Gastrointestinal Disorders: GERD Overview PDF

Gastrointestinal Disorders I. GASTROESOPHAGEAL REFLUX DISEASE (GERD) A. Definition: 1. GERD is defined by consensus as “symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung.” (Am J Gastroenterolog...

Gastrointestinal Disorders I. GASTROESOPHAGEAL REFLUX DISEASE (GERD) A. Definition: 1. GERD is defined by consensus as “symptoms or complications resulting from the reflux of gastric contents into the esophagus or beyond, into the oral cavity (including larynx) or lung.” (Am J Gastroenterology 2013;108:308-28). Strength of guideline evidence is rated by the GRADE system (Level of Evidence and Strength). 2. Definition subdivides GERD into the following categories: a. Symptoms without erosions on endoscopy (nonerosive reflux disease) b. Symptoms with erosions on endoscopy (erosive reflux disease) 3. Symptoms a. Typical symptoms: Heartburn (pyrosis), regurgitation, acidic taste in the mouth b. Extraesophageal or atypical symptoms: chronic cough, asthma-like symptoms, recurrent sore throat, laryngitis or hoarseness, noncardiac chest pain. Sinusitis, pneumonia, bronchitis, otitis media are less common atypical symptoms. These symptoms require referral for additional testing. c. Alarm symptoms: dysphagia, odynophagia, bleeding, weight loss, choking, chest pain, and epigastric mass. These symptoms warrant immediate referral for more invasive testing. 4. Aggravating factors: recumbency (gravity), elevated intra-abdominal pressure, reduced gastric motility (e.g., gastroparesis), decreased lower esophageal sphincter (LES) tone, and direct mucosal irritation. 5. Long-term complications: esophageal erosion, strictures, obstruction, Barrett esophagus (replacement of squamous epithelial cells with columnar epithelial cells within the lower esophagus, resulting in increased risk of esophageal carcinoma), and reduction in quality of life. B. Diagnosis 1. Symptoms a. A presumptive diagnosis of GERD can be made given typical heartburn and regurgitation symptoms. Empiric therapy with a proton pump inhibitor (PPI) is recommended (Strong recommendation/Moderate level of evidence). b. Screening for H. pylori is not recommended (Strong/Low). H. pylori screening is recommended in patients with PUD, a history of a documented peptic ulcer, or gastric mucosa-associated lymphoid tissue (MALT) lymphoma. c. Patients with noncardiac chest pain that is suspected to be due to GERD should have a diagnostic evaluation before initiation of therapy (Strong/Low). 2. Endoscopy: Upper endoscopy is not necessary in the presence of typical GERD symptoms. Endoscopy is recommended in the presence of alarm symptoms and in the screening of patients at high risk of complications. Repeated endoscopy is not indicated in patients without Barrett esophagus in the absence of new symptoms (Strong/Moderate). 3. Manometry: Testing to determine esophageal pressure is recommended for preoperative evaluation, but it has no role in the diagnosis of GERD (Strong/Low). 4. Ambulatory pH testing a. Ambulatory esophageal reflux monitoring is indicated before considering endoscopic or surgical therapy in patients with nonerosive reflux disease as part of the evaluation of patients who are refractory to PPI therapy and when the diagnosis of GERD is in question (Strong/Low). b. Ambulatory reflux monitoring is the only test that can assess reflux symptom association (Strong/ Low). c. Ambulatory reflux monitoring is not necessary in the presence of short- or long-segment Barrett esophagus to establish a diagnosis of GERD (Strong/Moderate). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-117 Gastrointestinal Disorders C. Treatment Strategies for GERD 1. Nonpharmacologic interventions and lifestyle modifications are unlikely to control symptoms in most patients. American College of Gastroenterology (ACG) guidelines cite insufficient evidence to advocate lifestyle modifications for all patients; rather, they advocate use in targeted populations. Thus, the following lifestyle modifications should be implemented only in the patient populations specified. a. Dietary modifications to avoid foods that trigger GERD symptoms and to avoid eating meals 2-3 hours before bed (Conditional/Low). b. Weight loss if overweight or obese (Moderate/Strong) c. Avoid tobacco products or smoking (Conditional/Low) d. Elevate head of bed if nocturnal symptoms present (Conditional/Low). 