OTC PPI Therapy in Frequent Heartburn

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Randolph Harris
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1 Page 1 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Conflicts of Interest Gatekeeper to the Appropriate Use of OTC PPI Therapy in Colin W. Howden, MD, FRCP (Glasg), FACP, FACG, FCP Professor of Medicine Northwestern University Feinberg School of Medicine Chicago, IL This activity is supported by an educational grant from Novartis Consumer Healthcare. Speaker: Dr. Colin Howden graduated from the medical school of the University of Glasgow in Scotland in He then trained in Internal Medicine, Gastroenterology, and Clinical Pharmacology in Glasgow, and at McMaster University, Hamilton, ON, Canada. He moved to the USA in He is currently a Professor of Medicine at Northwestern University Feinberg School of Medicine, Chicago, IL Speaker disclosure: Dr. Howden has received speaking honoraria from Taekda and Santarus. He has consulted for Takeda, Santarus, XenoPort, Procter & Gamble, Novartis Consumer Health, Novartis Oncology, Merck / Schering-Plough Healthcare and KV Pharmaceuticals. 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 Acknowledgments Accreditation: Pharmacist L01-P Target Audience: Pharmacists CE Credits: 1.0 Credit hour or 0.1 CEU for pharmacists Program Overview: 50 million Americans are estimated to have frequent heartburn, defined as symptoms occurring at least 2 days a week. Probably the best way to manage these patients is with a proton pump inhibitor, which can be purchased OTC. Often heartburn sufferers seek the advice of a pharmacist on how they should best relieve their symptoms. This knowledge based webinar aims to provide helpful pointers on who is at risk of frequent heartburn, what questions to ask to diagnose the condition and how to decide who is appropriate for OTC PPI treatment and who should be recommended to see their physician. To help bring this into a real work perspective there is a case scenario built into the presentation which provides the opportunity to discuss many of the key issues relating to the management of this common condition. This activity is supported by an educational grant from Novartis Consumer Healthcare This activity is jointly sponsored by PharmCon, Strategic Consultants International (SCI) and Postgraduate Institute for Medicine (PIM) Objectives: Identify individuals with frequent heartburn. Identify those individuals who are appropriate for OTC PPI treatment in the pharmacy setting. Discuss the dose, treatment response and duration of OTC PPI. PharmCon, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

2 Page 2 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Objectives By participating in this activity, learners will be better able to: Identify individuals with frequent heartburn Identify those individuals who are appropriate for OTC PPI treatment in the pharmacy setting Discuss the dose, treatment response and duration of OTC PPI A quick update on gastroesophageal reflux disease (GERD) Definitions Demographics Impact on QoL Pathophysiology, risk factors Complications of inadequately treated disease GERD is defined as symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus. 1 American College of Gastroenterology (ACG) definition a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications. 2 Montreal definition Characteristics of GERD Most characteristic symptoms of GERD are retrosternal burning (i.e., heartburn) regurgitation Diagnosis can be made on the basis of typical symptoms and/or on the results of diagnostic testing definition is based on troublesome symptoms and/or complications 1 DeVault et al, Am J Gastroenterol 2005; 100: Vakil et al, Am J Gastroenterol 2006; 101: Vakil et al, Am J Gastroenterol 2006; 101:

Page 3 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Importance of GERD in the US How many Americans have frequent heartburn (at least 2 days a week)? 1. 150 million 2. 100 million 3.

