Treatment Options for Patients with GERD Kristina F. Skarbinski, MSN, FNP-BC MGH GI- NP Leader, Swallowing & Heartburn Center Motility NP, Neurointestinal Health Center May 03, 2019

Synergy Pharmaceuticals – Consulting. Disclosures Synergy Pharmaceuticals – Consulting.

Objectives Identify GERD in the clinical setting by understanding the many different presentations commonly seen in this diagnosis Explain basic pathophysiology in how GERD manifests in patients Understand different medication and dietary/lifestyle treatment approaches in GERD Identify some of the commonly associated risks seen with poorly treated GERD Become associated with different testing methods for GERD and when to use them Understand and describe three common surgical options available for patients with refractory GERD and common risks seen post-op

GERD- Symptoms Atypical Cough* Hoarseness* Throat clearing* Post-nasal drip* Sore throat* Non-cardiac chest pain* Typical Heartburn Acid/food regurgitation Intermittent dysphagia* *Only once other causes have been excluded! Do not presume this is due to GERD.

GERD: Alarm Symptoms New onset trouble swallowing Pain swallowing Unexplained, persistent weight loss Iron deficiency anemia Especially in the context of: Smokers Family history of esophageal cancer

GERD-Facts Most reflux episodes occur during transient relaxations of the LES that are triggered by gastric distention. Some patients with GERD have an incompetent LES (< 10 mmHg) that results in acid reflux, especially when supine or when intra-abdominal pressures are increased by lifting or bending, exercise, pregnancy. Most uncomplicated cases do not require further testing. Reference: McPhee Papadakis, 2011. Current Medical Diagnosis and Treatment

GERD-Facts Approximately 1/3 of patients have endoscopic abnormalities such as erosive esophagitis, Barrett’s esophagus, peptic stricture or Schatzki ring. Hiatal hernias: most are asymptomatic (usually < 3cm- small). Can be a risk factor for GERD. Abnormal acid reflux is defined as a pH of LESS than 4 in the esophagus. Total acid exposure time is also important! McPhee S. J., Papadakis M.A. & Rabow M.W. (2011). Current Medical Diagnosis and Treatment. 5th edition , McGraw Hill.

Disease related risk factors: Obesity Pregnancy Presence of a hiatal hernia Connective tissue disorder (scleroderma) Gastroparesis Behavioral risk factors: Cigarette smoking Alcohol Carbonated beverages High fat diet Medications (NSAIDs, medication administration)

Case 1: 32 year old female CC: Heartburn and acid regurgitation in the setting of 15 lb weight gain over the last 3 months, increased stress at work and limited physical activity. Symptoms worsen at night when lying supine or after eating spicy meals. She takes an OTC antacid prn with minimal benefit. No dysphagia, nausea or vomiting

Case 1: 32 year old female PMH: Generalized Anxiety Disorder, Tension Headaches, Eczema PSH: few suspicious but ultimately benign mole removals in her 20s. Medications: Celexa 30 mg daily, OTC antacid prn, hydrocortisone 2.5% prn, Excedrin prn headaches Wt: 185 lbs Ht: 5’5” BMI: 30.8 BP: 130/86 HR 75 O2 sat: 99% RA Physical Exam: Normal.

What is your next step? Switch to OTC liquid Gaviscon TID prn Start ranitidine 150 mg bid prn Start omeprazole 20 mg bid, ½ hour before meals for 6-8 weeks. Counsel on dietary and lifestyle changes. Do nothing, recommend living with her symptoms

Medication Therapy Antacid H2RA PPI

Antacids Speed of relief vs length of effect Gaviscon vs antacids PRN use vs chronic use

H2 Blockers Medium reaction; medium effect Less dependent on food In the primary care setting, this is a common starting medication.

Proton Pump Inhibitors How it works H K ATPase Administration with food Strength of response versus speed of response Acid rebound The importance of tapering Placebo relief: I feel great immediately after my PPI!

