1. Understanding Gastroparesis Enterra ® Therapy

2. 2 Anatomical Overview

3. 3 What is Gastroparesis? –A symptomatic chronic disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. –In a healthy digestive system, strong muscular contractions move food from the stomach through the digestive tract. –With gastroparesis, stomach muscles work poorly (or not at all), thus preventing the stomach from emptying properly.

4. 4 Symptoms Most patients present with upper-gastrointestinal symptoms or with symptoms related to disordered gastric motor function. These include: –Nausea and vomiting –Abdominal bloating –Abdominal pain –Feelings of fullness after only a few bites of food (early satiety) –Heartburn or gastroesophageal reflux disease (GERD) –Changes in blood sugar levels –Lack of appetite –Excessive weight loss

5. 5 Prevalence The true prevalence of gastroparesis is not known; however, it has been estimated that up to 5 million people in the US may suffer from this condition. * In a survey patients with documented chronic gastroparesis patients, it was found that the origins were about 36 percent idiopathic and 29 percent diabetic, with the remaining amount attributed to several other causes. ** * Abell T, et al.. Nutrition in Clinical Practice 2006. ** Soykan I, et al.Dig Dis Sci. 1998.

6. 6 Causes and Risk Factors The most common causes of gastroparesis are: –Idiopathic –Diabetes, either type 1 or type 2 The impact of gastroparesis on physical well-being can be devastating. It can cause chronic nausea and vomiting and lead to malnutrition and inadequate blood sugar levels. Living with gastroparesis also affects emotional well-being – the constant discomfort of chronic nausea and vomiting can have an impact on school and work performance, family and personal relationships, and social activities.

7. 7 Etiologies In a study of 146 patients, the most common origins were: – Idiopathic (35%) – Diabetic (29%) – Postsurgical (13%) – Others: Parkinson’s disease, vascular disease, pseudo-obstruction Soykan I et al. Dig Dis Sci 1998.

8. 8 Idiopathic Gastroparesis Delayed gastric emptying without apparent cause or underlying abnormality may be the most common form of gastroparesis Symptoms fluctuate: patient may have episodes of pronounced symptoms interspersed with relatively symptom- free intervals Patients are frequently young or middle-aged women Kendall, McCallum. Gastroenterology 1993. Parkman et al. Gastroenterology 2004.

9. 9 Symptoms may resolve after months or even years – Patients with a viral trigger tend to have slow resolution of their symptoms over several years – Patients without a viral trigger tend to show less improvement over time Idiopathic Gastroparesis Parkman et al. Gastroenterology 2004.

10. 10 In a study of 146 patients, 52 patients had idiopathic gastroparesis: – 23% had sudden onset of symptoms after viral syndrome, suggesting a potential viral etiology – 48% had severe abdominal pain – 19% had gastroesophageal reflux disease and non- ulcerative dyspepsia – 23% had depression – 8% had onset post-cholecystectomy Idiopathic Gastroparesis Soykan I et al. Dig Dis Sci 1998,

11. 11 Diabetic Gastroparesis Gastroparesis is a recognized complication of diabetes mellitus – Primarily among patients with long-standing type 1 diabetes and other associated complications Gastroparesis affects: – 40-50% of people with Type 1 diabetes – 30-40% of people with Type 2 diabetes Parkman. Gastroenterology 2004. Diabetes Institute Foundation Website. 2005

12. 12 Likely to result from impaired neural control of gastric motility, possibly at the level of the vagus nerve Problems with blood glucose control may be the first indication that a diabetic patient is developing gastroparesis – Gastroparesis contributes to poor glycemic control because of unpredictable delivery of food into the duodenum – Delayed gastric emptying with continued insulin administration may produce hypoglycemia Diabetic Gastroparesis Parkman. Gastroenterology 2004.

13. 13 Post-surgical* Gastroparesis Any surgery of the upper intestinal tract (esophagus, stomach or duodenum) may result in injury to the vagus nerve** Gastroparesis may occur as a complication of a variety of surgical procedures*** – Post-vagotomy - Most often peptic ulcer surgery with vagotomy – Post-fundoplication - Complication of fundoplication to treat GERD – Post-bariatric - Most commonly Roux-en-Y gastric bypass for obesity – Post lung and heart-lung transplantation * Use of gastric electrical stimulation for post-surgical gastroparesis is not an approved indication for Enterra ® Therapy. **American College of Gastroenterolgy Website. 2005 ***Parkman et al. Gastroenterology 2004.

