Practical Guide to Safety of PPIs What to Tell Your Patient. Proton Pump Inhibitors

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1 Practical Guide to Safety of PPIs What to Tell Your Patient Joel E Richter, MD, FACP, MACG Professor and Director Division of Digestive Diseases and Nutrition Joy Culverhouse Center for Esophageal Diseases University of South Florida Tampa, Florida Proton Pump Inhibitors Over 20 years of extensive use throughout the world 2 nd most used class of drugs behind statins Sales of PPIs > $20 billion per year world wide Over 720 million prescription risks Diarrhea and headache are well known side effects, but the class is very well tolerated However, even rare PPI complications could affect many patients with their very common use 1

2 Mechanisms of PPI Side Effects Inhibition of acid secretion and resulting hypergastrinemia Immunosuppression Idiosyncratic reactions Metabolic interactions with hepatic cytochrome P450 Potential Side Effects of PPIs Cancer risk gastric carcinoids/polyps and colon cancer Infections pneumonia and enteric infections Small bowel bacterial overgrowth Vitamins and minerals calcium and osteoporosis vitamin B12 iron magnesium Acute interstitial nephritis Interaction with PPIs and clopidogrel 2

3 Increase in PPI Safety Articles Published Yang YX and Metz DC Gastroenterology 2010 Stay Calm and Stay the Course Most of the following reports are retrospective case control studies with the inherent limitations due to bias and/or confounding factors This data only demonstrates very modest association not causality No large prospective randomized trials to substantiate these claims BUT these have caused some patient concerns, confused the cardiologists and the FDA is quite reactionary to this data (black box warning) 3

4 Fundic Gland Polyps and Long-term PPIs 599 patients, 322 on PPIs No PPI use: 277 (32%-fundic polyps) PPIs< 1 yr: 162 (18%) PPIs> 1 yr: 160 (57%) Risk increases over time: < 1 yr: OR % CI: yr: OR % CI: > 5 yr: OR % CI: Low grade dysplasia found in 1 fundic gland polyp Jalving M et al. Aliment Pharmacol Ther 2006 Pneumonia PPIs diminish defense mechanisms allowing gastric colonization of oral flora 2 Dutch case controlled studies reported 50-80% increase in community acquired pneumonias with current PPI use (1,2) but inverse relationship with duration of use UK General Practice Database found no overall risk and highest association with PPI use in past 48 hours (3) Possible protopathic bias drugs given for early sxs may be associated with subsequent illness 1. Labej et al JAMA Gulmez et al Arch Intern Med Sakar et al Ann IM

5 Association between Duration 0f Acid Suppression and Risk of Pneumonia Eom CS et al. CMAJ 2011 RCTs with PPIs and Pneumonia Sultan N et al Can Journal Gastroenterol published trials with 2586 pts followed 1-6months --no significant difference Estborn l and Joelson S Drug Safety trials with 28,627 pts followed 1-6 months --no significant ifi differences between PPIs and placebo for respiratory tract infections or pneumonia --BUT study done by Astra-Zeneca using their safety database from II-IV randomized controlled studies 5

6 Infections Community-acquired pneumonia PPIs: RR % CI: H2RAs: RR % CI: Enteric infections C. difficile: OR: % CI: Salmonella, Campylobacter and others: OR: % CI: Spontaneous bacterial peritonitis: OR: % CI: Laheij RJF et al JAMA 2004 Leonard J Am J Gastroenterol 2007 Bajaj J et al. Am J Gastroenterol 2009 Clostridium difficile Rates in the UK Practice Research Database 1672 patients identified over 10 years Dial S, et al. JAMA

7 Increased Incidence of Small Bowel Bacterial Overgrowth with PPI Therapy Lombardo et al. Clinical Gastroenterology and Hepatology 2010 Severity of Small Bowel Overgrowth Symptoms Increase with PPI Duration Lombardo et al. Clinical Gastroenterology and Hepatology

8 Potential Pathways for PPI Therapy to Decrease Bone Strength Low Power Yang and Metz, Gastroenterology 2010 Hip Fracture Risk Linked to Duration of PPI Therapy Adjusted odds ratios based on an analysis of 13,566 cases matched to 135,386 outpatient controls in the United Kingdom General Practice Research Database Yang YX, et al. JAMA

