Comparative Effectiveness of Management Strategies for

Adults With Gastroesophageal Reflux Disease:

An UpdatePrepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

Introduction to GERD and treatment interventions Systematic review methods The clinical questions addressed by the CER Results of studies and evidence-based conclusions

about the effectiveness and harms of GERD treatment

Gaps in knowledge and future research needs What to discuss with patients and their caregivers

Outline of Material

Chronic GERD is one of the most common health conditions affecting Americans.

Many patients have frequent, severe symptoms that require long-term, regular use of acid-reducing medications.

Considerable uncertainty remains about how the treatment objectives should be achieved for patients with GERD.

Background: Health Impact of GERD

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.Brook RA, Wahlqvist P, Kleinman NL, et al. Pharmacol Ther 2007;6(6):889-898. PMID: 17767473.Forgacs I, Loganayagam A. BMJ 2008;336(7634):2-3. PMID: 18174564.

GERD results from frequent exposure of the esophagus to gastric contents that may be harmful to esophageal epithelium.

The physical barrier to reflux is the lower esophageal sphincter, which is anchored by the crural diaphragm.

The antireflux barrier may be disrupted by a hiatal hernia or a hypotensive lower esophageal sphincter, alone or in combination.

Background: Pathophysiology of GERD

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Generally, the goals of therapy for chronic GERD are: An improvement in symptoms An improvement in quality of life Healing of erosive esophagitis Prevention of complications

Medical treatment of GERD often involves intermittent, periodic, or continuous use of medications, especially: Histamine type 2 receptor antagonists (H2RAs) Proton pump inhibitors (PPIs)

Background: Treatment of GERD (1 of 2)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29. Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Standard treatment often involves: An 8-week trial of PPIs. Lifestyle modification (e.g., weight loss, limiting

tobacco and alcohol). Surgical management of GERD, another treatment

option, is based on repair and strengthening of the physical antireflux barrier.

More recently, endoscopic treatments have been developed, but they are mostly reserved for use in clinical trials.

Background: Treatment of GERD (2 of 2)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Challenges to the diagnosis of GERD include how to evaluate: Patients with refractory symptoms. Patients with extraesophageal presentations.

An October 2010 reminder from the U.S. Food and Drug Administration warns that the concomitant use of clopidogrel and the PPI omeprazole (Prilosec®) can result in significant reductions in the antiplatelet activity of clopidogrel.

Background: Additional Issues

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development

Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.

A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issues. The research questions and the results of the report are subject to expert input, peer review, and public comment.

The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Key Question 1: What is the evidence of the comparative effectiveness of

medical, surgical, and other newer forms of treatments for improving objective and subjective outcomes in patients with chronic GERD?

Is there evidence that effectiveness varies by specific technique, procedure, or medication?

Objective outcomes addressed include esophagitis healing, ambulatory pH monitoring, other indicators of reflux, medication need, healthcare utilization, and incidence of esophageal stricture, Barrett's esophagus, or esophageal adenocarcinoma.

Subjective outcomes include symptom frequency and severity, sleep/productivity, and overall quality of life.

Clinical Questions Addressed by the CER (1 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Key Question 2: Is there evidence that effectiveness of medical, surgical,

and newer forms of treatments vary for specific patient subgroups?

What are the characteristics of patients who have undergone these therapies, including the nature of previous medical therapy, severity of symptoms, age, sex, weight, and other demographic and medical factors?

What are the provider characteristics for procedures including provider volume and setting (e.g., academic vs. community)?

Clinical Questions Addressed by the CER (2 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Key Question 3: What are the short-term and long-term adverse events

associated with specific medical, surgical, and other, newer forms of therapies for GERD?

Does the incidence of adverse events vary with duration of followup, specific surgical intervention, or patient characteristics?

Clinical Questions Addressed by the CER (3 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Eligible studies were comparative, randomized, nonrandomized, and cohort studies of adults (≥18 years) with chronic GERD.

Studies that focused exclusively on patients with postsurgical GERD; pregnancy-induced GERD; duodenal or peptic ulcer; gastritis; primary esophageal motility disorder; scleroderma; diabetic gastroparesis; radiation esophagitis; Zollinger-Ellison syndrome; Zenker’s diverticulum; previous antireflux surgery; and esophagitis caused by infections, pills, or chemical burns were excluded.

Comparative Effectiveness Review Study Criteria (1 of 2)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Studies on medical treatment of GERD included randomized controlled trials (RCTs) using a PPI or H2RA for the treatment of acute symptoms or as maintenance therapy.

Studies with surgical procedures for GERD included only RCTs or cohort studies examining total (Nissen and Nissen-Rossetti) or partial (Toupet) fundoplication, either as an open or as a laparoscopic procedure.

For studies with endoscopic procedures for GERD, only RCTs or cohort studies examining products approved in the United States were included.

Comparative Effectiveness Review Study Criteria (2 of 2)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

The strength of evidence was classified into four broad categories:

Rating the Strength of Evidence From the CER

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Two major comparators: H2RAs and PPIs PPIs were superior to H2RAs for esophagitis

healing, patient satisfaction and compliance, and symptom remission.

