Comparative Effectiveness of Management Strategies for Adults With Gastroesophageal Reflux Disease: An Update

1
Comparative Effectiveness of Management
Strategies for Adults With Gastroesophageal
Reflux DiseaseAn Update

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
Outline of Material

• 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

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Background Health Impact of GERD

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm. B
rook RA, Wahlqvist P, Kleinman NL, et al.
Pharmacol Ther 20076(6)889-898. PMID
17767473. Forgacs I, Loganayagam A. BMJ
2008336(7634)2-3. PMID 18174564.
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Background Pathophysiology of GERD

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
5
Background Treatment of GERD (1 of 2)

• 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)

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
6
Background Treatment of GERD (2 of 2)

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
7
Background Additional Issues

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
8
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.

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Clinical Questions Addressed by the CER (1 of 3)

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
10
Clinical Questions Addressed by the CER (2 of 3)

• 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)?

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
11
Clinical Questions Addressed by the CER (3 of 3)

• 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?

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
12
Comparative Effectiveness Review Study Criteria
(1 of 2)

• 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 Zenkers
  diverticulum previous antireflux surgery and
  esophagitis caused by infections, pills, or
  chemical burns were excluded.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
13
Comparative Effectiveness Review Study Criteria
(2 of 2)

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
14
Rating the Strength of Evidence From the CER

• The strength of evidence was classified into four
  broad categories

High ??? Further research is very unlikely to change the confidence in the estimate of effect.
Moderate ??? Further research may change the confidence in the estimate of effect and may change the estimate.
Low ??? Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient ??? Evidence either is unavailable or does not permit estimation of an effect.
Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
15
Findings of the Comparative Effectiveness Review
Medication (1 of 3)

• 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
16
Findings of the Comparative Effectiveness Review
Medication (2 of 3)

• 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
17
Findings of the Comparative Effectiveness Review
Medication (3 of 3)

• 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
18
Findings of the Comparative Effectiveness Review
Surgery (1 of 3)

• 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
19
Findings of the Comparative Effectiveness Review
Surgery (2 of 3)

• Older age, morbid obesity, female sex, presence
  of baseline symptoms or esophagitis, and a hiatal
  hernia gt3 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
20
Findings of the Comparative Effectiveness Review
Surgery (3 of 3)

• 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
21
Findings of the Comparative Effectiveness Review
Medication Versus Surgery

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
22
Findings of the Comparative Effectiveness Review
Endoscopic Treatments (1 of 2)

• 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
23
Findings of the Comparative Effectiveness Review
Endoscopic Treatments (2 of 2)

• 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

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
24
Conclusions

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
25
Knowledge Gaps and Future Research Needs

• 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.

Ip S, Chung M, Moorthy D, et al. AHRQ Comparative
Effectiveness Review No. 29. Available at
www.effectivehealthcare.ahrq.gov/gerdupdate.cfm.
26
What To Discuss With Your Patients

• 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

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