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Influence of Gastric Emptying and Gut Transit Testing on Clinical Management Decisions in Suspected Gastroparesis

Influence of Gastric Emptying and Gut Transit Testing on Clinical Management Decisions in... Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/04/2020 ARTICLE 1 Influence of Gastric Emptying and Gut Transit Testing on Clinical Management Decisions in Suspected Gastroparesis 1 2 3 4 5 William L. Hasler, MD , Satish S. C. Rao, MBBS , Richard W. McCallum, MD , Richard A. Krause, MD , Linda A. Nguyen, MD , 6 1 7 8 9 3 Michael I. Schulman, DO , Allen A. Lee, MD , Baharak Moshiree, MD , John M. Wo, MD , Henry P. Parkman, MD , Irene Sarosiek, MD , 10 11 Gregory E. Wilding, PhD and Braden Kuo, MD INTRODUCTION: Gastric emptyingscintigraphy (GES)or wireless motility capsules (WMCs)canevaluateupper gastrointestinal symptoms in suspected gastroparesis; WMC tests can also investigate lower gut symptoms. We aimed to determine whether these tests impact treatment plans and needs for additional diagnostic evaluation. METHODS: In a prospective, multicenter study, 150 patients with gastroparesis symptoms simultaneously underwent GES and WMC testing. Based on these results, investigators devised management plans to recommend changes in medications, diet, and surgical therapies and order additional diagnostic tests. RESULTS: Treatment changes were recommended more often based on the WMC vs GES results (68% vs 48%) (P < 0.0001). Ordering of additional test(s) was eliminated more often with WMC vs GES (71% vs 31%) (P < 0.0001). Prokinetics (P 5 0.0007) and laxatives (P < 0.0001) were recommended more often based on the WMC vs GES results. Recommendations for prokinetics and gastroparesis diets were higher and neuromodulators lower in subjects with delayed emptying on both tests (all P £ 0.0006). Laxatives and additional motility tests were ordered more frequently for delayed compared with normal WMC colonic transit (P £ 0.02). Multiple motility tests were ordered more often on the basis of GES vs WMC findings (P £ 0.004). Antidumping diets and transit slowing medications were more commonly recommended for rapid WMC gastric emptying (P £ 0.03). DISCUSSION: WMC transit results promote medication changes and eliminate additional diagnostic testing more often than GES because of greater detection of delayed gastric emptying and profiling the entire gastrointestinal tract in patients with gastroparesis symptoms. TRANSLATIONAL Gastric scintigraphy and WMCs have differential impact on management decisions in suspected IMPACT: gastroparesis. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/CTG/A100, http://links.lww.com/CTG/A101, http://links.lww.com/CTG/A102 Clinical and Translational Gastroenterology 2019;10:e00084. https://doi.org/10.14309/ctg.0000000000000084 INTRODUCTION measure gastric emptying by detecting pH increases during capsule Gastric emptying testing is performed to diagnose gastroparesis (1). passage into the duodenum (4,5). Breath tests also quantify gastric Gastric emptying scintigraphy (GES) measures retention of 99mTc- emptying by measuring 13CO production after 13C-labeled meals labeled meals (2,3). Wireless motility capsules (WMCs) also (6). Two prospective concurrent GES and WMC studies and other 1 2 Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan, USA; Division of Gastroenterology and Hepatology, Medical College of 3 4 Georgia, Augusta, Georgia, USA; Section of Gastroenterology, Texas Tech University, El Paso, Texas, USA; Clin Search, LLC, Chattanooga, Tennessee, USA; 5 6 7 Division of Gastroenterology, Stanford University, Palo Alto, California, USA; Florida Digestive Health Associates, Largo, Florida, USA; Atrium Health Gastroenterology and Hepatology, Carolinas HealthCare System Digestive Health-Morehead Medical Plaza, Charlotte, North Carolina, USA; Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA; Section of Gastroenterology, Temple University, Philadelphia, Pennsylvania, 10 11 USA; Department of Biostatistics, University of Buffalo, Buffalo, New York, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA. Correspondence: William L. Hasler, MD. E-mail: whasler@umich.edu. Received April 20, 2019; accepted August 16, 2019; published online October 28, 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/04/2020 2 Hasler et al. investigations performing each test separately determined these Delayed gastric emptying on WMC testing was defined as.5-hour tests identify similar but not identical subgroups with emptying gastric emptying time (GET) (21). Rapid gastric emptying on delays (4,7,8). WMC testing was defined as GET ,1:45 hours (21). Delayed Patients with suspected gastroparesis may report symptoms re- transit times in the small bowel (SBTT) and colon (CTT) on WMC ferable to other transit impairments in the stomach and extragastric testing were defined as .6and .58:45 hours, respectively (21). regions (9–12). Rapid gastric emptying can present with symptoms Rapid SBTT on WMC testing was defined as ,2:15 hours (21). indistinguishable from gastroparesis (13–15). Furthermore, delays in small intestinal and colon transit with WMCs have been described Management decision protocol in 15.5% and 33.5% of suspected gastroparesis, respectively (13). Analyses were conducted according to a priori planned study Scintigraphy is usually limited to the stomach because of multiple endpoints (MA-501 Clinical Trial Protocol, 3/15/2015, pages visits required to measure small bowel and colon transit (16). 25–27, see Supplementary Digital Content 2, http://links.lww.com/ Whether transit findings influence management of suspected CTG/A101). Five to 28 days after testing, site investigators com- gastroparesis is uncertain. In an older series, GES had little impact pleted 3 management plans on standardized forms describing on clinical decisions, although most patients had postvagotomy treatment recommendations, including changes to medications complications (17). WMC findings promoted medication and nu- and diet (gastroparesis diets, liquid or other diets, and enteral or tritional changes in 60% and 14%, and additional tests were elimi- parenteral nutrition) and referrals for surgery (feeding tube and nated in one retrospective series (18). New prokinetic, antiemetic, gastric stimulator or resection). Management forms also docu- antidepressant, and laxative therapies were described in 50% in mented recommendations for additional diagnostic testing. another report (18,19). In the only prospective study published to Investigators entered names of medications and additional tests on date, GES findings influenced management decisions in 60% of management forms. The first plan was based on one test (GES or patients including recommendations to change the diet in those WMCs) in alternating order with blinding to the other test; the with delayed gastric emptying and to eliminate selected medications second plan was based on the other test but unblinded to thefirst on in individuals with normal gastric emptying (20). These inves- separate days; the third plan was based on combining GES and tigations did not determine whether GES and WMCs have differ- WMC results. Management forms were reviewed separately by 2 ential impact on decisions in suspected gastroparesis. investigators (W.L.H. and A.A.L.), confirming their accuracy. We performed a prospective, multicenter concurrent GES and These investigators initially disagreed on management decisions WMC study in patients with suspected gastroparesis. Site inves- for 6/150 subjects (4%). A final arbiter (B.K.) uninvolved in initial tigators completed management plans, recommending treatment reviews resolved these differences. changes and additional testing based on transit findings. We aimed to characterize whether: (i) GES and WMCs had differ- Data comparisons ential impact on clinical decisions, (ii) specific treatments and Primary endpoints. Coprimary endpoints were defined as changes testing recommendations were influenced by gastric emptying, in treatment and diagnostic testing based on transit tests. Additional and (iii) additional management recommendations were made forms were completed that recorded whether medication (proki- based on extragastric delays or rapid transit. netics, antiemetics, and neuromodulators) or diet changes or sur- gical referrals were recommended. Medication changes were defined METHODS as starting a new drug category. Starting a prokinetic de novo or Subject population switching from a prokinetic to antiemetic was considered a change, One hundred sixty-seven patients (18–80 years) with $2 symp- whereas switching from one prokinetic to another (e.g., metoclo- toms suggesting gastroparesis (nausea/vomiting, fullness/early sa- pramide to domperidone) was not a change, unless the original and tiety, bloating/distension, and upper abdominal discomfort/pain) new drugs targeted different gut regions. Adding a neuromodulator for $12 weeks were referred for gastroparesis care to 10 centers with potential mechanistic benefits in patients with gastroparesis from 2013 to 2016 (ClinicalTrials.gov NCT02022826). Esoph- symptoms (e.g., tricyclic agent, mirtazapine, olanzapine, or neuro- agogastroduodenoscopy or radiography excluded organic dis- pathic pain modulator for nausea and/or abdominal pain; buspirone orders. Exclusion criteria included dysphagia, previous to enhance fundic accommodation) who already were prescribed gastrointestinal surgery (except appendectomy, cholecystectomy, neuromodulators in different classes for other indications (e.g., se- and hysterectomy), abdominopelvic surgery within 3 months, in- rotonin or serotonin-norepinephrine reuptake inhibitors for de- flammatory bowel disease, chronic nonsteroidal anti-inflammatory pression; benzodiazepines for anxiety) was considered a medication drug use, diverticulitis, intestinal strictures, HbA1c . 10%, change. A separate item on the form asked whether transit findings implanted cardiac devices, and body mass index . 