NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE

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1 NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview gastroelectrical stimulation for gastroparesis Introduction This overview has been prepared to assist members of the Interventional Procedures Advisory Committee (IPAC) in making recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This overview was prepared in September Procedure names Gastroelectrical stimulation for gastroparesis (nausea and vomiting secondary to gastroparesis). Gastroelectrical mechanical stimulation for gastroparesis. Specialty societies British Society of Gastroenterology. Royal College of Physicians. Royal College of Surgeons of Edinburgh. Description Indications Gastroparesis is a chronic disorder of the stomach, in which food empties from the stomach much more slowly than normal (referred to as delayed gastric emptying) in the absence of any type of mechanical obstruction. Although gastroparesis may be asymptomatic, in many patients it can cause significant morbidity 1. Severe nausea and protracted vomiting are the most common symptoms associated with the condition. Other symptoms include abdominal bloating and pain. Gastroparesis is a common complication of type-1 diabetes and can occur after surgery or in association with other disorders such as anorexia nervosa or abdominal migraine. In severe cases patients may be hospitalised because of dehydration and significant weight loss, and may require nutritional support. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 1 of 18

2 Current treatments and alternatives Medical therapy is effective in the majority of patients with gastroparesis. However, approximately 2% of patients are refractory to drug therapy. For these patients treatment is limited 2. Surgical options include the palliative procedures of jejunostomy tube for feeding, gastrostomy tube for stomach decompression, and pyloroplasty for gastric emptying. Gastroelectrical mechanical stimulation is an option for the treatment of patients with chronic, intractable (drug-refractory) nausea and vomiting secondary to gastroparesis. What the procedure involves Electrical stimulation is delivered via an implanted system that consists of two intramuscular leads and a neurostimulator. Under general anaesthesia the stimulating electrode of each intramuscular lead is fixed to the muscle of the lower stomach. The connector end of each lead is then attached to the neurostimulator which is placed through an incision in a small pocket in the abdominal wall. The neurostimulator is turned on and electrical impulses are delivered by the leads. A programmer can adjust the stimulation rates and amplitude. Efficacy Evidence on efficacy is based on the results for a small number of patients, in primarily uncontrolled studies. In these studies frequency of vomiting was noted to improve during stimulation and fewer patients required nutritional support following the procedure. However improvement in symptoms did not always correlate with improved gastric emptying In an uncontrolled report of 33 patients, 24 with 12 months follow up, vomiting frequency had reduced from a median of 17.3 episodes per week to 4.8 episodes a week at 12 months (72% reduction). Total symptom scores were also significantly improved at 12 months. In a second uncontrolled study of 39 patients all outcomes were improved at 12 months follow up, however the improvement in gastric emptying as assessed at 6 months was not sustained at 12 months. Only one study attempted to blind participants to stimulation. These results are based on short-term follow-up of a small number of patients and show that at 2 months, self-reported vomiting frequency was significantly lower in those patients receiving stimulation. One of the difficulties in interpreting the evidence on this procedure is the lack of a comparative group and reliance on self-reported measures of symptom relief. The Specialist Advisors expressed uncertainties regarding the efficacy of this procedure; in particular that it was uncertain whether the procedure benefits patients solely by altering symptoms rather than accelerating gastric emptying. Safety Data collected on patients from two multicentre clinical studies reported that 27% (14/51) of patients experienced pain and 22% (11/51) of patients experienced deviceor implant-related adverse events including infection (n = 2), device erosion (n = 1), IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 2 of 18

