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Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

Gastric Electrical Stimulation An Evidence-Based Analysis

August 2006

Medical Advisory Secretariat Ministry of Health and Long-Term Care

Suggested Citation This report should be cited as follows: Medical Advisory Secretariat. Gastric electrical stimulation: an evidence-based analysis. Ontario Health Technology Assessment Series 2006; 6(16) Permission Requests All inquiries regarding permission to reproduce any content in the Ontario Health Technology Assessment Series should be directed to [email protected] How to Obtain Issues in the Ontario Health Technology Assessment Series All reports in the Ontario Health Technology Assessment Series are freely available in PDF format at the following URL: www.health.gov.on.ca/ohtas Print copies can be obtained by contacting [email protected] Conflict of Interest Statement All analyses in the Ontario Health Technology Assessment Series are impartial and subject to a systematic evidence-based assessment process. There are no competing interests or conflicts of interest to declare. Peer Review All Medical Advisory Secretariat analyses are subject to external expert peer review. Additionally, the public consultation process is also available to individuals wishing to comment on an analysis prior to finalization. For more information, please visit http://www.health.gov.on.ca/english/providers/program/ohtac/public_engage_overview.html Contact Information The Medical Advisory Secretariat Ministry of Health and Long-Term Care 20 Dundas Street West, 10th floor Toronto, Ontario CANADA M5G 2N6 Email: [email protected] Telephone: 416-314-1092

ISSN 1915-7398 (Online) ISBN 978-1-4249-4322-7 (PDF)

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About the Medical Advisory Secretariat The Medical Advisory Secretariat is part of the Ontario Ministry of Health and Long-Term Care. The mandate of the Medical Advisory Secretariat is to provide evidence-based policy advice on the coordinated uptake of health services and new health technologies in Ontario to the Ministry of Health and Long-Term Care and to the healthcare system. The aim is to ensure that residents of Ontario have access to the best available new health technologies that will improve patient outcomes. The Medical Advisory Secretariat also provides a secretariat function and evidence-based health technology policy analysis for review by the Ontario Health Technology Advisory Committee (OHTAC). The Medical Advisory Secretariat conducts systematic reviews of scientific evidence and consultations with experts in the health care services community to produce the Ontario Health Technology Assessment Series. About the Ontario Health Technology Assessment Series To conduct its comprehensive analyses, the Medical Advisory Secretariat systematically reviews available scientific literature, collaborates with partners across relevant government branches, and consults with clinical and other external experts and manufacturers, and solicits any necessary advice to gather information. The Medical Advisory Secretariat makes every effort to ensure that all relevant research, nationally and internationally, is included in the systematic literature reviews conducted. The information gathered is the foundation of the evidence to determine if a technology is effective and safe for use in a particular clinical population or setting. Information is collected to understand how a new technology fits within current practice and treatment alternatives. Details of the technology’s diffusion into current practice and information from practicing medical experts and industry, adds important information to the review of the provision and delivery of the health technology in Ontario. Information concerning the health benefits; economic and human resources; and ethical, regulatory, social and legal issues relating to the technology assist policy makers to make timely and relevant decisions to maximize patient outcomes. If you are aware of any current additional evidence to inform an existing Evidence-Based Analysis, please contact the Medical Advisory Secretariat: [email protected]. The public consultation process is also available to individuals wishing to comment on an analysis prior to publication. For more information, please visit http://www.health.gov.on.ca/english/providers/program/ohtac/public_engage_overview.html

Disclaimer This evidence-based analysis was prepared by the Medical Advisory Secretariat, Ontario Ministry of Health and Long-Term Care, for the Ontario Health Technology Advisory Committee and developed from analysis, interpretation and comparison of scientific research and/or technology assessments conducted by other organizations. It also incorporates, when available, Ontario data, and information provided by experts and applicants to the Medical Advisory Secretariat to inform the analysis. While every effort has been made to do so, this document may not fully reflect all scientific research available. Additionally, other relevant scientific findings may have been reported since completion of the review. This evidencebased analysis is current to the date of publication. This analysis may be superceded by an updated publication on the same topic. Please check the Medical Advisory Secretariat Website for a list of all evidence-based analyses: http://www.health.gov.on.ca/ohtas

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Table of Contents Abbreviations.............................................................................................7 Glossary ......................................................................................................8 Executive Summary ..................................................................................9 Objective ........................................................................................................................................ 9 Background ................................................................................................................................... 9 The Device.................................................................................................................................... 11 Regulatory Status........................................................................................................................ 11 Review Strategy........................................................................................................................... 12 Findings........................................................................................................................................ 13 Economic Analysis ...................................................................................................................... 14 Conclusion ................................................................................................................................... 15

Objective...................................................................................................17 Background ..............................................................................................17 Gastroparesis............................................................................................................................... 17 Epidemiology ............................................................................................................................................. 17 Relationship Between Symptoms and Delayed Gastric Emptying ....................................................... 18 Effects of Blood Glucose Concentration on Gastric Emptying............................................................. 18 Effects of Gastric Emptying on Blood Glucose Concentration............................................................. 19 Diagnosis .................................................................................................................................................... 19 Measuring Gastric Emptying................................................................................................................... 19

Morbid Obesity ........................................................................................................................... 21 Treatment For Morbid Obesity ............................................................................................................... 21

Gastric Electrical Stimulation - Treatment Procedure .......................................................... 21 Patterns of Electrical Stimulation ........................................................................................................... 21 Gastric Electrical Stimulation for Chronic Symptomatic Gastroparesis ............................................ 23 Gastric Electrical Stimulation for Morbid Obesity ............................................................................... 23

Regulatory Status ....................................................................................23 Canada ......................................................................................................................................... 23 United States................................................................................................................................ 24

Literature Review on Effectiveness .......................................................24 Objective ...................................................................................................................................... 24 Methodology ................................................................................................................................ 24 Results of Literature Search ...................................................................................................... 26 Gastric Electrical Stimulation for Gastroparesis: Study with the Highest Level of Evidence ....................................................................................................................................................... 26 Alberta Heritage Foundation for Medical Research , January 2006 ................................................... 32

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National Institute for Clinical Excellence: Interventional Procedures Programme, September 2003 .................................................................................................................................................................... 33 O-01 Trial .................................................................................................................................................. 35

GES for Morbid Obesity: International Health Technology Assessments............................ 36 Swedish Council of Technology Assessment in Healthcare, March 2004 ............................................ 36

Gastric Electrical Stimulation for Morbid Obesity Trials Underway or Unpublished........ 36 Screened Health Assessment and Pacer Evaluation (SHAPE) ............................................................. 36 Appetite Suppression Induced by Stimulation Trial (ASSIST) ............................................................ 37

GRADE Quality of the Evidence .......................................................37 Economic Analysis...................................................................................40 Literature Review ....................................................................................................................... 40 Canadian Costs............................................................................................................................ 44 Ontario Context .......................................................................................................................... 44 Gastroparesis in Ontario.......................................................................................................................... 44 Morbid Obesity in Ontario ...................................................................................................................... 44