2. Pharmacologic therapies a. Initial treatment depends on the severity, frequency, and duration of symptoms. i. “Step-down” treatment: starting with maximal therapy, such as therapeutic doses of PPIs, is always appropriate as a first-line strategy in patients with documented esophageal erosion. Advantages: rapid symptom relief, avoidance of over-investigation. Disadvantages: potential overtreatment, higher cost, increased potential for adverse effects. ii. “Step-up” treatment: starting with lower-dose over-the-counter (OTC) products for patients with less severe symptoms without evidence of esophageal erosion. Advantages: avoids overtreatment, has lower initial cost. Disadvantages: potential undertreatment (partial symptom relief; may take longer for symptom control; may lead to over-investigation). b. The ACG and American Gastroenterological Association treatment guideline recommendation summary follows in Table 1. Table 1. American College of Gastroenterology (ACG) and American Gastroenterological Association (AGA) Treatment Guideline Recommendation Area Treatment Recommendation (Level/Strength) Treatment duration of 4-8 weeks (AGA) or 8 weeks (ACG, strong/moderate) of once-daily PPI Use maintenance PPIs if return of symptoms or complications (Strong/Moderate) Long-term maintenance should be the lowest effective dose, on demand, or intermittent therapy (Conditional/Low) Bedtime H2RAs can be used if morning PPI and nighttime symptoms, but tachyphylaxis develops (Conditional/Low) Dosing Further testing needed before use of metoclopramide or baclofen (Conditional/Moderate) Traditional PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole) should be given 30–60 minutes before meals (Strong/Moderate) Newer PPIs (omeprazole-sodium bicarbonate and dexlansoprazole) offer dosing flexibility in relation to meals (Conditional/Moderate) Initiate PPIs once daily before a.m. meal (Strong/Moderate) Twice-daily PPIs if partial response to once-daily PPIs or nighttime symptoms (Strong/Low) Twice daily if partial response to once daily or can switch to another PPI (Conditional/Low) H 2RA = histamine-2 receptor antagonist; PPI = proton pump inhibitor. Strength of recommendations is based on the GRADE system of Strong/Conditional strength of evidence and High/Moderate/Low levels of evidence. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-118 Gastrointestinal Disorders c. d. Antacids i. Calcium-, aluminum-, and magnesium-based products are available OTC in a variety of formulations (capsules, tablets, chewable tablets, and suspensions). ii. Neutralizing acid and raising intragastric pH results in decreased activation of pepsinogen and increased LES pressure; rapid onset of action but short duration, necessitating frequent dosing. iii. Some products (Gaviscon) also contain the antirefluxant alginic acid, which forms a viscous layer on top of gastric contents to act as a barrier to reflux (variable added efficacy). iv. Used as first-line therapy for intermittent (less than twice weekly) symptoms or as breakthrough therapy for those on PPI/histamine-2 receptor antagonist (H2RA) therapy; not appropriate for healing established esophageal erosions. v. Adverse reactions: Constipation (aluminum, calcium), diarrhea (magnesium), accumulation of aluminum and magnesium in renal disease with repeated dosing vi. Drug interactions: Chelation (e.g., fluoroquinolones, tetracyclines); reduced absorption because of increases in pH (e.g., ketoconazole, itraconazole, iron, atazanavir, rilpivirine, ledipasvir, velpatasvir, nelfinavir) H2RAs i. Reversibly inhibit histamine-2 receptors on the parietal cell ii. All agents available as prescription and/or OTC products; a variety of formulations available; generics exist for all prescription products. See Table 2 for available H2RA formulations. iii. Recent U.S. Food and Drug Administration (FDA) safety alerts have resulted in withdrawal from the market of ranitidine products because of the presence of N-nitrosodimethylamine (NDMA), a carcinogen. Table 2. Histamine-2 Receptor Antagonists Agent Cimetidine (Tagamet) Oral OTC Formulations 200-mg tablet (Tagamet-HB) Oral Prescription Formulations 200-, 300-, 400-, 800-mg tablets Usual GERD therapeutic dose 400 mg PO QID or 800 mg PO BID 150 mg PO BID 20 or 40 mg PO BID Nizatidine (Axid) Not available 300 mg/5 mL of solution 150-mg/300-mg capsules Famotidine (Pepcid, Zantac) 10- and 20-mg tablets 15 mg/mL of solution 20-mg/40-mg tablets Pepcid Complete 10 mg + 800 mg of calcium carbonate + 165 mg of magnesium hydroxide chewable tablets (Pepcid Complete) 40-mg/5-mL suspension BID = twice daily; OTC = over the counter. iv. OTC H2RAs can be used for on-demand therapy for intermittent mild-to-moderate GERD symptoms; preventive dosing before meals or exercise is also possible. Higher prescription doses are often necessary for more severe symptoms or for maintenance dosing. Prolonged use is associated with the development of tolerance and reduced efficacy (tachyphylaxis). v. H2RAs are less effective than PPIs in healing erosive esophagitis. vi. Adverse effects: Most are well tolerated. Central nervous system (CNS) effects such as headache, dizziness, fatigue, somnolence, and confusion are the most common. Older adults and patients with reduced renal function are at higher risk. Prolonged cimetidine use is associated rarely with gynecomastia. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-119 Gastrointestinal Disorders e. vii. Drug interactions: Can affect the absorption of drugs dependent on lower gastric pH (e.g., ketoconazole, itraconazole, iron, atazanavir) or increases in absorption leading to potential toxicity (e.g., raltegravir). Cimetidine also inhibits cytochrome P450 (CYP) enzymes 1A2, 2C9, 2D6, and 3A4. Warfarin, theophylline, and other agents metabolized by these enzymes can be affected. Cimetidine can also compete with medications and creatinine for tubular secretion in the kidney. Proton pump inhibitors i. Irreversibly inhibit the final step in gastric acid secretion; greater degree of acid suppression achieved and typically longer duration of action than H2RAs ii. Most effective agents for short- and long-term management of GERD and for management of erosive disease iii. Several PPIs are available as generic prescription-strength products (e.g., omeprazole, lansoprazole, pantoprazole). Omeprazole, lansoprazole, and esomeprazole are available OTC. The OTC products are considered safe and effective for intermittent short-term (2 weeks) use in patients with typical heartburn symptoms. Long-term use of OTC products should be discussed with prescriber to prevent loss of follow-up or to assess for potential over or undertreatment. iv. Most effective when taken orally before meals; for divided dosing, give evening dose before evening meal instead of at bedtime. See Table 3 for available PPI products and Table 4 for alternative PPI administration options. Table 3. Proton Pump Inhibitors Product Dexlansoprazole Formulations Delayed-release capsule (30 mg/60 mg) (Dexilant) Esomeprazole Delayed-release capsule (Nexium) IV solution (Nexium 24HR OTC) Delayed-release oral suspension Standard dose (High dose)a 30 mg once daily (60 mg once daily) 20 mg once daily (40 mg twice daily) Delayed-release capsule Delayed-release capsule or tablet Delayed-release capsule (49.3 mg equivalent to 40 mg esomeprazole) Lansoprazole (Prevacid) Prevacid 24HR delayed-release capsule Esomeprazole strontium 49.3 mg once daily (Prevacid 24HR) 30 mg once daily (30 mg twice daily) Delayed-release capsule Delayed-release oral suspension Omeprazole (Prilosec) Delayed-release orally disintegrating tablet Delayed-release capsule Prilosec OTC Delayed-release tablet (magnesium salt) Zegerid OTC Immediate-release powder for oral suspension; sodium bicarbonate buffer = 460 mg of Na+/dose (two 20-mg packets are not equivalent to one 40-mg packet) 20 mg once daily (40 mg twice daily) Zegerid OTC immediate-release capsules with sodium bicarbonate ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-120 Gastrointestinal Disorders Table 3. Proton Pump Inhibitors (Cont’d) Product Pantoprazole Formulations Delayed-release tablet (20 mg/40 mg) (Protonix) IV solution (40 mg/vial) Rabeprazole Pantoprazole granules 40 mg/packet Delayed-release enteric-coated tablet (20 mg) (AcipHex) Sprinkle capsule (5 mg, 10 mg) Standard dose (High dose)a 40 mg once daily (40 mg twice daily) 20 mg once daily (20 mg twice daily) High-dose therapy is reserved for patients with inadequate response to standard doses. IV = intravenous; OTC = over the counter. a Table 4. Alternative administration of PPIs Product Omeprazole (Prilosec) Esomeprazole (Nexium) Zegerid Lansoprazole (Prevacid) Rabeprazole (AcipHex) Pantoprazole (Protonix) Dexlansoprazole (Dexilant) Alternative Administration Technique Open capsules; mix with applesauce or juice Simplified omeprazole suspension; contents dissolved in bicarbonate (NG/OG) Open esomeprazole capsules and mix with 60 mL of water by NG tube, or dissolve oral suspension in 15 mL of water and administer by NG tube; IV bolus, or continuous infusion Zegerid mix packet with 20 mL water in syringe (NG) Open capsules; mix with applesauce, ENSURE, cottage cheese, pudding, yogurt, or strained pears, or 60 mL of tomato, orange, or apple juice Open capsules + 40 mL of apple juice (NG/OG) Simplified lansoprazole suspension; contents dissolved in bicarbonate (NG/OG) Do not use oral suspension for NG/OG; mix packet with 30 mL of water and swallow Orally disintegrating tablet by oral syringe: Use 4 mL of water for 15 mg tablet or 10 mL of water for 30 mg tablet Orally disintegrating tablet by NG tube (> 8 French): Same preparation as for oral syringe Do not crush Empty sprinkle capsule contents into liquid or soft food and administer within 