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Gastric electrical stimulation for refractory gastroparesis
February 2004
CORRESPONDENCE
unchanged with adenomatous lesions without dysplasia on endoscopic biopsies. In 1993, 1995, 1996, the endoscopic biopsies showed adenomatous lesions with moderate dysplasia. Between 1989 and 1996, the patient was treated with sulindac (300 mg/d). In 1996, the posology was increased to 400 mg/d. This treatment was continued until 2003. In 1997 the biopsies showed only mild dysplasia. In 1998, 1999, 2000, 2001, 2002, endoscopic aspect and biopsies were normal. Since 1979, regular endoscopic polypectomies have been made on the rectal stump. The son, born in 1975, had 15 small adenomatous polyps in the caecum in 1997. He refused the colectomy and was treated by sulindac (400 mg/d) since 1997. In 1998, 2000, 2002, coloscopy was normal. In 2002, ampulla of Vater was endoscopically normal and biopsies showed adenomatous lesions with moderate dysplasia. The 2 patients have mutation of the APC gene at codon 1078 in exon 15. These cases show that sulindac can normalize an adenomatous ampulla of Vater and can induce the elimination of moderate dysplasia. If the drug is inefficient, it can be useful to increase the posology. In a given patient the drug can act on ampulla of Vater and not on the colon or the rectum and reciprocally. The future is probably in classic nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors4 associated with interventional endoscopy.5 This must be evaluated in prospective studies. CHRISTIAN THEODORE Service de Gastro-Ente´rologie Centre Me´dical de Forcilles Fe´rolles-Attilly, France 1. Burke C. Risk stratification for periampullary carcinoma in patients with familial adenomatous polyposis: does Theodore know what to do now? Gastroenterology 2001;121:1246 –1248. 2. Theodore C, Ronsse H, Leymarios J, Vitaux J, Fournier R, Breil P, Molas G, Paologgi JA. Adenomas of the ampulla of Vater in Gardner’s syndrome. What is to be done? N Engl J Med 1981;304:731. 3. Theodore C, Fournier R, Julien P-E, Molas G, Bard A, Leymarios J, Paolaggi JA. Les le´ sions ade´ nomateuses de la papille dans les polyposes ade´ nomateuses recto-coliques familiales. Inte´ re ˆt de la duode´ noscopie. Gastroenterol Clin Biol 1983;7:864 – 867. 4. Chau I, Cunningham D. Cyclooxygenase inhibition in cancer–a blind alley or a new therapeutic reality? N Engl J Med 2002;346: 1085–1087. 5. Saurin J-C. Prise en charge clinique de la polypose ade´ nomateuse familiale. Gastroenterol Clin Biol 2001;25:B31–B37. doi:10.1053/j.gastro.2003.12.031
Gastric Electrical Stimulation for Refractory Gastroparesis Dear Sir: The recent article regarding gastric electrical stimulation for the treatment of refractory gastroparesis by Abell et al.1 represents the most rigorous published investigation of this therapy to date. The
629
authors are to be congratulated for their ongoing efforts to provide effective symptomatic relief to these unfortunate and difficult patients. The published data are from the Medtronic-sponsored World Wide Anti-Vomiting and Electrical Stimulation Trial and have been previously been submitted to the FDA to obtain a Humanitarian Device Exemption.2 The patient demographics for both reports are identical. There are, however, significant discrepancies in the reported weekly vomiting frequency for the subjects in phase I of the trial randomized to the “device-on” mode. As shown in Table 1, the data submitted to the FDA led to the conclusion that gastric electrical stimulation significantly reduced vomiting severity and the magnitude of reduction was similar with the device turned on or off. This raises the strong possibility of a placebo response. The current iteration of the data leads one to conclude that gastric electrical stimulation effectively reduces vomiting frequency and that this occurs only if the device is functioning. These are very different conclusions. I applaud the efforts of these investigators for their pioneering work in this area. I would now ask them to clarify what appears to be a post hoc change in a primary study endpoint. MICHAEL P. JONES Northwestern University Medical School Division of Gastroenterology Chicago, Illinois 1. Abell T, McCallum R, Hocking M, Koch K, Abrahamsson H, LeBlanc I, Lindberg G, Konturek J, Nowak T, Quigley EMM, Tougas G, Starkebaum W. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. 2. U.S. Food and Drug Administration. H990014-EnterraTM Therapy System (formerly named Gastric Electrical Stimulation (GES) System). Issued: 31 March 2000; Accessed: 2 August 2003. http://www.fda.gov/cdrh/ode/H990014sum.html. doi:10.1053/j.gastro.2003.12.032