3 device migration (n = 1) and stomach wall perforation (n = 1). These complications necessitated removal of the device in 8% (4/51) of patients. The manufacturer of the device used in this procedure states that patients may not be treated with any type of diathermy because the energy from diathermy can be transferred through the implanted system, causing tissue damage and can potentially result in severe injury or death. The Specialist Advisors did not have any particular safety concerns relating to this procedure. They listed potential complications as being infection of the neurostimulator when it is placed in the abdominal pouch, possible small bowel obstruction and erosion of leads into the stomach mucosa. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to gastroelectrical stimulation for gastroparesis. Searches were conducted using the following databases: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and Science Citation Index, and covered the period from their commencement to June 2003 (Appendix B). Trial registries and the Internet were also searched. No language restriction was applied to the searches. The following selection criteria (Table 1) were applied to the abstracts identified by the literature search. Where these criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Characteristic Publication type Patient Intervention/test Outcome Language Inclusion criteria for identification of relevant studies Criteria Clinical studies included. Emphasis was placed on identifying good quality comparative studies. s were excluded where no clinical outcomes were reported, or the paper was a review, editorial, laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising methodology. Patients with gastroparesis (drug-refractory nausea and vomiting secondary to gastroparesis). Gastroelectrial mechanical stimulation for gastroparesis. Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. Studies included in the overview This overview is based on nine papers from five studies; including results from the Gastro Electro Mechanical Stimulation (GEMS) study 3-4, the Worldwide Anti- Vomiting Electrical Stimulation Study (WAVESS) 5-6,. Both the GEMS and WAVES studies were conducted in two phases. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 3 of 18

4 The GEMS study was the first large study evaluating this procedure; and is termed a feasibility study by the authors. Based on the results of this study, the WAVES study was then set up. Three smaller studies on this procedure have also been published 7-11, and one unpublished study was found. All five studies have in part been funded by the device manufacturer. Information from the FDA submission on the safety and probable benefit of the procedure is also included in the overview 12. Appendix A lists relevant evidence not included in the summary tables. The substantial majority of this information is reported in abstracts. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 4 of 18

5 Table 2 Summary of key efficacy and safety findings Study details Key efficacy findings Key safety findings Comments Abell et al (2003) 5, 6 Phase I results All patients Complications Phase I (WVF) OFF ON 1 patient lead perforation of the Double blind randomised cross-over trial Weekly vomiting frequency 13.5 ( ) 6.8 ( ) stomach (removal of (reported in diaries median interquartile range) (p < 0.05) device) Patients were randomised to stimulation either ON or OFF for 1 month then crossed over to the other mode for 1 month. Phase II Uncontrolled All patients had stimulator turned ON, 6 and 12 month follow up. 11 centres US, Canada and Europe 33 patients 17 patients diabetic 16 patients idiopathic Age range years old Median vomiting 17.3 episodes per week and with mean vomiting and nausea severity scores of 3.5 and 3.3 Phase I intention to treat analyses 2 months Phase II n = 24 available for 12 month follow up. Only 20 patients had gastric emptying data. Analysis done on treatment received. Duration of symptoms: mean 6.2 years Parameters: Amplitude 5 ma Pacing frequency: 14 Hz Pulse width 330 microseconds Total symptom score (TSS) 13.9 ± ± 1.0 (mean sum of 6 symptoms, rated 0 absent, 4 extremely severe) Patient preference 7 21 Authors note a 50% decrease in median vomiting frequency between stimulation OFF and ON. Phase II All patients Baseline 6 months 12 months WVF 17.3 ( ) (33) 2.6 ( ) (27)* 4.8 ( ) (24)* TSS 16.8 ± 0.9 (33) 11.1 ± 1.3 (27)* 11.4 ± 1.3 (24)* PCS 25.8 ± 1.5 (33) 33.5 ± 2.0 (29)* 32.4 ± 2.2 (24)* MCS 36.1 ± 2.2 (33) 43.7 ± 2.4 (27)* 45.1 ± 2.1 (24)* GET(2) 78 (67 84)(33) 65 (53 80) (26)* 56 (45 74) (20)* GET(4) 34 (26 57) (33) 27 (14 54) (26) 22 (11 37) (20)* * p < 0.05 Nutrition support Baseline: 14 patients required support; at 12 months, 7 patients required support. SF-36 PCS = physical composite score SF 36 MCS = mental composite score GET = gastric emptying results 8 SF-36 subscales also reported in the published report. 2 patients infection of the neurostimulator pocket (removal of device) 1 patient generator eroded through the skin (removal of device) 1 patient pain from migration (device repositioned) Randomisation done by random number table. Initial study plan provided for an enrolment of 40 diabetic and 40 idiopathic patients. Slow recruitment lead to the sponsor stopping enrolment at 33 patients. 63 patients were screened for the study 30 did not meet criteria. Patient, physician and study coordinator were blinded to stimulation status during phase I, and a person not involved in the patient s care performed all programming and interrogation of the gastric stimulator. Patients were asked to discontinue medication 2 to 3 days before gastric emptying test. 2 patients lost to follow-up Considerable number of patients were unevaluable (max 13 patients 39%). Subgroup analysis also performed for diabetic and idiopathic patients. Figures between the two papers do not always reconcile. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 5 of 18