40 kg/m .In- prompted investigators to recommend eliminating additional tests. stitutional review board approval was obtained at each center. Investigators determined whether management changes were based Subjects provided written informed consent. on GES, WMCs, or both tests together. GES and WMC methodology Specific decisions. Specific changes in medication categories, Subjects underwent concurrent GES and WMCs; transit was de- diets, referrals for surgery, and additional testing were de- termined for subjects completing management plans (see Supple- termined from the lead author (W.L.H.) review of site manage- mental Methods, Supplementary Digital Content 1, http://links. ment forms. Greater impact of one test (GES or WMCs) vs the lww.com/CTG/A100) (5,21–23). Transit abnormalities on GES other on management decisions was defined when that test led to and WMC testing were determined using previously reported more treatment or fewer additional test recommendations. Spe- values. Delayed gastric emptying on GES testing was defined as cific medication categories included prokinetics, antiemetics, .10% meal retention at 4 hours (3). Rapid gastric emptying on neuromodulators, laxatives, and agents to slow transit (retard- GES testing was defined as ,38% meal retention at 1 hour (2,3). ants) (see Supplemental Methods, Supplementary Digital Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 3 Figure 1. GES and WMC findings are shown for a subject with suspected gastroparesis. Scintigraphy images and emptying profiles of the radiolabeled meal are shown in (a). This individual exhibited mildly delayed gastric emptying at 4 hours. The WMC and tracing with the pH tracing in red, pressure tracing in blue, and temperature tracing in green are shown in (b). This subject exhibited generalized transit delays in GET, SBTT, and CTT. CTT, colon transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; SBTT, small bowel transit time; WMC, wireless motility capsule. Content 1, http://links.lww.com/CTG/A100). Gastroparesis (low Supplementary Digital Content 1, http://links.lww.com/CTG/ fat, fiber, or residue and/or liquid and/or frequent, small meals) A100). Site investigators made decisions based on individual and antidumping (separate liquids from solids and/or avoid practice patterns. The first analyses compared new treatment and simple sugars) diets were recorded. Additional testing categories testing recommendations for delayed vs normal GES or WMC included endoscopy/imaging, motility, and other tests (see Sup- gastric emptying. Second, comparisons related management to plemental Methods, Supplementary Digital Content 1, http:// delayed vs normal WMC extragastric and generalized transit. links.lww.com/CTG/A100). Motility test ordering was further Third, comparisons examined decisions for rapid vs normal GES stratified into recommending (i) any motility tests and (ii) mul- or WMC gastric emptying. Additional comparisons ascertained tiple motility tests ($2 tests for any subject). Additional testing whether specific medications were preferentially advocated for was recommended by site investigators based on the resources particular transit profiles, including comparing specific proki- available at each study center. As is commonly observed in clinical netics and neuromodulators for delayed vs normal gastric emp- practice, methods of additional ordered tests likely exhibited tying and specific laxatives with delayed vs normal CTT. differences between sites. However, these testing methods were not queried as part of this study. We excluded recommendations Statistical analysis for additional GES made on the basis of WMC findings or WMCs Descriptive statistics and confidence intervals associated with made on the basis of GES findings. binary variables were computed (24). Comparisons of treatment changes and additional test ordering between tests were per- Relating decisions to transit. Management recommendations formed using an exact calculation McNemar test for binary were related to transit (see Supplemental Methods, endpoints. Fisher exact testing analyzed binary endpoints on American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 4 Hasler et al. Figure 2. Differential effects of GES and WMC findings on treatment recommendations in suspected gastroparesis are shown. WMC testing led to greater changes in medication therapies vs GES (a). Of the 74% of subjects with recommended medication changes, more were informed by WMC results alone compared with GES results alone (b). More than 40% of medication changes were recommended based on both abnormal GES and WMC findings. There were no differences in diet changes made in response to WMC vs GES testing. GES, gastric emptying scintigraphy; WMC, wireless motility capsule. independent subgroup comparisons of GES or WMCs. Table 1B, Supplementary Digital Content 3, http://links.lww.com/ Assessing subgroup differences on GES and WMCs with over- CTG/A102). Smaller numbers showed rapid gastric or small bowel lapping samples used permutation testing based on portion transit. Gastric emptying delays were more common with WMC differences as appropriate, with P values obtained from per- than GES testing (P , 0.001), whereas rapid gastric emptying was mutation test distributions based on 10,000 Monte Carlo sim- detected more often by GES than WMCs (P , 0.001). ulations. Analyses used SAS version 9.4 software (Cary, NC). Primary endpoints RESULTS Medication and diet changes were recommended for 74% and 25% Clinical features of subjects based on combined GES and WMC results. Medication Management plans were completed for 150/167 subjects. Most changes were more often recommended based on WMCs vs GES subjects reported diverse symptoms of gastroparesis; many also (68% vs 48%, P , 0.0001) (Figure 2A) and more often when only reported lower abdominal pain and bowel disturbances (see WMC was abnormal (and GES was normal) than when only GES Table 1A, Supplementary Digital Content 3, http://links.lww.com/ was abnormal (and WMC was normal) (26% vs 6%, P , 0.0001) CTG/A102). Figure 1A shows scintiscans displaying increased (Figure 2B), showing greater impact of WMCs than GES on 4-hour retention (delayed gastric emptying). Figure 1B shows that treatment decisions. subject’s WMC tracing displaying prolonged GET, SBTT, and CTT Additional tests were recommended for 81% of subjects based on (generalized delays). Subject subsets exhibited transit delays in the combined GES and WMC results. Fewer tests were ordered based stomach, small bowel, and/or colon, some of which were isolated to on WMCs (P5 0.0002), and more were eliminated based on WMCs single regions, whereas others were generalized to $2 regions (see (P , 0.0001) vs GES (Figure 3A). Fewer additional tests were Figure 3. Differential effects of GES and WMC findings on recommendations for additional diagnostic testing in suspected gastroparesis are shown. WMC testing promoted less additional test ordering and higher rates of eliminating additional testing (a). Of subjects who were recommended to undergo additional testing, fewer were referred based on WMC alone vs GES alone (b). Of those with elimination of additional testing, more tests were eliminated by WMC alone vs GES alone. More than 50% of additional diagnostic test ordering was recommended based on both abnormal GES and WMC findings. GES, gastric emptying scintigraphy; WMC, wireless motility capsule. Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 5 Table 1. Impact of GES vs WMC testing on clinical decision making A. Impact of GES vs WMC testing on treatment changes Recommended for change in treatment GES WMC New treatment recommended Fraction (%) of subjects Fraction (%) of subjects P value Test with greater impact on management Change in prokinetic 45/150 (30.0) 69/150 (46.0) 0.0007 WMC > GES Change in antiemetic 22/150 (14.7) 21/150 (14.0) 1.00 Same Change in neuromodulator 82/150 (54.7) 71/150 (47.3) 0.10 Same Change in laxative 26/150 (17.3) 54/150 (36.0) ,0.0001 WMC > GES Change in transit retardant 2/150 (1.4) 7/150 (4.7) 0.12 Same Any change in diet 46/150 (30.7) 52/150 (34.7) 0.36 Same Referral for surgery or supplemental feeding 1/150 (0.7) 0/150 (0) — Same B. Impact of GES vs WMC testing on additional diagnostic test recommendations Recommended for additional diagnostic testing GES WMC Additional tests recommended Fraction (%) of subjects Fraction (%) of subjects P value Test with greater impact on management Endoscopy/imaging tests 25/150 (16.7) 15/150 (10.0) 0.09 Same Any motility tests 60/150 (40.0) 51/150 (34.0) 0.14 Same Multiple motility tests ($2 tests for any 33/150 (22.0) 6/150 (4.0) ,0.0001 WMC > GES subject) Other tests 42/150 (28.0) 43/150 (28.7) 1.00 Same GES, gastric emptying scintigraphy; WMC, wireless motility capsule. ordered (P5 0.0002) and more eliminated (P, 0.0001) when only Recommendations for specific prokinetics and neuromodulators WMC was abnormal (and GES was normal) than when only GES were similar for both tests regardless of emptying delays (see was abnormal (and WMC was normal) (Figure 3B), showing greater Table 2A, Supplementary Digital Content 3, http://links.lww. impact of WMCs than GES on additional test recommendations. com/CTG/A102). Multiple motility tests were recommended more often for normal GES vs normal WMC gastric emptying (P5 0.0003) and Specific decisions normal WMC transit in all regions (P 5 0.0007) and for delayed Prokinetics (P 5 0.0007) and laxatives (P , 0.0001) but not other therapies were recommended more often based on WMC vs GES gastric emptying by GES vs WMCs (P 5 0.004) (Table 3). Rec- results (Table 1A). Recommendations for endoscopy/imaging tests ommendations for any motility test (P 5 0.03) and multiple trended higher (P 5 0.09) based on the GES vs WMC results motility tests (P5 0.006) were greater for normal GES vs normal (Table 1B). Recommendations for any additional motility testing WMC transit in all regions, showing greater impact of WMCs vs were similar based on GES vs WMCs. Multiple motility tests were GES on test ordering in different gastric emptying subsets. recommended more often based on GES than WMCs (P, 0.0001), Specific motility tests included radiopaque markers and ano- showing greater impact of WMCs than GES on specific treatment rectal and antroduodenal manometry (see Table 2B, Supplementary and testing decisions. Digital Content 3, http://links.lww.com/CTG/A102). Radiopaque markers were recommended more often for GES vs WMCs when Relating transit to decisions gastric emptying was delayed (P 5 0.02) or normal (P 5 0.001). Related to delayed gastric emptying. Prokinetics and gastro- paresis diets were recommended more often and neuromodulators