Evidence-Based Approaches to Common GI Conditions

Educational Objectives

The goal of this program is to improve management of dyspepsia and irritable bowel syndrome (IBS). After hearing and assimilating this program, the clinician will be better able to:

1.   Determine the probable etiology of a patient’s dyspeptic symptoms.

2.   Provide appropriate evidence-based therapy targeted at the source of a patient’s dyspepsia.

3.   Adhere to an algorithm that produces diagnosis and remission of uninvestigated dyspepsia with the lowest av­erage cost.

4.   Review the findings and recommendations of the American College of Gastroenterology (ACG) task force on IBS.

5.   Apply the recommendations of the ACG task force to the management of patients with IBS.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning commit­tee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any iden­tified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. The following has been disclosed: Dr. Inadomi is on the Speakers’ Bureau for Takeda, has received a re­search grant from BARRX, and has been a consultant for Ethicon Endo Surgery. Dr. Dantzler and the planning committee reported nothing to disclose. In their lectures, Drs. Inadomi and Dantzler present information related to off-label or investi­gational use of a therapy, product, or device.

Acknowledgments

Dr. Inadomi was recorded at the 37th Annual Advances in Internal Medicine, held June 22-29, 2009, in San Fran­cisco, CA, and sponsored by the Department of Medicine at the University of California, San Francisco, School of Medicine. Dr. Dantzler was recorded at Evidence Based Drug Therapy Update, held May 7-9, 2009, in Charleston, SC, and sponsored by The Medical University of South Carolina, Department of Family Medicine, Office of Continu­ing Medical Education, College of Medicine and cosponsored by the Division of Continuing Education, the Office of Continuing Education, South Carolina College of Pharmacy (MUSC Campus) and the Office of Continuing Educa­tion, College of Nursing. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Evidence-based Approach to Dyspepsia

John Inadomi, MD, Professor of Medicine, University of California, San Francisco, School of Medicine

Etiology and symptomatology: dyspepsia is symptom, so establishing etiology critical; common etiologies  —  functional dyspepsia (»50%; no structural abnormalities); reflux disease (20%); peptic ulcer (10%); cancer (£1%); other (»19%); common causes  —medications; biliary disease; pancreatic disease; celiac disease or lactose intoler­ance (associated with malabsorption, diarrhea, and anemia (especially with celiac disease); gastroparesis; irritable bowel syndrome (IBS); uncommon causes  —  eosinophilic enteritis or gastritis; Crohn’s disease; sarcoidosis; lead poisoning, hypercalcemia; hepatoma; steatohepatitis

Gastric cancer: “alarm” symptoms  —  warrant immediate attention (eg, upper endoscopy); include symptom onset at age 45 yr to 55 yr, dysphagia, weight loss, overt or occult gastrointestinal (GI) bleeding, iron deficiency anemia, and family history of gastric cancer; prevalence of gastric cancer low, so negative and positive predictive values of tests skewed; study  found that presence of alarm symptoms did not correlate with presence of structural disease; however, American Gastroenterological Association (AGA) guidelines continue to recommend endoscopy for pa­tients with  alarm symptoms

Functional dyspepsia: for 2 most common types, symptoms must occur at least several times weekly for ³3 mo and have onset ³6 mo before diagnosis; postprandial distress subtype  —associated with bloating or early satiety after typical meals; epigastric pain subtype  —  ulcer-like pain and epigastric burning; typically moderate nonlocalized pain occurring at least once weekly; pain not relieved by defecation and does not meet criteria for biliary or pancre­atic pain

Absence of warning symptoms or signs: primary diagnostic tests  —  upper endoscopy, Helicobacter pylori (test and treat), empiric trial of antisecretory agent (4-8 wk); other tests  —ultrasonography (US), computed tomography (CT), gastric emptying test, endoscopic retrograde cholangiopancreatography (ERCP), electrogastrography (EGG), functional magnetic resonance imaging (fMRI); alternative diagnostics typically produce low yields; gastric empty­ing frequently shows abnormalities, but results infrequently affect disease management; US reveals abnormalities in 1% to 3% of cases, but results typically unrelated to symptoms (eg, related to gallstones)