15 min of preparation. Sprinkle capsule should not be swallowed whole or contents chewed or crushed Do not crush IV (bolus or continuous infusion) Pantoprazole suspension (compounded with bicarbonate) Open capsules and sprinkle on applesauce IV = intravenous; NG = nasogastric; OG = orogastric. iv. Adverse reactions (a) Overall, well tolerated; possible adverse effects include headache, dizziness, nausea, diarrhea, and constipation. Long-term use is not associated with significant increases in endocrine neoplasia or symptomatic vitamin B12 deficiency. As an option, the 2013 American Gastroenterological Association guidelines list the switching of PPIs in patients having adverse effects (Conditional/Low). (b) Summary of major adverse effects of PPIs and prevention and management strategies can be found in Table 5. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-121 Gastrointestinal Disorders Table 5. Summary of Major Adverse Effects of PPIs and Prevention and Management Strategies Adverse Effect Acute interstitial nephritis (AIN) Risk of fracture (hip, wrist, spine) Hypomagnesemia, iron deficiency, B12 deficiency Clostridioides difficile– associated diarrhea Community-acquired pneumonia Prevention and Management Limit the dose and duration of PPIs. Renal function monitoring may not be necessary for short-term use (4–8 weeks) use; consider annual monitoring, dose reduction, and deprescribing in patients with long-term use. AIN may recur with PPI rechallenge Concern about fractures should not affect decision to use PPIs, except in patients with other risk factors for hip fracture (Strong/Moderate); patients with osteoporosis can remain on PPIs; limit dose and duration; ensure adequate calcium and vitamin D; BMD screening if at risk of low bone mass; weight-bearing exercise Reevaluate need of PPI use; limit dose and duration; consider baseline testing if risk factors for deficiciency are present; supplementation Reevaluate need of PPI use; limit dose and duration; evaluate for C. difficile if patient receiving PPI has diarrhea that is not improving; have patients report diarrhea Short-term use may increase risk; long-term risk is not elevated (Conditional/ Moderate); assess vaccine status BMD = bone mineral density; PPI = proton pump inhibitor. v. Drug interactions (a) Inhibition of CYP450: Omeprazole inhibits the metabolism of substrates, such as diazepam, through CYP2C19 inhibition. (1) Potential reduced effectiveness of clopidogrel through inhibition of CYP2C19mediated conversion to active metabolite by omeprazole. Recommendations from the FDA are to avoid omeprazole and to use pantoprazole as an alternative. The 2013 ACG guidelines consider the PPI/clopidogrel interaction not clinically significant (Strong/High). (2) Interaction with high-dose intravenous methotrexate. The labeling for both intravenous methotrexate and the PPIs has been updated to include this interaction, which places patients at higher risk of methotrexate toxicity. Proposed mechanisms include reduced methotrexate excretion by PPI inhibition of BCRP (breast cancer resistance protein), an efflux pump that transports methotrexate across membranes, or reduced renal excretion by inhibition of renal H+/K+-ATPase. Patients receiving high-dose intravenous methotrexate should avoid PPI use, with a switch to an H2RA if needed. Holding the PPI dose for 2 days before and after methotrexate administration can prevent the interaction. (b) Drugs with pH-dependent absorption (e.g., ketoconazole, itraconazole, atazanavir, rilpivirine, ledipasvir, velpatasvir) f. Promotility agents i. Current guidelines recommend against prokinetic agents for GERD treatment unless there is objective evidence of gastroparesis (Low/Strong). ii. Metoclopramide: dopamine antagonist; dosed several times a day; associated with adverse effects such as dizziness, fatigue, drowsiness, extrapyramidal symptoms (EPS), and hyperprolactinemia; 5- and 10-mg ODT formulations are available; used for GERD and diabetic gastroparesis. iii. Bethanechol: cholinergic agonist; poorly tolerated because of adverse effects such as diarrhea, blurred vision, and abdominal cramping; may also increase gastric acid production. Used for urinary retention, off-label for GERD g. Sucralfate is not recommended in the routine treatment of GERD except in the setting of pregnancy (Low/Strong). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-122 Gastrointestinal Disorders h. Surgical therapy i. Surgical therapy (Nissen fundoplication) is a laparoscopic procedure for long-term therapy in patients with GERD (Strong/High). ii. Surgical therapy is generally not recommended in patients who do not respond to PPI therapy (Strong/High). iii. Surgical therapy is as effective as medical therapy for carefully selected patients with chronic GERD when performed by an experienced surgeon (Strong/High). iv. Patients with obesity contemplating surgical therapy for GERD should be considered for bariatric surgery. Gastric bypass would be the preferred operation in these patients (Conditional/ Moderate). v. Current endoscopic therapy or transoral incisionless fundoplication cannot be recommended as an alternative to medical or traditional surgical therapy (Strong/Moderate). D. Management of dyspepsia was recently reviewed by ACG and the Canadian Association of Gastroenterology. The recommendations include endoscopy for patients at risk for serious outcomes, testing and eradicating H. pylori, and using PPIs, tricyclic antidepressants, prokinetic agents, and psychotherapy to manage symptoms. Patient Case 1. A 55-year-old man with an 8-month history of GERD symptoms 4–5 days/week has been receiving lansoprazole 15 mg daily by mouth, with the use of magnesium hydroxide for breakthrough symptoms. His symptoms are still present 3–4 days/week and are disruptive to his daily life. He has implemented lifestyle modifications and has been adherent to lansoprazole. His medical history is significant for hypothyroidism. He takes levothyroxine 100 mcg once daily. An endoscopy last week revealed no ulcers or erosions. Which treatment approach is best for this patient? A. Add metoclopramide 10 mg four times daily. B. Increase lansoprazole to 15 mg twice daily. C. Switch to omeprazole 20 mg daily. D. Add sucralfate 1000 mg four times daily. II. PEPTIC ULCER DISEASE A. Classification of peptic ulcer disease (PUD) 1. Duodenal ulcer a. Common causes: H. pylori infection (95%), NSAIDs, low-dose aspirin b. Uncommon causes: Zollinger-Ellison syndrome, hypercalcemia, granulomatous diseases, neoplasia, infections (cytomegalovirus, herpes simplex, tuberculosis) c. Presentation: epigastric pain, possibly worse at night; often, pain occurs 1–3 hours after a meal and may be relieved by eating. Pain may also be episodic. Associated symptoms can include heartburn, belching, a bloated feeling, nausea, and anorexia. 2. Gastric ulcer a. Common causes: NSAIDs, H. pylori infection b. Uncommon causes: Crohn disease (CD), infections (cytomegalovirus, herpes simplex) c. Presentation: epigastric pain, often made worse by eating; associated symptoms may include heartburn, belching, a bloated feeling, nausea, and anorexia ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-123 Gastrointestinal Disorders 3. Complications of PUD a. Bleeding b. Gastric outlet obstruction c. Perforation 4. Patients at risk of NSAID-induced GI toxicity: Risk factors for NSAID-induced GI complications can be found in Table 6. Table 6. Risk Factors for NSAID-Induced Gastrointestinal Complications Category High risk Risk Factors History of complicated ulcer Moderate risk Several (> 2) risk factors Age > 65 yr (1 or 2 risk factors) High-dose NSAID therapy (e.g., ibuprofen 2400 mg/day, naproxen 1000 mg/day) History of uncomplicated ulcer Low risk Concurrent use of aspirin (including low dose), corticosteroids, or anticoagulants No risk factors NSAID = nonsteroidal anti-inflammatory drug. a. Some NSAIDs such as ibuprofen, diclofenac, and nabumetone are intrinsically less toxic to the GI tract than naproxen, which is considered a moderate risk. Other agents such as piroxicam, indomethacin, and ketorolac are considered high-risk agents. b. Duration of NSAID use (higher risk in first 3 months). The presence of chronic debilitating disorders, such as rheumatoid arthritis or cardiovascular (CV) disease, could also contribute to the increased GI toxicity of NSAIDs, but these are not generally considered independent risk factors. c. H. pylori infection is thought to confer additive risk of GI toxicity in NSAID users; however, evidence of H. pylori eradication in patients using NSAIDs is not conclusive.. 5. Diagnosis a. Symptom presentation b.  Testing for H. pylori infection: Practitioners must be willing to treat if test results are positive, because H. pylori is a known carcinogen. i. Testing is indicated for patients with active ulcer disease, history of PUD, or gastric MALT lymphoma. ii.  