Dietary and Lifestyle Changes Low fat diet Limit carbonated drinks Small frequent meals Limit alcohol or remove completely Weight loss

Dietary and Lifestyle Changes Limit foods high in acidity (such as citrus fruits, tomatoes, apple juice, orange juice, tomato sauce, coffee, chocolate!! ) Eat no later than 4 hours before bedtime Elevate entire head of bed with cinderblocks vs wedge or pillow

Case 1: 32 year old female Patient returns for follow up 3 months after being initiated on omeprazole 20 mg bid and following dietary and lifestyle changes. She has lost 8 lbs and while her symptoms have improved dramatically, she is concerned about long term effects related to omeprazole use.

PPIs in the News Osteoporosis Risk!- vit D, prophylaxis, Dementia!- debunked Interstitial nephritis!- rare C. Difficile! Infections with acid decrease Cytochrome P450 interactions: Anti-coagulants TAKE HOME MESSAGE: risk benefit ratio: quality of life vs life threatening issues Kidney disease Interstitial nephritis. Rare and hard to predict (Sierra et al., 2007). Those starting PPIs: 2x short term risk of hospitalization for acute kidney injury (Antoniou et al., 2015). Higher risk of CKD diagnosis the longer the patient uses PPIs (Hung et al., 2018). Increase risk of ESRD in those with kidney disease, thus consider dose reduction (Peng et al., 2016). Calcium. PPIs reduce bioavailability of calcium. Hypergastrinemia and mild hypomagnesemia stimulate PTH, leading to bone resorption. PPIs inhibit osteoclast proton pumps, leading to increased osteoclast activity and alteration of bone metabolism. Fracture (related to calcium inhibition) Study found that PPI users had a lower bone density at baseline compared to non PPI users, however PPI use over 10 years was not associated with an acceleration in bone loss (Targownik et al., 2012). C Difficile PPIs may change gut flora, predisposing to C Diff. Association but not necessarily causation (Villafuerte-Galvez & Kelly, 2019). Pneumonia Possible interaction with clopidogrel Dementia No convincing association (Lochhead et al., 2017). Kidney disease: Most common cause of acute interstitial nephritis is drug induced. PPIs considered one of them. omeprazole use associated with an increased risk of end stage renal disease (ESRD) in those with kidney disease. NOT associated with H2RAs. Kidney diseases: nephritis, glomerulonephritis, nephropathy, CKD, renal function impairment. Dose reduction recommended. Consider that the patients may also be taking medications that are processed by the kidney. PPIs metabolized by CY p450. PPI related IN rare, hard to predict. Need clinical suspicion.

Case 1: 32 year old female She decides to taper off the PPI. Taper schedule: 20 mg daily for 1-2 weeks, then 20 mg every other day for a week and then stop.

Case 2: 55 year old male History of longstanding GERD well controlled on omeprazole 20 mg bid for 18 years. Initial symptoms prior to therapy: heartburn and acid regurgitation Presents to local GI provider for consult. Symptoms include increased acid regurgitation and new dysphagia to solids and intermittent non-exertional chest pain. Stress test: NEGATIVE.

Case 2: 55 year old male PMH: HTN, hyperlipidemia, Type II DM A1C 7.5, GERD PSH: appendectomy as a child, cholecystectomy age 40 Allergies: none Meds: ASA 81 mg, atorvastatin 40 mg QD, Metformin 500 mg bid, lisinopril 10 mg daily

Case 2: 55 year old male You decide to do the following interventions: Increase pantoprazole to 40 mg bid, 30 minutes before breakfast and dinner Counsel on dietary and lifestyle restrictions for GERD management Schedule an upper endoscopy Age and length of symptoms >10 years

Upper Endoscopy Assess type and extent of tissue damage in reflux patients. Detecting other lesions that may mimic GERD. Detect GERD-related complications such as: esophageal stricture, esophageal adenocarcinoma, Barrett's metaplasia

Barrett's esophagus Squamous epithelium of the esophagus changes--> metaplastic columnar epithelium containing goblet and columnar cells. (ie. Intestinal metaplasia) Due to chronic injury of esophageal mucosa from frequent untreated exposure to acid reflux. Short segment vs Long segment PPIs indicated to reduce acid exposure risk ---> decrease chances of esophageal cancer development No evidence of regression of disease! Reference: McPhee S. J., Papadakis M.A. & Rabow M.W. (2011). Current Medical Diagnosis and Treatment. 5th edition , McGraw Hill.