 Management trials: early endoscopy vs empiric acid suppression  —no clear benefits from early endoscopy, and costs greater; early endoscopy vs H pylori “test and treat”  —    endoscopy associated with increased long-term reso­lution of symptoms but at substantial cost increase (average $7000 per remission of dyspepsia); empiric acid sup­pression vs placebo  —  proton pump inhibitor (PPI) therapy achieved 35% reduction in symptoms; PPIs more effective for heartburn than for epigastric pain; H pylori screening and eradication vs empiric acid suppression  —  testing and treating for H pylori more effective in several trials; baseline demographic prevalence of H pylori fre­quently skews results; University of Michigan study  —empiric acid suppression significantly superior to H pylori “test and treat” methodology; low prevalence of H pylori in subject population may explain results; empiric PPI vs H₂-receptor antagonist (H2RA) or placebo  —  PPI treatment found superior

Endoscopy: difficult to quantify value of negative endoscopy; prompt endoscopy vs empiric H2RA  —  study found higher satisfaction rates in patients who received endoscopy; open-access endoscopy study  —  endoscopy produced 50% decrease in consultations for dyspepsia; cohort study of dyspepsia (no control arm)  —  patients receiving en­doscopy reported improvements in preoccupation with health and fear of illness; studies evaluating endoscopy fre­quently confirm value; results remain difficult to quantify and must be weighed against costs

Proton pump inhibitors: peptic ulcers  —  90% of patients receiving empiric PPI therapy have relief of symptoms and cure of initial ulcer; atypical reflux disease  —  19% of dyspeptic patients; PPIs successfully treat 50% to 80% of cases; functional dyspepsia  —30% to 50% of patients respond to PPIs; empiric PPI therapy  —alleviation of symp­toms  by PPIs rules out certain causes of dyspepsia (eg, gastric cancer), and  indicates gastroesophageal reflux dis­ease (GERD) or functional dyspepsia as probable etiology; Ofman and Spiegel study  —  for maximum cost-effectiveness, study recommends 1) applying H pylori test-and-treat methodology, 2) providing empiric PPI ther­apy to unresponsive patients, 3) performing endoscopy as final recourse; study did not evaluate quality of life asso­ciated with outcomes

Noninvasive H pylori testing: rapid “near patient” tests  —   in-clinic antibody tests; provide results rapidly and in­expensively; not widely accepted; alternatives include enzyme-linked immunosorbent assay (ELISA) serology, urea breath test (UBT), and stool antigen assays; near-patient and ELISA tests have lower sensitivity and specific­ity; UBT and stool antigen assays best noninvasive tests (measure active infection; have high sensitivity and speci­ficity); ELISA remains positive even after successful eradication of H pylori; guidelines recommend UBT or stool antigen assays; esophagogastroduodenoscopy (EGD)  —  several methods facilitate screening for H pylori during EGD; rapid urease test (RUT)  —  conducted on biopsied tissue; urease produced only by H pylori; inexpensive and yields 80% to 95% sensitivity; GI bleeding interferes with assay; hematoxylin and eosin (H and E) histology  —  expensive and requires 48 hr; culture  —  costly and tedious; valuable for measuring specific antibiotic sensitivities

Pre- vs post-treatment testing for H pylori: primary care physicians currently advised to attempt eradication of H pylori before endoscopy; Laine study  —  after therapy, antral and body histology plus antral biopsy and rapid urease test (RUT) recommended

Treatments for functional dyspepsia: acid suppression  —   11 trials of H2RAs produced heterogeneous results; un­able to confirm efficacy; PPI therapy  —  shown superior to placebo in 8 trials; produced modest improvement of symptoms (14%); H Pylori eradication  —  demonstrated superiority to placebo in 13 trials involving >3000 subjects without ulcer disease; produced relief from symptoms in only 9% of patients; number needed to treat (NNT) 17; prokinetic agents  —  14 studies of >1000 participants showed 50% reduction in symptoms (10% to 15% with con­ventional therapies); all but one study evaluated cisapride (discontinued due to potentially fatal effects); tegaserod (also discontinued) demonstrated significant benefits in 2 placebo-controlled trials; antidepressants  —  meta-analy­sis found antidepressants more effective than placebo;  (NNT 3); majority of studies focused on amitriptyline; sin­gle double-blind placebo-controlled crossover study reported 60% reduction of symptoms in patients taking amitriptyline nightly; psychologic therapy  —  4 trials attempted 1) applied relaxation, 2) psychodynamic psycho­therapy, 3) cognitive therapy, 4) hypnotherapy; each modality produced some relief of symptoms in dyspeptic pa­tients

