Perplexed by PPI s Should I be Worried? James R Gray Gastroenterology Vancouver

Perplexed by PPI s Should I be Worried? James R Gray Gastroenterology Vancouver

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Anti-Secretory Drug Consumption Am J Gastro 2016

Overuse of Antisecretory Therapy in the Ambulatory Care Setting Am J Managed Care 2010; 16: e228

The Concerns Fractures Drug-drug interactions Infections Clostridium difficile infections Enteric infections Pneumonia Micronutrient Malabsorption Vitamin B12 deficiency Hypomagnesemia Gastric mucosal changes Neoplasia Microscopic colitis Spontaneous bacterial peritonitis in cirrhotics Interstitial nephritis Dementia Death Acid rebound

PPIs and Adverse Events with Proven and Unproven Causality Nat Rev Gastro Hep doi.10.1038/nrgastro.2017.11.7

The Issue Balancing Potential Harms and Documented Benefits

PPI s and Fractures Data from retrospective observational studies Reported risks are low Mechanism for an association not clear

Association between continuous exposure to proton pump inhibitors and osteoporosis-related fractures Targownik CMAJ 2008;179:319-326

PPI s and Bone Health Women s Health Initiative (n= 1,005,126 person year F/U) PPI Non-User 1 PPI User < 1 year 1.27 (1.13-1.44) PPI User 1-3 years 1.19 (1.05-1.35) PPI User > 3 years 1.30 (1.03-1.64) Fracture Risk (Hip, spine, forearm) H2RA Non-User 1 H2RA User < 1 year 1.09 (0.99-1.20) H2RA User 1-3 years 1.08 (1.00-1.18) H2Ra User > 3 years 1.06 (0.96-1.16) Gray. Arch Int Med 2010; 170: 765

Lack of Duration Effect of PPI Exposure and Hip Fracture Am J Gastro 2011; 106: 1209

PPIs and Hip Fracture NNH = 2,672 Am J Gastro 2011; 106: 1209

PPI s and Bone Health Theoretical Explanations Calcium malabsorption? Impaired bone metabolism? Hyperparathyroidism Reduced plasma homocysteine secondary to malabsorption of folate, B12 and riboflavin by acid suppression? (Proton pump inhibition of osteoclast activity)

Dietary Calcium Gastric Acid Release Ionized Calcium Low serum Calcium Calcium absorption Parathyroid activation PTH release Osteoclastic activity Bone mass, fracture risk

Inhibiting Gastric Acid for 5 days does not Affect Calcium Absorption J Bone and Min Res 2010; 25: 2205

30 days of Omeprazole does not affect calcium absorption J Bone and Min Res 2010; 25: 2786

Lack of Effect of PPI s on Bone Mineral Density over 10 Years Follow-up Hip Femur Lumbar Spine Continuous PPI use 0.9% (-1.0-2.9%) -0.5% (-2.9-1.8%) -0.7% (-3.3-1.9%) PPI use > 50 years old 0.1% (-2.0-2.2%) -0.9% (-3.4-1.6%) -0.5% (-3.4-2.4%) Current PPI use -0.5% (-1.1-0.2%) -0.6% (-1.4-0.1%) -0.1% (-1.0-0.7%) Targownik. Am J Gastro 2012; 107: 1361

Arch Int Med 2010; 170: 763

PPI s and Fractures Conclusion Number Needed to Harm (NNH) 234 post menopausal diabetic women 1000 s young women or men Pharmacotherapy 2008; 28: 951 J Clin Endo Metab 2006; 91: 3404

PPIs and Clopidogrel Is There GI Benefit or Cardiovascular Harm?

