Fast Facts In OTC PPI s

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1 Page 1 Fast Facts in OTC PPI s Fast Facts in OTC PPIs James M. Scheiman, MD Professor of Internal Medicine Division of Gastroenterology University of Michigan Medical School Ann Arbor, Michigan This program has been supported by an educational grant from Novartis Consumer Healthcare Accreditation: Pharmacists: L1-P CE Credits: 1. contact hour Target Audience: Pharmacists Program Overview: This knowledge based webinar aims to provide pointers on who is at risk of frequent heartburn, how to recognize symptoms and alarm symptoms, how to decide who is appropriate for OTC PPI treatment, and who should be recommended to see their physicians, as well as discussing safety concerns. The webinar is based on a series of frequently asked questions to provide an opportunity to discuss many of key issues relating to the management of frequent heartburn and OTC PPI s. Objectives: Explain the prevalence of, and risk factors for, frequent heartburn, it s presentation and management in the community setting. Describe the rationale for OTC PPI s in the treatment of frequent heartburn, their mechanism of action and efficacy in controlling day and night time symptoms. Describe current PPI safety concerns and place into clinical perspective with respect to OTC usage. PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. Fast Facts in OTC PPI s Speaker:James M. Scheiman, MD is Professor of Internal Medicine, Division of Gastroenterology at the University of Michigan Medical School, as well as Director of Endoscopic Research and the Advanced Endoscopy Training Program. He is a Fellow of the American Gastroenterology Association as well as the American College of Physicians, American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy. His research has focused on the pathogenesis and management of NSAID and aspirin associated ulcers as well as H pylori and other acid related conditions. Dr. Scheiman is the author of more than 2 scientific publications and book chapters. Speaker disclosure: Dr. James M. Scheiman has consulted for AstraZeneca, Novartis, Pfizer, Bayer, Takeda, Pozen, NiCox; and has received honorarium from Takeda and AstraZeneca This activity is supported by an educational grant from Novartis Consumer Healthcare PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education Objectives By participating in this activity, learners will be better able to: Explain the prevalence of, and risk factors for, frequent heartburn, its presentation and management in the community setting Describe the rationale for OTC PPIs in the treatment of frequent heartburn, their mechanism of action and efficacy in controlling daytime and nighttime symptoms Describe current PPI safety concerns and place into clinical perspective with respect to OTC usage Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity.

2 Page 2 Summary of Webinar 2 Relieving frequent heartburn day through night OTC PPI treatment is appropriate and FDA-approved for self-management of frequent day and nighttime heartburn (i.e., occurring 2 days/week) Important to identify potential consumers who may not be appropriate for this and who may require medical assessment OTC PPI treatment is generally safe in appropriate users Pharmacists will be asked for advice about OTC PPIs and potential interactions with other medicines What is the scale of the GERD problem? Definitions Daytime GERD a disorder that occurs when the reflux of gastric contents into the esophagus causes troublesome symptoms and/or complications 1 Nocturnal GERD reflux that takes place during the night when the patient is recumbent 2,3 Definition of heartburn a burning retrosternal discomfort that radiates upwards toward the neck Frequent heartburn is defined as heartburn which occurs two or more days of the week GERD: A rapidly escalating condition The prevalence of GERD in the US is estimated at 18.6 million 1 GERD prevalence has been increasing in recent decades 2 Diagnosed with esophagitis on specialist referral = 3.6% 1987 = 16.8% 1 Vakil et al, Am J Gastroenterol 26; 11: Frazzun et al, Aliment Pharmacol Ther 23; 18: Orr et al, Am J Gastroenterol 1994; 89: Sandler et al, Gastroenterology 22; 122: El-Serag, Clin Gastroenterol Hepatol 27; 5: 17 26