Existing Guidelines Regarding the Use of the Technology .....44 American Motility Society Task Force on Gastroparesis, April 2006 ................................... 44 National Institute for Clinical Excellence (NICE), December 2004 ....................................... 45 American Gastroenterological Association: Technical Review on the Diagnosis and Treatment of Gastroparesis, November 2004 .......................................................................... 45 Refractory GP ........................................................................................................................................... 45 Gastric Electrical Stimulation.................................................................................................................. 45

Centers for Medicare and Medicaid Services, United States, November 2003 ..................... 45 American Society for Bariatric Surgery, United States, 2004 ................................................ 46

Conclusion .............................................................................................46 Appraisal ..................................................................................................48 Survey of Provinces/Territories................................................................................................. 48 Survey of Some Insurers in United States ................................................................................ 48

Appendix 1 ...............................................................................................50 Gastric Electrical Stimulation – Search Strategy .................................................................... 50

Appendix 2 ...............................................................................................52 Data Submitted to the United States Food and Drug Administration for Humanitarian Device Exemption Approval of Gastric Electrical Stimulation for the Treatment of GP ... 52 World Wide Anti-Vomiting Electrical Stimulation Study (WAVESS)................................................ 52 Compassionate Use Electrical Stimulation Study .................................................................................. 54

Appendix 3..............................................................................................57 Gastric Electrical Stimulation for Gastroparesis: Studies of Lesser Quality than Abell et al. (55)........................................................................................................................................... 57

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Appendix 4 ...............................................................................................64 Studies That Assessed Gastric Electrical Stimulation for Gastroparesis in the Alberta Heritage Foundation for Medical Research Report* .............................................................. 64

Appendix 5 ...............................................................................................67 Studies That Assess the Use of Gastric Electrical Stimulation in Patients with Morbid Obesity. ........................................................................................................................................ 67

Appendix 6 ...............................................................................................69 Gastric Electrical Stimulation for Morbid Obesity: Studies of Lesser Quality than the O01 Trial......................................................................................................................................... 69 DIGEST Trial............................................................................................................................................ 69

References..............................................................................................73

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Abbreviations AHFMR BMI CI CUESS EWL FDA GEMS GES GP HDE HOMA HQOL HTA HTPA Hz ITT LOSS MCS NA NICE OR OGGT QoL RR SBU SD SEM SHAPE Tc99 TSS WAVESS

Alberta Heritage Foundation for Medical Research Body mass index Confidence interval Compassionate Use of Electrical Stimulation Study Excess weight loss Food and Drug Administration Gastric Electro-Mechanical Stimulation Gastric electrical stimulation Gastroparesis Humanitarian device exemption Homeostatic Model Assessment Insulin Resistance Index Health related quality of life Health technology assessment Health technology policy assessment Hertz Intent to treat Laparoscopic Obesity Stimulation Survey Mental composite score Not applicable National Institute for Clinical Excellence Odds ratio Oral glucose tolerance test Quality of life Relative risk Swedish Council of Technology Assessment in Healthcare Standard deviation Standard error of the mean Screened Health Assessment and Pacer Evaluation Technetium99 Total symptom score Worldwide Antivomiting Electrical Stimulation Study

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Glossary Antiemetic drug: A drug that prevents or alleviates nausea and vomiting Body mass index: Body weight expressed in kilograms (kg) divided by height expressed in square metres (m2). Dumping Syndrome: A group of symptoms that occur when food or liquid enters the small intestine too rapidly. These symptoms include cramps, nausea, diarrhea and dizziness. Dyspepsia: Impairment of digestion, usually applied to epigastric discomfort following meals. Enteral: A method of nutrient delivery where fluid is given directly into the gastrointestinal tract. Excess weight loss: Percentage of excess weight los = (weight loss/excess weight) x 100 (where excess weight = total preoperative weight – ideal weight). Fundoplication: The upper curve of the stomach (the fundus) is wrapped around the esophagus and sewn into place so that the lower portion of the esophagus passes through a small tunnel of stomach muscle. This surgery strengthens the valve between the esophagus and stomach which stops acid from backing up into the esophagus as easily. Gastric electrical stimulation: Electrical stimulation delivered to the stomach via an implanted system that consists of a neurostimulator and 2 leads. Gastroparesis: A disorder characterized by symptoms of and evidence for gastric retention in the absence of mechanical obstruction. Hertz: The System International unit of frequency. One hertz (Hz) is defined as the reciprocal second. Idiopathic: Characterizing a disease arising primarily, and not in consequence of some other disease or injury. Jejunostomy: Surgical formation of an opening through the abdominal wall into the jejunum, usually for enteral hyperalimentation. 2

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Morbid obesity: Body mass index of at least 40 kg/m or at least 35 kg/m with comorbid conditions. Obesity: Body mass index greater than 30 kg/m2. Prokinetic drug: A drug that increases the number and strength of GI muscle contractions. Pylorus: The opening from the stomach to the intestine. Technetium-99: An isotope of technetium which is used in many medical radioactive isotope tests because of its short half-life (6.01 hours), the energy of the gamma radiation it emits, and its ability to bind chemically to many biologically active molecules. Vagus nerve: A nerve that enervates the gastrointestinal tract, heart and larynx.

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Executive Summary Objective The objective of this analysis was to assess the effectiveness, safety and cost-effectiveness of gastric electrical stimulation (GES) for the treatment of chronic, symptomatic refractory gastroparesis and morbid obesity.

Background Gastroparesis - Epidemiology Gastroparesis (GP) broadly refers to impaired gastric emptying in the absence of obstruction. Clinically, this can range from the incidental detection of delayed gastric emptying in an asymptomatic person to patients with severe nausea, vomiting and malnutrition. Symptoms of GP are nonspecific and may mimic structural disorders such as ulcer disease, partial gastric or small bowel obstruction, gastric cancer, and pancreaticobiliary disorders. Gastroparesis may occur in association with diabetes, gastric surgery (consequence of peptic ulcer surgery and vagotomy) or for unknown reasons (idiopathic gastroparesis). Symptoms include early satiety, nausea, vomiting, abdominal pain and weight loss. The majority of patients with GP are women. The relationship between upper gastrointestinal symptoms and the rate of gastric emptying is considered to be weak. Some patients with markedly delayed gastric emptying are asymptomatic and sometimes, severe symptoms may remit spontaneously. Idiopathic GP may represent the most common form of GP. In one tertiary referral retrospective series, the etiologies in 146 GP patients were 36% idiopathic, 29% diabetic, 13% postgastric surgery, 7.5% Parkinson’s disease, 4.8% collagen vascular disorders, 4.1% intestinal pseudoobstruction and 6% miscellaneous causes. The true prevalence of digestive symptoms in patients with diabetes and the relationship of these symptoms to delayed gastric emptying are unknown. Delayed gastric emptying is present in 27% to 58% of patients with type 1 diabetes and 30% with type 2 diabetes. However, highly variable rates of gastric emptying have been reported in type 1 and 2 diabetes, suggesting that development of GP in patients with diabetes is neither universal nor inevitable. In a review of studies examining gastric emptying in patients with diabetes compared to control patients, investigators noted that in many cases the magnitude of the delay in gastric emptying is modest. GP may occur as a complication of a number of different surgical procedures. For example, vagal nerve injury may occur in 4% to 40% of patients who undergo laparoscopic fundoplication1 for gastroesophageal reflux disease. The prevalence of severe, refractory GP is scantily reported in the literature. Using data from a past study, 1