Related to delayed extragastric transit. Prokinetics were recom- less for delayed vs normal gastric emptying by GES or WMCs (P# mended more often for delayed vs normal SBTT (P , 0.0001) 0.0006) (Table 2). Prokinetics (P5 0.01) and laxatives (P5 0.0001) (Table 4). This difference disappeared when SBTT delays were iso- were recommended more often and neuromodulators less (P 5 lated. Laxatives were recommended more often for delayed vs nor- 0.03) for normal WMC gastric emptying vs normal GES. Differ- mal CTT (P , 0.0001). This difference persisted when CTT delays ences disappeared when normal WMC transit in all regions was were isolated abnormalities (P , 0.0001). Specific laxatives (poly- compared with normal GES. Treatment recommendations were ethylene glycol 3350, linaclotide, and lubiprostone) were similarly similar for delayed GES vs WMC gastric emptying. This shows that advocated for delayed vs normal CTT (see Table 3A, Supplementary finding delayed vs normal gastric emptying has a different impact Digital Content 3, http://links.lww.com/CTG/A102). Prokinetics on treatment decisions made after both WMC and GES testing. capable of stimulating colon transit (pyridostigmine and pruca- Specific recommended prokinetics included metoclopramide, lopride) were recommended more often for delayed (7/45, 15.6%) domperidone, macrolides, and pyridostigmine. Common neu- than normal CTT (2/101, 2.0%) (P 5 0.004). Prokinetics were rec- romodulators were mirtazapine, tricyclics, and gabapentin. ommended more often (P 5 0.0001) with generalized vs isolated American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 6 Hasler et al. Table 2. Impact of GES and WMC testing on treatment changes in relation to gastric emptying delays Recommended for change in treatment Gastric emptying comparison New treatment recommended Percent of subjects P value Test with greater impact on management Delayed GES (n 5 36) vs normal GES Prokinetic change 80.6% vs 15.2% ,0.0001 Delayed > normal GES Antiemetic change 19.4% vs 16.3% 0.79 Same (n 5 92) Neuromodulator change 19.4% vs 68.5% ,0.0001 Normal > delayed GES Laxative change 25.0% vs 14.1% 0.19 Same Transit-retardant change 2.8% vs 1.1% 0.48 Same Gastroparesis diet change 63.9% vs 16.3% ,0.0001 Delayed > normal GES Delayed GET (n 5 53) vs normal GET Prokinetic change 83.0% vs 26.4% ,0.0001 Delayed > normal GET Antiemetic change 20.8% vs 11.0% 0.14 Same (n 5 91) Neuromodulator change 28.3% vs 58.2% 0.0006 Normal > delayed GET Laxative change 34.0% vs 37.4% 0.72 Same Transit-retardant change 1.9% vs 4.4% 0.65 Same Gastroparesis diet change 50.9% vs 17.6% 0.0001 Delayed > normal GET Normal GES (n 5 92) vs normal GET Prokinetic change 15.2% vs 26.4% 0.01 Normal GET > normal GES Antiemetic change 16.3% vs 11.0% 0.19 Same (n 5 91) Neuromodulator change 68.5% vs 58.2% 0.03 Normal GES > normal GET Laxative change 14.1% vs 37.4% 0.0001 Normal GET > normal GES Transit-retardant change 1.1% vs 4.4% 0.20 Same Gastroparesis diet change 16.3% vs 17.6% 0.75 Same Normal GES (n 5 92) vs normal WMC Prokinetic change 15.2% vs 17.9% 0.11 Same Antiemetic change 16.3% vs 10.7% 0.32 Same transit in all regions (n 5 56) Neuromodulator change 68.5% vs 60.7% 0.051 Same Laxative change 14.1% vs 21.4% 0.16 Same Transit-retardant change 1.1% vs 7.1% 0.06 Same Gastroparesis diet change 16.3% vs 17.9% 0.41 Same Delayed GES (n 5 36) vs delayed GET Prokinetic change 80.6% vs 83.0% 0.52 Same Antiemetic change 19.4% vs 20.8% 0.76 Same (n 5 53) Neuromodulator change 19.4% vs 28.3% 0.43 Same Laxative change 25.0% vs 34.0% 0.17 Same Transit-retardant change 2.8% vs 1.9% 0.50 Same Gastroparesis diet change 63.9% vs 50.9% 0.11 Same GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule. delays (Table 4). This shows differential impact of different WMC Supplementary Digital Content 3, http://links.lww.com/CTG/ extragastric findings on treatment decisions. A102). This shows the impact of rapid GES and WMC transit on Additional motility tests were recommended more often with management decisions. delayed vs normal SBTT (P 5 0.03) (Table 5). This difference disappeared when SBTT delays were isolated. Additional motility DISCUSSION tests were recommended more often with delayed vs normal CTT Although gastric emptying testing is used for patients with sus- (P 5 0.02). This difference still trended higher when CTT delays pected gastroparesis, there is little evidence to suggest these tests were isolated (P 5 0.06). Specific motility test recommendations influence management choices. This investigation prospectively were similar for delayed and normal CTT (see Table 3B, Supple- compared how GES and WMC testing informs recommendations mentary Digital Content 3, http://links.lww.com/CTG/A102). for treatments and additional diagnostic evaluations in these Testing recommendations were similar for generalized and isolated patients. Its unique features include its large size, diverse patient delays. This shows differential impact of different WMC extra- cohort, standardized transit methods, and structured character- gastric findings on test ordering. ization of management recommendations. This comprehensive, multicenter study did not have the drawbacks of previous retro- Related to rapid transit. Transit-retardant medications were spective publications. There was also no bias from practice patterns recommended more often for rapid vs normal GET (P 5 0.03) of any single provider. Thus, these decisions more closely reflected (see Table 4A, Supplementary Digital Content 3, http://links. the diverse management approaches of clinicians in varied medical lww.com/CTG/A102). Antidumping diets were recommended settings. more often for rapid GET (P 5 0.01) and trended higher for Previous studies evaluating impact of transit tests on decisions rapid GES (P 5 0.09) vs normal emptying. Prokinetic medi- in suspected gastroparesis had deficiencies. Three limited retro- cations were recommended more often when SBTT was rapid spective series used medical record review, which may not con- than when it was normal (P 5 0.04). Additional testing rec- sistently capture management choices (13,16,17). One ommendations did not relate to rapid transit (see Table 4B, prospective study described the influence of GES on medication Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 7 Table 3. Impact of GES and WMC testing on additional diagnostic test recommendations in relation to gastric emptying delays Recommended for additional diagnostic testing Gastric emptying comparison Additional test recommended Percent of subjects P value Test with greater impact on management Delayed GES (n 5 36) vs normal GES Endoscopy/imaging tests 8.3% vs 18.5% 0.19 Same Any motility tests 38.9% vs 41.3% 0.84 Same (n 5 92) Multiple ($2) motility tests 19.4% vs 23.9% 0.65 Same Other tests 19.4% vs 29.3% 0.28 Same Delayed GET (n 5 53) vs normal GET Endoscopy/imaging tests 9.4% vs 11.0% 1.00 Same Any motility tests 35.8% vs 33.0% 0.72 Same (n 5 91) Multiple ($2) motility tests 1.9% vs 5.5% 0.41 Same Other tests 26.4% vs 29.7% 0.71 Same Normal GES (n 5 92) vs normal GET Endoscopy/imaging tests 18.5% vs 11.0% 0.14 Same Any motility tests 41.3% vs 33.0% 0.19 Same (n 5 91) Multiple ($2) motility tests 23.9% vs 5.5% 0.0003 Normal GET > normal GES Other tests 29.3% vs 30.0% 0.81 Same Normal GES (n 5 92) vs normal WMC Endoscopy/imaging tests 18.5% vs 14.3% 0.78 Same Any motility tests 41.3% vs 23.2% 0.03 Normal WMC > normal GES transit in all regions (n 5 56) Multiple ($2) motility tests 23.9% vs 5.4% 0.0007 Normal WMC > normal GES Other tests 29.3% vs 32.1% 0.67 Same Delayed GES (n 5 36) vs delayed GET Endoscopy/imaging tests 8.3% vs 9.4% 0.74 Same Any motility tests 38.9% vs 35.8% 0.95 Same (n 5 53) Multiple ($2) motility tests 19.4% vs 1.9% 0.004 Delayed GET > delayed GES Other tests 19.4% vs 26.4% 0.27 Same GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule. and diet changes made by 30 physicians but offered few details on publications (25–27). Neuromodulators were recommended specific medications and did not discuss additional diagnostic more often for normal GES than normal WMCs unless all gut testing or compare GES with WMCs (20). regions had normal transit, suggesting that the WMC extragastric Our coprimary endpoints uncovered differences in how clini- results influenced these decisions. cians use GES and WMCs to make decisions. Medication changes In addition to experiencing symptoms of gastroparesis, some were recommended more frequently, and ordering of diagnostic subjects reported lower abdominal pain and bowel disturbances tests was less frequent with WMCs vs GES. Specific choices included potentially originating in the distal gut. Similar high degrees of greater recommendations for prokinetics and laxatives for WMCs lower abdominal symptoms have been observed in published and increased ordering of multiple motility tests with GES. Because large gastroparesis cohorts (9,10,28). Our findings illustrate WMC results led to recommending more treatments and fewer advantages of WMC extragastric measurements, which may be additional tests than GES, we concluded that WMCs have greater relevant to these symptoms. Small bowel delays promoted more impact on decision making in managing suspected gastroparesis. prokinetic recommendations, but sample sizes were small and Subgroup analyses were designed to test whether these differences disappeared after excluding other regional delays. coprimary endpoint findings resulted from greater sensitivity of Delayed colon transit correlated with recommending increased detecting delayed gastric emptying, extragastric delays, or rapid laxative use. Some patients with CTT delays were prescribed transit. Delayed gastric emptying by either test increased proki- colonic prokinetic agents, confirming that WMCs can direct netic recommendations, indicating a pathophysiological man- specific decisions in treating constipation. Further investigations agement approach. Prokinetics were recommended more often will determine whether interventions targeting extragastric after WMC testing because of the greater sensitivity of WMCs findings will translate into better outcomes in suspected gastro- over GES to detect delayed gastric emptying. Higher recom- paresis, although one pediatric study reported that laxatives can mendations of prokinetics for normal WMC gastric emptying