The H. pylori test-and-treat strategy is also acceptable for patients with unevaluated dyspepsia without alarm symptoms who are younger than 60 years. c. Diagnostic tests for H. pylori infection i. Noninvasive tests are preferred over invasive tests for ease of use. (a) Serologic tests (QuickVue H. pylori gII, FlexSure HP): Detect immunoglobulin (Ig) G to H. pylori in the serum by enzyme-linked immunosorbent assay (85% sensitive, 79% specific). Cannot distinguish between active infection and past exposure. Because antibodies persist for long periods after eradication, cannot use to test for eradication after treatment. (b) Urea breath test (UBT; BreathTek UBT, PYtest) detects the exhalation of radiolabeled CO2 after the ingestion of 13C- or 14C-radiolabeled urea. H. pylori hydrolysis of the radiolabeled urea results in CO2 production (97% sensitive, 95% specific. It is used to make a diagnosis and to test for eradication. Recent use of antibiotics or PPIs can cause false-negative results in up to 40% of patients. Patients should discontinue antisecretory agents or antibiotics at least 2 weeks before UBT testing or wait 4 weeks after treatment has ended before having the UBT performed. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-124 Gastrointestinal Disorders (c) Stool antigen tests (Premier Platinum HpSA, ImmunoCard STAT! HpSA) are polyclonal or monoclonal antibody tests that detect the presence of H. pylori in stool (88%–92% sensitive, 87% specific). They can be used to make a diagnosis and to confirm eradication. Recent use of bismuth, antibiotics, or PPIs can also cause false-negative results. Patients should discontinue antisecretory agents or antibiotics at least 2 weeks before stool antigen testing or wait 4 weeks after treatment has ended before having the stool antigen test performed. ii. Invasive (endoscopic) tests are used less frequently than noninvasive tests. (a) Histology: 90%–95% sensitive, 98%–99% specific, subject to sampling error (b)  Rapid urease tests (Campylobacter-like organism [CLO] test, Hp-fast, and PyloriTek) detect the presence of ammonia (NH3) in a sample generated by H. pylori urease activity (80%–95% sensitive, 95%–100% specific). False-negative results can be caused by a partly treated infection, GI bleeding, achlorhydria, or use of PPIs, H2RAs, or bismuth. Patients should discontinue antisecretory agents for at least 1 week before the test is performed. (c) Culture is costly, time-consuming, and technically difficult (100% specific). B. Treatment of H. pylori–associated ulcers 1. General recommendations, based on ACG guidelines, are to include an antisecretory agent (preferably a PPI) plus at least two antibiotics (clarithromycin and amoxicillin or metronidazole) in the eradication regimen. Specific treatment regimens are listed in Table 7. 2. Quadruple therapy with bismuth subsalicylate, metronidazole, tetracycline (or doxycycline in the case of drug shortages), and a PPI is considered an alternative first-line treatment. Pylera, a quadruple based therapy formulated with tetracycline, bismuth subcitrate, and metronidazole in 1 capsule, can be used by patients with aspirin allergy. 3. Sequential therapy involves administration of a PPI and amoxicillin given for the first 5 days, followed by a PPI, clarithromycin, and tinidazole for an additional 5 days. This therapy requires further validation before widespread use will be accepted. 4. A bismuth-based quadruple therapy for 14 days or a levofloxacin-based triple therapy for 10 days can be used in patients who have not responded to initial regimens as salvage therapy. 5. Follow-up testing for eradication should be performed in patients with a history of ulcer complication, MALT lymphoma, early gastric cancer, or recurrence of symptoms. 6. UBTs or stool antigen tests are preferred for confirming eradication (should wait at least 4 weeks after treatment for both). 7. Patients should be asked about prior use of antibiotics, and this information should be considered when the treatment regimen is chosen (ACG). Table 7. Recommended Treatment Regimens for Helicobacter pylori Infection Regimen Clarithromycin triple Bismuth quadruple Drugs and doses PPI (standard or double dose) BID + amoxicillin 1000 mg BID or metronidazole 500 mg TID + clarithromycin 500 mg BID for 14 days PPI (standard dose) BID + Bismuth subsalicylate 300 mg QID or Bismuth subcitrate 120-300 mg QID + metronidazole 250 QID or 500 mg TID-QID + tetracycline 500 mg QID x 10-14 days Notes Avoid if clarithromycin resistance rate is known to be > 15% or in patients with prior macrolide exposure Initial treatment choice if clarithromycin resistance rates are high or patient has prior macrolide exposure. Also beneficial to patients with penicillin allergy ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-125 Gastrointestinal Disorders Table 7. Recommended Treatment Regimens for Helicobacter pylori Infection (continued) Regimen Concomitant Sequential Hybrid Levofloxacin triple Levofloxacin sequential LOAD Drugs and doses PPI (standard dose) BID + clarithromycin 500 mg BID + amoxicillin 1000 mg BID + metronidazole or tinidazole 500 mg BID for 10-14 days PPI (standard dose) BID + amoxicillin 1000 mg BID for 5–7 days; then PPI BID + clarithromycin 500 mg BID + metronidazole or tinidazole 500 mg BID for 5–7 days PPI (standard dose) BID + amoxicillin 1000 mg BID for 7 days; then PPI BID + amoxicillin 1 g BID + clarithromycin 500 mg BID + metronidazole or tinidazole 500 mg BID for 7 days PPI (standard dose) BID + levofloxacin 500 mg daily + amoxicillin 1000 mg BID for 10–14 days PPI (standard or double dose) BID + amoxicillin 1000 mg BID for 5-7 days; then PPI BID + amoxicillin 1000 mg BID + levofloxacin 500 mg daily + metronidazole or tinidazole 500 mg BID for 5-7 days PPI (double dose) daily + levofloxacin 250 mg daily + metronidazole or tinidazole 500 mg BID + doxycycline 100 mg daily Notes Appears at least as effective as clarithromycin triple therapy, although not validated in North America Efficacy subject to geographic variation of resistance rates; complexity of regimen makes it less desirable as first line therapy Regimen not studied in North America; complexity of regimen makes it less desirable as first line therapy Lack of North American data; concerns for high levofloxacin resistance rates. Additional risks associated with fluoroquinolone therapy such as high North American resistance rates and adverse affects should be considered Lack of North American data; may be more effective than levofloxacin triple therapy Lack of North American data; may be more effective than levofloxacin triple therapy BID = twice daily; PPI = proton pump inhibitor; QID = four times daily; TID = three times daily. C. Primary prevention of NSAID-induced ulcers 1. Implement risk factor modification. 2. Test and treat for H. pylori infection if the patient is beginning long-term NSAID therapy. 3. Determine the level of GI-related risk (low, medium, high) using Table 6. See Box 1 for strategies to prevent GI complications in patients receiving NSAIDs based on their CV risk. 4. Because of the association of increased risk of CV events with NSAID use, the patient’s CV risk should be determined as well. The ACG guidelines define those at high CV risk as patients who require low-dose aspirin for the prevention of cardiac events. Naproxen is the only NSAID that does not appear to increase the risk of CV events; therefore, its use is preferred in patients with CV risk factors per the ACG guidelines. However, in 2015, the FDA required that warnings regarding the risk of myocardial infarction and strokes be attached to NSAID products (https://www.fda.gov/ drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-nonaspirin-nonsteroidal-anti-inflammatory). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-126 Gastrointestinal Disorders Box 1. Preventive Strategies Based on Risk of NSAID-Related GI Complications and CV Risk If low CV risk and: Low GI riska → NSAID (lowest dose of least ulcerogenic agent) Moderate GI riskb → NSAID + PPI or misoprostol High GI riskc → COX-2 inhibitor + PPI or misoprostol If high CV risk (requirement for low-dose aspirin) and: Low GI riska → Naproxen + PPI or misoprostol Moderate GI riskb → Naproxen + PPI or misoprostol High GI riskc → Avoid NSAIDs or COX-2 inhibitors No risk factors. One or two risk factors present (see Table 6). c Positive history of ulcer complication or several (more than two) risk factors or use of steroids and anticoagulants. COX-2 = cyclooxygenase-2; CV = cardiovascular; NSAID = nonsteroidal anti-inflammatory drug. a b 5. Misoprostol (Cytotec) should be given at full doses (800 mcg/day in four divided doses); however, this therapy is poorly tolerated because of excessive nausea, vomiting, diarrhea, and abdominal cramping. 6. Concomitant use of antiplatelet agents and NSAIDs a. Need for antiplatelet therapy should first be evaluated. b. If antiplatelet therapy is deemed necessary, assess for the presence of GI risk factors (see Table 6). Dyspepsia or GERD symptoms are additional risk factors. c. Test and treat for H. pylori in patients with a history of a nonbleeding ulcer and in those with a history of an ulcer-related complication. Eradicating H. pylori before beginning long-term antiplatelet therapy is optimal. d. PPIs are the preferred gastroprotective agents for both treatment and prevention of aspirin- and NSAID-associated GI injury. e. Gastroprotective therapy should be prescribed for patients with GI risk factors who require the use of any NSAID (including OTC and cyclooxygenase-2 [COX-2] inhibitors) in conjunction with lowdose aspirin. f. Gastroprotective therapy should be prescribed for patients with GI risk factors who require lowdose aspirin. Aspirin doses greater than 81 mg/day should not be used in patients with GI risk factors during the long-term phase of aspirin therapy. g. PPIs should be prescribed for patients receiving concomitant aspirin and anticoagulant therapy (unfractionated