6 Study details Key efficacy findings Key safety findings Comments Abell et al (2003) 3 Intermediate and long term results Complications (Short-term results are also presented in the paper - 0,3,6 and 12 1 patient had removal months) of device (infection) Uncontrolled 12 patients 3 patients diabetic 9 patients idiopathic Age range years, mean age 35.7 years : 5 years (10 patients) 10 available at 1, 2 and 5 years (1 patients removal of device, 1 patient died unrelated to procedure/illness) Parameters: Amplitude 5 ma Pacing frequency: 12/minute Pulse width 330 microseconds Total symptom score (reports on 7 symptoms, max score 50 worst) Baseline 1 2 yrs 5 yrs % improve % ( p < 0.05) Weekly vomiting frequency Score (0 absent 4 Extremely frequent (=7/week) Baseline 1 2 yrs 5 yrs % improve 3.9 ± ± ± (p < 0.01) Weight (kg) Baseline 1 2 yrs 5 yrs % improve 69.9 ± ± ±5.9 <5 p = 0.8 Body mass index (BMI) Baseline 1 2 yrs 5 yrs % improve 24.1 ± ± ±2 <5 p = 0.8 Nutrition support At 5 years, 9 patients were receiving oral nutrition only and 1 was receiving nutrition orally or with tube. (baseline 8 patients were receiving oral nutrition) Authors do not specifically report on complications Subset of the Gastric Electro- Mechanical Stimulation Study Group (GEMS) unclear why chosen as a subset was it because had 5 year follow up? Aim was to follow the nutritional status of patients. Study reporting was not of high quality. Health-related quality of life (self-report 3 worst to +3 best) Improvement at 5 years, score +2 to +1.2 (median/mean) (unclear baseline measurement) Overall quality of life (self-report 3 worst to +3 best) Improvement at 5 years, score +3 to +2.1 (median/mean) (unclear baseline measurement) IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 6 of 18

7 Study details Key efficacy findings Key safety findings Comments Abell (2002) 4 Phase I (38 patients) Complications Phase I Vomiting Nausea (median weekly frequency) Device related Uncontrolled initial assessment of temporary Baseline patients had stimulation for 2 4 weeks. Median 0 2 inadvertent 38 patients deactivation of the There was no improvement in the T50 for solid gastric emptying during pulse generator (stray 9 patients diabetic phase I magnetic fields) 24 patients idiopathic Phase II (33 patients) (baseline presented in brackets) 8 patients returned to 5 post-surgical Vomiting Nausea hospital because of increase in symptoms Age range years old 3 months (21) 0.25 (21) 1 4 patients infection 6 months (on) (21) 0 (21) 0 (requiring removal) Phase II 6 months (off) (17.5)1 (25) 7 Uncontrolled 33 patients (5 patients did not qualify) 12 months (21) 1 (28) 1 Disease related Gastric emptying (not all patients assessed only a percentage of those with follow up) Did not have placebo phases, but patients voluntarily had device deactivated for 1 week at 6 months : mean 11.0 months (range months) 3 months (25 patients) 22 patients for more than 6 months 23 patient for more than 12 months Parameters: Amplitude 5 ma Pacing frequency: 12/minute Pulse width 330 microseconds Temporary 3 mths 6 mths 12 mths Number 34/38 21/31 22/30 15/29 Improved 8/34 9/31 11/30 7/29 Worsened 9/34 1/31 3/30 2/29 No change 17/34 11/31 8/30 6/29 Weight Gain (more than 12 months follow up) Average weight gain for the 23 patients 8.4%, 15/23 gain > 5 % body weight, 3/23 lost > 5%, remainder no change. Nutritional support (enteral or parenteral support) Baseline: 14/23 patients receiving support 12 months 5/23 patients receiving support Medication (patients with 12 months follow up) Patients managed without medication increased from 5 to 14 Authors also report on results of patients who had stimulator turned off (voluntarily) at 6 months for 1 week report worsening of results but unclear if due to placebo or procedure (detail in published paper (4)). 6 patients pain 3 paints obstruction 2 patients hepatitis 2 infection 2 electrode dislodgment 2 stimulation of the adnominal rectus 1 insomnia 1 transient ischaemic attack 1 rib fracture 2 kidney failure 3 J tube correction 3 diarrhoea 2 patients underwent total gastrectomy Authors note that no cardiac arrhythmia was detected. Termed a feasibility study GEMS. Note this is not to be confused with the results from the WAVVES study again with two phases. Unclear how baseline measurements calculated for phase II based on the number of people who were followed up. Five patients could not eat at all during the study period excluded from vomiting analysis. Additional exclusions five patients who refused follow up and 1 patient who could quantify symptoms. Not an intent-to-treat analysis. Authors note that complications occurred with 7424 generator. Authors note that a subset (27 patients) were available and willing to be re-examined more than 12 months after last follow up. Authors note improved in symptoms but not correlated with improved gastric emptying. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 7 of 18