The upper curve of the stomach (the fundus) is wrapped around the esophagus and sewn into place so that the lower portion of the esophagus passes through a small tunnel of stomach muscle. This surgery strengthens the valve between the esophagus and stomach which stops acid from backing up into the esophagus as easily. Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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it has been estimated that the prevalence of severe, symptomatic and refractory GP in the United States population is 0.017%. Assuming an Ontario population of 13 million, this would correspond to approximately 2,000 people in Ontario having severe, symptomatic, refractory GP. The incidence of severe refractory GP estimated by the United States Food and Drug Administration (FDA) is approximately 4,000 per year in the United States. This corresponds to about 150 patients in Ontario. Using expert opinion and FDA data, the incidence of severe refractory GP in Ontario is estimated to be about 20 to 150 per year. Treatment for Gastroparesis To date, there have been no long-term studies confirming the beneficial effects of maintaining euglycemia on GP symptoms. However, it has been suggested that consistent findings of physiologic studies in healthy volunteers and diabetes patients provides an argument to strive for near-normal blood glucose levels in affected diabetes patients. Dietary measures (e.g., low fibre, low fat food), prokinetic drugs (e.g., domperidone, metoclopramide and erythromycin) and antiemetic or antinausea drugs (e.g, phenothiazines, diphenhydramine) are generally effective for symptomatic relief in the majority of patients with GP. For patients with chronic, symptomatic GP who are refractory to drug treatment, surgical options may include jejunostomy tube for feeding, gastrotomy tube for stomach decompression and pyloroplasty for gastric emptying. Few small studies examined the use of botulinum toxin injections into the pyloric sphincter. However, the contribution of excessive pyloric contraction to GP has been insufficiently defined and there have been no controlled studies of this therapy. Treatment with GES is reversible and may be a less invasive option compared to stomach surgery for the treatment of patients with chronic, drug-refractory nausea and vomiting secondary to GP. In theory, GES represents an intermediate step between treatment directed at the underlying pathophysiology, and the treatment of symptoms. It is based on studies of gastric electrical patterns in GP that have identified the presence of a variety of gastric arrhythmias. Similar to a cardiac pacemaker, it was hypothesized that GES could override the abnormal rhythms, stimulate gastric emptying and eliminate symptoms. Morbid Obesity Epidemiology 2

Obesity is defined as a body mass index (BMI) of at last 30 kg/m . Morbid obesity is defined as a BMI of 2

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at least 40 kg/m or at least 35 kg/m with comorbid conditions. Comorbid conditions associated with obesity include diabetes, hypertension, dyslipidemias, obstructive sleep apnea, weight-related arthropathies, and stress urinary incontinence. 2

In the United States, the age-adjusted prevalence of extreme obesity (BMI > 40 kg/m ) for adults aged 20 years and older has increased significantly in the population, from 2.9% (1988–1994) to 4.7% (1999– 2000). An expert estimated that about 160,000 to 180,000 people are morbidly obese in Ontario.

Treatment for Morbid Obesity Diet, exercise, and behavioural therapy are used to help people lose weight. Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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Bariatric surgery for morbid obesity is considered an intervention of last resort for patients who have attempted first-line forms of medical management. Gastric stimulation has been investigated for the treatment of morbid obesity; the intention being to reduce appetite and induce early satiety possibly due to inhibitory effects on gastric motility and effects on the central nervous system (CNS) and hormones related to satiety and/or appetite. Possible advantages to GES for the treatment of morbid obesity include reversibility of the procedure, less invasiveness than some bariatric procedures, e.g., gastric bypass, and less side effects (e.g., dumping syndrome).

The Device Electrical stimulation is delivered via an implanted system that consists of a neurostimulator and 2 leads. The surgical procedure can be performed via either an open or laparoscopic approach. An external programmer used by the physician can deliver instructions to the GES, i.e., adjust the rate and amplitude of stimulation (Figure 1). GES may be turned off by the physician at any time or may be removed. The battery life is approximately 4-5 years For treatment of GP, the GES leads are secured in the muscle of the lower stomach, 10 cm proximal to the pylorus (the opening from the stomach to the intestine), 1 cm apart and connected to an implantable battery-powered neurostimulator which is placed in a small pocket in the abdominal wall For treatment of morbid obesity, GES leads are implanted along the lesser curvature of the stomach where the vagal nerve branches spread, approximately 8 cm proximal to the pylorus. However, the implant positioning of the leads has been variably reported in the literature.

Regulatory Status The Enterra Therapy System and the Transcend II Implantable Gastric Stimulation System (Medtronic Inc.) are both licensed as class 3 devices by Health Canada (license numbers 60264 and 66948 respectively). The Health Canada indications for use are: Enterra Therapy System  “For use in the treatment of chronic intractable (drug-refractory) nausea and vomiting.” Transcend II Implantable Gastric Stimulation System  “For use in weight reduction for obese adults with a body mass index greater than 35.” The GES device that is licensed by Health Canada for treatment of GP, produces high-frequency GES. Most clinical studies examining GES for GP have used high-frequency (4 times the intrinsic slow wave frequency, i.e., 12 cycles per minute), low energy, short duration pulses. This type of stimulation does not alter gastric muscular contraction and has no effect on slow wave dysrhythmias. The mechanism of action is unclear but it is hypothesized that high-frequency GES may act on sensory fibers directed to the CNS.

The GES device licensed by Health Canada for treatment of morbid obesity produces low-frequency GES, which is close to or just above the normal/native gastric slow wave cycle (approximately 3 cycles/min.). This pacing uses low-frequency, high-energy, long-duration pulses to induce propagated Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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slow waves that replace the spontaneous ones. Low-frequency pacing does not invoke muscular contractions. Most studies examining the use of GES for the treatment of morbid obesity use low-frequency GES. Under normal circumstances, the gastric slow wave propagates distally and determines the frequency and propagation direction of gastric peristalsis. Low-frequency GES aims to produce abnormal gastric slow waves that can induce gastric dysrhythmia, disrupt regular propagation of slow waves, cause hypomotility of the stomach, delay gastric emptying, reduce food intake, prolong satiety, and produce weight loss. In the United States, the Enterra Therapy System is a Humanitarian Use Device (HUD), meaning it is a medical device designated by the FDA for use in the treatment of medical conditions that affect fewer than 4,000 individuals per year.2 The Enterra Therapy System is indicated for “the treatment of chronic, drug- refractory nausea and vomiting secondary to GP of diabetes or idiopathic etiology” (not postsurgical etiologies). GES for morbid obesity has not been approved by the FDA and is for investigational use only in the United States.

Review Strategy The Medical Advisory Secretariat systematically reviewed the literature to assess the effectiveness, safety, and cost-effectiveness of GES to treat patients who have: a) chronic refractory symptomatic GP; or b) morbid obesity.

The Medical Advisory Secretariat used its standard search strategy to retrieve international health technology assessments and English-language journal articles from selected databases. The GRADE approach was used to systematically and explicitly make judgments about the quality of evidence and strength of recommendations.