vs reduce gastroparesis symptoms (29). Prokinetics were recom- normal GES disappeared when small bowel and colon transit mended more often for generalized vs isolated delays, because of delays were excluded, indicating that prokinetics were likely increased gastric emptying delays with generalized (28/32, 87.5%) prescribed for extragastric transit impairments. Although treat- vs isolated (22/53, 41.5%) transit impairments (P , 0.0001). ment of functional dyspepsia (including postprandial distress) Agents that slow transit were advocated more often for rapid has been extensively studied, the literature on managing sus- WMC gastric emptying. Prokinetics were ordered more for rapid pected gastroparesis patients with normal gastric emptying is SBTT. Although this might seem counterintuitive, 2 of 3 patients limited. This study provides the first report affirming preferential with rapid SBTT exhibited delayed gastric emptying by GES or neuromodulator use in this large patient subset with normal WMCs providing a pathophysiologic rationale for use of this drug emptying. Tricyclics are reportedly ineffective in gastroparesis class. Rapid CTT was not evaluated because it is not an established but are beneficial for functional dyspepsia with normal gastric measure, as defecation can occur any time after the onset of co- emptying; thus, our observations corroborate previous lonic high-amplitude propagating contractions (30,31). American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 8 Hasler et al. Table 4. Impact of GES and WMC testing on treatment changes in relation to extragastric transit delays Recommended for change in treatment Extragastric transit comparison New treatment recommended Percent of subjects P value Test with greater impact on management Delayed SBTT (n 5 33) vs normal SBTT Prokinetic change 75.8% vs 33.6% ,0.0001 Delayed > normal SBTT Antiemetic change 15.2% vs 13.6% 0.78 Same (n 5 110) Neuromodulator change 45.5% vs 50.9% 0.69 Same Laxative change 36.4% vs 36.4% 1.00 Same Transit-retardant change 6.1% vs 4.5% 0.66 Same Delayed SBTT as isolated WMC abnormality Prokinetic change 54.5% vs 33.6% 0.20 Same Antiemetic change 0.0% vs 13.6% 0.36 Same (n 5 11) vs normal SBTT (n 5 110) Neuromodulator change 54.5% vs 50.9% 1.00 Same Laxative change 27.3% vs 36.4% 0.74 Same Transit-retardant change 9.1% vs 4.5% 0.44 Same Delayed CTT (n 5 45) vs normal CTT Prokinetic change 55.6% vs 39.6% 0.10 Same Antiemetic change 15.6% vs 12.9% 0.79 Same (n 5 101) Neuromodulator change 42.2% vs 51.5% 0.37 Same Laxative change 75.6% vs 18.8% ,0.0001 Delayed > normal CTT Transit-retardant change 2.2% vs 5.9% 0.44 Same Delayed CTT as isolated WMC abnormality Prokinetic change 25.0% vs 39.6% 0.31 Same Antiemetic change 5.0% vs 12.9% 0.46 Same (n 5 20) vs normal CTT (n 5 101) Neuromodulator change 50.0% vs 51.5% 1.00 Same Laxative change 75.0% vs 18.8% ,0.0001 Isolated CTT delay > normal CTT Transit-retardant change 0% vs 5.9% 0.59 Same Generalized WMC delay (n 5 32) vs isolated Prokinetic change 90.6% vs 49.1% 0.0001 Generalized > isolated delay Antiemetic change 18.8% vs 11.3% 0.35 Same WMC delay (n 5 53) Neuromodulator change 37.5% vs 43.4% 0.65 Same Laxative change 56.2% vs 39.6% 0.18 Same Transit-retardant change 3.1% vs 1.9% 1.00 Same CTT, colon transit time; GES, gastric emptying scintigraphy; SBTT, small bowel transit time; WMC, wireless motility time. Diet recommendations were influenced by transit results. suggested that marker retention profiles may be different in slow Gastroparesis diets were preferentially advocated for delayed transit constipation than with outlet obstruction, although this was gastric emptying, supporting a controlled diabetic gastroparesis not subsequently confirmed (36). It is possible that some site trial reporting benefits of small particle diets (32). Antidumping investigators wished to measure regional colon transit delays in diets were advocated more for rapid gastric emptying, again some of their study patients. reflecting a physiologic basis for treatment (33). Although rapid This investigation had limitations. Each center had different emptying can be found in functional dyspepsia, diabetes, and resources and practice standards, which influenced local man- cyclic vomiting, the pathophysiologic relevance of rapid transit agement options. We considered this a strength of this study, as it remains unproved (15,16,34). reflected real-life practice patterns across diverse settings. Site Recommendations for additional testing differed based on investigators were afforded leeway in making decisions, which did transit. Multiple motility tests were more often advised based on not consider medication affordability, insurance coverage, or GES vs WMCs regardless of delays probably because GES provides acceptance of invasive testing. It was beyond the scope of this no extragastric information. More additional motility tests were investigation to determine whether differences in the impact of recommended for delayed vs normal small bowel and colon transit; WMC vs GES findings on management decisions translated into differences trended higher when colon delays were isolated. WMC different symptom and quality of life outcomes. Furthermore, it testing did not eliminate decisions to perform anorectal manom- was not possible to quantify longitudinal outcomes relating to etry to exclude dyssynergia as a cause of constipation (35). Ano- management decisions that were made based on findings of either rectal manometry was similarly advocated for 39 patients after WMCs or GES as individual tests; rather, any outcome would be obtaining GES results vs 42 patients after obtaining WMC results. influenced by clinical decisions that were made by site inves- However, anorectal manometry was not ordered significantly more tigators based on knowledge of both the WMC and GES results often in those with delayed WMC CTT (17/45, 37.8%) than with taken together. We plan to correlate transit findings with symp- normal CTT (25/101, 24.8%) (P5 0.12), indicating that the WMC tom profiles at baseline and follow-up in future reports. Never- colon transit interpretation was not the sole determining factor in theless, our detailed findings provide unique insights into how ordering this test. By contrast, radiopaque marker studies were clinicians approach management decisions in patients with pre- ordered more often after GES reflecting the inability of gastric test possibilities of having gastroparesis. scintigraphy to measure colon transit. Curiously, small numbers of In conclusion, gastric emptying and gut transit testing influ- radiopaque marker tests were ordered on the basis of WMC enced management decisions in suspected gastroparesis. WMC findings, although WMC CTT results were available. Older studies findings led to greater medication changes and fewer Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 9 Table 5. Impact of gastric emptying scintigraphy and WMC testing on additional diagnostic test recommendations in relation to extragastric transit delays Recommended for additional diagnostic testing Extragastric transit comparison Additional test recommended Percent of subjects P value Test with greater impact on management Delayed SBTT (n 5 33) vs normal SBTT Endoscopy/imaging tests 9.1% vs 9.1% 1.00 Same (n 5 110) Any motility tests 48.5% vs 27.3% 0.03 Delayed > normal SBTT Multiple ($2) motility tests 6.1% vs 3.6% 0.62 Same Other tests 36.4% vs 25.5% 0.27 Same Delayed SBTT as isolated WMC abnormality Endoscopy/imaging tests 9.1% vs 9.1% 1.00 Same Any motility tests 45.5% vs 27.3% 0.29 Same (n 5 11) vs normal SBTT (n 5 110) Multiple ($2) motility tests 0% vs 3.6% 1.00 Same Other tests 36.4% vs 25.5% 0.48 Same Delayed CTT (n 5 45) vs normal CTT Endoscopy/imaging tests 6.7% vs 9.9% 0.75 Same Any motility tests 46.7% vs 26.7% 0.02 Delayed > normal CTT (n 5 101) Multiple ($2) motility tests 4.4% vs 4.0% 1.00 Same Other tests 28.9% vs 28.7% 1.00 Same Delayed CTT as isolated WMC abnormality Endoscopy/imaging tests 5.0% vs 9.9% 0.69 Same Any motility tests 50.0% vs 26.7% 0.06 Same (n 5 20) vs normal CTT (n 5 101) Multiple ($2) motility tests 5.0% vs 4.0% 1.00 Same Other tests 15.0% vs 28.7% 0.27 Same Generalized delay (n 5 32) vs isolated Endoscopy/imaging tests 9.4% vs 3.8% 0.36 Same Any motility tests 46.9% vs 37.7% 0.50 Same delay (n 5 53) Multiple ($2) motility tests 6.2% vs 1.9% 0.55 Same Other tests 34.4% vs 22.6% 0.31 Same CTT, colon transit time; SBTT, small bowel transit time; WMC, wireless motility capsule. recommendations for additional motility testing compared with MA501). Matilde Lourd, a Medtronic employee, provided some GES. Recommendations for prokinetics, neuromodulators, and initial data analyses for the primary endpoints of this study before its gastroparesis diets were influenced by gastric emptying delays, presentation at the 2017 World Congress of Gastroenterology whereas laxative recommendations and ordering of additional meeting; statistical analyses of these data were verified by Gregory E. coloanal motility tests were influenced by extragastric delays. Wilding, and all additional statistical analyses relating to specific management decisions and decisions related to gut transit abnormalities were conducted by Gregory E. Wilding, a consultant CONFLICTS OF INTEREST for Medtronic as described below. All initial data collection was Guarantor of the article: William L. Hasler, MD. performed by site investigators. Data were transferred to a central Specific author contributions: W.L.H.: Study design, experimental database supervised by Medtronic. Medtronic did not participate in conduct, data collection, data analysis, manuscript preparation, and study design, data interpretation, writing support, or other approval of the final manuscript version. S.S.C.R: Experimental preparation assistance for this article. conduct, data collection, manuscript preparation, and approval of the Potential competing interests: W.L.H.: Received grant funding from final manuscript version. R.W.M.: Experimental conduct, data Medtronic for conduct of research as site principal investigator at collection, and approval of the final manuscript version. R.A.K.: University of Michigan, Ann Arbor, MI. S.S.C.R.: Received grant Experimental conduct, data collection, and approval of the final funding from Medtronic for conduct of research as site