8 Study details Key efficacy findings Key safety findings Comments Forster et al (2003) 7 Outcomes Baseline 6 mths 12 mths Complications. Baseline and follow ups were Uncontrolled Gastric emptying 45%± %±4.0 38%±5.3 4 patients had devices done by a self-administered April 1998 November 2001 removed because of questionnaire. infections (all diabetic) Total symptom score (0 absent 5 severe) 3 patients had the It would appear that some 55 patients Severity 20± ± ±1.2 device moved or patients (n = 41) in this study 39 patients diabetic Frequency 21± ± ±1.2 replaces (migration) were part of other clinical 9 patients post surgical GES 7 patients idiopathic Scores were significantly improved (p < 0.05) at 6 and 12 months 6 patients died (unrelated causes) studies. Quality of life (mean score for general population is 50) All operations done via an open Age range years, mean age 40.5 years Physical composite 24± ± ± 1.7 approach. Average duration of disease: 9.9 years Mental composite 37± ± ± 1.6 Scores were significantly improved (p < 0.05) at 6 and 12 months Sponsored in part by Medtronic. : 12 months Hospitalisation prior to implant average hospitalised was 57 days, in 12 months this average was 17 days. Parameters: Pulse width 330 microseconds Body weight (kg) 64.5± ± ± 1.9 Body mass index 22.9± ± ± 0.6 Nutritional support Baseline 25 patients had jejunostomy tubes 12 months 8 patients had j-tubes From end comment from author it would appear that a substantial number of patients have been lost to follow up (15 patients from the initial study). It is unclear if these patients improved or worsened. Haemoglobin 9.8%± %± %± 0.45 IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 8 of 18

9 Study details Key efficacy findings Key safety findings Comments Forster et al (2001) 8 Mean 4-hour gastric emptying time. Complications. Uncontrolled April 1998 September patients 19 patients diabetic 3 patients post surgical GES 3 patients idiopathic Age range years, mean age 41 years Average duration of disease: 7.2 years : 25 patients 3 months 24 patients 6 months 11 patients 12 months Parameters: Pulse width 300 microseconds The only significant change occurred from baseline to 3 months, and after 6 months gastric emptying remained at greater than 30%. 14/21 patients had improvement at 3 months. Severity and frequency of nausea/vomiting (self-report) Patients showed on average a significant decrease in both nausea and vomiting by 3 months, with sustained reduced symptoms at 6 and 12 months. Overall: 16 patients showed improvement at 3 months 3 patients improvement in nausea alone at 3 months 1 vomiting worsened at 3 months 1 patient improvement only in frequency of nausea and vomiting at 6 months 1 patient improvement of nausea and vomiting at 6 months 1 patient improvement in vomiting 6 months 3 patients appeared to have not benefit Nutritional support Baseline 14 patients had jejunostomy tubes 3 months 7 patients had j-tubes 6 months 3 patients had j tubes 3 patients had devices had been removed because of infections 1 patient died (unrelated causes) Authors note that two or three cases of infection were related to potentially avoidable factors Appears that this is a earlier report of 7 however some of these patients may not be included (lost to follow up) in the later paper. Baseline and follow ups were done by a self-administered questionnaire. No raw data given in the paper. Results are presented in figures and are not described in detail in the text. Severity: (0 absent, 4 extremely severe). Frequency: (0 absent, 4 extremely frequent). Sponsored in part by Medtronic. It would appear that patients in this study were part of another clinical trial. Weight Average weight at surgery 60.1 ± 2.2 kg and at 6 months had increased to 62.6 ± 2.7 kg at 6 months Study reporting was not of high quality. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 9 of 18