14. 14 Complications of Gastroparesis Esophagitis: an inflamation of the esophagus Mallory-Weiss tear: Tear in mucosal layer at the junction of the esophagus and stomach Vegetable-laden bezoars: an accumulation of undigested food that cannot pass through the pylorus

15. 15 Effects of Gastroparesis Severe nausea and vomiting can: –be debilitating –Compromise quality of life –Lead to the inability to work or go to school If not controlled, patients can suffer from potentially life-threatening complications that may require hospitalization, such as: –Electrolyte imbalances –Dehydration –Malnutrition –Poor glycemic control (diabetics)

16. 16 Costs for Gastroparesis Health care expenditures for gastroparesis care are significant* One study estimated healthcare costs for a gastroparesis patient at $6972/month**, which includes –Hospitalization –Total parental nutrition Better glycemic control may result in significant cost savings per diabetic patient per year*** * Parkman et al. Gastroenterology 2004. ** Abell et al. Am J Gastroenterol 2001..

17. 17 Economic Impact Better glycemic control may result in significant cost savings per diabetic patient per year*** *** Ordog et al. Diabetes 2000. Wagner et al. JAMA 2001. Patients with gastroparesis often have prolonged hospital stays due to dehydration and the need for nutritional support* * Parkman et al. Gastroenterology 2004.

18. 18 Impact on Quality of Life For patients with gastroparesis: Meal times must be carefully timed and portions controlled, which may make dining out difficult, if not impossible. May not know when nausea and vomiting episodes will occur. Feeding tubes or intravenous feedings can be restrictive which may limit patient activity and have serious medical complications.

19. 19 Diagnosing The diagnosis of gastroparesis is confirmed through the following test: –Radioisotope gastric-emptying scan: The patient eats food containing a radioisotope, which is a slightly radioactive substance (not dangerous) that shows up on the scan. After eating, the patient lies under a machine (at set time periods) that detects the radioisotope and shows an image of food in and leaving the stomach. If greater than 60 percent of the food remains at 2 hours or greater than 10 percent after 4 hours then gastroparesis may be diagnosed. –a physician may do an upper endoscopy or an ultrasound to rule out other causes for delayed gastric emptying. During endoscopy the lining of the stomach is checked for any abnormalities. An ultrasound is used to examine the outline and shape of the gallbladder and pancreas to rule out gallbladder disease or pancreatitis.

20. 20 Treatment Options Treatment options for both diabetic and non-diabetic patients include, changes in eating habits, oral medications and, in severe cases, feeding tubes and intravenous feeding. An innovative treatment option from Medtronic is Enterra® Therapy which uses mild electrical pulses for gastric stimulation to help control the chronic, drug refractory nausea and vomiting secondary with gastroparesis of diabetic and idiopathic origin (see Enterra fact sheet). –Gastric electrical stimulation (GES) therapy was approved by the FDA in 2000 as a humanitarian use device based on a finding of safety and probable benefit. However, the effectiveness of Enterra Therapy for this use has not been demonstrated.

21. 21 References Abell TL et al. Gastric electrical stimulation is superior to standard pharmacological treatment in reducing health care costs and hospital stays and in improving quality of life in patients with severe upper GI motor disorders (abst). Am J Gastroenterol 2001;235:s258. Abell T, Malinowski S, Minocha A. Nutrition Aspects of Gastroparesis and Therapies for Drug-Refractory Patients. Nutrition in Clinical Practice 2006;21:23-33. Cutts TF, Lou J, Starkebaum W, Rashed H, Abell TL.Is gastric electrical stimulation superior to standard pharmacologic therapy in improving GI symptoms, healthcare resources, and long-term healthcare benefits? Neurogastroenterol Motil (2005) 17, 35-43. Parkman HP et al. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 2004 Nov;127(5):1592-1622. Parkman HP et al. American Gastroenterological Association medical position statement: diagnosis and treatment of gastroparesis. Gastroenterology 2004 Nov;127(5):1589-9. Ordog T et al. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes. 2000 Oct;49(10):1731-9. Wagner EH et al. Effect of improved glycemic control on health care costs and utilization. JAMA 2001 Apr 18:285(15):1963-64. Soykan I, Sivri B, Sarosiek I, Kiernan B, McCallum RW. Demography, clinical characteristics, psychological and abuse profiles, treatment, and long-term follow-up of patients with gastroparesis. Dig Dis Sci. 1998;43(11):2398-2404.