Reply. The issue raised by Jones was also raised by the reviewers prior to publication in GASTROENTEROLOGY. In our early reports on this study presented at DDW, ACG, and AMS as well as the FDA, vomiting frequency derived from the patient diary records was originally computed as follows: For idiopathic patients, we computed vomiting frequency as the total number of vomiting episodes recorded divided by the number of weeks in the diary period (i.e., 2), yielding a “normal average” vomiting frequency. For the diabetic patients, we defined weekly vomiting frequency as the number of episodes in a 7-day window within the 4-week diabetic diary period in which the number of episodes was the maximum for that diary period. The diabetic diary period was 4 weeks because it was felt that vomiting symptoms fluctuate more in diabetic patients than idiopathic patients, and therefore the worst week of the diary period was most representative of the patients overall symptoms. In preparing this manuscript, we decided for the sake of consistency to analyze vomiting frequency for both etiologies in the same way. Thus, for
Table 1. Reported Weekly Vomiting Frequency for all Subjects from the WAVESS Study as Reported to the FDA and Published in GASTROENTEROLOGY FDA Submission
Mean (SD) Median (25th–75th) aP
Gastroenterology Publication
Baseline
ON
OFF
Baseline
ON
OFF
47.6 (52.6) 26.3
23.0 (35.5)a 12.0a
29.0 (38.2)a 14.0a
NR 17.3 (11.8–45.7)
NR 6.8 (3.9–16.5)ab
NR 13.5 (5.5–25.4)
⬍ 0.05 vs. baseline; bP ⬍ 0.05 for “on” vs. “off.”
CORRESPONDENCE
unchanged with adenomatous lesions without dysplasia on endoscopic biopsies. In 1993, 1995, 1996, the endoscopic biopsies showed adenomatous lesions with moderate dysplasia. Between 1989 and 1996, the patient was treated with sulindac (300 mg/d). In 1996, the posology was increased to 400 mg/d. This treatment was continued until 2003. In 1997 the biopsies showed only mild dysplasia. In 1998, 1999, 2000, 2001, 2002, endoscopic aspect and biopsies were normal. Since 1979, regular endoscopic polypectomies have been made on the rectal stump. The son, born in 1975, had 15 small adenomatous polyps in the caecum in 1997. He refused the colectomy and was treated by sulindac (400 mg/d) since 1997. In 1998, 2000, 2002, coloscopy was normal. In 2002, ampulla of Vater was endoscopically normal and biopsies showed adenomatous lesions with moderate dysplasia. The 2 patients have mutation of the APC gene at codon 1078 in exon 15. These cases show that sulindac can normalize an adenomatous ampulla of Vater and can induce the elimination of moderate dysplasia. If the drug is inefficient, it can be useful to increase the posology. In a given patient the drug can act on ampulla of Vater and not on the colon or the rectum and reciprocally. The future is probably in classic nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors4 associated with interventional endoscopy.5 This must be evaluated in prospective studies. CHRISTIAN THEODORE Service de Gastro-Ente´rologie Centre Me´dical de Forcilles Fe´rolles-Attilly, France 1. Burke C. Risk stratification for periampullary carcinoma in patients with familial adenomatous polyposis: does Theodore know what to do now? Gastroenterology 2001;121:1246 –1248. 2. Theodore C, Ronsse H, Leymarios J, Vitaux J, Fournier R, Breil P, Molas G, Paologgi JA. Adenomas of the ampulla of Vater in Gardner’s syndrome. What is to be done? N Engl J Med 1981;304:731. 3. Theodore C, Fournier R, Julien P-E, Molas G, Bard A, Leymarios J, Paolaggi JA. Les le´ sions ade´ nomateuses de la papille dans les polyposes ade´ nomateuses recto-coliques familiales. Inte´ re ˆt de la duode´ noscopie. Gastroenterol Clin Biol 1983;7:864 – 867. 4. Chau I, Cunningham D. Cyclooxygenase inhibition in cancer–a blind alley or a new therapeutic reality? N Engl J Med 2002;346: 1085–1087. 5. Saurin J-C. Prise en charge clinique de la polypose ade´ nomateuse familiale. Gastroenterol Clin Biol 2001;25:B31–B37. doi:10.1053/j.gastro.2003.12.031