3 Page 3 Importance of GERD in the US Single most common GI disorder diagnosed in US 1 Prevalence of GERD symptoms increasing by around 5% per year 2 Between 1998 and 21, there was a 47% increase in visits to PCPs because of GERD 3 frequent heartburn is defined as symptoms occurring at least 2 days a week 5 million Americans are estimated to have frequent heartburn 3 Economic impact of GERD is significant $9.3 billion spent annually on direct costs 1 consultation, testing, and treatment $75 billion in indirect costs estimated annually 2 Productivity losses due to GERD h/wk due to absenteeism 6 7 h/wk due to presenteeism 15 h/wk due to presenteeism in patients with sleep disturbance from nocturnal GERD 1 Dent et al, Gut 25; 54: El-Serag, Clin Gastroenterol Hepatol 27; 5: National Heartburn Alliance 1 http :// 1 American Gastroenterological Association (AGA). The Burden of Gastrointestinal Diseases. Bethesda, Md: AGA; 21 2 Wahlqvist et al, Aliment Pharmacol Ther 26; 24: Risk factors for heartburn What are the risk factors for GERD? Overweight / obesity Eating large meals Eating late in the evening Specific dietary factors high fat foods carbonated beverages alcohol mint / citrus / tomatoes vary among patients Smoking Medicines (anticholinergics, ß-blockers, Ca +2 blockers, benzodiazepines) Stress (?) Hiatus hernia not a prerequisite for GERD but, when present, may worsen tendency to reflux

4 Page 4 Obesity contributes to the frequency of GERD symptoms Presentation of GERD Association of BMI with the risk of frequent GERD symptoms in women Odds ratio An increase in BMI of 3.5 was associated with increased risk of frequent GERD symptoms, even in women with normal baseline weight p<.1 Multivariate odds in women with at least weekly GERD symptoms (n=236) Typical Extra-esophageal Complications Heartburn Regurgitation Asthma, chronic cough Hoarseness (laryngitis) Chest pain Globus Worse after: Meals On bending Recumbency Bleeding Barrett s esophagus Esophageal adenocarcinoma Relieved by: Antacids Antisecretories.5 < Alarm features Dysphagia, odynophagia Anemia Weight loss Jacobson et al, N Engl J Med 26; 354: Prevalence of nocturnal GERD symptoms Adults with frequent GERD symptoms 26% Nocturnal GERD symptoms reported What effect do nocturnal GERD symptoms have on a patient s quality of life? 54% reported waking from sleep Among 78% who reported nocturnal heartburn, 4% reported impact on ability to function the next day 74% Nocturnal GERD symptoms not reported Farup et al, Arch Intern Med 21; 161: 45 52

5 Page 5 Please answer the Poll Question What proportion of patients report nocturnal heartburn? Reflux during sleep Sleep 1. Approximately 3% of patients Recumbent position Heartburn perception UES pressure Primary peristalsis Salivation 2. Approximately 5% of patients 3. Approximately 8% of patients Prolonged acid exposure due to poor acid clearance 4. Approximately 95% of patients Respiratory complications Reflux complications Sleep disturbances Orr, Curr Gastroenterol Rep 26; 8: 22 7 Impact of nocturnal GERD on quality-of-life Nighttime reflux increases risks of GERD complications SF-36 score Physical Functioning Rolephysical Bodily pain General health Week Vitality Social functioning SF-36 = Medical outcomes study short-form 36 health survey p<.1 for all scales except role-emotional US population Nocturnal GERD n=1264 Roleemotional Mental health Farup et al, Arch Intern Med 21; 161: Esophageal disease progression Erosive esophagitis 1 Complicated erosive esophagitis 2 ulceration strictures Barrett s esophagus Adenocarcinoma 3 Atypical manifestations Asthma 4 Aspiration pneumonia Chronic cough Other symptoms Sleep deprivation 4 1 Orr et al, Am J Gastroenterol 1994; 89: Robertson et al, Gut 1987; 28: Lagergren et al, N Engl J Med 1999; 34: Gislason et al, Chest 22; 121:

6 Page 6 Foods that affect GERD What lifestyle measures should patients take? Carminative (e.g., peppermint, spearmint) Chocolate Citrus fruit juices Coffee (caffeinated) Cola beverages Fat Onion Tomato juice Orlando et al, Textbook of Gastroenterology, JB Lippincott Co 1996: 1214 Weinberg et al, Med Clin North Am 1996; 8: Lifestyle modifications for patients with GERD Agents that decrease LES pressure Elevate the head of the bed 4 8 inches Reduce the size of meals Lose weight (if overweight) Lifestyle changes Avoid foods / agents that decrease LES pressure Avoid smoking and alcohol ingestion Medications Anticholinergics Barbiturates β-adrenergic agonists Calcium channel blockers (DHP) Benzodiazepines Narcotic analgesics Miscellaneous Alcohol Smoking Pregnancy Avoid eating for a minimum of 3 hours before retiring Theophylline Genval conference and Reference from PSAP IV Orlando et al, Textbook of Gastroenterology, JB Lippincott Co 1995: 1214 Weinberg et al, Med Clin North Am 1996; 8:

7 Improvement Page 7 Goal of treatment: Achieve acid control Goals of acid suppressive therapy for GERD 1 eliminate symptoms maintain gastric ph >4 prevent complications Why PPIs? A primary goal of acid suppressive therapy is to maintain gastric ph >4, which has been shown to 2 : prevent mucosal injury promote healing of erosive esophagitis Nocturnal acid control refers to maintenance of intragastric ph >4 during the nighttime period 3 1 Modlin et al, Acid Related Diseases: Biology and Treatment. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins 24; Hunt, Arch Intern Med 1999; 159: Castell et al, Aliment Pharmacol Ther 25; 21: Intragastric ph control with conventional PPIs PPI treatment is the most effective therapy for esophagitis and heartburn relief Mean time ph>4 on day 5 (%) * 5.5 * 49.2 * 48. * 41.9 Esomeprazole 4 mg Rabeprazole 2 mg Omeprazole 2 mg Lansoprazole 3 mg Pantoprazole 4 mg 134 trials; n=35,978 1 Relative risk of esophagitis (RR) trials; n=9,457 2 Relative risk for heartburn remission (RR) way crossover study found 1 14 hours of ph control with conventional PPIs *p<.1 vs esomeprazole.2.22 Prokinetics H 2RAs Standarddose PPI All vs placebo.2 Prokinetics H 2RAs Standarddose PPI All vs placebo Miner et al, Am J Gastroenterol 23; 98: Khan et al, Cochrane Database Syst Rev 27; (2): CD van Pinxteren et al, Cochrane Database Syst Rev 26; (3): CD295

8 Page 8 How do PPIs act? PPIs will only inhibit active proton pumps 1 Proton pumps are activated following a meal proportion of proton pumps are inactive and inaccessible, and therefore are unable to be shut down by a PPI dose 2,3 How do PPIs suppress gastric acid? Proton pumps are constantly being generated to provide acid production later in the day 2,3 Any proton pumps activated after PPI concentrations fall below effective plasma levels may not be inhibited 3 1 Del Valle et al, Acid peptic disorders. In: Yamada et al,, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 23: Blair et al, J Clin Invest 1987; 79: Sachs, Pharmacotherapy 1997; 17: Un-stimulated parietal cell Proton pumps become activated in response to food 1 H 2 On activation, proton pumps insert into the secretory membrane After activation, the parietal cell undergoes a series of changes, allowing proton pumps to reach the surface of the parietal cell 1 H 2 ACh Unstimulated proton pumps ACh Active proton pumps H 2 = Histamine H 2 = Histamine Gastrin Inactive Parietal Cell ACh = Acetylcholine Gastrin Active Parietal Cell ACh = Acetylcholine 1 Del Valle et al, Acid peptic disorders. In: Yamada et al, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 23: Del Valle et al, Acid peptic disorders. In: Yamada et al, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 23:

9 Page 9 Activated parietal cells secrete gastric acid via the proton pumps Only active proton pumps can secrete acid 1 Not all proton pumps are active at any given time However, not all pumps become activated 1,2 H+ H+ K+ K+ K+ K+ H+ H+ H+ H+ Unstimulated proton pumps in cytoplasmic tubules H+ H+ H 2 = Histamine H 2 = Histamine Active Parietal Cell ACh = Acetylcholine Active Parietal Cell ACh = Acetylcholine 1 Del Valle et al, Acid peptic disorders. In: Yamada et al, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 23: Blair et al, J Clin Invest 1987; 79: Sachs, Pharmacotherapy 1997; 17: PPIs bind to, and inhibit activated proton pumps PPIs only bind to active proton pumps 1 PPI Unstimulated proton pumps remain Who is suitable for OTC PPIs? PPI 1 Del Valle et al, Acid peptic disorders. In: Yamada et al, eds. Textbook of Gastroenterology. 4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 23:

10 Page 1 Identifying who is / is not appropriate for OTC PPI treatment Potential users of OTC PPI include: those with typical heartburn who are: treatment-naïve using less effective OTC therapy without satisfactory control those experiencing frequent heartburn Patients who are not appropriate for OTC PPI treatment include those who: have been experiencing symptoms over a long period who may derive greater benefit from regular / long-term PPI therapy have chest pain as a predominant symptom have epigastric discomfort as the predominant symptom Can a patient take more than one OTC dose to reach the equivalent prescription dose? OTC PPIs should be taken only once every 24 hours for 14 days It may take up to 4 days for full effect Do not take more than one tablet every 24 hours How well do OTC PPIs work?

11 Page 11 Effects of lansoprazole 15 mg and omeprazole 2 mg qd on intragastric ph Crossover study of 5 days lansoprazole 15 mg vs omeprazole 2 mg qd Mean 24-hour intragastric ph on Day 5 NS n=17 healthy adult males OTC omeprazole for the management of frequent heartburn A total of 3124 patients with frequent heartburn took part in 2 RCTs of omeprazole 1 mg vs 2 mg vs placebo for 14 days Heartburn-free at day 14 Omeprazole 2 mg Placebo Study *** 32.6 Study *** 32.1 Lansoprazole 3 mg Lansoprazole 15 mg Omeprazole 2 mg ***p<.1 Tolman et al, J Clin Gastroenterol 1997; 24: 65 7 Allgood et al, J Clin Pharm Ther 25; 3: Two randomized, placebo-controlled trials of OTC lansoprazole 15 mg qd for frequent heartburn Lansoprazole 15 mg (n=57) Placebo (n=564) 24-h days with no heartburn (%) 6 *** 45 Nights with no heartburn (%) 62 *** 45 Patients with no heartburn during Day 1 (%) Patients with heartburn severity none or mild after 14 days (%) 5 *** Do PPIs offer symptom relief over the 24 hour period? Kushner et al, Postgrad Med 29; 121: 67 75

12 Page 12 Omeprazole 2 mg vs placebo for the treatment of frequent heartburn Lansoprazole 15 or 3 mg for treatment of frequent nighttime heartburn in self-treating patients Randomized, controlled trial comparing omeprazole 2 mg and placebo once daily for 14 days in a total of 3124 patients with frequent heartburn Patients heartburn-free for 24 hours (%) 1 Nights with no heartburn (%) 1 24-hour days with no heartburn (%) 1 ** 49.7 ** *** *** *** *** Placebo Omeprazole 2 mg 29.5 **p<.1 vs placebo Study 1 Study 2 Placebo (n=284) Lansoprazole Lansoprazole 15 mg (n=291) 3 mg (n=277) ***p<.1 vs placebo Placebo (n=284) Lansoprazole Lansoprazole 15 mg (n=291) 3 mg (n=277) Allgood et al, J Clin Pharm Ther 25; 3: Peura et al, Aliment Pharmacol Ther 29; 3: hour days and nights with no heartburn during treatment with lansoprazole 15 mg 24-hour days with no heartburn (%) 1 *** *** Nights with no heartburn (%) 1 ** *** Can pregnant women take PPIs? n= n= Study Study 2 Study Study 2 **p<.3 vs placebo ***p<.1 vs placebo Placebo Lansoprazole 15 mg Kushner et al, Postgrad Med 29; 121: 67 75