Clopidogrel Proton Pump Inhibitor CYP-4502C19 Active metabolite Inactive Metabolite

PPI s and Clopidogrel Initial concerns from in vitro studies of platelet reacitivity leading to FDA warning Best quality clinical studies fail to show adverse CV outcomes PPI co-therapy reduces UGI complications

PPI s and Platelet Function No clear or consistent interaction in platelet function studies Kwok. Drug Safety 2012; 35: 127 Gastro 2011; 140: 791

Benefit of Omeprazole with Clopidogrel and ASA in Coronary Artery Disease (COGENT study) Probability of Remaining Free of a Primary GI Event NEJM 2010; 363: 1909

No Difference in Serious CVD Outcome With or Without PPI Ray. Ann Int Med 2010; 152: 337

Mortality Rates from UGI Bleed or Perforation Over Time Date of Publication All Cases Mortality (%) Cases Using NSAIDs (%) Before 1997 11.6 (11.0-12.2) 14.7 (13.6-15.8) 1997-2008 7.4 (7.2-7.6) 20.9 (18.8-22.9) BMC Gastro 2009; 9:41

NSAID Ulcer Complications: Risk Factors Prior complicated ulcer 13.5 Multiple NSAIDs (aspirin) 9 High dose Anticoagulant Prior uncomplicated ulcer Age>70 7 6.4 6.1 5.6 H. pylori 3.5 Steroids 2.2 0 2 4 6 8 10 12 14 16 Odds ratio Gabriel SEl. Ann Intern Med 1991;115(10):787-96; Garcia Rodriguez LA. Lancet 1994;343:769; Silverstein FEl. Ann Intern Med 1995;123(4):241-9; Huang JQl. Lancet 2002;359:14

Clopidogrel vs Placebo + ASA in Acute Coronary Syndrome (n=12,562) CURE Trial. NEJM 2001; 345: 494

Reduced Adverse GI Events with Clopidogrel and ASA by PPI Drug Safety 2011; 34: 47

Outcomes with Clopidogrel Alone or with PPI Open Heart 2015; 2: e000248

Outcomes with Clopidogrel alone or with PPI Open Heart 2015; 2: e000248

Reduced Risk of GI Bleeding by Taking PPIs and NSAIDs in Post-MI Patients BMJ 2015; 351: h5096

J Am Coll Card 2008; 52: 1502

Drugs don t work in patients who don t take them. C Everett Koop US Surgeon General

PPIs and Infections Gastrointestinal infections C difficle Community or travellers enteritis Respiratory infections Community acquired Hospital acquired

Shift of Gut Microbiome Towards Oral Microbiome in PPI Users Gut 2016; 65: 740

Acid Suppression and Enteric Infections H2RA PPI Am J Gastro 2007; 102: 2047

Risk of C difficile Infection with PPI Use NNH = 67 Am J Gastro 2012; 107: 1011

PPI s and C difficile Estimates of Risk Population NNT for harm Unselected hospital admissions without PPI 67 (48-110) PPI users admitted to hospital 22 (9-670) Hospital admissions with antibiotics 28 (21-42) Hospital admissions without antibiotics 202 (144-307) Community patients 899 (638-1369) Kwok. Am J Gastro 2012; 107: 1011

Microscopic Colitis Chronic watery diarrhea > 60 years old Females > males Represents etiology in 7.5% with chronic diarrhea Two subtypes Lymphocytic Collagenous Cause unknown but several drug associations

Risk of Microscopic Colitis and Drugs APT 2016; 43: 1004

PPI s and Community Acquired Pneumonia (n= 364, 683) Adjusted Relative Risk Current PPI use 1.89 (1.36-2.62) Current H2RA use 1.63 (1.07-2.48) Low dose PPI 1.23 (0.78-1.93) Standard dose PPI 1.94 (1.41-2.68) High dose PPI 2.28 (1.26-4.10) Laheij. JAMA 2004; 292: 1955

PPI s and Hospital-Acquired Pneumonia (n=63,878 admissions) Adjusted Relative Risk Hospital-acquired pneumonia 1.3 (1.1-1.4) Aspiration pneumonia 1.4 (1.1-1.8) Non-aspiration pneumonia 1.2 (1.1-1.4) PPI use 1.3 (1.1-1.4) H2RA use 1.2 (0.98-1.4) Herzig. JAMA 2009; 301: 2120

Duration of Acid suppression and Risk of Pneumonia Nat Rev Gastro Hep 2012; 9: 132

Comorbidities of Patients Receiving PPIs and Risk of Developing Pneumonia Nat Rev Gastro Hep 2012; 9: 132

Lack of Association Between PPI Use and Community Acquired Pneumonia Gut 2014; 63: 552