Gastric Electrical Stimulation for Refractory Gastroparesis Dear Sir: The recent article regarding gastric electrical stimulation for the treatment of refractory gastroparesis by Abell et al.1 represents the most rigorous published investigation of this therapy to date. The
629
authors are to be congratulated for their ongoing efforts to provide effective symptomatic relief to these unfortunate and difficult patients. The published data are from the Medtronic-sponsored World Wide Anti-Vomiting and Electrical Stimulation Trial and have been previously been submitted to the FDA to obtain a Humanitarian Device Exemption.2 The patient demographics for both reports are identical. There are, however, significant discrepancies in the reported weekly vomiting frequency for the subjects in phase I of the trial randomized to the “device-on” mode. As shown in Table 1, the data submitted to the FDA led to the conclusion that gastric electrical stimulation significantly reduced vomiting severity and the magnitude of reduction was similar with the device turned on or off. This raises the strong possibility of a placebo response. The current iteration of the data leads one to conclude that gastric electrical stimulation effectively reduces vomiting frequency and that this occurs only if the device is functioning. These are very different conclusions. I applaud the efforts of these investigators for their pioneering work in this area. I would now ask them to clarify what appears to be a post hoc change in a primary study endpoint. MICHAEL P. JONES Northwestern University Medical School Division of Gastroenterology Chicago, Illinois 1. Abell T, McCallum R, Hocking M, Koch K, Abrahamsson H, LeBlanc I, Lindberg G, Konturek J, Nowak T, Quigley EMM, Tougas G, Starkebaum W. Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 2003;125:421– 428. 2. U.S. Food and Drug Administration. H990014-EnterraTM Therapy System (formerly named Gastric Electrical Stimulation (GES) System). Issued: 31 March 2000; Accessed: 2 August 2003. http://www.fda.gov/cdrh/ode/H990014sum.html. doi:10.1053/j.gastro.2003.12.032
Reply. The issue raised by Jones was also raised by the reviewers prior to publication in GASTROENTEROLOGY. In our early reports on this study presented at DDW, ACG, and AMS as well as the FDA, vomiting frequency derived from the patient diary records was originally computed as follows: For idiopathic patients, we computed vomiting frequency as the total number of vomiting episodes recorded divided by the number of weeks in the diary period (i.e., 2), yielding a “normal average” vomiting frequency. For the diabetic patients, we defined weekly vomiting frequency as the number of episodes in a 7-day window within the 4-week diabetic diary period in which the number of episodes was the maximum for that diary period. The diabetic diary period was 4 weeks because it was felt that vomiting symptoms fluctuate more in diabetic patients than idiopathic patients, and therefore the worst week of the diary period was most representative of the patients overall symptoms. In preparing this manuscript, we decided for the sake of consistency to analyze vomiting frequency for both etiologies in the same way. Thus, for
Table 1. Reported Weekly Vomiting Frequency for all Subjects from the WAVESS Study as Reported to the FDA and Published in GASTROENTEROLOGY FDA Submission
Mean (SD) Median (25th–75th) aP
Gastroenterology Publication
Baseline
ON
OFF
Baseline
ON
OFF
47.6 (52.6) 26.3
23.0 (35.5)a 12.0a
29.0 (38.2)a 14.0a
NR 17.3 (11.8–45.7)
NR 6.8 (3.9–16.5)ab
NR 13.5 (5.5–25.4)
⬍ 0.05 vs. baseline; bP ⬍ 0.05 for “on” vs. “off.”