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The regulation provides for the submission of a humanitarian device exemption (HDE) application, which is similar in both form and content to a premarket approval application (PMA), but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations showing that the device is effective for its intended purpose. The application must however contain sufficient information for the FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury and that the probable benefit to health outweighs the risk of injury or illness from its use. A HUD may only be used after IRB approval has been obtained for the use of the device for the FDA approved indication. Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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Findings As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence in Tables 1 and 2. High Further research is very unlikely to change our confidence in the estimate of effect. Moderate Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very Low Any estimate of effect is very uncertain

Table 1: GRADE Quality of Studies – Gastroparesis Outcome Reduced vomiting & nausea

Design RCT (Abell et al. 2003)

Low

__________ Case Series

________________________ Same as above.

Open label portion of Abell et al. 2003

Low

(1° end point)

Improved gastric emptying (2° end point)

Quality

&

Consistency

Directness

Some uncertainty.

Some uncertainty.

Why? Why? 1. Confounders related to 1. Only 1 RCT diabetes. (with different 2. Possible Type 2 error for results for FDA subgroup analyses. and publication). 3. Subjective self-reported end point. 4. Posthoc change in primary end point analysis. 5. No sample size justification. 6. Concomitant prokinetic/antiemetic therapy.

Why? Same limitations as above. Not a 1° end point. No intent-to-treat analysis.

Wide variation in improvement.

Overall Quality Low

Why? 1. GES originally hypothesized to correct gastric rhythms, stimulate gastric emptying and therefore eliminate symptoms. 2. Now hypothesized to directly act on neurons to the CNS to control symptoms. 3. Weak correlation between symptoms and gastric emptying. 4. Unclear whether gastric emptying is still considered an end point to investigate. Same uncertainties as above.

Low/Very Low

Same uncertainties as above.

Case series

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Table 2: GRADE Quality of Studies – Morbid Obesity Outcome Weight Loss

Design RCT “O-01 Trial” According to Shikora (2004), considered “update of ongoing clinical trials”.

Resolution of Comorbidities

Quality Low

Consistency Some uncertainty.

Directness

Overall Quality

Generally direct (%EWL).

Very Low

? Scanty data

Very Low

Why? Why? 1. No sample size calculation. 1. Only 1 RCT 2. Small sample size. (technically 3. No ITT analysis. grey 4. Lack of detail regarding literature). dropouts. 5. Possible Type 2 error. 6. Sparse details about randomization/blinding. 7. Full, final results not published.

_____________ Case series

___________________________ Same as above.

Case series

Same as above

? Scanty data

Economic Analysis No formal economic analysis was identified in the literature search. The Alberta Heritage Foundation for Medical Research reported that the cost of implanting a GES in the United States for the treatment of GP is estimated to be $30,000 US. In Canada, the device costs approximately $10,700 Cdn; this does not include costs associated with the physician’s training, the implantation procedure, or device programming and maintenance. Ontario Context There is no Schedule of Benefits code for GES. There is no Canadian Classification of Health Interventions Index (CCI) procedure code for GES. Since the ICD-10 diagnosis code for gastroparesis falls under K31.8 “Other specified diseases of the stomach and duodenum”, it is impossible to determine how many patients in Ontario had discharge abstracts because of gastroparesis. In 2005, there were less than 5 out-of-country requests for GES (for either consultation only or for surgery).

Gastroparesis The prevalence of severe, refractory GP is variably reported in the literature. The Alberta Heritage Foundation for Medical Research estimated that the prevalence of severe, symptomatic and medically refractory GP in the United States population was 0.017%. Assuming a total Ontario population of 13 million, this would correspond to a budget impact of approximately $23.6 M

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Cdn ($10,700 Cdn x 2,210 patients) for the device cost alone. The incidence of severe refractory GP estimated by the FDA is approximately 4,000 per year in the United States. This corresponds to about 150 patients in Ontario. Using expert opinion and FDA data, the incidence of severe refractory GP in Ontario is estimated to be about 20 to 150 per year. This corresponds to a budget impact of approximately $107,000 Cdn to $1.6M Cdn per year for the device cost alone. Morbid Obesity An expert in the field estimated that there are 160,000 to 180,000 people in Ontario who are morbidly obese. This would correspond to a budget impact of approximately $1.7B Cdn to $1.9B Cdn for the device cost alone (assuming 100% uptake). However, the true uptake of GES for morbid obesity is unknown in relation to other types of bariatric surgery (which are more effective).

Conclusion As per the GRADE Working Group, overall recommendations consider 4 main factors.  The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.  The quality of the evidence.  Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.  Uncertainty about the baseline risk for the population of interest. The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 3 shows the overall trade-off between benefits and harms and incorporates any risk/uncertainty. For GP, the overall GRADE and strength of the recommendation is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality, consistency and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $107,000 Cdn to $1.6M Cdn for the device cost alone, while the cost-effectiveness of GES is unknown and difficult to estimate considering that there are no high-quality studies of effectiveness. Further evidence of effectiveness should be available in the future since there is a RCT underway that is examining the use of GES in patients with severe refractory GP associated with diabetes and idiopathic etiologies (ClinicalTrials.gov identifier NCT00157755). For morbid obesity, the overall GRADE and strength of the recommendation is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and consistency), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $1.7B Cdn to $1.9B Cdn for the device cost alone (assuming 100% uptake) while the cost-effectiveness of GES is unknown and difficult to estimate considering that there are no high quality studies of effectiveness. However, the true uptake of GES for morbid obesity is unknown in relation to other types of bariatric surgery (which are more effective).

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Table 3: Overall GRADE and Strength of Recommendation (Including Uncertainty) Quality

Severe, chronic refractory GP

Low

Estimated Prevalence in Ontario Incidence ~ 20 to 150

CostEffectiveness ?

Cost in Ontario Cdn $107,000 to $1.6M

Risks/Burden

Removal rate ~ 5-10% of cases due to infection, stomach perforation, device migration/erosion. Cost effectiveness unknown. Ongoing/lifetime monitoring of patient.

Benefits

Overall Grade & Strength of Recommendation

Uncertain Weak short/long- term benefits (reduced frequency of vomiting/nausea; improved gastric emptying; quality of life).

Battery change ~ 5 years. Post hoc change in end point analysis. Another RCT is underway. Morbid obesity

Very Low

~ 160,000 to 180,000

?

Uptake not determined in relation to other types of bariatric surgery (which are more effective).

Adverse effects – stomach perforation and lead dislodgment – difficult to determine rate given mid-study changes in surgical technique.

Uncertain Weak short/long-term benefits (EWL and improvement / resolution of comorbidities).

Cost effectiveness and uptake unknown. Ongoing/lifetime monitoring of patient. Battery change ~ < 5 years?

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Objective The objective of this analysis was to assess the effectiveness, safety and cost-effectiveness of GES for the treatment of chronic, symptomatic refractory gastroparesis and morbid obesity.