10 Study details Key efficacy findings Key safety findings Comments 9, 10 McCallum (1998) Gastric retention time (mean 2 hour) Authors reported that All patients were taking Uncontrolled Baseline 77% ± 3.3% to 56.6 %± 8.6% (p < 0.05) there were no infections prokinetic drugs throughout the study. November 1994 September 1996 Gastric retention at 2 hours was < 70% in 6/9 patients (67%) at the end of the study 9 patients with severe gastroparesis 5 patients diabetic 3 patients idiopathic 1 patient postsurgical : Duration of outpatient study: 1 3 months, mean 49 days. Parameters: Pacing frequency: 12 cpm Pulse width 300 microseconds Kadirkamanathan SS (2004) (unpublished) Uncontrolled (UK registry data) December 2000 March patients 6 patients diabetic 7 patients idiopathic Duration of symptoms: 6.3 ± 3.2 years Follow-up: median 3 months (range 1 36 months) Symptom score (self report 0 none to 3 severe) developed for study assessing 4 symptoms comparing week 1 with last week Week 1: 2.8 ± 0.4 Week 4: 1.3 ± 0.4 Week 5: 1.6 ± 0.4 Nutritional support At the end of the study 8/9 patients no longer required J-tube feeding Weekly vomiting episodes (median) Baseline 3 months Last follow up 24 (13 patients) 1.5 (6 patients) 1.5 (11 patients) Improvement in vomiting (last follow-up) 2 patients < 50% improvement 1 patient 50 74% improvement 4 patients 75 99% improvement 4 patients 100% improvement Weekly nausea episodes (median) Baseline 3 months Last follow up 26 (13 patients) 6.0 (6 patients) 5.0 (11 patients) Complications: 1 patient died (unrelated) Technical problems 4 stages of the study protocol. Small study. Sponsored in part by Medtronic. Presentation limited information. 2 patients follow up data. Patient diaries were used to evaluate symptoms. Gastric emptying presented in figure format. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 10 of 18

11 Study details Key efficacy findings Key safety findings Comments Lin Z (2004) 11 Effect on slow wave frequency and regularity Surgical complications Uncontrolled trial USA 15 patients (27% male) mean age 41yrs (range 27 to 66 yrs) with severe gastroparesis. 11 type 1 diabetes Inclusion criteria: diagnosis of gastroparesis for 1+ yr refractory to antiemetics or prokinetics, 7+ emetic episodes per week, delayed gastric emptying. Exclusion criteria: organ transplant, pseudo obstruction, previous gastric surgery, primary eating or swallowing disorders, chemical dependency, pregnancy. Gastric electrical stimulation (GES) by a pulse generator and the placement of two permanent serosal electrodes in the muscularis propria layer on the greater curvature of the stomach at 9.5 and 10.5 cm proximal to the pylorus. GES pulse width of 330 µs, amplitude 5mA, and frequency of 12cpm. Bipolar temporary electrodes were sewed to the serosa for recording gastric myoelectrical activity (GMA). Recordings were taken in fasting state and for 2 hrs after a test meal, at baseline, 1 week post surgery, and at 3 months. A five point symptom interview form and a 4 hr standard gastric emptying test also undertaken at 3 months The mean frequency of the gastric slow rate wave at baseline was similar to that after initiation of GES and at 3 months Effect on amplitude of the gastric slow wave The postprandial power (amplitude) of the Gastric myoelectric activity during GES was significantly increased from baseline scores (P<0.05) Baseline Initial GES 3 months Power change of GMA (db) 0.1 ± ± ± 4.7 Effect on propagation velocity of the slow wave There was a significant increase in the propagation velocity of the slow wave following the insertion of GEM at one week and at 3 months (p<0.05) Baseline Initial GES 3 months Propagation velocity (cm s -1 ) 0.5 ± ± ± 0.4 Symptoms Symptom severity of nausea and vomiting were reduced from baseline to 3 months (p<0.01 for both), but there was no significant change in gastric retention to 3 months follow up. The implanted device was removed at 3 months in 7% (1/15) of patients. Due to a superficial wound infection progressing to the neuro-stimulator Patient acceptability No pain or other sensations were reported with the use of GEM ANOVA or t-test used to compare scores from baseline, and significance taken as p<0.05. Patients were allowed prokinetic medication during the study which may have confounded the effect of GES, although inclusion criteria required being refractory to these drugs. Confirmed that a high frequency and low energy stimulus improves symptoms but not gastric emptying. Scinitgraphy and gastric myoelectrical emptying studies not done on the same day. In one patient the experimental solid meal was changed during post operative outcome assessment as could not be tolerated. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 11 of 18