25 million Single most common GI disorder diagnosed in US 1 Prevalence of GERD symptoms increasing by around 5% per year 2 Between 1998 and 2001, there was a 47% increase in visits to PCPs because of

3 Page 3 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Importance of GERD in the US How many Americans have frequent heartburn (at least 2 days a week)? million million million million Single most common GI disorder diagnosed in US 1 Prevalence of GERD symptoms increasing by around 5% per year 2 Between 1998 and 2001, 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 50 million Americans are estimated to have frequent heartburn 3 1 Dent et al, Gut 2005; 54: El-Serag, Clin Gastroenterol Hepatol 2007; 5: National Heartburn Alliance: Typical GERD symptoms Prevalence of nocturnal GERD symptoms Heartburn a burning retrosternal discomfort that radiates towards the neck should not be confused with epigastric pain Regurgitation effortless movement of gastric contents into the esophagus / pharynx should not be confused with vomiting GERD sufferers may refer to this symptom as reflux often aggravated by recumbence or bending over. May be relieved by antacids many have daytime and nighttime symptoms Adults with frequent GERD symptoms 2 Nocturnal GERD symptoms reported Nocturnal GERD symptoms not reported 54% reported waking from sleep Among 78% who reported nocturnal heartburn, 40% reported impact on ability to function the next day Farup et al, Arch Intern Med 2001; 161: 45 52

Page 4 Gate Keeper to the Appropriate Use of OTC PPI Therapy for GERD symptoms can impair quality-of-life (QoL) Impact of nocturnal GERD on QoL Results of a national survey revealed that GERD

4 Page 4 Gate Keeper to the Appropriate Use of OTC PPI Therapy for GERD symptoms can impair quality-of-life (QoL) Impact of nocturnal GERD on QoL Results of a national survey revealed that GERD patients reported lower QoL than unaffected subjects 1 patients with nocturnal GERD symptoms had lower physical and mental QoL scores than GERD patients without nocturnal symptoms healthy controls SF-36 score US population Nocturnal GERD (n=1264) 40 Physical functioning Bodily pain General health Vitality Social functioning Rolephysical Roleemotional Mental health Farup et al, Arch Intern Med 2001; 161: Farup et al, Arch Intern Med 2001; 161: Economic impact of GERD is significant $9.3 billion spent annually on direct costs 1 consultation, testing, and treatment In normal circumstances Pathophysiology of GERD Acid refluxes into the esophagus Impaired esophageal clearance $75 billion in indirect costs estimated annually 2 Productivity losses due to GERD in US population 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 American Gastroenterological Association (AGA). The Burden of Gastrointestinal Diseases. Bethesda, MD: AGA; Wahlqvist et al, Aliment Pharmacol Ther 2006; 24: Peristalsis and gravity return most acid reflux to the stomach After peristalsis, a small amount of acid can remain in the esophagus Saliva neutralizes the remaining acid in the esophagus Relaxation of lower esophageal sphincter When patients experience heartburn: GERD occurs when protective mechanisms are overwhelmed Possible delayed or esophageal acid increases to gastric emptying pathological levels, causing heartburn Richter, Gastroesophageal reflux disease and its Complications. In: Feldman et al, eds. Gastrointestinal and Liver Disease. 8th ed. Philadelphia, PA: Saunders; 2006:

Prevalence of esophageal Injury (%) Median duration of longest reflux episode (min) Page 5 Gate Keeper to the Appropriate Use of OTC PPI Therapy for There is a relationship between reflux episodes

5 Prevalence of esophageal Injury (%) Median duration of longest reflux episode (min) Page 5 Gate Keeper to the Appropriate Use of OTC PPI Therapy for There is a relationship between reflux episodes and esophageal damage Reflux during sleep 70 Injury prevalence Episode duration 30 Nocturnal heartburn Recumbent position Heartburn perception UES pressure Primary peristalsis Salivation Prolonged acid exposure due to poor acid clearance 0 Post-prandial Upright Supine (n=41) (n=74) (n=129) Longer episodes associated with more damage 0 Respiratory complications Reflux complications Sleep disturbances Campos et al, Arch Surg 1999; 134: Orr, Curr Gastroenterol Rep 2006; 8: Demographic factors associated with GERD Gender ratio in GERD 1 erosive esophagitis (EE): M > F endoscopy-negative reflux: F > M Caucasians have a higher prevalence of EE than other racial groups 2 heartburn and regurgitation prevalence was similar across racial groups Which is NOT a risk factor for heartburn? 1. Obesity 2. Eating before going to bed 3. Female gender 4. Stress 1 Richter, Gastroesophageal reflux disease and its complications. In: Feldman et al, eds. Gastrointestinal and Liver Disease. 8th ed. Philadelphia, Pa: Saunders; 2006: El-Serag et al, Gastroenterology 2004; 126:

6 Page 6 Gate Keeper to the Appropriate Use of OTC PPI Therapy for 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 (?) Risk factors for heartburn Hiatus hernia not a prerequisite for GERD but, when present, may worsen tendency to reflux Obesity contributes to the frequency of GERD symptoms 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<0.001 Multivariate odds in women with at least weekly GERD symptoms (n=2306) Jacobson et al, N Engl J Med 2006; 354: Obesity and risk of esophageal adenocarcinoma Older GERD patients are more likely to have severe esophagitis but less likely to have severe heartburn Less risk Greater risk Patients (%) 50 Pooled analysis of baseline characteristics from 5 RCTs (n=11,945) Vaughan et al, 1995 Brown et al, 1995 Chow et al, Lagergren et al, 1999 Cheng et al, 2000 Wu et al, LA class C and D erosive esophagitis Severe heartburn 2.78 (95% CI ) Adjusted odds ratio Hampel et al, Ann Intern Med 2005; 143: < >70 Age (years) n = p< for severe heartburn and severe esophagitis Johnson & Fennerty, Gastroenterology 2004; 126: 660 4

Page 7 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Potential consequences of inadequately treated GERD More severe grades of erosive esophagitis Ulcers and hemorrhage Stricture Barrett

Saunders 2006: 905 36 Costa et al, Am J Gastroenterol 2001; 96; 47 51 A 44-year-old businessman who frequently entertains clients and eats late at night Overweight (BMI=31) Case study Occasional,

7 Page 7 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Potential consequences of inadequately treated GERD More severe grades of erosive esophagitis Ulcers and hemorrhage Stricture Barrett s esophagus major risk factor for esophageal adenocarcinoma Today s case in point Richter et al, Gastrointestinal and Liver Disease 8th Ed, Philadelphia, PA. Saunders 2006: Costa et al, Am J Gastroenterol 2001; 96; A 44-year-old businessman who frequently entertains clients and eats late at night Overweight (BMI=31) Case study Occasional, typical heartburn for 2 years partially relieved by antacids Recently, heartburn has become worse now experiencing it on 2 3 days per week, occasionally at night He is not sleeping well and this is adding to his already stressful life-style He comes to the pharmacy and asks your advice Pharmacist as gatekeeper to appropriate OTC PPI therapy Pharmacists play an important role in ensuring best use of OTC PPIs. Opportunity to: provide most effective therapy for those with typical heartburn identify those who are not currently receiving medical care identify subjects not suitable for OTC therapy who should be referred for medical assessment

Page 8 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Identifying frequent heartburn: Some questions to consider How would you describe your symptom?

8 Page 8 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Identifying frequent heartburn: Some questions to consider How would you describe your symptom? How long have you experienced this problem? Have you consulted a doctor about this problem? How often and when does the symptom occur? Are there any trigger factors? Do antacids relieve the symptom? Have you previously taken a course of (OTC) H 2 RA / PPI? Do you take any other medicines? Describe your typical diet Does this person have typical heartburn? Is he suitable for OTC PPI therapy? or Should I recommend he goes to a doctor? Spot the item which is NOT typical of heartburn? 1. Burning in chest 2. Crushing / squeezing chest pain 3. Temporary symptom relief using OTC therapy 4. Worse on lying down How would you describe your symptom? Heartburn is experienced in the chest Discomfort should be in the midline behind the breastbone Discomfort may be described as burning Typically spreads upwards towards neck Should not be described as crushing / squeezing! Should not be closely linked to exertion consider possibility of heart disease May be worse after eating / lying down May be helped by antacid Have you previously taken a course of (OTC) H 2 RA / PPI? Most H 2 -receptor antagonists are available OTC cimetidine, ranitidine, famotidine Three PPIs are currently available OTC omeprazole, lansoprazole, immediate-release omeprazole with sodium bicarbonate OTC products widely used by individuals with upper digestive symptoms including heartburn Improvement in symptom(s) with OTC H 2 RA / PPI implies likelihood of acid-related cause Complete failure of OTC H 2 RA / PPI to improve symptom(s) suggests they are not acid-related