Background Gastroparesis Epidemiology Gastroparesis (GP) broadly refers to impaired gastric emptying in the absence of obstruction. (1) Clinically, this can range from the incidental detection of delayed gastric emptying in an asymptomatic person, to patients with severe nausea, vomiting and malnutrition. Symptoms of GP are nonspecific and may mimic structural disorders such as ulcer disease, partial gastric or small bowel obstruction, gastric cancer, and pancreaticobiliary disorders. Gastroparesis may occur in association with diabetes, gastric surgery (consequence of peptic ulcer surgery and vagotomy) or for unknown reasons (idiopathic gastroparesis). (1) Symptoms include early satiety, nausea, vomiting, abdominal pain and weight loss. The majority of patients with GP are women. (2) Women exhibit slower emptying rates than men, especially during the latter half of the menstrual cycle. (3) Idiopathic Gastroparesis Idiopathic GP may represent the most common form of GP. (3;4) In one tertiary referral retrospective series, the etiologies in 146 GP patients were 36% idiopathic, 29% diabetic, 13% postgastric surgery, 7.5% Parkinson’s disease, 4.8% collagen vascular disorders, 4.1% intestinal pseudoobstruction and 6% miscellaneous causes. (2) The associated clinical states of the idiopathic group were: patients presenting after an acute viral gastroenteritis-like illness (23%); gastroesophageal reflux disease and nonulcer dyspepsia (19%); an abdominal-pain-dominated subset (48%); patients who were thought to be depressed or who had received antidepressants in the recent past or were being currently given antidepressants (23%); and a subgroup whose symptoms started immediately after a cholecystectomy (8%). (2) Gastroparesis Associated With Diabetes The true prevalence of digestive symptoms in patients with diabetes and the relationship of these symptoms to delayed gastric emptying are unknown. Delayed gastric emptying is present in 27% to 58% of patients with type 1 diabetes and 30% with type 2 diabetes. (5) However, highly variable rates of gastric emptying, including acceleration of transit, have been reported in type 1 and 2 diabetes, suggesting that development of GP in patients with diabetes is neither universal nor inevitable. (3;6;7) Kong and Horowitz (8) reviewed studies examining gastric emptying in patients with diabetes compared to control patients and noted that in many cases, the magnitude of the delay in gastric emptying is modest and suggested that a distinction should be made between the term ‘gastroparesis’ and ‘delayed gastric emptying’ with a diagnosis of GP restricted to patients in whom gastric emptying is grossly delayed.

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Postsurgical Gastroparesis GP may occur as a complication of a number of different surgical procedures. Vagal nerve injury may occur in 4% to 40% of patients who undergo laparoscopic fundoplication3 for gastroesophageal reflux disease. Some cases of GP have been reported after heart and lung transplantation; this is mostly likely due to vagal nerve injury. (3) Refractory Gastroparesis The prevalence of severe, refractory GP is scantily reported in the literature. Tougas et al. (9) examined the prevalence of upper gastrointestinal (GI) symptoms among a sample of 1,036 Canadians. One hundred and fifty-three of the participants surveyed reported having substantial GI symptoms for greater than 3 months. Eighty-four of the 153 participants reported dysmotility-like symptoms (e.g., early satiety, nausea, vomiting, or postprandial [after a meal] fullness) as predominant symptoms. Forty-nine of the 84 participants were diagnosed by a physician; diagnoses consisted of peptic ulcer, reflux disease, gallstones, and hiatus hernia. Thirty-seven of the 153 participants were prescribed drugs for their chronic symptoms. A major limitation to the paper by Tougas et al. was reliance on patient self-reported symptoms, rather than physician diagnoses. (10) “Gastroparesis” was neither reported nor discussed in the paper by Tougas et al. Using data from Abell and Minocha (11), the Alberta Heritage Foundation for Medical Research (AHFMR) estimated that the prevalence of severe, symptomatic and refractory GP in the United States population was 0.017%. (10) Assuming an Ontario population of 13 million (12), this would correspond to approximately 2,210 people in Ontario having severe, symptomatic, refractory GP. The incidence of severe refractory GP estimated by the United States Food and Drug Administration (FDA) is approximately 4,000 per year in the United States. This corresponds to about 150 patients in Ontario (3.8% of 4,000). Using expert opinion and FDA data, the incidence of severe refractory GP in Ontario is estimated to be about 20 to 150 cases per year. Relationship Between Symptoms and Delayed Gastric Emptying In the past it was generally assumed that upper gastrointestinal symptoms are a direct result of a delay in gastric emptying, but this concept is now generally recognized to be overly simplistic. (13;14) In most studies of delayed gastric emptying, symptoms were not evaluated using validated measures and total symptom scores rather than severity of individual symptoms were quantified. The relationship between upper gastrointestinal symptoms and the rate of gastric emptying is considered to be weak. (8;13;14) Some patients with markedly delayed gastric emptying are asymptomatic and sometimes, severe symptoms may remit spontaneously. (5;8;15) Effects of Blood Glucose Concentration on Gastric Emptying Acute changes in the blood glucose concentration (both hyper-and hypoglycemia) have a substantial and reversible effect on gastric motility in both healthy subjects and patients with diabetes. (8;16) Marked hyperglycemia slows gastric emptying in uncomplicated Type 1 and Type 2 diabetes patients and in 3