Strength of Evidence = Moderate All of the commercially available PPIs appeared to

be similarly effective for relieving symptoms and healing esophagitis for up to 1 year.

Strength of Evidence = Moderate

Findings of the Comparative Effectiveness Review: Medication (1 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Continuous therapy with a PPI appeared to be more effective than on-demand therapy for symptom control and quality of life in patients with GERD.

Strength of Evidence = Moderate Obesity, baseline symptoms, and severe baseline esophagitis

were associated with worse outcomes. Older age was associated with improved symptom control.

Strength of Evidence = Moderate PPIs demonstrated no difference from placebo in resolving

hoarseness but did demonstrate some improvement inconsistently in resolving cough.

Strength of Evidence = Low

Findings of the Comparative Effectiveness Review: Medication (2 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Findings concerning the effectiveness of treatment of GERD on asthma symptoms were inconsistent.Strength of Evidence = Insufficient

Adverse Effects: Potential adverse effects from PPI treatment included diarrhea, nausea or vomiting, abdominal pain, dyspepsia, headache, intestinal infection, pneumonia, and increased risk of bone fracture. Strength of Evidence = Low

Findings of the Comparative Effectiveness Review: Medication (3 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Major comparators: Laparoscopic total and partial fundoplication Laparoscopic fundoplication with and without

division of short gastric vessels Open total and partial fundoplication

There were no significant differences in effectiveness between the above comparators.

Strength of Evidence = Moderate

Findings of the Comparative Effectiveness Review: Surgery (1 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Older age, morbid obesity, female sex, presence of baseline symptoms or esophagitis, and a hiatal hernia >3 centimeters at baseline were inconsistently associated with worse surgical outcomes.

Strength of Evidence = Low Evidence was inconclusive regarding the

effectiveness of surgical treatment on extraesophageal manifestations of GERD.

Strength of Evidence = Insufficient

Findings of the Comparative Effectiveness Review: Surgery (2 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Adverse Effects: Serious adverse effects included bloating and dysphagia. Fundoplication was also associated with procedural complications such as postoperative infections and incisional hernia.

Strength of Evidence = Low

Findings of the Comparative Effectiveness Review: Surgery (3 of 3)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Fundoplication was as effective as continued medical treatment in controlling GERD-related symptoms.

Strength of Evidence = Moderate Serious adverse effects could be more common for

surgery than for medical treatment.

Strength of Evidence = Low Evidence was insufficient to determine whether

prevention of long-term complications is equivalent between medical and surgical treatments.

Findings of the Comparative Effectiveness Review: Medication Versus Surgery

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Three evaluated types: the EndoCinch™ Suturing System, Stretta®, and EsophyX™

A number of sham-controlled and cohort studies examining the effectiveness of the individual procedures were reviewed. No studies directly comparing endoscopic treatments

were identified. Evidence of the effectiveness of the endoscopic

treatment EndoCinch was mixed regarding improvement in symptoms, quality of life, and healing of esophagitis.Strength of Evidence: Low

Findings of the Comparative Effectiveness Review: Endoscopic Treatments (1 of 2)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Evidence was insufficient to evaluate endoscopic procedures for GERD other than EndoCinch or to compare endoscopic treatments to medication or surgery.

Lesser degrees of esophagitis were associated with a reduction in the need for PPIs after treatment. Sex did not appear to influence outcomes. Strength of Evidence: Low

Adverse Effects: Common adverse effects from endoscopic suturing included chest or abdominal pain, bleeding, dysphagia, and bloating. Strength of Evidence: Low

Findings of the Comparative Effectiveness Review: Endoscopic Treatments (2 of 2)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

PPIs are superior to H2RAs for the treatment of chronic GERD.

Comparisons among different PPIs or among different dosages and dosing regimens of PPIs show few consistent differences.

Limited studies suggest that continuous daily dosing provides improved symptom control and quality of life at 6 months when compared to on-demand dosing.

Through up to 3 years of followup, surgery is as effective as medication, but serious adverse effects may be more common with surgical treatments.

Evidence to evaluate endoscopic treatments is lacking.

Conclusions

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

Currently, the long-term (i.e., 5+ years) comparative effectiveness of laparoscopic fundoplication versus medical treatments for GERD cannot be determined.

Most studies do not evaluate options for patients whose disease does not respond well to medications.

Evidence is lacking to determine the role and value of endoscopic procedures.

Evidence is sparse regarding the prevention of long-term complications or the treatment of extraesophageal manifestations of GERD.

Behavioral modifications to ameliorate GERD symptoms are not discussed in this report.

Knowledge Gaps and Future Research Needs

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.

The need for consistent use of GERD medications if prescribed

The availability of GERD treatments without a prescription

The U.S. Food and Drug Administration warning about clopidogrel and omeprazole

The effect of obesity on GERD treatment outcomes The advantages and disadvantages of medical

versus surgical GERD treatments

What To Discuss With Your Patients

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative Effectiveness Review No. 29.Available at www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.