Algorithm for uninvestigated dyspepsia: heartburn  —  patients excluded from dyspepsia subcategory and should re­ceive acid suppression (similar to patients with GE reflux); nonsteroidal anti-inflammatory drugs (NSAIDs)  —  advise patient to discontinue or switch NSAIDs or add PPI; reflux and NSAIDs excluded  —  with age >55 yr or alarm symptoms, patients should receive upper endoscopy; otherwise, test for H Pylori; patients with positive tests should receive eradication therapy; initiate 4-to 6-wk PPI trial after negative tests or lack of response to H pylori therapy; after PPI trial, consider EGD; majority of patients have normal EGDs, indicating functional dyspepsia; functional dyspepsia  —  repeat testing (eg, RUT, histology) to confirm absence of H pylori; consider salvage regi­mens if positive; alternative therapies  —  try if H pylori test negative; cognitive therapy modalities (eg, symptom di­aries) occasionally valuable in resistant disease

Evidence-based Management of
Irritable Bowel Syndrome

Todd E. Dantzler, MD, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston

Epidemiology: irritable bowel syndrome (IBS) affects 7% to 10% of global population; prevalence increased by 1.5 fold in women; more common in patients <50 yr of age and in groups with lower socioeconomic status; diarrhea-predominant IBS (IBS-D) and mixed IBS (IBS-M) more prevalent than constipation-predominant IBS (IBS-C)

Diagnostic criteria: 2 sets of criteria (Manning (1978) and Rome III (2006) most commonly used; in Rome III, pres­ence of abdominal pain required for diagnosis of IBS; accuracy  —most recent criteria not yet assessed; pooled data from 4 studies (574 patients) evaluating Manning criteria  show sensitivity of 78% and specificity of  72%; exclud­ing organic disease  —celiac disease and lactose maldigestion have significantly higher prevalence in patients with IBS, and should be ruled out

Treatments for IBS

Diet: 60% to 70% of patients report exacerbation of IBS symptoms by specific foods; eliminate lactose and monitor response; exclusion diets  —  in 8 studies (540 patients),) found little correlation between foods associated with IBS symptoms and results of food allergy tests; American College of Gastroenterology (ACG) task force concluded  in­sufficient evidence for effectiveness of  diets or food allergy testing

Fiber: quality of evidence poor; most studies did not use criteria-based diagnosis, sealed allocation, or adequate blinding; wheat bran  —  single study (without placebo) indicated improvement of symptoms; psyllium  —  4 of 6 studies indicated global reduction of IBS symptoms, (NNT 6); fiber received lowest grade from ACG task force

Laxatives: small study using polyethylene glycol (PEG)-based laxative found improved stool frequency in adoles­cents with IBS-C; no effect on pain intensity; weak recommendation from ACG task force

Antispasmodics: 4 of 22 trials evaluated antispasmodics available in United States; trials included >1700 patients; relative risk (RR) of symptoms persisting  0.68,  (NNT 5); best evidence for hyoscine (study of 400 patients; NNT 4); most common adverse events cholinergic side effects; weak recommendation from ACG; peppermint oil  —  smooth muscle relaxant; compared to placebo in 4 studies (392 patients); RR of IBS symptoms persisting was 0.43 (NNT 2.5); weak recommendation from ACG, mainly due to small number of patients; speaker recommends pa­tients use for “quick fix”

Antidiarrheal agents: loperamide only agent sufficiently evaluated in randomized controlled trials (RCTs); 2 trials involved 442 patients with IBS-D; both reported improvement in stool consistency in 100% of loperamide group (vs 20%-45% in controls); RR of stool frequency not improving 0.2; low ACG recommendation because loper­amide no more effective than placebo at reducing abdominal pain and global symptoms of IBS; however, speaker prescribes in IBS-D

Antibiotics: rifaximin demonstrated efficacy in 3 RCTs of 545 patients; patients 8% to 23% more likely to experi­ence global improvement in IBS symptoms, bloating, or both; largest rifaximin study  —  RCT (388 patients with IBS-D) showed significant improvement, mostly after completion of treatment; rifaximin therapy received strong recommendation from ACG task force; recurrent IBS symptoms may respond to repeated courses of rifaximin

Probiotics: evaluated in 19 studies  (»1700 patients); in 11 trials, RR of persistent IBS symptoms in probiotic group was 0.71  (NNT 4); Lactobacillus, Bifidobacterium, and Streptococcus roughly equal in efficacy; in 14 studies (1351 patients), probiotics associated with significant reductions in IBS symptoms; ACG task force assigned lowest recommendation to Bifidobacterium and probiotic combinations