12 Table 3 Additional safety data on gastroelectrical stimulation for gastroparesis (taken from the FDA submission 12 ) Adverse effects data were collected on 51patients with drug-refractory gastroparesis of diabetic or idiopathic aetiologies in two clinical studies conducted in the USA, Canada, and Europe. The table below summarises those adverse events reported through to 30 September 1999 Event Number of events Number of patients % of patients Device or implant related Lead impedance out of range Device infections Device erosion Device migration Stomach wall perforation Underlying disease related Upper GI symptoms Extra abdominal pain Feeding tube complications Lower GI symptoms Dehydration Bone and joint related Acute diabetic complications Dysphagia Cardiovascular/renal related Other therapy complications Feeding tube or IV complications Miscellaneous Urinary tract infections Stress incontinence Fever Other infections: sinus, pink eye, herpes zoster IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 12 of 18

13 Validity and generalisability of the studies There was only one study that attempted to blind patients to stimulation, 5 albeit for a short period. Given the nature of this procedure, it is possible that patients experienced a placebo response. The studies report on a small number of patients and although 12-month data is reported it is not available for all patients assessed in these studies. As such, 12 months follow up or greater is available for around 100 patients. For some outcomes such as gastric emptying, only a percentage of patients were considered evaluable and it is unclear whether this has now been dismissed as an endpoint. It is also unclear whether some of the same patients are included in more than one report. 8,7 Patients were a heterogeneous group and included diabetic, idiopathic and postsurgical patients. In some reports, separate analysis of these groups was undertaken. It unclear whether the underlying cause of gastroparesis influences efficacy outcomes. Procedure parameters also varied among studies. It is unclear what impact this may have on efficacy outcomes, particularly given that the mechanism underlying this procedure is still relatively unknown. The majority of outcomes (symptom scores) were based on self-reports (that is, diary entries on the frequency of vomiting) or obtained at follow-up visits by the investigators. These types of outcomes, and their corresponding methods of assessment, are more liable to bias. Many of the studies did not used validated measures to assess outcomes Gastric emptying was measured by scintigraphy. However, as already noted, not all patients were assessed for this outcome and this was not considered a primary outcome despite delayed gastric emptying being a requirement for participation in the study. Many of the patients included in the studies continued to receive medication, despite undergoing gastro electrical mechanical stimulation. 5, 9,10 It is unclear what effect this has on efficacy outcomes. It is unclear what is the most appropriate primary endpoint in relation to this procedure. In general the reports of these studies were not written well, this makes it difficult to ascertain whether some cases of deficiencies are methodological or literary. It is also worth noting that the results presented in the reports on the WAVESS study 5, 6, 11 in some cases do not reconcile with the most recent reports reporting a re-analysis of the results. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 13 of 18