principal manuscript version. L.A.N.: Experimental conduct, data collection, and investigator at Medical College of Georgia, Augusta, GA. R.W.M.: approval of the final manuscript version. M.I.S.: Experimental conduct, Received grant funding from Medtronic for conduct of research as data collection, and approval of the final manuscript version. A.A.L.: site co-principal investigator at Texas Tech University, El Paso, TX. Experimental conduct, data collection, manuscript preparation, and R.A.K.: Received grant funding from Medtronic for conduct of re- approval of the final manuscript version. B.M.: Experimental conduct, search as site principal investigator at ClinSearch, Chattanooga, TN. data collection, and approval of the final manuscript version. J.M.W.: L.A.N.: Received grant funding from Medtronic for conduct of re- Experimental conduct, data collection, and approval of the final search as site principal investigator at Stanford University, Palo Alto, manuscript version. H.P.P.: Experimental conduct, data collection, and CA. M.I.S.: Received grant funding from Medtronic for conduct of approval of the final manuscript version. I.S.: Experimental conduct, research as site principal investigator at Florida Digestive Health data collection, and approval of the final manuscript version. G.E.W.: Associates, Largo, FL. A.A.L.: Received grant funding from Med- Study design and statistical analysis of data. B.K.: Study design, tronic for conduct of research as site principal investigator at the experimental conduct, data collection, data analysis, manuscript University of Vermont, Burlington, VT (he has since moved to the preparation, and approval of the final manuscript version. University of Michigan, Ann Arbor, MI). B.M.: Received grant Financial support: The parent study supporting the data and funding from Medtronic for conduct of research as site principal analyses included in this article were funded by Medtronic (grant investigator at the University of Miami, Miami, FL (she has since American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 10 Hasler et al. with suspected gastroparesis. Clin Gastroenterol Hepatol 2019;17: moved to Carolinas HealthCare System, Charlotte, NC). J.M.W.: 1770–9.e2. Received grant funding from Medtronic for conduct of research as 8. Stein E, Berger Z, Hutfless S, et al. Wireless Motility Capsule Versus Other site principal investigator at Indiana University, Indianapolis, IN. Diagnostic Technologies for Evaluating Gastroparesis and Constipation: H.P.P.: Received grant funding from Medtronic for conduct of re- A Comparative Effectiveness Review. Agency for Healthcare Research search as site principal investigator at Temple University, Phila- and Quality; 2013. 9. Parkman HP, Yates K, Hasler WL, et al. Clinical features of idiopathic delphia, PA. I.S.: Received grant funding from Medtronic for conduct gastroparesis vary with sex, body mass, symptom onset, delay in gastric of research as site co-principal investigator at Texas Tech University, emptying, and gastroparesis severity. Gastroenterology 2011;140:101–15. El Paso, TX. G.E.W.: Received compensation as a consultant by 10. Parkman HP, Yates K, Hasler WL, et al. Similarities and differences Medtronic for statistical analyses of study data. B.K.: Received grant between diabetic and idiopathic gastroparesis. Clin Gastroenterol funding from Medtronic for conduct of research as site principal Hepatol 2011;9:1056–64. investigator at Massachusetts General Hospital, Boston, MA. None of 11. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal disorders. Gastroenterology 2016;150:1380–92. the investigators is an employee of Medtronic, none owns stocks or 12. Arora Z, Parungao JM, Lopez R, et al. Clinical utility of wireless motility shares in Medtronic, and none owns patents with Medtronic. capsule in patients with suspected multiregional gastrointestinal Clinical trial registry: Analyses included in this article were dysmotility. Dig Dis Sci 2015;60:1350–7. conducted according to a priori planned secondary study endpoints 13. Hasler WL, May KP, Wilson LA, et al. Relating gastric scintigraphy and of a registered clinical trial (ClinicalTrials.gov NCT02022826). symptoms to motility capsule transit and pressure findings in suspected gastroparesis. Neurogastroenterol Motil 2018;30. 14. Delgado-Aros S, Camilleri M, Cremonini F, et al. Contributions of gastric Study Highlights volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia. Gastroenterology 2004;127:1685–94. WHAT IS KNOWN 15. Bharucha AE, Camilleri M, Forstrom LA, et al. Relationship between clinical features and gastric emptying disturbances in diabetes mellitus. 3 Gastric emptying is measured by GES or WMCs; the latter also Clin Endocrinol (Oxf) 2009;70:415–20. 16. Rao SS, Camilleri M, Hasler WL, et al. Evaluation of gastrointestinal assesses extragastric transit. transit in clinical practice: Position paper of the American and European 3 Patients with suspected gastroparesis report diffuse Neurogastroenterology and Motility Societies. Neurogastroenterol Motil symptoms suggesting possible generalized dysmotility. 2011;23:8–23. 3 Impacts of GES and WMCs on management decisions are 17. Galil MA, Critchley M, Mackie CR. Isotope gastric emptying tests in poorly defined. clinical practice: Expectation, outcome, and utility. Gut 1993;34:916–9. 18. Kuo B, Maneerattanaporn M, Lee AA, et al. Generalized transit delay on WHAT IS NEW HERE wireless motility capsule testing in patients with clinical suspicion of gastroparesis, small intestinal dysmotility, or slow transit constipation. 3 More treatment changes were recommended, and ordering Dig Dis Sci 2011;56:2928–38. of additional motility tests was eliminated more based on 19. Rao SS, Mysore K, Attaluri A, et al. Diagnostic utility of wireless motility WMCs—testing which detected more gastric and extragastric capsule in gastrointestinal dysmotility. J Clin Gastroenterol 2011;45: 684–90. abnormalities. 20. Tseng AS, Crowell MD, DiBaise JK. Clinical utility of gastric emptying 3 These tests provided information that differentially influenced scintigraphy: Patient and physician perspectives. Neurogastroenterol clinical decisions in suspected gastroparesis. Motil 2018;30:e13279. 21. Wang YT, Mohammed SD, Farmer AD, et al. Regional gastrointestinal TRANSLATIONAL IMPACT transit and pH studied in 215 healthy volunteers using the wireless motility capsule: Influence of age, gender, study country and testing 3 These detailed findings provide novel insight about how protocol. Aliment Pharmacol Ther 2015;42:761–72. motility specialists use gut transit data to make decisions on 22. Rao SS, Kuo B, McCallum RW, et al. Investigation of colonic and whole- treating and ordering other testing in patients with suspected gut transit with wireless manometry capsule and radiopaque markers in gastroparesis. constipation. Clin Gastroenterol Hepatol 2009;7:537–44. 23. Camilleri M, Thorne NK, Ringel Y, et al. Wireless pH-motility capsule for colonic transit: Prospective comparison with radiopaque markers in chronic constipation. Neurogastroenterol Motil 2010;22:874–82. 24. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated REFERENCES in the case of binomial. Biometrika 1934;26:404–13. 1. Hasler WL. 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Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/04/2020 ARTICLE 1 Influence of Gastric Emptying and Gut Transit Testing on Clinical Management Decisions in Suspected Gastroparesis 1 2 3 4 5 William L. Hasler, MD , Satish S. C. Rao, MBBS , Richard W. McCallum, MD , Richard A. Krause, MD , Linda A. Nguyen, MD , 6 1 7 8 9 3 Michael I. Schulman, DO , Allen A. Lee, MD , Baharak Moshiree, MD , John M. Wo, MD , Henry P. Parkman, MD , Irene Sarosiek, MD , 10 11 Gregory E. Wilding, PhD and Braden Kuo, MD INTRODUCTION: Gastric emptyingscintigraphy (GES)or wireless motility capsules (WMCs)canevaluateupper gastrointestinal symptoms in suspected gastroparesis; WMC tests can also investigate lower gut symptoms. We aimed to determine whether these tests impact treatment plans and needs for additional diagnostic evaluation. METHODS: In a prospective, multicenter study, 150 patients with gastroparesis symptoms simultaneously underwent GES and WMC testing. Based on these results, investigators devised management plans to recommend changes in medications, diet, and surgical therapies and order additional diagnostic tests. RESULTS: Treatment changes were recommended more often based on the WMC vs GES results (68% vs 48%) (P < 0.0001). Ordering of additional test(s) was eliminated more often with WMC vs GES (71% vs 31%) (P < 0.0001). Prokinetics (P 5 0.0007) and laxatives (P < 0.0001) were recommended more often based on the WMC vs GES results. Recommendations for prokinetics and gastroparesis diets were higher and neuromodulators lower in subjects with delayed emptying on both tests (all P £ 0.0006). Laxatives and additional motility tests were ordered more frequently for delayed compared with normal WMC colonic transit (P £ 0.02). Multiple motility tests were ordered more often on the basis of GES vs WMC findings (P £ 0.004). Antidumping diets and transit slowing medications were more commonly recommended for rapid WMC gastric emptying (P £ 0.03). DISCUSSION: WMC transit results promote medication changes and eliminate additional diagnostic testing more often than GES because of greater detection of delayed gastric emptying and profiling the entire gastrointestinal tract in patients with gastroparesis symptoms. TRANSLATIONAL Gastric scintigraphy and WMCs have differential impact on management decisions in suspected IMPACT: gastroparesis. SUPPLEMENTARY MATERIAL accompanies this paper at http://links.lww.com/CTG/A100, http://links.lww.com/CTG/A101, http://links.lww.com/CTG/A102 Clinical and Translational Gastroenterology 2019;10:e00084. https://doi.org/10.14309/ctg.0000000000000084 INTRODUCTION measure gastric emptying by detecting pH increases during capsule Gastric emptying testing is performed to diagnose gastroparesis (1). passage into the duodenum (4,5). Breath tests also quantify gastric Gastric emptying scintigraphy (GES) measures retention of 99mTc- emptying by measuring 13CO production after 13C-labeled meals labeled meals (2,3). Wireless motility capsules (WMCs) also (6). Two prospective concurrent GES and WMC studies and