9 Risk of Spine Fracture with PPI or H 2 RA Use Kwok CS, et al. J Bone 2010 Risk of Hip Fracture with PPI or H 2 RA Use Kwok CS et al J Bone

10 Risk of Any Fracture with PPI or H 2 RA Use Kwok CS, et al. J Bone 2010 Risk of Any Fracture Comparing Longer and Shorter Duration of PPI Exposure Kwok CS, et al. J Bone

11 Other Vitamins and Minerals Vitamin B 12: Acid important for B 12 absorption --releases bound dietary B12 to bind with intrinic factor --prevents small bowel overgrowth Studies of long-term PPI users are conflicting May be useful to check B12 level in elderly PPI user Iron: Acid is most important luminal factor for reducing ferric iron (food form) absorption in duodenum Little human data ZES pts on PPIs for 6 yrs had no iron deficiency Dharmarajan et al Nature GI 2008 Stewart et all APT 1998 Magnesium the Newest Threat At least 23 cases of severe magnesium deficiency with life threatening tetany, seizures, and arrhythmias No evidence of GI malabsorption or renal wasting Some recalcitrant to high dose IV Mg replacement Resolved after stopping PPIs for 1 wk or switch to H2RAs Several cases recurred with rechallenge Mechanism is unknown FDA Black Box warning in March 2011 for all PPIs in pts taking PPIs for over year Broeren et al Ann Int Med

12 Acute Interstitial Nephritis Humoral and cell mediated hypersensitivity reaction resulting in renal inflammation First report with omeprazole in 1992 over 100 cases reported to date Not dose-dependent and usually recurs with rechallenge New Zealand PPIs most common cause of acute interstitial nephritis Stop PPIs in unexplained acute renal deterioration Clopidogrel and PPIs Biotransformation of clopidogrel to active metabolite requires cytochrome P450 isoform CYP2C19 Meta-analysis: analysis: 23 studies with 93,278 patients --propensity matched or randomized trials showed NO associated cardiovascular risks with PPIs --other observational studies generally showed a significant association --No studies showed significant association between PPIs and increased mortality (RR 1.09, 95% CI: ) Nov 2009 FDA warning on potential for reduced effectives of clopidogrel taken with omeprazole/esomeprazole Kwok CS, et al. Aliment Pharmacol Ther

13 Patients on PPIs Have More Concurrent Medical Problems Ho PM et al. JAMA 2009 Clopidogrel / ASA and Omeprazole in CAD Primary GI Events Omp-1.1% Plac-2.9% HR: 0.34 CI: Bhatt DL, et al. NEJM

14 Clopidogrel / ASA and Omeprazole in CAD Primary Cardiovascular Events Omp-4.9% Plac-5.7% HR, 0.99 CI: Bhatt DL, et al. NEJM 2010 Influence of Esomeprazole on Platelet Aggregation Clopidogrel/esomeprazole 20mg vs. clopidogrel 253 patients with history of peptic ulcer disease Ulcer recurrence at 6 mo Clopidogrel 11% Clopid/Eso---1.2% p=.009 Hsu P, et al. Gastroenterology

15 ACG and American Heart Association Consensus on Concomitant Use of PPIs and Thienopyridines Routine use of PPIs/H2RAs not recommended with clopidogrel for patients with low risk of GI bleeding Clinical decisions to use PPIs/clopidogrel together must balance overall GI/cardiovascular risks and benefits Pharmacokinetic studies suggest that concomitant use of a PPI and clopidogrel reduces its antiplatelet effects --the strongest evidence for this interaction is with omeprazole/esomeprazole Because of short plasma half-lives (<2 hrs) of both drugs, interaction between PPIs and thienopyridines might be minimized by separating the timing of drug administration Abraham NS, et al. Am J Gastroenterology 2010 Appropriate Use of PPIs Keep Calm and Carry On Prescribe PPIs only when there is an appropriate clinical indication Lowest effective dose and avoid BID dosing unless confirmed indication: persistent esophagitis abnormal ph test on PPI On-demand PPIs or drug holidays Appropriate maintenance dose when needed 15