13 Page 13 Pregnancy Lifestyle modification is the key for treating mild symptoms smaller meals not eating late at night elevation of the head of the bed avoiding foods and medications causing heartburn PPIs should only be used during pregnancy in women with well-defined complicated GERD, not responding to lifestyle changes, or antacids A pregnant patient should seek the advice of a doctor before taking OTC PPI Systematic review of safety of PPI use during pregnancy Review of 5 cohort studies of rate of birth malformations following exposure to PPIs during first trimester of pregnancy Almost 6 exposed pregnancies Relative risk of major malformation = 1.18 (95% CI = ; NS) PPIs present no major teratogenic risk when used in the 1 st trimester of pregnancy Richter, Aliment Pharmacol Ther 25; 22: Nikfar et al, Dig Dis Sci 22; 47: Please answer the Poll Question Is it safe for pregnant women to take OTC PPI with no previous history of frequent heartburn? 1. PPIs should only be taken in pregnancy in a woman with well defined complicated GERD 2. PPIs can be taken in pregnancy if frequent heartburn occurs on a daily basis 3. PPIs can be taken in pregnancy for 14 days every 3 months throughout the pregnancy 4. PPIs should be avoided by pregnant women FDA use in pregnancy ratings for PPIs Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Key to FDA use in pregnancy ratings B. No evidence of risk in humans C. Risk cannot be ruled out Unknown if any PPI excreted in human breast milk. Consider discontinuing treatment or discontinuing breast feeding. B B C B B Physicians Desk Reference, 22: 56 th edition

14 Page 14 Antisecretory therapy and C. difficile infection discharges from a tertiary care medical center over a 5-year period 1 The risk of C. difficile infection after adjustment for comorbidities, age, antibiotics What is the evidence that PPI therapy is associated with increased risk for C. difficile infection? OR (95% CI) H 2 RA 1.53 ( ) Once daily PPI 1.74 ( ) More frequent PPI 2.36 ( ) Dose-response effect of acid inhibition and C. difficile infection Observational studies may suggest association; channeling bias always a concern Howell et al, Arch Intern Med 21; 17: A pragmatic solution to C. difficile infection and antisecretory therapy OTC PPI doses are not associated with high level of risk 1 This is an observation which is more relevant to hospitalized patients PPIs should be continued when patients are admitted to hospital at the lowest effective maintenance dose and with careful attention to hand washing 2 What is the evidence that PPI therapy is associated with increased risk for community-acquired pneumonia? 1 Howell et al, Arch Intern Med 21; 17: Metz, Am J Gastroenterol 28; 13:

15 Page 15 PPI therapy and risk of community acquired pneumonia (CAP) The data concerning a possible associate between PPI therapy and the risk of acquiring CAP is conflicting In a meta-analysis of six studies, an association was found with PPI use (OR 1.36, 95% CI ) shorter periods of use associated with greater risk than maintenance PPI What is the evidence that PPI therapy is associated with increased risk for osteopenic hip fracture? Johnstone et al, Aliment Pharm Ther 21; 31: PPI therapy and osteopenic fractures Nested case-control study in patients with hip fractures (n=13,556) and controls (n=135,386) Risk of hip fracture (adjusted odds ratio) Increasing cumulative duration of PPI therapy (years) Risk of hip fracture (adjusted odds ratio) 5 Study limitations include differences in prevalence of known risk factors and co-morbidity between cases and controls before adjustment <1.75 >1.75 Average daily PPI dose Yang et al, JAMA 26; 296: PPI therapy and risk of hip fracture Drugs that inhibit gastric acid over periods of 7 or more years might increase risk of hip fracture 1 A large study compared patients with diagnosed hip / femur fractures vs matched controls without hip fracture, n=13,471 2 patients with hip fractures are at greater risk of having received a PPI (OR=1.3) or H 2 RA (OR=1.18) higher doses caused increased risk excess fracture risk only present among patients with at least one other known risk factor (e.g., osteoporosis) 1 Targownik et al, CMAJ 28; 179(4): Corley et al, Gastroenterology 21, epub