PPIs and Absorption B12 Iron Magnesium

PPI s and B12 No association with long-term PPI use and B12 status Den Elzen. APT 2008; 27: 491 Valuck. J Clin Epidem 2004; 57: 422 B12 deficiency more likely after more than 2 years of PPI Lam. JAMA 2013; 310: 2435

PPI s and Iron Absorption No evidence for iron deficiency with PPI use Stewart. APT 1998; 12: 83

PPI s and Hypomagnesemia 36 cases since first reported 2006 PPI use 2 weeks to 13 years (mean 5.5 yrs) Class effect - all PPI s Beware with loop diuretics Fast recovery after discontinuation but recurrence with re-challenge Mechanism not clear, not urine excretion Hess. APT 2012; 36: 405 Mackay. QJMed 2010; 103: 387

Low Prevalence of Hypomagnesemia in Long-term Users of PPIs Clin Gastro Hep 2016; 14: 317

PPI s and Acute Interstitial Nephritis 64 cases (60% female, mean age 78) PPI use mean of 13 weeks Average recovery 35.5 weeks, 3 required dialysis Initial symptoms: nausea, vomiting, fever Sierra. APT 2007; 26: 545 Geevasinga. Clin Gastro Hep 2006; 4: 597

Concomitant Meds in PPI Users With Interstitial Nephritis N=60 N=60 N=34 APT 2007; 26: 545

Chronic Kidney Disease and PPI Use JAMA Int Med 2016; 176: 238

Association of PPI and Dementia JAMA Neurol Feb 15, 2016

Am J Gastro 2017; 112: 1084

Cumulative Incidence of Ischemic Stroke Over 120 Days Am J Gastro 2017; 112: 1084

Duration of PPI Exposure and Risk of Death N=166,098 BMJ Open July 3, 2017

The Challenge of Observational Studies Comorbidities in Patients on PPIs Nature Reviews Gastro Hep 2012; 9: 132

PPI s and Cancer Risk Colorectal cancer No increased risk PPI Use Never or rare 1.0 Adjusted Odds Ratio Recent 1.14 (0.98-1.34) Former 1.11 (0.88-1.39) Robertson. Gastro 2007; 133: 755 van Soest. Am J Gastro 2008; 103: 966 Yang. Gastro 2007; 133: 748

PPI s and Cancer Risk Gastric cancer No increased risk (accounting for reverse causation with a one year lag time) Medication exposure Risk of gastric cancer PPI use 1.2 (0.8-2.0) H2RA use 1.2 (0.8-1.2) Poulsen. Br J Cancer 2009; 100: 1503

Reported Associations with PPI Use and Adverse Events Adverse Event Hazard Ratio 95% CI Hip fracture with PPI use > 1 year 1.44 1.30-1.59 Hip fracture with long-term PPI use 2.65 1.80-3.90 Community acquired pneumonia 1.49 1.16-1.92 Clostridium difficile infection 2.10 1.20-3.50 Acute interstitial nephritis 5.16 2.21-12.05 Acute kidney injury 1.72 1.27-2.32 Hypomagnesaemia 1.78 1.01-1.24 Myocardial infarction 1.16 1.09-1.24 Dementia 1.44 1.36-1.52 Nat Rev Gastro Hep. March 16, 2016

Acid Rebound Gastro 2009; 137: 20

Acid-Related Symptoms After Withdrawal of PPI in Healthy Volunteers Gastro 2009; 137: 80

Summary PPIs effective for erosive and non-erosive UGI disorders Generally well tolerated but potential side effects to be considered Concerns for alleged risks poorly supported but include fractures, Clopidogrel interaction, pneumonia and malabsorption Strongest risk associations are with enteric infections and interstitial nephritis

References Adverse effects associated with PPIs. JAMA Int Med 2016; 176: 172 Safety of Long-term PPI therapy. Best Pract Res Clin Gastro 2013; 27: 443 Side effects and Complications of PPI Use: Dissecting the Evidence. Clin Gastro Hep 2013; 11: 458 Prescribing PPIs. Is it time to pause and rethink? Drugs 2012; 72: 437 A Benefit-risk Assessment of PPIs in the Elderly. Drugs Aging 2014; 31: 263 PPIs and MI. Gastroenterol 2015; 149: 830