The upper curve of the stomach (the fundus) is wrapped around the esophagus and sewn into place so that the lower portion of the esophagus passes through a small tunnel of stomach muscle. This surgery strengthens the valve between the esophagus and stomach which stops acid from backing up into the esophagus as easily. Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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diabetes patients with autonomic neuropathy. (17;18) It is not known whether the response to hyperglycemia is dependent on the rate of gastric emptying during euglycemia (normal blood glucose concentration), previous long-term glycemic control or autonomic nerve function. (8) Changes in the blood glucose concentration within the normal postprandial range can also influence gastric emptying and motility. Emptying of solids and liquids is slower at blood glucose of 8 mmol/l than 4 mmol/l in healthy subjects, and patients with type 1 diabetes. In patients with type 1 diabetes (as well as autonomic neuropathy), gastric emptying is accelerated during hypoglycemia. The effect of hypoglycemia on gastric emptying in patients with severe GP has not been studied. (8) There is some evidence that the blood glucose concentration may also affect perception of gastrointestinal sensations (e.g., satiety) in patients with type 1 and 2 diabetes. (8;16) The mechanism by which hyperglycemia affects gut perception/symptoms is unknown. (8) Effects of Gastric Emptying on Blood Glucose Concentration Gastric emptying is a determinant of postprandial glycemia and accounts for approximately 35% of the variance in peak postprandial glucose levels after oral glucose in both healthy subjects and in patients with type 2 diabetes. (8;16) In patients with type 1 diabetes and GP, it has been shown that less insulin is initially required to maintain euglycemia after a meal compared to patients having type 1 diabetes with normal gastric emptying. (8) It is unknown if treatment with prokinetic (to increase gastric motility) drugs improves glycemic control in patients with type 1 diabetes. (8) In the past, delayed gastric emptying was considered to confer a poor prognosis for patients with diabetes; however, its high prevalence (~ 30% to 50% in patients with diabetes) and recent studies suggest that this may be incorrect. (19) Jones et al. (20) showed that neither the rate of emptying nor symptoms changed markedly in 20 patients with diabetes over a mean follow-up period of 12 years. Diagnosis GP is diagnosed by demonstrating delayed gastric emptying in a symptomatic patient after exclusion of other potential etiologies of symptoms and obstruction with endoscopy and radiological imaging. (4) Patients with GP may present with nausea, vomiting, early satiety, bloating, discomfort or pain and belching. Rapid gastric emptying, dumping or gastric dysaccomodation may also result in similar symptoms that would not respond to a prokinetic agent; therefore it has been suggested to measure gastric emptying rather than assume symptoms reflect delayed gastric emptying. (4) Measuring Gastric Emptying Gastric emptying scintigraphy of a solid-phase meal is considered the gold standard for the diagnosis of GP because this test quantifies the emptying of a physiologic caloric meal. (3) Measurement of gastric emptying in patients with diabetes should be done during euglycemia. (8) Rayner and Horowitz (21) point out that many studies have either not controlled or not reported the blood glucose concentration in diabetes patients with GP. In the past literature on gastric emptying, there was generally a lack of standardization of scintigraphic techniques, with variation between different centres, particularly in relation to the volume and composition of the test meal, timing of imaging and the calculation of gastric emptying rates (e.g., Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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percentage of the meal remaining at 2 hours or half-emptying time). (8;21-23) This made comparisons between studies difficult and required each lab to have access to an appropriate control range. (8;22) Many centres in the past obtained frequent scans over a period of 90 minutes and used a computergenerated curve to predict gastric emptying rates (e.g., half-time). (24) If the emptying rate has not reached 50%, the extrapolated value for the half-time may be unreliable. Camilleri et al. (24) state that the current preferred strategy is to use actual data at 2 and 4 hours postprandially? since it has high predictive value for identifying dumping and stasis respectively. (24) The Society of Nuclear Medicine Procedure Guideline for Gastric Emptying and Motility states that images should be obtained for up to 4 hours, since retention of greater than 10% of the meal in the stomach at 4 hours is considered abnormal. (25-27) A commercially prepared meal of technetium- ( 99mTc) labeled egg whites with standard imaging at 0, 1, 2 and 4 hours postprandially, has been proposed to facilitate standardization between different centres. (23) Camilleri et al. (24) reported that scintigraphic gastric emptying measurements have coefficients of variation of almost 15% (below 10% is considered good). In terms of clinical interpretation of a single test, only unequivocal results are clinically important. (24) Treatment for Chronic, Symptomatic Gastroparesis To date, there have been no long-term studies confirming the beneficial effects of maintaining euglycemia in GP symptoms. However, it has been suggested that consistent findings of physiologic studies in healthy volunteers and diabetes patients provide an argument to strive for near-normal blood glucose levels in affected diabetes patients. (3;8) Dietary measures (e.g., low fibre, low fat food), prokinetic drugs (e.g., domperidone, metoclopramide, erythromycin, tegaserod, and itopride [still in clinical trials]) and antiemetic or antinausea drugs (e.g., phenothiazines, diphenhydramine, dimenhydrinate, ondansetron, desipramine, nortriptyline, amitriptyline, scopolamine, hyoscyamine, and aprepitant [not listed in the Health Canada Drug Product Database but approved by the FDA on July 11 2006]) are generally effective for symptomatic relief in the majority of patients with GP. (28;29) Talley (15) conducted a meta-analysis of trials examining the use of prokinetics in patients with diabetes and GP, and suggested that prokinetics are associated with better improvement in symptoms than in measured gastric emptying. For patients with chronic, symptomatic GP who are refractory to drug treatment, surgical options may include jejunostomy tube for feeding, gastrotomy tube for stomach decompression and pyloroplasty for gastric emptying. (29;30) Few small studies (N=10 and N=3) have examined the use of botulinum toxin injections into the pyloric sphincter. (31;32) However, the contribution of excessive pyloric contraction to GP has been insufficiently defined and there have been no controlled studies of this therapy. (21) Treatment with GES is reversible and may be a less invasive option compared to stomach surgery for the treatment of patients with chronic, drug-refractory nausea and vomiting secondary to GP. In theory, GES represents an intermediate step between treatment directed at the underlying pathophysiology and the treatment of symptoms. (14) It is based on studies of gastric electrical patterns in GP that have identified the presence of a variety of gastric arrhythmias. Similar to a cardiac pacemaker, it was hypothesized that GES could override the abnormal rhythms, stimulate gastric emptying and eliminate symptoms. (14).

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Morbid Obesity 2

Obesity is defined as a body mass index (BMI) of at last 30 kg/m . Morbid obesity is defined as a BMI of 2

2

at least 40 kg/m or at least 35 kg/m with comorbid conditions. Comorbid conditions associated with obesity include diabetes, hypertension, dyslipidemias, obstructive sleep apnea, weight-related arthropathies, and stress urinary incontinence. 2

In the United States, the age-adjusted prevalence of extreme obesity (BMI > 40 kg/m ) for adults aged 20 years and older has increased significantly in the population, from 2.9% (1988–1994) to 4.7% (1999– 2000). An expert estimated that about 160,000 to 180,000 people are morbidly obese in Ontario (Personal communication, May 2006_) Treatment For Morbid Obesity Diet, exercise, and behavioural therapy are used to help people lose weight. Drugs may be used if behavioural interventions fail. However, estimates of efficacy may be confounded by high rates of noncompliance, in part owing to the side-effects of the drugs. Bariatric surgery for morbid obesity is considered an intervention of last resort for patients who have attempted first-line forms of medical management, such as diet, increased physical activity, behavioural modification, and drugs. Gastric stimulation has been investigated for the treatment of morbid obesity; the intention being to reduce appetite and induce early satiety, possibly due to inhibitory effects on gastric motility and effects on the central nervous system (CNS) and hormones related to satiety and/or appetite. In animal studies, Chen (33) showed that chronic gastric stimulation impairs the intrinsic gastric myoelectrical activity in the fed state. This is associated with impaired digestion and emptying of the stomach, which may lead to early satiety and reduced food intake. (34;35) GES may also induce gastric distention in the fasting state, which results in activation of stretch receptors causing satiety. It has also been hypothesized that, depending on the stimulation parameters, GES may affect postprandial contractions, leading to reduced food intake. (35;36) Possible advantages to GES for the treatment of morbid obesity include reversibility of the procedure; less invasiveness than some bariatric procedures e.g., gastric bypass, and fewer side-effects (e.g., dumping syndrome).

Gastric Electrical Stimulation - Treatment Procedure Patterns of Electrical Stimulation In general, 3 patterns of electrical stimulation have been studied in the literature. 1. “Low frequency GES” (in the sub Hertz range4) – Close to or just above the normal/native gastric slow wave cycle (approximately 3 cycles/min.). This pacing is called gastric electrical pacing and uses low-frequency, high-energy, long-duration pulses to induce propagated slow waves that replace the spontaneous ones. (1) This pacing does not release acetylcholine (which in turn does not invoke