Barrett's esophagus Treatment goal: reduce changes to esophageal mucosa. Complications of chronic untreated Barrett's esophagus include adenocarcinoma of the esophagus thought to be related to dysplastic epithelium in Barrett's esophagus. Screening: Women over age 60 and Men over age 50 who have GERD symptoms. Known Barrett's esophagus without dysplasia: surveillance endoscopy every 3 years to assess for low or high grade dysplasia Known low grade dysplasia: repeat upper endoscopy in 6 months then yearly if no high grade dysplasia found on pathology. Treatments for dysplastic esophageal mucosa: ablation therapy, esophagectomy Reference: McPhee S. J., Papadakis M.A. & Rabow M.W. (2011). Current Medical Diagnosis and Treatment. 5th edition , McGraw Hill.

Peptic Stricture → Occurs in 5% of patients who have esophagitis → dysphagia to solids often gradual but progressive over several months to years → Often noted on upper endoscopy near the GE junction → Biopsies of the stricture to rule out carcinoma → Esophageal dilation during endoscopy is helpful but acid suppression should be initiated or increased s/p procedure → May require several esophageal dilations Reference: McPhee S. J., Papadakis M.A. & Rabow M.W. (2011). Current Medical Diagnosis and Treatment. 5th edition , McGraw Hill.

Schatzki Ring Hx of steakhouse syndrome, intermittent solid food dysphagia -Marshmallow vs tablet test -Role of acid suppression -Role of esophageal dilation

Case 2: 55 year old male Patient was found to have Barrett’s esophagus with intestinal metaplasia but no dysplasia, Schatzki ring (dilated with tissue disruption). Patient symptoms resolved (dysphagia s/p dilation and symptoms with increase in PPI). Patient remained on high dose acid suppression long term with Q3 year endoscopic surveillance.

Case 3: 68 year old woman Long standing GERD for 20 years. Treated with omeprazole 20 mg bid. Presents to the office with concerns for increasing heartburn, acid and food regurgitation as well as intermittent solid food dysphagia easily cleared by drinking water. She also has had a persistent non-productive cough worse at night. CXR with PCP, negative. No fevers or wheezing. She takes Zantac 150 mg prn bid for breakthrough symptoms. You send her for an upper endoscopy and it shows SEVERE LA Grade D esophagitis What next?

Esophagitis Classifications A to D

Case 3: 68 year old woman You increase her PPI to 40 mg bid, 30 minutes before breakfast and dinner as well as add in Zantac 300 mg bid. For breakthrough, she is recommended to try OTC liquid Gaviscon, especially if any nocturnal symptoms as well as elevating head of bed at night.

Case 3: 68 year old woman A repeat upper endoscopy 3 months from initiating new dose of acid suppression showed a normal appearing esophagus. Normal esophageal biopsies; negative eosinophilic esophagitis and no evidence of celiac disease on duodenal biopsies. She returns to clinic for follow up and reports 80% improvement but still has a persistent cough that occurs nocturnally.

You decide to? Ensure proper medication administration Encourage continued acid suppression and dietary/lifestyle changes Schedule esophageal manometry Schedule ph testing

Esophageal Manometry Role of manometry? Placement of ph catheter Ineffective Esophageal Motility from GERD Esophageal Motility Disorder

Esophageal Manometry Low LES pressures (3 mm Hg (nl 15 to 45) and decreased LES relaxation, 56% ineffective swallows 44% weak swallows

Wireless Bravo pH study Esophageal pH testing What type of pH study? 2 channel pulmonary Impedance pH 1 channel gastric BRAVO pH study Wireless Bravo pH study ON vs OFF acid medication? Ambulatory pH study

pH impedance testing On acid suppression In the pH sensor in the distal esophagus, there were 80 acid reflux episodes noted (nl<50).   Total % time pH<4 was 13.7% (nl<4.5), upright 17.9% (nl<6), supine 22.0% (nl<2).      pH-based symptom association probability (SAP) for cough:  96.5 (Probability that symptom and reflux are not associated solely by chance, >95% is significant)   DeMeester score: 22.3 (abnl >14.72)  

Some Surgical Options Nissen fundoplication Linx TIF- Transoral Incision-less Fundoplication

Pre-Testing Barium Swallow Upper Endoscopy Esophageal manometry pH study – what kind?

