorCOX-2 selective inhibitorsTraditional NSAID diclofenacDouble-blind trialCardiovascular event ratesTreatment of patientsAnti-inflammatory drugsClinical trial designSelective inhibitorLong-term useMultinational EtoricoxibCardiovascular outcomesCardiovascular riskPatient demographicsNoninferiority criteriaControl armCOX-2
2004
Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: A double-blind trial
Laine L, Maller ES, Yu C, Quan H, Simon T. Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: A double-blind trial. Gastroenterology 2004, 127: 395-402. PMID: 15300570, DOI: 10.1053/j.gastro.2004.05.001.Peer-Reviewed Original ResearchMeSH KeywordsAgedAnti-Inflammatory Agents, Non-SteroidalAspirinCyclooxygenase 2Cyclooxygenase 2 InhibitorsCyclooxygenase InhibitorsDouble-Blind MethodDrug Therapy, CombinationFemaleGastric MucosaHumansIbuprofenIncidenceIsoenzymesLactonesMaleMembrane ProteinsMiddle AgedOsteoarthritisProstaglandin-Endoperoxide SynthasesRisk FactorsStomach UlcerSulfonesTablets, Enteric-CoatedConceptsNonselective nonsteroidal anti-inflammatory drugsLow-dose aspirinCOX-2 selective inhibitorsDouble-blind trialUlcer incidenceNonselective NSAIDsLow-dose enteric-coated aspirinLow-dose aspirin usersCyclooxygenase-2 selective inhibitorSelective inhibitorNonsteroidal anti-inflammatory drugsEnteric-coated aspirinGastrointestinal mucosal injuryNumber of erosionsRisk of ulcerAnti-inflammatory drugsCOX-2 selective inhibitionYears of ageBaseline endoscopyAspirin usersDose aspirinErosive esophagitisCumulative incidenceMucosal injuryRepeat endoscopyProton pump inhibitor co-therapy with nonsteroidal anti-inflammatory drugs--nice or necessary?
Laine L. Proton pump inhibitor co-therapy with nonsteroidal anti-inflammatory drugs--nice or necessary? Gastroenterological Disorders 2004, 4 Suppl 4: s33-41. PMID: 15580145.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsNonsteroidal anti-inflammatory drugsUpper GI symptomsNonselective nonsteroidal anti-inflammatory drugsLow-dose aspirinAnti-inflammatory drugsGI symptomsGI complicationsGI riskSide effectsDevelopment of NSAIDDaily proton pump inhibitor therapyHistamine-2 receptor antagonistsNSAID-induced gastric ulcersProton pump inhibitor therapyNSAID-induced ulcersGI side effectsUpper GI bleedingAnti-pyretic effectsGastrointestinal toxicityGI bleedingNSAID usersUlcer complicationsCardiovascular prophylaxisInhibitor therapyStandard doses