16 Page 16 PPI use and fractures: Is there any association? Three case-control studies assessed PPI use and fractures Study of all subjects with fracture in Denmark in 2 adjusted OR = 1.18 ( ) for PPI use within last year Study of hip fractures in UK patients 5 years adjusted OR = 1.44 ( ) for >1 year of PPIs Study of vertebral, wrist, and hip fractures in Manitoba patients 5 years adjusted OR =.99 ( ) for 1 year of continuous PPI association became significant 7 years (OR = 1.92, ) Any increase in risk for fractures with PPIs, if present, would be of relatively low magnitude PPIs and osteopenic hip fracture: AGA guidelines It is good medical practice to screen and treat the elderly for osteoporosis irrespective of PPI use There is inadequate evidence to mandate bone density studies and calcium supplementation solely because of PPI use PPI use is strongly justified when clinically indicated Laine, Am J Gastroenterol 29; 14(Suppl. 2): S21 6 Kahrilas et al, Gastroenterology 28; 135: Recent FDA labeling change May 21 The FDA has reviewed seven published studies, six of which reported an increased risk of fractures of the hip, wrist, and spine with the use of PPIs Based on the available data, it is not clear at this time if the use of PPIs is the cause of the increased risk of fractures seen in some studies The FDA is revising the labels for both the prescription and the over-the-counter PPIs to include new safety information about the possible increased risk of fractures of the hip, wrist, and spine with the use of these medications What is the evidence that PPI therapy is associated with increased risk for reducing anticoagulant effectiveness of clopidrogrel (omeprazole effect)?

17 Page 17 Clopidogrel bisulfate and Proton Pump Inhibitors: The latest FDA guidance On November 17, 29, the FDA updated the warning about the drug interaction between clopidogrel bisulfate and omeprazole and esomeprazole the FDA cited new, unpublished data showing that omeprazole substantially reduces anticoagulant effects of clopidogrel bisulfate This means that patients at risk for heart attacks or strokes may not receive the full anticoagulant effects of clopidogrel bisulfate if they are also taking omeprazole Why do some patients not respond to clopidogrel bisulfate? Several mechanisms may to lead to a poor response to clopidogrel bisulfate 1 lack of compliance 1 clinical factors 1 genetic polymorphisms that affect the function of the CYP2C19 enzyme 1 concomitant administration of another drug metabolized by CYP2C19, such as the PPIs, which may reduce the level of activity of clopidogrel bisulfate 2 DrugSafetyInformationforHeathcareProfessionals/ucm19787.htm. Accessed January 13, Simon et al, N Engl J Med 29; 36: Gilard et al, J Am Coll Cardiol 28; 51: Why is there a potential problem with taking clopidogrel bisulfate and a PPI together? CYP2C19 is an important enzyme involved in the hepatic metabolism of both clopidogrel bisulfate and PPIs There are concerns that the consequent drugdrug interaction may decrease the clinical effects of clopidogrel bisulfate Pharmacodynamic effect and clinical efficacy of clopidogrel with or without a PPI 6,795 patients with acute coronary syndrome randomly assigned to clopidogrel; 33% on PPI at randomization Treated with a PPI Not treated with a PPI Adjusted HR (95% CI) CV death, MI, or stroke (%) ( ) All-cause death (%) (.47.96) MI (%) ( ) Stent thrombosis (ARC definite or probable) (%) ( ) Net clinical outcome (death, MI, stroke, ( ) or TIMI major non-cabg bleeding) (%) Findings do not support the need to avoid concomitant use of PPIs in patients receiving clopidogrel Laine et al, Am J Gastroenterol 21; 15: O Donoghue et al, Lancet 29; 374:

18 Page 18 TRITON: 1 Outcome stratified by use of a PPI CV death, MI or stroke 14% 12% 1% 8% 6% 4% 2% PPI use at randomization (n=4529) % No PPI PPI PPI No PPI Clopidogrel PPI vs no PPI: Adj HR.94, 95% CI Prasugrel PPI vs no PPI: Adj HR 1., 95% CI Clopidogrel Prasugrel O Donoghue et al, Lancet 29; 374: COGENT trial Multicenter, international, randomized, double-blind, double-dummy, placebo-controlled, parallel group, phase 3 efficacy and safety study of CGT-2168, a fixed-dose combination of clopidogrel (75 mg) and omeprazole (2 mg), compared with clopidogrel Patients were stratified based on two baseline factors: H. pylori serology (positive or negative) and concomitant use of any NSAID All patients were to receive enteric coated aspirin at a dose of 75 to 325 mg COGENT: Composite ischemic events Survival curves for PPI treated vs placebo composite cardiovascular events Survival probability 1. COGENT: Composite GI events Survival curves for PPI treated vs placebo composite GI events Survival probability Placebo.98 Placebo Placebo: 67 events, 1821 at risk Treated: 69 events, 186 at risk Treated HR = % CI = Placebo: 67 events, 1895 at risk Treated: 38 events, 1878 at risk Treated HR =.55 95% CI =.36;.85 p=.7 (preliminary) Days Adjustment through Cox proportional hazards model Adjusted to positive NSAID use and positive H. pylori status Days Bhatt et al, Transcatheter Cardiovascular Therapeutics conference. September 29; San Francisco, CA Bhatt et al, Transcatheter Cardiovascular Therapeutics conference. September 29; San Francisco, CA

19 Page 19 How does this apply to lansoprazole? According to the FDA there is insufficient information to make specific recommendations about co-administration of clopidogrel bisulfate and PPIs other than omeprazole and esomeprazole 1 The clopidogrel bisulfate label now states that coadministration with omeprazole or esomeprazole should be avoided 2 However, the FDA is continuing to investigate the potential for drug interactions 1 FDA recommendations for clopidogrel and PPI usage Clopidogrel should continue to be prescribed and taken as directed clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke The need for starting or continuing PPI treatment in patients taking clopidogrel should be re-evaluated Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including OTC options 1 Food and Drug Administration. InformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ ucm19787.htm. Accessed December 2, 29 2 Plavix [prescribing information]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 29 FDA Website, 13 May 29 PPI therapy and rebound hypersecretion Systematic review of rebound acid hypersecretion after discontinuation of PPIs What is the evidence that PPI therapy is associated with increased risk for hypersecretion? Eight studies 5 short-term studies: No evidence for rebound 3 longer-term studies (>8 weeks exposure) identified rebound No clear association between long-term PPI use and gastric acid hypersecretion no adverse clinical consequences to date Clinical implication consider tapering PPI therapy rather than abrupt discontinuation Hunfeld et al, Aliment Pharmacol Ther 27; 25: 39 46

20 Page 2 PPI therapy and symptoms due to hypersecretion in healthy volunteers 12 healthy volunteers randomized to 12 weeks of placebo or 8 weeks of esomeprazole 4 mg/d, followed by 4 weeks of placebo PPI (n=59) Placebo (n=59) 1.35 ** Mean severity of symptoms weeks = Absence of bothersome symptoms **p=.1 vs placebo 7 = Very bothersome symptoms PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal; symptoms observed caused mild discomfort Putting the risk-benefit of PPIs into perspective PPI therapy is widely used because it is generally safe and effective second most commonly prescribed class of drugs many millions of patient-years of experience However, as with all medications, the potential for side effects exist. These have to be weighed against the overall therapeutic gain PPIs should not be denied to patients likely to benefit from them use the lowest effective maintenance dose Reimer et al, Gastroenterology 29; 137: 8 7 NOTES NOTES