other 1 2 Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan, USA; Division of Gastroenterology and Hepatology, Medical College of 3 4 Georgia, Augusta, Georgia, USA; Section of Gastroenterology, Texas Tech University, El Paso, Texas, USA; Clin Search, LLC, Chattanooga, Tennessee, USA; 5 6 7 Division of Gastroenterology, Stanford University, Palo Alto, California, USA; Florida Digestive Health Associates, Largo, Florida, USA; Atrium Health Gastroenterology and Hepatology, Carolinas HealthCare System Digestive Health-Morehead Medical Plaza, Charlotte, North Carolina, USA; Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA; Section of Gastroenterology, Temple University, Philadelphia, Pennsylvania, 10 11 USA; Department of Biostatistics, University of Buffalo, Buffalo, New York, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA. Correspondence: William L. Hasler, MD. E-mail: whasler@umich.edu. Received April 20, 2019; accepted August 16, 2019; published online October 28, 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY Downloaded from http://journals.lww.com/ctg by BhDMf5ePHKbH4TTImqenVA5KvPVPZ0P5BEgU+IUTEfzO/GUWifn2IfwcEVVH9SSn on 06/04/2020 2 Hasler et al. investigations performing each test separately determined these Delayed gastric emptying on WMC testing was defined as.5-hour tests identify similar but not identical subgroups with emptying gastric emptying time (GET) (21). Rapid gastric emptying on delays (4,7,8). WMC testing was defined as GET ,1:45 hours (21). Delayed Patients with suspected gastroparesis may report symptoms re- transit times in the small bowel (SBTT) and colon (CTT) on WMC ferable to other transit impairments in the stomach and extragastric testing were defined as .6and .58:45 hours, respectively (21). regions (9–12). Rapid gastric emptying can present with symptoms Rapid SBTT on WMC testing was defined as ,2:15 hours (21). indistinguishable from gastroparesis (13–15). Furthermore, delays in small intestinal and colon transit with WMCs have been described Management decision protocol in 15.5% and 33.5% of suspected gastroparesis, respectively (13). Analyses were conducted according to a priori planned study Scintigraphy is usually limited to the stomach because of multiple endpoints (MA-501 Clinical Trial Protocol, 3/15/2015, pages visits required to measure small bowel and colon transit (16). 25–27, see Supplementary Digital Content 2, http://links.lww.com/ Whether transit findings influence management of suspected CTG/A101). Five to 28 days after testing, site investigators com- gastroparesis is uncertain. In an older series, GES had little impact pleted 3 management plans on standardized forms describing on clinical decisions, although most patients had postvagotomy treatment recommendations, including changes to medications complications (17). WMC findings promoted medication and nu- and diet (gastroparesis diets, liquid or other diets, and enteral or tritional changes in 60% and 14%, and additional tests were elimi- parenteral nutrition) and referrals for surgery (feeding tube and nated in one retrospective series (18). New prokinetic, antiemetic, gastric stimulator or resection). Management forms also docu- antidepressant, and laxative therapies were described in 50% in mented recommendations for additional diagnostic testing. another report (18,19). In the only prospective study published to Investigators entered names of medications and additional tests on date, GES findings influenced management decisions in 60% of management forms. The first plan was based on one test (GES or patients including recommendations to change the diet in those WMCs) in alternating order with blinding to the other test; the with delayed gastric emptying and to eliminate selected medications second plan was based on the other test but unblinded to thefirst on in individuals with normal gastric emptying (20). These inves- separate days; the third plan was based on combining GES and tigations did not determine whether GES and WMCs have differ- WMC results. Management forms were reviewed separately by 2 ential impact on decisions in suspected gastroparesis. investigators (W.L.H. and A.A.L.), confirming their accuracy. We performed a prospective, multicenter concurrent GES and These investigators initially disagreed on management decisions WMC study in patients with suspected gastroparesis. Site inves- for 6/150 subjects (4%). A final arbiter (B.K.) uninvolved in initial tigators completed management plans, recommending treatment reviews resolved these differences. changes and additional testing based on transit findings. We aimed to characterize whether: (i) GES and WMCs had differ- Data comparisons ential impact on clinical decisions, (ii) specific treatments and Primary endpoints. Coprimary endpoints were defined as changes testing recommendations were influenced by gastric emptying, in treatment and diagnostic testing based on transit tests. Additional and (iii) additional management recommendations were made forms were completed that recorded whether medication (proki- based on extragastric delays or rapid transit. netics, antiemetics, and neuromodulators) or diet changes or sur- gical referrals were recommended. Medication changes were defined METHODS as starting a new drug category. Starting a prokinetic de novo or Subject population switching from a prokinetic to antiemetic was considered a change, One hundred sixty-seven patients (18–80 years) with $2 symp- whereas switching from one prokinetic to another (e.g., metoclo- toms suggesting gastroparesis (nausea/vomiting, fullness/early sa- pramide to domperidone) was not a change, unless the original and tiety, bloating/distension, and upper abdominal discomfort/pain) new drugs targeted different gut regions. Adding a neuromodulator for $12 weeks were referred for gastroparesis care to 10 centers with potential mechanistic benefits in patients with gastroparesis from 2013 to 2016 (ClinicalTrials.gov NCT02022826). Esoph- symptoms (e.g., tricyclic agent, mirtazapine, olanzapine, or neuro- agogastroduodenoscopy or radiography excluded organic dis- pathic pain modulator for nausea and/or abdominal pain; buspirone orders. Exclusion criteria included dysphagia, previous to enhance fundic accommodation) who already were prescribed gastrointestinal surgery (except appendectomy, cholecystectomy, neuromodulators in different classes for other indications (e.g., se- and hysterectomy), abdominopelvic surgery within 3 months, in- rotonin or serotonin-norepinephrine reuptake inhibitors for de- flammatory bowel disease, chronic nonsteroidal anti-inflammatory pression; benzodiazepines for anxiety) was considered a medication drug use, diverticulitis, intestinal strictures, HbA1c . 10%, change. A separate item on the form asked whether transit findings implanted cardiac devices, and body mass index . 40 kg/m .In- prompted investigators to recommend eliminating additional tests. stitutional review board approval was obtained at each center. Investigators determined whether management changes were based Subjects provided written informed consent. on GES, WMCs, or both tests together. GES and WMC methodology Specific decisions. Specific changes in medication categories, Subjects underwent concurrent GES and WMCs; transit was de- diets, referrals for surgery, and additional testing were de- termined for subjects completing management plans (see Supple- termined from the lead author (W.L.H.) review of site manage- mental Methods, Supplementary Digital Content 1, http://links. ment forms. Greater impact of one test (GES or WMCs) vs the lww.com/CTG/A100) (5,21–23). Transit abnormalities on GES other on management decisions was defined when that test led to and WMC testing were determined using previously reported more treatment or fewer additional test recommendations. Spe- values. Delayed gastric emptying on GES testing was defined as cific medication categories included prokinetics, antiemetics, .10% meal retention at 4 hours (3). Rapid gastric emptying on neuromodulators, laxatives, and agents to slow transit (retard- GES testing was defined as ,38% meal retention at 1 hour (2,3). ants) (see Supplemental Methods, Supplementary Digital Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 3 Figure 1. GES and WMC findings are shown for a subject with suspected gastroparesis. Scintigraphy images and emptying profiles of the radiolabeled meal are shown in (a). This individual exhibited mildly delayed gastric emptying at 4 hours. The WMC and tracing with the pH tracing in red, pressure tracing in blue, and temperature tracing in green are shown in (b). This subject exhibited generalized transit delays in GET, SBTT, and CTT. CTT, colon transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; SBTT, small bowel transit time; WMC, wireless motility capsule. Content 1, http://links.lww.com/CTG/A100). Gastroparesis (low Supplementary Digital Content 1, http://links.lww.com/CTG/ fat, fiber, or residue and/or liquid and/or frequent, small meals) A100). Site investigators made decisions based on individual and antidumping (separate liquids from solids and/or avoid practice patterns. The first analyses compared new treatment and simple sugars) diets were recorded. Additional testing categories testing recommendations for delayed vs normal GES or WMC included endoscopy/imaging, motility, and other tests (see Sup- gastric emptying. Second, comparisons related management to plemental Methods, Supplementary Digital Content 1, http:// delayed vs normal WMC extragastric and generalized transit. links.lww.com/CTG/A100). Motility test ordering was further Third, comparisons examined decisions for rapid vs normal GES stratified into recommending (i) any motility tests and (ii) mul- or WMC gastric emptying. Additional comparisons ascertained tiple motility tests ($2 tests for any subject). Additional testing whether specific medications were preferentially advocated for was recommended by site investigators based on the resources particular transit profiles, including comparing specific proki- available at each study center. As is commonly observed in clinical netics and neuromodulators for delayed vs normal gastric emp- practice, methods of additional ordered tests likely exhibited tying and specific laxatives with delayed vs normal CTT. differences between sites. However, these testing