heparin, low-molecular-weight heparin, argatroban, warfarin, direct oral anticoagulants, and fondaparinux). h. The target INR range of 2–2.5 should be used in patients for whom warfarin is added to concomitant aspirin and P2Y12 inhibitor (e.g., clopidogrel, prasugrel, ticagrelor) therapy. The combination of both aspirin and clopidogrel with warfarin should be used only when benefit outweighs risk. i. Clopidogrel is not recommended as a substitute for patients with recurrent ulcer bleeding. Aspirin plus a PPI is superior to clopidogrel for GI bleed risk. j. The health care provider (HCP) who decides to discontinue aspirin therapy in patients with shortterm bleeding episodes should weigh the risks of subsequent GI or cardiac events. k. For patients receiving dual antiplatelet therapy (aspirin plus clopidogrel) who require elective endoscopy (particularly colonoscopy and polypectomy), consider deferring if patient is at high risk of cardiac events. Elective endoscopy should be deferred for 1 year after the placement of drug-eluting stents. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-127 Gastrointestinal Disorders D. Treatment and secondary prevention of NSAID-induced ulcers 1. Risk factor modification 2. Discontinue or lower NSAID dose, if possible. Ulcers will heal with appropriate treatment, but healing may take longer with continued NSAID use. 3. Test for H. pylori and treat, if present. 4. Drug therapy a. PPIs: Drugs of choice for healing and secondary prevention of NSAID-induced ulcers. Combination product Vimovo contains esomeprazole with naproxen in the same tablet (375 mg/20 mg or 500 mg/20 mg) but may be expensive. b. Misoprostol appears to be as effective as PPIs for healing and secondary prevention; however, it necessitates several doses per day, and it is poorly tolerated because of the high incidence of diarrhea and abdominal pain. c. COX-2 inhibitors: Celecoxib was shown to have rates of ulcer recurrence and bleeding comparable to those of a diclofenac plus omeprazole combination. The use of celecoxib may be limited by its association with CV effects. The use of celecoxib is also uncertain in combination with low-dose aspirin for secondary prevention of GI events. d. The combination of a COX-2 inhibitor and a PPI is not well studied, but it can be considered in high-risk patients, especially if receiving aspirin plus steroids or warfarin or have a history of a recent complicated GI event and require continued NSAID or aspirin use. e. H2RAs are inferior to misoprostol and PPIs in healing and preventing recurrence. f. Clopidogrel is not recommended as a substitute in patients with recurrent ulcer bleeding. Aspirin plus a PPI is superior to clopidogrel for GI bleed risk. 5. CV safety of COX-2 inhibitors and NSAIDs a. The main theory underlying the development of excess thrombotic events with COX-2 inhibitor use is that when COX-2–mediated prostacyclin production is reduced, the prothrombic prostaglandin thromboxane A continues to be produced by COX-1, leading to the development of a prothrombic state. b. Celecoxib was not associated with increases in CV events until the Adenoma Prevention with Celecoxib trial for cancer prevention was terminated in 2004. Daily doses of 400 and 800 mg of celecoxib conferred a 2.5- and 3.4-fold higher risk of fatal and nonfatal myocardial infarction respectively, which suggests a dose-related response for this toxicity. c. The AHA recommends a stepped approach for patients with CV disease or risk factors for ischemic heart disease who require analgesic treatment of musculoskeletal symptoms. i. Consider using acetaminophen, aspirin, tramadol, or short-term narcotics first. ii. Nonacetylated salicylates (e.g., salsalate, choline magnesium trisalicylate) can be considered next. iii. Non–COX-2-selective NSAIDs can be used next, followed by NSAIDs with some COX-2 activity. Use the lowest possible effective dose. iv. Celecoxib should be reserved as a last resort. In patients at increased risk of thromboembolic events, coadministration with aspirin and a PPI can be considered. v. Routinely monitor blood pressure, renal function, and signs of edema or GI bleeding. d. Methods to reduce CV risk, such as tobacco cessation, blood pressure reductions, lipid control, and glucose control, are recommended for NSAID users, but have not been proved to reduce NSAIDassociated CV risk. In patients for whom the risk of GI bleeding outweighs the CV risk, lower-risk NSAIDs such as ibuprofen, etodolac, diclofenac, or celecoxib should be used. In patients for whom the CV risk outweighs the risk of GI bleeding, COX-2 inhibitors should be avoided. Limit the dose and therapy duration, if possible. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 2-128