9 Page 9 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Do you take any other medicines? Drug interactions have been reported with PPIs mainly with omeprazole few if any are of clinical relevance Package inserts for OTC PPIs alert consumers taking digoxin, warfarin, theophylline, tacrolimus, atazanavir, antifungal agents consultation with a physician may be advisable Clopidogrel is a special case Do you have concerns about the long-term safety of PPI therapy? 1. Yes 2. No 3. Undecided Clopidogrel and PPIs Factors indicating referral to a doctor Clopidogrel is a pro-drug that requires conversion / activation via cytochrome P 450 Theoretical potential for PPI to slow conversion of clopidogrel to its active metabolite reduced anti-platelet effect in vitro no definitive evidence from clinical studies for a clinically meaningful effect FDA has advised that people on clopidogrel should avoid omeprazole (OTC and Rx) and esomeprazole 1 Alarm symptoms Weight loss, unintentional Vomiting of blood Melena (black feces / blood in stool) Difficulty swallowing Painful swallowing Severe symptoms Atypical symptoms Chest pain Predominant epigastric pain Hoarseness Sore throat Cough Risk factors for complex disease Age 55 or above New onset of symptoms in subjects >45 years FH gastric / esophageal cancer Co-morbidities Does not respond to 2 weeks of OTC PPI therapy 1 Haag et al, Digestion 2009: 80;

Page 10 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Having decided that the consumer has frequent heartburn, and does not require medical referral, what would you recommend? 1. Life-style advice 2.

drinking for 2 hours before bedtime Portion control Avoid bending, lying down or exercise after meals Stop smoking Lose weight (if overweight / obese) Avoid stressful situations Pregnancy is a

10 Page 10 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Having decided that the consumer has frequent heartburn, and does not require medical referral, what would you recommend? 1. Life-style advice 2. OTC treatment options Life-style and dietary advice Avoid foods that may worsen heartburn Fatty Spicy Acidic (tomatoes / citrus) Alcohol Chocolate Mint Adopt good life-style habits Avoid eating / drinking for 2 hours before bedtime Portion control Avoid bending, lying down or exercise after meals Stop smoking Lose weight (if overweight / obese) Avoid stressful situations Pregnancy is a frequent cause of heartburn Oliveria et al, Arch Intern Med Web MD Top 10 heartburn foods Web MD. Workouts without heartburn WebMD. Heartburn during pregnancy Effectiveness of lifestyle modifications on heartburn OTC treatment choices Avoidance of foods that may precipitate heartburn i.e., coffee, alcohol, chocolate, fatty foods, citrus, carbonated drinks, spicy foods Adoption of behaviors that limit esophageal acid exposure i.e., weight loss, smoking cessation, raising the head of the bed, avoiding recumbancy for 2 3 hours after meals Antacids Alginates H 2 RA PPI H + K + Alginate Proton pump PPI Gastrin Acetylcholine H 2 blockers Histamine Most evidence supporting such recommendations is weak 1 1 Kahrilas et al, Gastroenterology 2008; 135:

11 Page 11 Gate Keeper to the Appropriate Use of OTC PPI Therapy for PPI treatment is the most effective therapy for esophagitis and heartburn relief 134 trials; n=35,978 1 Relative risk of esophagitis (RR) Prokinetics H 2RAs Standard dose PPI All vs placebo 31 trials; n=9,457 2 Relative risk for heartburn remission (RR) Prokinetics H 2RAs Standarddose PPI All vs placebo I M P R O V E M E N T When should patients take their PPI? mins before going to bed mins before breakfast mins after breakfast 4. Doesn t matter about timing 1 Khan et al, Cochrane Database Syst Rev 2007; 2: CD van Pinxteren et al, Cochrane Database Syst Rev 2006; 3: CD 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 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 Bioavailability of oral lansoprazole and omeprazole Day 1 (%) Day 5 (%) Relative change (%) Lansoprazole Omperazole Andersson et al, Aliment Pharmacol Ther 2001; 15: Gralnek et al, Am J Gastroenterol 2001; 96: s54 6

Page 12 Gate Keeper to the Appropriate Use of OTC PPI Therapy for OTC omeprazole for the management of frequent heartburn A total of 3124 patients with frequent heartburn took part in 2 RCTs of

12 Page 12 Gate Keeper to the Appropriate Use of OTC PPI Therapy for OTC omeprazole for the management of frequent heartburn A total of 3124 patients with frequent heartburn took part in 2 RCTs of omeprazole 10 mg vs 20 mg vs placebo for 14 days Heartburn-free at day 14 Omeprazole 20 mg Placebo Effects of lansoprazole 15 mg and omeprazole 20 mg qd on intragastric ph Crossover study of 5 days lansoprazole 15 mg vs omeprazole 20 mg qd Mean 24-hour intragastric ph on Day 5 NS n=17 healthy adult males Study *** 32.6 Study *** 32.1 ***p<0.001 Lansoprazole 30 mg Lansoprazole 15 mg Omeprazole 20 mg Allgood et al, J Clin Pharm Ther 2005; 30: Tolman et al, J Clin Gastroenterol 1997; 24: Lansoprazole in treatment of heartburn in patients with erosive esophagitis 214 patients randomized to lansoprazole 15 mg (n=82), lansoprazole 30 mg (n=58), PBO (n=44) Free from day / night HB (Day 1) p=0.05 p=0.028 p=0.002 p=0.039 Two randomized, placebo-controlled trials of OTC lansoprazole 15 mg qd for frequent heartburn Lansoprazole 15 mg (n=570) Placebo (n=564) 24-h days with no heartburn (%) 60 *** 45 Nights with no heartburn (%) 62 *** 45 Patients with no heartburn during Day 1 (%) 50 *** 35 Patients with heartburn severity none or mild after 14 days (%) This study demonstrates the effectiveness of the lansoprazole 15 mg qd dose Richter et al, Aliment Pharmacol Ther 1999; 13: Kushner et al, Postgrad Med 2009; 121: 67 75

13 Page 13 Gate Keeper to the Appropriate Use of OTC PPI Therapy for Algorithm for pharmacy-based management of typical reflux symptoms Atypical symptoms or alarm features Referral to PCP Heartburn / regurgitation Symptoms persist Typical reflux symptoms OTC PPI for 14 days Relapse within 4 months Complete symptom relief Stop OTC PPI Relapse in >4 months Summary and conclusions OTC PPI treatment is appropriate and FDA-approved for self-management of frequent 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 Repeat 14 day OTC PPI Notes Notes

Page 1. Objectives. The Role of the Pharmacist as Gatekeeper to the Appropriate Use of OTC PPI Therapy in Frequent Heartburn

Page 1. Objectives. The Role of the Pharmacist as Gatekeeper to the Appropriate Use of OTC PPI Therapy in Frequent Heartburn Page 1 The Role of the Pharmacist as Gatekeeper to the Appropriate Use of OTC PPI Therapy in The Role of the Pharmacist as Gatekeeper to the Appropriate Use of OTC PPI Therapy in Colin W. Howden, MD, FRCP