5-Hydroxytryptamine₃ (5-HT₃) receptor antagonists: alosetron  —  approved by Food and Drug Administration (FDA) for women with IBS-D before voluntary removal from market; 8 placebo-controlled trials (»5000 patients); RR of IBS symptoms persisting 0.79 (NNT 8); separate RCT established patient satisfaction significantly greater with alosetron (69% vs 46% with placebo); moderate recommendation from ACG task force; single RCT found alosetron effective in men with IBS-D; however, significant rates of adverse events , eg, severe constipation, colonic ischemia, led to withdrawal of drug; now available via FDA prescribing program; contraindicated in liver disease; speaker uses for women with severe IBS-D refractory to other treatments

5-HT₄ receptor agonists: tegaserod  —  multiple RCTs (>9000 patients) reported 5% to 19% greater relief of global IBS symptoms; withdrawn from market due to potential cardiovascular side effects; cardiovascular events occurred in 0.11% of patients receiving tegaserod (vs .01% for placebo); available from FDA under emergency investiga­tional drug protocol; cisapride  —  no demonstrated improvement; available through compassionate use protocol

Selective C-2 chloride channel agonists: lubiprostone  —promotes chloride secretion into intestine; in pooled phase III study,  response rate 18% (10% for placebo); FDA granted approval for use in women with IBS-C; lubiprostone continuation studies  —  initial 12-wk study reported response rate improvements (from 15% to 37%); side effects dose-dependent; major contraindication mechanical GI obstruction; strong recommendation from ACG task force

Antidepressants: used when abdominal pain primary symptom; desipramine vs placebo  —  high-quality RCT mea­sured response in 216 patients with moderate to severe IBS; at 12 wk, 60% of patients responded (47% for placebo; not significant); 28% of subjects treated with desipramine discontinued, mainly due to anticholinergic side effects (helpful in patients with IBS-D); comorbid depression did not predict response; tricyclic antidepressants (TCAs)  —  demonstrated superiority to placebo in 9 trials with 575 patients (NNT 4); TCAs typically better for IBS-D and IBS-M; selective serotonin reuptake inhibitors (SSRIs)  —  5 trials; 230 patients  (NNT, 3.5); SSRIs potentially bet­ter-tolerated than TCAs, and preferred for patients with IBS-C; ACG task force strongly recommends antidepres­sant therapy

Psychologic therapies: 20 RCTs (1278 patients; NNT 4;);  0.67 RR of IBS failing to improve; total study quality as­sessed as low; relaxation therapy  —  no benefit alone; cognitive behavioral therapy, dynamic psychotherapy, and multicomponent psychologic therapy had equal efficacy; hypnotherapy  —consistent results between 2 studies; RR of IBS failing to improve 0.48, (NNT 2); all therapies (excluding relaxation therapy) superior to conventional care when measuring global symptom improvement; psychologic therapies received moderate recommendation from ACG task force

Alternative therapies: herbal  —  results confounded by variability of mixtures and concerns about toxicity; acupuncture  —  poor quality of trials; uncertain efficacy

Future directions: multiple emerging therapies

Therapies with best evidence of efficacy: rifaximin, alosetron, tegaserod, lubiprostone, TCAs, and SSRIs all re­ceived grade 1 recommendations from ACG task force; hypnotherapy, cognitive behavioral therapy, and psycho­therapy promising (grade 1C recommendations)

Suggested Reading

Bijkerk CJ et al: The role of different types of fibre in the treatment of irritable bowel syndrome. Alimentary Pharmacology & Thera­peutics 19:245, 2004; Choung RS et al: Do distinct dyspepsia subgroups exist in the community? A population-based Study. Ameri­can Journal of Gastroenterology 102:1983, 2007; Drossman D et al: Lubiprostone significantly improves symptom relief rates in adults with irritable bowel syndrome and constipation (IBS-C): Data from Two Twelve-Week, Randomized, Placebo-Controlled, Dou­ble-Blind Trials. Gastroenterology 132:2586, 2007; Ford AC et al: Meta-analysis: Helicobacter pylori “test and treat” compared with empirical acid suppression for managing dyspepsia. Alimentary Pharmacology & Therapeutics 28:534, 2008; Hiyama T et al: Meta-analysis of the effects of prokinetic agents