14 Specialist Advisors opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. Patients suitable for this procedure are very uncommon. The surgery can be performed either by open or laparoscopic surgery. Long-term studies need to be conducted. There is currently a UK registry. Unclear whether the procedure merely improves the symptoms of gastroparesis (nausea and vomiting versus gastric emptying). Analysis of the potential evidence base It would appear that this is a relatively low-volume procedure and as such it is unlikely that there will be large body of evidence on this procedure. There are a significant number of abstracts published on this procedure (see Appendix A). The majority appear to be written by authors already published on this procedure. Because the abstracts have not been assessed it is unclear whether the results presented refer to the same studies already included in the overview but with longer-term follow up, or to different studies and patients. Publication rates of full-text articles after presentation of abstracts at international meetings has been reported to range from 11% to 78% 12. This suggests that at least 32% of the abstracts presented are never published as complete articles in peer-reviewed journals. It is also unclear whether those authors who have already published preliminary results are more likely to publish the longer-term results of their study. If this is the case it is therefore possible, that these results may differ from the results of other studies that remain unpublished. The larger trials are more likely to have received support from manufacturers. There has been some suggestion that there is an association between funding and reporting of more positive outcomes. Issues for consideration by IPAC A European registry is being established to collect and analyse data. It is unclear what role the manufacturer will have in this registry. The largest trial on the procedure was stopped early by the manufacturer. References 1 McCallum RW, George SJ. Gastroparesis. Clinical Perspectives in Gastroenterology 2001; 4(3): Rabine JC, Barnett JL. Management of the patient with gastroparesis. Journal of Clinical Gastroenterology 2001; 32(1):11 8. IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 14 of 18

15 3 Abell T, Lou J, Tabbaa M, Batista O, et al. Gastric electrical stimulation for gastroparesis improves nutritional parameters at short, intermediate, and longterm follow-up. Jpen: Journal of Parenteral & Enteral Nutrition 2003; 27(4): Abell TL, Van Cutsem E, Abrahamsson H, Huizinga JD, et al. Gastric electrical stimulation in intractable symptomatic gastroparesis. Digestion 2002; 66(4): Abell TM. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003; 125(2): Lin Z, Forster J, Sarosiek I, McCallum RW. Treatment of gastroparesis with electrical stimulation. Digestive Diseases & Sciences 2003; 48(5): Forster J, Sarosiek I, Lin Z, Durham S, et al. Further experience with gastric stimulation to treat drug refractory gastroparesis. American Journal of Surgery 2003; 186(6): Forster J, Sarosiek I, Delcore R, Lin Z, et al. Gastric pacing is a new surgical treatment for gastroparesis. American Journal of Surgery 2001; 182(6): McCallum RW, Chen JD, Lin Z, Schirmer BD, et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998; 114(3): Lin ZY, McCallum RW, Schirmer BD, Chen JD. Effects of pacing parameters on entrainment of gastric slow waves in patients with gastroparesis. American Journal of Physiology 1998; 274(1 Pt 1):G Lin Z, Forster J, Sarosiek I, McCallum RW. Effect of high-frequency gastric electrical stimulation on gastric myoelectric activity in gastroparetic patients. Neurogastroenterol Motil 2004; 16(2): FDA licence application. Summary of safety and probably benefit. FDA October Hopewell S, McDonald S. Full publication of trials initially reported as abstracts in the Australian and New Zealand Journal of Medicine Internal Medicine Journal 2003; 33: IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 15 of 18