4

One hertz is defined as the reciprocal second. The Hertz (symbol Hz) is the System International unit of frequency. Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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muscular contractions) because previous administration of atropine5 does not block the appearance of induced slow waves. Most studies examining the use of GES for the treatment of morbid obesity use frequencies near this range. (37;38) Under normal circumstances, the gastric slow wave propagates distally and determines the frequency and propagation direction of gastric peristalsis. “Low frequency GES” aims to produce abnormal gastric slow waves that can induce gastric dysrhythmia, disrupt regular propagation of slow waves, cause hypomotility of the stomach, delay gastric emptying, reduce food intake, prolong satiety, and produce weight loss. (37) The positioning and number of electrodes/leads attached to the stomach varies in many studies (e.g., proximal versus distal section of the stomach, 1 or mutiple leads). (39) Seven studies (40-46) were identified in the literature that examined the use of “low frequency GES” for the treatment of GP. The studies showed that GES propagated slow waves but did not produce muscular contractions. Gastric emptying was shown to be enhanced in 1 published case series (46) which assessed the effect of GES (using 4 electrodes per patient) over a 1 to 3 month period in 9 patients. The case series was not placebo-controlled, not blinded and all 9 patients continued taking cisapride (a prokinetic drug) during the study; metoclopramide was also used by 4 patients. (46) Cisapride was withdrawn from the market by the FDA and Health Canada due to a high rate of potentially fatal cardiac arrhythmias associated with its use. 2. “High frequency GES” (still sub-Hertz range but higher than “low-frequency”) – Most clinical studies examining GES for GP have used high-frequency (4 times the intrinsic slow wave frequency, i.e., 12 cycles per minute), low-energy, short-duration pulses. This type of stimulation does not alter gastric muscular contraction (is unaffected by atropine), and has no effect on slow wave dysrhythmias. (1) The mechanism of action is unclear but it is hypothesized that “high-frequency GES” may act on sensory fibers directed to the CNS. (47) 3. “Very high frequency GES” (higher than 5-10 Hertz) – Induces a release of acetylcholine which in turn stimulates muscle cell contraction because previous administration of atropine prevents contraction. (48) This pacing is called neural gastric electrical stimulation. (49) An electrical frequency of 1000 times the frequency of the slow wave has been reported in dog studies. (47;49) To date, studies examining “very high frequency GES” have involved animals and have used sequential activation via a series of electrodes around the distal stomach. (48) No large studies of examining the effect of “very high frequency GES” on patients with chronic, symptomatic refractory GP have been published; the potential for symptomatic benefit is unclear. In animal studies, there has been investigation into neural gastric electrical stimulation using retrograde peristalsis to delay gastric emptying as a potential treatment for morbid obesity. (50) The Device Electrical stimulation is delivered via an implanted system that consists of a neurostimulator and 2 leads. The surgical procedure can be performed via either an open or laparoscopic approach. An external programmer used by the physician can deliver instructions to the GES, i.e., adjust the rate and amplitude of stimulation. GES may be turned off by the physician at any time, or may be removed. The battery life is approximately 4-5 years. 5

Atropine is a competitive antagonist of the muscarinic acetylcholine receptors. Generally, atropine lowers the "rest and digest" activity of all muscles and glands regulated by the parasympathetic nervous system. Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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Gastric Electrical Stimulation for Chronic Symptomatic Gastroparesis For treatment of GP, the GES leads are secured in the muscle of the lower stomach, 10 cm proximal to the pylorus (the opening from the stomach to the intestine), 1 cm apart and connected to an implantable battery-powered neurostimulator, which is placed in a small pocket in the abdominal wall. Gastric Electrical Stimulation for Morbid Obesity For treatment of morbid obesity, GES leads are implanted along the lesser curvature of the stomach where the vagal nerve branches spread, approximately 8 cm proximal to the pylorus. (51) However, the implant positioning of the leads has been variably reported in the literature.

Regulatory Status Canada The Enterra Therapy System and the Transcend II Implantable Gastric Stimulation System (Medtronic Inc.) are both licensed as class 3 devices by Health Canada (license numbers 60264 and 66948 respectively). The Health Canada indications for use are: Enterra Therapy System  “For use in the treatment of chronic intractable (drug-refractory) nausea and vomiting.” Transcend II Implantable Gastric Stimulation System  “For use in weight reduction for obese adults with a body mass index greater than 35.”

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United States In the United States, the Enterra Therapy System is a Humanitarian Use Device (HUD), meaning it is a medical device designated by the FDA for use in the treatment of medical conditions that affect fewer than 4,000 individuals per year.6 The Enterra Therapy System is indicated for “the treatment of chronic, drug refractory nausea and vomiting secondary to GP of diabetes or idiopathic etiology.” (not postsurgical etiologies) A petition by the Gastroparesis and Dysmotilities Association (52), which represents patients in Canada and the United States, was sent to the FDA in February 2004 to request the transfer of the Enterra Therapy System from a HDE approval status to a premarket approval (PMA).7 The request was denied by the FDA in November 2004 because “…after a preliminary review of the information…the agency does not believe that your summary of the clinical literature is sufficient or adequately complete to make scientific conclusions regarding the safety and effectiveness of the device in support of PMA approval.”8 GES for morbid obesity has not been approved by the FDA and is for investigational use only in the United States. (53)

Literature Review on Effectiveness Objective  

To assess the effectiveness, safety and cost-effectiveness of GES for the treatment of chronic, symptomatic refractory GP. To assess the effectiveness, safety and cost-effectiveness of GES for the treatment of morbid obesity.

Methodology Inclusion criteria:  English language articles (January 2000 – March 2006).  Journal articles that report primary data on the effectiveness or cost-effectiveness of GES treatment obtained in a clinical setting, or analysis of primary data maintained in registries or databases.  Study design and methods must be clearly described.

6

The regulation provides for the submission of a humanitarian device exemption (HDE) application, which is similar in both form and content to a premarket approval application (PMA), but is exempt from the effectiveness requirements of a PMA. An HDE application is not required to contain the results of scientifically valid clinical investigations showing that the device is effective for its intended purpose. The application must however contain sufficient information for the FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury and that the probable benefit to health outweighs the risk of injury or illness from its use. A HUD may only be used after IRB approval has been obtained for the use of the device for the FDA approved indication. 7 http://www.fda.gov/ohrms/dockets/dailys/04/feb04/022604/04p-0091-cp00001-vol1.pdf 8 http://www.fda.gov/ohrms/dockets/dailys/04/nov04/110504/04p-0091-pdn00001-vol1.pdf Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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

Systematic reviews, randomized controlled trials (RCTs), non-randomized controlled trials and/or cohort studies that have 10 or more patients, cost-effectiveness studies.

Exclusion criteria  Studies that are duplicate publications (superseded by another publication by the same investigator group, with the same objective and data).  Studies with less than 10 patients.  Non-English articles.  Nonsystematic reviews, letters and editorials.  Animal and in vitro studies.  Case reports.  Studies that do not examine the outcomes of interest. Literature Search Details of the search strategy are outlined in Appendix 1.      

Cochrane Library International Agency for Health Technology Assessment (INAHTA) database EMBASE OVID MEDLINE MEDLINE In-Process & Other Non-Indexed Citations Reference section from reviews and extracted articles

Outcomes of Interest Gastroparesis  Symptomatic relief – decreased nausea, vomiting and abdominal pain  Adverse effects  Nutritional improvement  Increased gastric emptying  Quality of life  Economics data Morbid Obesity  Weight loss  Resolution/improvement of obesity-related comorbidities  Quality of life  Economics analysis data

Strength of Recommendation The GRADE approach (54)was used to systematically and explicitly make judgments about the quality of evidence and strength of recommendations. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account study design, study quality, consistence and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability and the certainty of the baseline risks are all considered in judgments about the strength of recommendations.