22. 22 Enterra  Therapy for Gastroparesis: Product technical manual must be reviewed prior to use for detailed disclosure. Indications: The Medtronic Enterra Therapy System for gastric electrical stimulation (GES) is indicated for use in the treatment of chronic, intractable (drug refractory) nausea and vomiting secondary to gastroparesis of diabetic or idiopathic etiology. Contraindications: The Enterra Therapy System is contraindicated in patients whom the physician determines are not candidates for surgical procedures and/or anesthesia due to physical or mental health conditions. Do not use shortwave diathermy, microwave diathermy or therapeutic ultrasound diathermy (all now referred to as diathermy) on patients implanted with a neurostimulation system. Energy from diathermy can be transferred through the implanted system and can cause tissue damage at the location of the implanted electrodes, resulting in severe injury or death. Diathermy is further prohibited because it can also damage the neurostimulation system components resulting in loss of therapy, requiring additional surgery for system explantation and replacement. Warnings: This system has not been evaluated for pregnancy, pediatric use, or patients under the age of 18, or over the age of 70. Strong sources of electromagnetic interference (EMI) can result in serious injury, system damage, or operational changes to the system. Strong sources of EMI include MRI, electrocautery, radiofrequency (RF)/microwave ablation, external defibrillators, ultrasonic equipment, radiation therapy, and theft detectors. Patients on anticoagulation therapy may be at a greater risk for post-operative complications. The system may be affected by or adversely affect other implantable devices such as cardiac pacemakers and cardioverters/defibrillators. Rupture or piercing of the neurostimulator can result in severe burns. The use of non-Medtronic components with this system may result in damage to Medtronic components, loss of therapy, or patient injury. When possible, identify and treat any infections remote to the implant site prior to surgery. It is recommended that the neurostimulator implant site be irrigated with antibiotic solution during surgery and that IV antibiotics be administered perioperatively. Infections at the implant site almost always require the surgical removal of the implanted system. Avoid excess lead slack in the abdominal cavity. The lead can become entangled with or erode into the bowel, which may result in bowel obstruction, bowel perforation, intra-abdominal infection, bowel resection and may require system revision. Precautions: Clinicians and patients should follow programming guidelines and precautions provided in product manuals. Patients should avoid manipulating or rubbing the neurostimulator system components, which can cause component damage, skin erosion, or stimulation at the implant site. Patients should be detoxified from narcotics prior to implant so that the effects of stimulation can be properly assessed. Patients should avoid activities that may put undue stress on the implanted neurostimulation system components. Patients should not scuba dive below 10 meters of water or enter hyperbaric chambers above 2.0 atmosphere absolute (ATA). Electromagnetic interference, postural changes, and other activities may cause shocking or jolting. Adverse Events: Adverse events related to the system include infection, stomach wall perforation, migration/erosion of the neurostimulator, programming difficulty, undesirable change in stimulation, implant site pain, hemorrhage, hematoma, migration/dislodgement of the lead, extra- abdominal pain, seroma, concomitant muscle stimulation, allergenic or immune system response to implanted materials, loss of therapeutic effect, and gastrointestinal complications including upper and lower gastro-intestinal (GI) symptoms. Humanitarian Device: Authorized by Federal law for use in the treatment of chronic intractable (drug refractory) nausea and vomiting secondary to gastroparesis of diabetic or idiopathic etiology. The effectiveness of this device for this use has not been demonstrated. For further information, please call Medtronic at 1-800-328-0810 and/or consult Medtronic’s website at www.medtronic.com. USA Rx Only. Rev 0709