16 Appendix A: Additional relevant papers not included in the summary tables Study details Nowak T. Effect of gastric electrical stimulation on satiety and liquid meal volume in patients with Gastroparesis. Neurogastroenterology & Motility 2003; 15(3):339 Anand CP. Response to gastric electrical stimulation for drugrefractory gastroparesis: does solid gastric emptying improve or not over time? Neurogastroenterology & Motility 2003; 15(3): Sarosiek I. Gastric Electrical Stimulation for Medically Refractory Diabetic Gastroparesis: A Single Center Experience. Diabetes 2003; 52(supplement 1):A462. Abell T, Curuchi A, Al-Juburi A, Blanchard K, et al. Effects of Gastric Electrical Stimulation on Outcome and Mortality of Diabetic Gastroparesis. Diabetes 2003; 52(Supplement 1):A191. Sarosiek I. Gastric Electrical Stimulation: A New Treatment for Diabetic Gastroparesis. Diabetes 2002; 51(Supplement 2):A114. Mccallum Rw. Effects of High-Frequency Electrical Stimulation of the Stomach on Gastric Slow Wave, Gastric Emptying and Symptoms in Diabetic Gastroparesis. Diabetes 2001; 50(supplement 2):A Abell Tl. Results of Long-Term High Frequency Gastric Electrical Stimulation (GES) for Treatment of Diabetic Gastroparesis Refractory to Standard Medical Therapy. Diabetes 2001; 50(supplement 2):A71. Lin ZY, McCallum RW, Schirmer BD, Chen JD. Effects of pacing parameters on entrainment of gastric slow waves in patients with gastroparesis. American Journal of Physiology 1998; 274(1 Pt 1):G McCallum RW, Sarosiek I, Lin Z, Forster J, Abell T, Rashed H et al. Gastric electrical stimulation (GES) improves symptoms in patients with drug refractory gastroparesis. The American Journal of Gastroenterology 2002; 97(1):S56. Skole KS, Panganamamula KV, Bromer MQ, Thomas P, et al. Efficacy of gastric electrical stimulation for gastroparesis refractory to medical therapy; a single center experience. The American Journal of Gastroenterology 2002; 97(1):S48. McCallum RW, Lin Z, Sarosiek I, Forster J. Effects of longterm high-frequency electrical stimulation of the stomach on solid gastric emptying and clinical symptoms and HBA1C in diabetic gastroparesis. The American Journal of Gastroenterology 2003; 98(1):S53 4. Sobrino MA, Patterson DJ, Thirlby RC. Health-realted quality of life with gastric electrical stimulation for gastroparesis. The American Journal of Gastroenterology 2002; 97(1):S57. Anaud CP, Al Juburi A, Familoni B, Voeller G, et al. Response to gastric electrical stimulation for drug-refractory gastroparesis: comparision of clinical outcome with duration. The American Journal of Gastroenterology 2002; 97(1):S280. Abell Thomas L, Luo J, Voeller G, Beech D, et al. Gastric electrical stimulation improves both GI symptoms and gastric emptying in patients with post-surgical gastroparesis. The American Journal of Gastroenterology 2001; 96(1):S46. Patients/ 9 patients. Mean follow up 12 months 56 patients Mean follow up 24 months. 38 patients 12 months 41 patients Up to 8 years follow up 22 patients 12 months 15 patients 6 months Comments Patients from 3 FDA studies: WAVESS, WCU, CUESS.. Compassionate Use Study (CUESS). Looking at high frequency waves. 17 patients Results of the 12 months diabetic arm of the WAVES study. 13 patients Full report No relevant efficacy outcomes. 36 patients Unclear if part of WAVESS study. 11 patients 6 months 49 patients 12 months 15 patients 12 months 58 patients 12 months 9 patients 12 months Compassionate Use Study (CUESS). Quality of life. Surgery-related gastroparesis patients from GEMS IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 16 of 18

17 Study details McCallum R, Sarosiek I, Lin Z, Forster J, et al. Results of long-term gastric electrical stimulation (GES) for treatment of gastroparesis refractory to standard medical therapy. The American Journal of Gastroenterology 2001; 96(1):S46 7. George S, Lin Z, Sarosiek I, McCallum R. A comparison of high frequency vs. low frequency gastric stimulation in treating gastroparesis. The American Journal of Gastroenterology 2001; 96(1):S61. Patients/ 48 patients 12 months 3 patients 2 months 2 years Comments and WAVESS. Compassionate Use Study (CUESS). IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 17 of 18

18 Appendix B: Literature search for gastroelectrical stimulation for gastroparesis The following search strategy was used to identify papers in Medline. A similar strategy was used to identify papers in EMBASE, Current Contents, PredMedline and all EMB databases. For all other databases a simple search strategy using the key words in the title was employed. # Search History 1 gastroparesis.mp. or exp GASTROPARESIS/ electric stimulation therapy.mp. or exp Electric Stimulation 2 Therapy/ 3 exp Electric Stimulation/ or electrostimulation.mp. 4 gastric pacing.mp. (gastric adj2 electri$).mp. [mp=title, abstract, cas registry/ec 5 number word, mesh subject heading] 6 GES.tw. 7 or/ and 7 9 from 8 keep 1-58 IP overview: Gastroelectrical mechanical stimulation for gastroparesis Page 18 of 18