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Results of Literature Search The Cochrane and INAHTA databases yielded 4 health technology assessments on GES. A search of Medline and Embase since the last assessment was conducted, which yielded119 citations, of which 15 met the inclusion criteria. The quality of the studies for GES treatment of: 1) GP and 2) morbid obesity is presented below (Table 1). Table 1. Quality of Evidence Study Design

Number of Eligible Number of Eligible Level of Studies: Studies: Evidence Gastroparesis Morbid Obesity

Large randomized controlled trial, systematic reviews of RCTs

1

Large randomized controlled trial unpublished but reported to an international scientific meeting

1(g)

Small randomized controlled trial

2

Small randomized controlled trial unpublished but reported to an international scientific meeting

2(g)

Nonrandomized study with contemporaneous controls

3a

Nonrandomized study with historical controls

3b

Nonrandomized study presented at international conference

3(g)

Surveillance (database or register)

4a

Case series (multi-site)

4b

2

Case series (single site)

4c

4

Retrospective review, modeling

4d

3

Case series presented at international conference

4(g)

1 1 1

3

g=grey literature

Gastric Electrical Stimulation for Gastroparesis: Study with the Highest Level of Evidence The following is a detailed analysis of the study with the highest level of evidence identified by the literature search (Level 2 evidence). Abell et al. (55) studied 33 patients (17 diabetes and 16 idiopathic) with GP that were unresponsive to standard medical therapy. The 12-month study was conducted in 2 phases. Phase 1 was a 2-month, randomized, placebo-controlled, double-blind crossover study, and Phase 2 was a 10-month open-label study. Patients were evaluated at baseline and at 4 follow-up visits at 1, 2, 6, and 12 months. This is the same study that was presented to the FDA for HDE approval in 1999 (Appendix 2). Inclusion criteria consisted of: More than 7 episodes of vomiting per week. Delayed gastric emptying (>60% retention at 2 hours and >10% at 4 hours on the basis of a standardized

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scintigraphic method for solid meals). Symptoms consistent with GP for longer than 12 months. Refractoriness or intolerance to 2 of 3 classes of prokinetic drugs and 2 of 3 classes of antiemetics. Exclusion criteria consisted of: Documented intestinal pseudo obstruction. Prior gastric surgery. Vagotomy. Organ transplantation. Seizures. Primary swallowing disorders. Chemical dependency. Pregnancy. Psychogenic vomiting. Medical unstable or at high surgical risk. Phase 1 Patients were randomized to stimulation either ON or OFF, and after the first month, the GES was programmed to the opposite mode for another month. The primary outcome measure was the difference in vomiting frequency with the stimulation OFF compared with ON. To monitor vomiting frequency, patients recorded daily vomiting episodes in either 2-week (idiopathic) or 4-week (diabetes) diaries before baseline and at each follow-up visit (because “diabetes symptoms fluctuate more”); the authors did not provide any evidence to support this statement. The secondary end point was the patients’ preference for stimulation ON or OFF; at the end of the second month, while still blinded, patients were asked for their preference (month 1 or month 2) as a global measure of quality of life in Phase 1. Phase 2 All the patients’ GES were programmed to ON. The subjective severity of upper GI tract symptoms (vomiting, nausea, early satiety, bloating, postprandial fullness, and epigastric pain) at baseline and each follow-up visit (1, 2, 6, and 12 months) was assessed by using a 5-point symptom interview questionnaire in which symptoms were rated by the study coordinator. The sum of the severity ratings of the 6 symptoms was used as an overall total symptom score (TSS). For Phase 2, the primary outcome measures were the changes between baseline and the 6- and 12-month follow-up visits for weekly vomiting frequency, symptom severity, gastric emptying, and health-related quality of life (HQOL). Gastric emptying was not an end point that was assessed during the randomized Phase 1 study. Gastric emptying was quantified after a solid meal at baseline and at the 6- and 12-month follow-up visits by using a standardized scintigraphy method and a low-fat test meal. According to the authors, this method was developed specifically for this study to standardize the measurement of solid food emptying over 4 hours. Patients were asked to discontinue prokinetic medication 2 to 3 days before the test. HQOL was assessed at baseline, and at the 1-, 2-, 6- and 12-month follow-up visits by using the SF-36 Health Status Survey questionnaire. Two summary scores, the Physical Composite Score (PCS) and the Mental Composite Score (MCS), in addition to 8 subscores, were derived from the SF-36. Patients were instructed to continue their current antiemetic or prokinetic therapy during the 12-month study. A sample size calculation was not reported by the authors. Abell et al. (55) stated that Gastric Electrical Stimulation - Ontario Health Technology Assessment Series 2006; Vol. 6, No. 16

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“The initial study plan provided for an enrollment of 40 diabetes and 40 idiopathic patients. Because of slow recruitment, the sponsor stopped the study after enrollment of 33 patients in total. These 33 patients were randomized to Phase 1, continued to Phase 2 and form the basis of this report.” Patient Enrollment Sixty-three patients were screened for the study. Of these, 5 vomited before completing the gastric emptying test 20 did not meet the gastric emptying requirements 1 had a history of seizures 3 were unstable or at high surgical risk 1 did not meet the etiology requirement. Phase 1 data were analyzed on an intent-to-treat (ITT) basis. The 33 patients continued into Phase 2 and between the 2nd and 6th month, 1 patient dropped out because of lead perforation of the stomach, 2 were lost to follow-up and 1 was too ill to complete the 6 month follow-up visit. Of the 29 patients eligible for the 6- month follow-up, diary data were unavailable for 2 and gastric emptying data were incomplete for 3 (1 patient refused and 2 patients vomited after the test meal). Five of the 29 patients did not complete the 12-month follow-up: 1 was pregnant, 2 had infection at the implant site, 1 died of cardiopulmonary arrest, and 1 was lost to follow-up. Therefore, 24 patients were eligible for the 12-month follow-up. Of the 24 patients, 2 and 4 hour gastric emptying data were not reported for 5 patients (1 had illness unrelated to GP or GES; 1 refused the test, 2 completed their tests more than 2 months later than scheduled, and 1 had unavailable 4 hour gastric emptying data (due to vomiting during the test). Phase 2 data were analyzed on a treatment-received basis. Results Baseline The median weekly vomiting frequency at baseline was 17.3 (11.8-45.7) episodes per week. Most patients received antiemetic (n=25) or prokinetic (n=28) therapy, and 14 required some form of enteral or parenteral feeding. Phase 1 The results after 1 month from Phase 1 showed a statistically significant decrease in vomiting frequency and preference for stimulation ON (Table 2). When patient subgroups were examined separately, there were no significant differences in vomiting frequency in both the diabetes and idiopathic subgroups, and no significant difference in ON or OFF preference in the diabetes subgroup. The study was not designed to show a difference between ON and OFF within the patient subgroups

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Table 2: Results of Phase 1. Outcome

†

All patients (N=33) OFF

Diabetes patients (n=17)

ON

OFF

Weekly vomiting frequency 13.5 (5.5-25.4) 6.8 (3.9-16.5)* Median (interquartile range) Total symptom score 13.9 + 1.1 12.5 + 1.0 Mean (standard error) Patient preference

†

7

Idiopathic patients (n=16)

ON

OFF

ON

12.8 (5.5-24.2)

6.0 (3.0-14.8)

13.8 (5.4-27.8)

12.8 (4.0-20.3)

13.2 + 1.7

11.3 + 1.5

14.8 + 1.3

13.8 + 1.4

4

10

3

11*

21*

* P