methods were not queried as part of this study. We excluded recommendations Statistical analysis for additional GES made on the basis of WMC findings or WMCs Descriptive statistics and confidence intervals associated with made on the basis of GES findings. binary variables were computed (24). Comparisons of treatment changes and additional test ordering between tests were per- Relating decisions to transit. Management recommendations formed using an exact calculation McNemar test for binary were related to transit (see Supplemental Methods, endpoints. Fisher exact testing analyzed binary endpoints on American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 4 Hasler et al. Figure 2. Differential effects of GES and WMC findings on treatment recommendations in suspected gastroparesis are shown. WMC testing led to greater changes in medication therapies vs GES (a). Of the 74% of subjects with recommended medication changes, more were informed by WMC results alone compared with GES results alone (b). More than 40% of medication changes were recommended based on both abnormal GES and WMC findings. There were no differences in diet changes made in response to WMC vs GES testing. GES, gastric emptying scintigraphy; WMC, wireless motility capsule. independent subgroup comparisons of GES or WMCs. Table 1B, Supplementary Digital Content 3, http://links.lww.com/ Assessing subgroup differences on GES and WMCs with over- CTG/A102). Smaller numbers showed rapid gastric or small bowel lapping samples used permutation testing based on portion transit. Gastric emptying delays were more common with WMC differences as appropriate, with P values obtained from per- than GES testing (P , 0.001), whereas rapid gastric emptying was mutation test distributions based on 10,000 Monte Carlo sim- detected more often by GES than WMCs (P , 0.001). ulations. Analyses used SAS version 9.4 software (Cary, NC). Primary endpoints RESULTS Medication and diet changes were recommended for 74% and 25% Clinical features of subjects based on combined GES and WMC results. Medication Management plans were completed for 150/167 subjects. Most changes were more often recommended based on WMCs vs GES subjects reported diverse symptoms of gastroparesis; many also (68% vs 48%, P , 0.0001) (Figure 2A) and more often when only reported lower abdominal pain and bowel disturbances (see WMC was abnormal (and GES was normal) than when only GES Table 1A, Supplementary Digital Content 3, http://links.lww.com/ was abnormal (and WMC was normal) (26% vs 6%, P , 0.0001) CTG/A102). Figure 1A shows scintiscans displaying increased (Figure 2B), showing greater impact of WMCs than GES on 4-hour retention (delayed gastric emptying). Figure 1B shows that treatment decisions. subject’s WMC tracing displaying prolonged GET, SBTT, and CTT Additional tests were recommended for 81% of subjects based on (generalized delays). Subject subsets exhibited transit delays in the combined GES and WMC results. Fewer tests were ordered based stomach, small bowel, and/or colon, some of which were isolated to on WMCs (P5 0.0002), and more were eliminated based on WMCs single regions, whereas others were generalized to $2 regions (see (P , 0.0001) vs GES (Figure 3A). Fewer additional tests were Figure 3. Differential effects of GES and WMC findings on recommendations for additional diagnostic testing in suspected gastroparesis are shown. WMC testing promoted less additional test ordering and higher rates of eliminating additional testing (a). Of subjects who were recommended to undergo additional testing, fewer were referred based on WMC alone vs GES alone (b). Of those with elimination of additional testing, more tests were eliminated by WMC alone vs GES alone. More than 50% of additional diagnostic test ordering was recommended based on both abnormal GES and WMC findings. GES, gastric emptying scintigraphy; WMC, wireless motility capsule. Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 5 Table 1. Impact of GES vs WMC testing on clinical decision making A. Impact of GES vs WMC testing on treatment changes Recommended for change in treatment GES WMC New treatment recommended Fraction (%) of subjects Fraction (%) of subjects P value Test with greater impact on management Change in prokinetic 45/150 (30.0) 69/150 (46.0) 0.0007 WMC > GES Change in antiemetic 22/150 (14.7) 21/150 (14.0) 1.00 Same Change in neuromodulator 82/150 (54.7) 71/150 (47.3) 0.10 Same Change in laxative 26/150 (17.3) 54/150 (36.0) ,0.0001 WMC > GES Change in transit retardant 2/150 (1.4) 7/150 (4.7) 0.12 Same Any change in diet 46/150 (30.7) 52/150 (34.7) 0.36 Same Referral for surgery or supplemental feeding 1/150 (0.7) 0/150 (0) — Same B. Impact of GES vs WMC testing on additional diagnostic test recommendations Recommended for additional diagnostic testing GES WMC Additional tests recommended Fraction (%) of subjects Fraction (%) of subjects P value Test with greater impact on management Endoscopy/imaging tests 25/150 (16.7) 15/150 (10.0) 0.09 Same Any motility tests 60/150 (40.0) 51/150 (34.0) 0.14 Same Multiple motility tests ($2 tests for any 33/150 (22.0) 6/150 (4.0) ,0.0001 WMC > GES subject) Other tests 42/150 (28.0) 43/150 (28.7) 1.00 Same GES, gastric emptying scintigraphy; WMC, wireless motility capsule. ordered (P5 0.0002) and more eliminated (P, 0.0001) when only Recommendations for specific prokinetics and neuromodulators WMC was abnormal (and GES was normal) than when only GES were similar for both tests regardless of emptying delays (see was abnormal (and WMC was normal) (Figure 3B), showing greater Table 2A, Supplementary Digital Content 3, http://links.lww. impact of WMCs than GES on additional test recommendations. com/CTG/A102). Multiple motility tests were recommended more often for normal GES vs normal WMC gastric emptying (P5 0.0003) and Specific decisions normal WMC transit in all regions (P 5 0.0007) and for delayed Prokinetics (P 5 0.0007) and laxatives (P , 0.0001) but not other therapies were recommended more often based on WMC vs GES gastric emptying by GES vs WMCs (P 5 0.004) (Table 3). Rec- results (Table 1A). Recommendations for endoscopy/imaging tests ommendations for any motility test (P 5 0.03) and multiple trended higher (P 5 0.09) based on the GES vs WMC results motility tests (P5 0.006) were greater for normal GES vs normal (Table 1B). Recommendations for any additional motility testing WMC transit in all regions, showing greater impact of WMCs vs were similar based on GES vs WMCs. Multiple motility tests were GES on test ordering in different gastric emptying subsets. recommended more often based on GES than WMCs (P, 0.0001), Specific motility tests included radiopaque markers and ano- showing greater impact of WMCs than GES on specific treatment rectal and antroduodenal manometry (see Table 2B, Supplementary and testing decisions. Digital Content 3, http://links.lww.com/CTG/A102). Radiopaque markers were recommended more often for GES vs WMCs when Relating transit to decisions gastric emptying was delayed (P 5 0.02) or normal (P 5 0.001). Related to delayed gastric emptying. Prokinetics and gastro- paresis diets were recommended more often and neuromodulators Related to delayed extragastric transit. Prokinetics were recom- less for delayed vs normal gastric emptying by GES or WMCs (P# mended more often for delayed vs normal SBTT (P , 0.0001) 0.0006) (Table 2). Prokinetics (P5 0.01) and laxatives (P5 0.0001) (Table 4). This difference disappeared when SBTT delays were iso- were recommended more often and neuromodulators less (P 5 lated. Laxatives were recommended more often for delayed vs nor- 0.03) for normal WMC gastric emptying vs normal GES. Differ- mal CTT (P , 0.0001). This difference persisted when CTT delays ences disappeared when normal WMC transit in all regions was were isolated abnormalities (P , 0.0001). Specific laxatives (poly- compared with normal GES. Treatment recommendations were ethylene glycol 3350, linaclotide, and lubiprostone) were similarly similar for delayed GES vs WMC gastric emptying. This shows that advocated for delayed vs normal CTT (see Table 3A, Supplementary finding delayed vs normal gastric emptying has a different impact Digital Content 3, http://links.lww.com/CTG/A102). Prokinetics on treatment decisions made after both WMC and GES testing. capable of stimulating colon transit (pyridostigmine and pruca- Specific recommended prokinetics included metoclopramide, lopride) were recommended more often for delayed (7/45, 15.6%) domperidone, macrolides, and pyridostigmine. Common neu- than normal CTT (2/101, 2.0%) (P 5 0.004). Prokinetics were rec- romodulators were mirtazapine, tricyclics, and gabapentin. ommended more often (P 5 0.0001) with generalized vs isolated American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 6 Hasler et al. Table 2. Impact of GES and WMC testing on treatment changes in relation to gastric emptying delays Recommended for change in treatment Gastric emptying comparison New treatment recommended Percent of subjects P value Test with greater impact on management Delayed GES (n 5 36) vs normal GES Prokinetic change 80.6% vs 15.2% ,0.0001 Delayed > normal GES Antiemetic change 19.4% vs 16.3% 0.79 Same (n 5 92) Neuromodulator change 19.4% vs 68.5% ,0.0001 Normal > delayed GES Laxative change 25.0% vs 14.1% 0.19 Same Transit-retardant change 2.8% vs 1.1% 0.48 Same Gastroparesis diet change 63.9% vs 16.3% ,0.0001 Delayed > normal GES Delayed GET (n 5 53) vs normal GET Prokinetic change 83.0% vs 26.4% ,0.0001 Delayed > normal GET Antiemetic change 20.8% vs 11.0% 0.14 Same (n 5 91) Neuromodulator change 28.3% vs 58.2% 0.0006 Normal > delayed GET Laxative change 34.0% vs 37.4% 0.72 Same Transit-retardant change 1.9% vs 4.4% 0.65 Same Gastroparesis diet change 50.9% vs 17.6% 0.0001 Delayed > normal GET Normal GES (n 5 92) vs normal GET Prokinetic change 15.2% vs 26.4% 0.01 Normal GET > normal GES Antiemetic change 16.3% vs 11.0% 0.19 Same (n 5 91) Neuromodulator change 68.5% vs 58.2% 0.03 Normal GES > normal GET Laxative change 14.1% vs 37.4% 0.0001 Normal GET > normal GES Transit-retardant change 1.1% vs 4.4% 0.20 Same Gastroparesis diet change 16.3% vs 17.6% 0.75 Same Normal GES (n 5 92) vs normal WMC Prokinetic change 15.2% vs 17.9% 0.11 Same Antiemetic change 16.3% vs 10.7% 0.32 Same transit in all regions (n 5 56) Neuromodulator