Nissen fundoplication GOLD STANDARD Excellent long term efficacy

Nissen fundoplication Criteria Well documented GERD No swallowing disorder BMI < 32 Responsive to acid suppression Generally laparoscopic, but may convert to open chest wall if complications arise. Belching and vomiting after surgery?

Potential complications Post op dysphagia Surgical wrap failure Vagal nerve injury Abdominal bloating Nausea, diarrhea

LINX There is no anatomic alteration of the stomach. Reference: Torax Medical Devices, 2017

LINX Criteria Well documented GERD No swallowing disorder BMI < 32 Hiatal hernia < 2 cm in size. No prior esophageal/gastric surgery. No metal allergy (titanium, stainless steel, nickel, ferrous) Responsive to acid suppression Safety and effectiveness of LINX device not yet evaluated in patients with Barrett's or severe esophageal inflammation. Reference: Torax Medical Devices, 2017

Potential complications Device erosion Post-operative dysphagia May have to spend more time in airport security. Not compatible with most MRI; different versions of this device*

TIF Why choose it? Incisionless– No scars. No cutting of tissue. Via Mouth cavity. Reversible. Picture/Resource: Endogastric Solutions, 2016

Indications: Contraindications: GERD >1 year with daily symptoms Objective GERD by EGD, pH study, or barium swallow Tried and failed medical management > 6 months Contraindications: Hiatal hernia > 2 cm Morbid obesity BMI > 35 ( Ideally want to be less than 32) LA Grade C or D esophagitis Barrett’s > 2 cm Prior esophageal or gastric surgery/intervention Chimukangara, Surg Endoscopy, 2018

Potential complications Post-operative dysphagia Injury to mouth tissues/teeth as the procedure is via the mouth. Minimal adverse effects at short and intermediate follow up intervals Chimukangara, Surg Endoscopy, 2018

Clinical Pearls for Anti-Reflux Surgery Good medical response predicts good surgical response PPI refractory cases generally do not do well with anti-reflex surgery BMI less than 32 is most ideal Pre-op dysphagia is a good predictor of post-op dysphagia Post-op diet and recommendations Can I vomit after the surgery? What if I have the flu? Gas bloat syndrome? Hiatal hernia

Case 3: 68 year old woman Patient had complete a Nissen fundoplication and did well post-operatively. She is completely asymptomatic and has been able to wean off of all acid suppression However, she returns a year later with recurrent heartburn. She was restarted on omeprazole 20 mg bid by her PCP and she has ZERO benefit from taking it. What now?

Testing! Repeat esophageal manometry and pH study Recommend 2 channel pulmonary pH study OFF Acid suppression pH testing is negative without any abnormal reflux and poor symptom correlation of heartburn with reflux events

Visceral Hypersensitivity Medication Options gabapentin amitriptyline, nortriptyline, desipramine trazodone topiramate pregabalin buspirone Role of Cognitive Behavioral Therapy

Case 3: 68 year old woman Over the course of 6 months, she starts taking gabapentin and finds 100% relief in her heartburn with 300 mg TID which she increases towards slowly.*

Other References: Chimunkangara, M. et al. (2019). Long-term reported outcomes of transoral incisionless fundoplication: an 8-year cohort study. Surgical Endoscopy, 33, 1304- 1309. Lochhead, P. et al. (2017). Association between proton pump inhibitor use and cognitive function in women. Gastroenterology, 153, 971-979. Khalili, H. et al. (2012). Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective study. BMJ. McPhee S. J., Papadakis M.A. & Rabow M.W. (2011). Current Medical Diagnosis and Treatment. 5th edition , McGraw Hill.

Special Thank You’s Massachusetts General Hospital Neurointestinal Center Swallowing and Heartburn Center