change 68.5% vs 60.7% 0.051 Same Laxative change 14.1% vs 21.4% 0.16 Same Transit-retardant change 1.1% vs 7.1% 0.06 Same Gastroparesis diet change 16.3% vs 17.9% 0.41 Same Delayed GES (n 5 36) vs delayed GET Prokinetic change 80.6% vs 83.0% 0.52 Same Antiemetic change 19.4% vs 20.8% 0.76 Same (n 5 53) Neuromodulator change 19.4% vs 28.3% 0.43 Same Laxative change 25.0% vs 34.0% 0.17 Same Transit-retardant change 2.8% vs 1.9% 0.50 Same Gastroparesis diet change 63.9% vs 50.9% 0.11 Same GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule. delays (Table 4). This shows differential impact of different WMC Supplementary Digital Content 3, http://links.lww.com/CTG/ extragastric findings on treatment decisions. A102). This shows the impact of rapid GES and WMC transit on Additional motility tests were recommended more often with management decisions. delayed vs normal SBTT (P 5 0.03) (Table 5). This difference disappeared when SBTT delays were isolated. Additional motility DISCUSSION tests were recommended more often with delayed vs normal CTT Although gastric emptying testing is used for patients with sus- (P 5 0.02). This difference still trended higher when CTT delays pected gastroparesis, there is little evidence to suggest these tests were isolated (P 5 0.06). Specific motility test recommendations influence management choices. This investigation prospectively were similar for delayed and normal CTT (see Table 3B, Supple- compared how GES and WMC testing informs recommendations mentary Digital Content 3, http://links.lww.com/CTG/A102). for treatments and additional diagnostic evaluations in these Testing recommendations were similar for generalized and isolated patients. Its unique features include its large size, diverse patient delays. This shows differential impact of different WMC extra- cohort, standardized transit methods, and structured character- gastric findings on test ordering. ization of management recommendations. This comprehensive, multicenter study did not have the drawbacks of previous retro- Related to rapid transit. Transit-retardant medications were spective publications. There was also no bias from practice patterns recommended more often for rapid vs normal GET (P 5 0.03) of any single provider. Thus, these decisions more closely reflected (see Table 4A, Supplementary Digital Content 3, http://links. the diverse management approaches of clinicians in varied medical lww.com/CTG/A102). Antidumping diets were recommended settings. more often for rapid GET (P 5 0.01) and trended higher for Previous studies evaluating impact of transit tests on decisions rapid GES (P 5 0.09) vs normal emptying. Prokinetic medi- in suspected gastroparesis had deficiencies. Three limited retro- cations were recommended more often when SBTT was rapid spective series used medical record review, which may not con- than when it was normal (P 5 0.04). Additional testing rec- sistently capture management choices (13,16,17). One ommendations did not relate to rapid transit (see Table 4B, prospective study described the influence of GES on medication Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 7 Table 3. Impact of GES and WMC testing on additional diagnostic test recommendations in relation to gastric emptying delays Recommended for additional diagnostic testing Gastric emptying comparison Additional test recommended Percent of subjects P value Test with greater impact on management Delayed GES (n 5 36) vs normal GES Endoscopy/imaging tests 8.3% vs 18.5% 0.19 Same Any motility tests 38.9% vs 41.3% 0.84 Same (n 5 92) Multiple ($2) motility tests 19.4% vs 23.9% 0.65 Same Other tests 19.4% vs 29.3% 0.28 Same Delayed GET (n 5 53) vs normal GET Endoscopy/imaging tests 9.4% vs 11.0% 1.00 Same Any motility tests 35.8% vs 33.0% 0.72 Same (n 5 91) Multiple ($2) motility tests 1.9% vs 5.5% 0.41 Same Other tests 26.4% vs 29.7% 0.71 Same Normal GES (n 5 92) vs normal GET Endoscopy/imaging tests 18.5% vs 11.0% 0.14 Same Any motility tests 41.3% vs 33.0% 0.19 Same (n 5 91) Multiple ($2) motility tests 23.9% vs 5.5% 0.0003 Normal GET > normal GES Other tests 29.3% vs 30.0% 0.81 Same Normal GES (n 5 92) vs normal WMC Endoscopy/imaging tests 18.5% vs 14.3% 0.78 Same Any motility tests 41.3% vs 23.2% 0.03 Normal WMC > normal GES transit in all regions (n 5 56) Multiple ($2) motility tests 23.9% vs 5.4% 0.0007 Normal WMC > normal GES Other tests 29.3% vs 32.1% 0.67 Same Delayed GES (n 5 36) vs delayed GET Endoscopy/imaging tests 8.3% vs 9.4% 0.74 Same Any motility tests 38.9% vs 35.8% 0.95 Same (n 5 53) Multiple ($2) motility tests 19.4% vs 1.9% 0.004 Delayed GET > delayed GES Other tests 19.4% vs 26.4% 0.27 Same GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule. and diet changes made by 30 physicians but offered few details on publications (25–27). Neuromodulators were recommended specific medications and did not discuss additional diagnostic more often for normal GES than normal WMCs unless all gut testing or compare GES with WMCs (20). regions had normal transit, suggesting that the WMC extragastric Our coprimary endpoints uncovered differences in how clini- results influenced these decisions. cians use GES and WMCs to make decisions. Medication changes In addition to experiencing symptoms of gastroparesis, some were recommended more frequently, and ordering of diagnostic subjects reported lower abdominal pain and bowel disturbances tests was less frequent with WMCs vs GES. Specific choices included potentially originating in the distal gut. Similar high degrees of greater recommendations for prokinetics and laxatives for WMCs lower abdominal symptoms have been observed in published and increased ordering of multiple motility tests with GES. Because large gastroparesis cohorts (9,10,28). Our findings illustrate WMC results led to recommending more treatments and fewer advantages of WMC extragastric measurements, which may be additional tests than GES, we concluded that WMCs have greater relevant to these symptoms. Small bowel delays promoted more impact on decision making in managing suspected gastroparesis. prokinetic recommendations, but sample sizes were small and Subgroup analyses were designed to test whether these differences disappeared after excluding other regional delays. coprimary endpoint findings resulted from greater sensitivity of Delayed colon transit correlated with recommending increased detecting delayed gastric emptying, extragastric delays, or rapid laxative use. Some patients with CTT delays were prescribed transit. Delayed gastric emptying by either test increased proki- colonic prokinetic agents, confirming that WMCs can direct netic recommendations, indicating a pathophysiological man- specific decisions in treating constipation. Further investigations agement approach. Prokinetics were recommended more often will determine whether interventions targeting extragastric after WMC testing because of the greater sensitivity of WMCs findings will translate into better outcomes in suspected gastro- over GES to detect delayed gastric emptying. Higher recom- paresis, although one pediatric study reported that laxatives can mendations of prokinetics for normal WMC gastric emptying vs reduce gastroparesis symptoms (29). Prokinetics were recom- normal GES disappeared when small bowel and colon transit mended more often for generalized vs isolated delays, because of delays were excluded, indicating that prokinetics were likely increased gastric emptying delays with generalized (28/32, 87.5%) prescribed for extragastric transit impairments. Although treat- vs isolated (22/53, 41.5%) transit impairments (P , 0.0001). ment of functional dyspepsia (including postprandial distress) Agents that slow transit were advocated more often for rapid has been extensively studied, the literature on managing sus- WMC gastric emptying. Prokinetics were ordered more for rapid pected gastroparesis patients with normal gastric emptying is SBTT. Although this might seem counterintuitive, 2 of 3 patients limited. This study provides the first report affirming preferential with rapid SBTT exhibited delayed gastric emptying by GES or neuromodulator use in this large patient subset with normal WMCs providing a pathophysiologic rationale for use of this drug emptying. Tricyclics are reportedly ineffective in gastroparesis class. Rapid CTT was not evaluated because it is not an established but are beneficial for functional dyspepsia with normal gastric measure, as defecation can occur any time after the onset of co- emptying; thus, our observations corroborate previous lonic high-amplitude propagating contractions (30,31). American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 8 Hasler et al. Table 4. Impact of GES and WMC testing on treatment changes in relation to extragastric transit delays Recommended for change in treatment Extragastric transit comparison New treatment recommended Percent of subjects P value Test with greater impact on management Delayed SBTT (n 5 33) vs normal SBTT Prokinetic change 75.8% vs 33.6% ,0.0001 Delayed > normal SBTT Antiemetic change 15.2% vs 13.6% 0.78 Same (n 5 110) Neuromodulator change 45.5% vs 50.9% 0.69 Same Laxative change 36.4% vs 36.4% 1.00 Same Transit-retardant change 6.1% vs 4.5% 0.66 Same Delayed SBTT as isolated WMC abnormality Prokinetic change 54.5% vs 33.6% 0.20 Same Antiemetic change 0.0% vs 13.6% 0.36 Same (n 5 11) vs normal SBTT (n 5 110) Neuromodulator change 54.5% vs 50.9% 1.00 Same Laxative change 27.3% vs 36.4% 0.74 Same Transit-retardant change 9.1% vs 4.5% 0.44 Same Delayed CTT (n 5 45) vs normal CTT Prokinetic change 55.6% vs 39.6% 0.10 Same Antiemetic change 15.6% vs 12.9% 0.79 Same (n 5 101) Neuromodulator change 42.2% vs 51.5% 0.37 Same Laxative change 75.6% vs 18.8% ,0.0001 Delayed > normal CTT Transit-retardant change 2.2% vs 5.9% 0.44 Same Delayed CTT as isolated WMC abnormality Prokinetic change 25.0% vs 39.6% 0.31 Same Antiemetic change 5.0% vs 12.9% 0.46 Same (n 5 20) vs normal CTT (n 5 101) Neuromodulator change 50.0% vs 51.5% 1.00 Same Laxative change 75.0% vs 18.8% ,0.0001 Isolated CTT delay > normal CTT Transit-retardant change 0% vs 5.9% 0.59 Same Generalized WMC delay (n 5 32) vs isolated Prokinetic change 90.6% vs 49.1% 0.0001 Generalized > isolated delay Antiemetic change 18.8% vs 11.3% 0.35 Same WMC delay (n 5 53) Neuromodulator change 37.5% vs 43.4% 0.65 Same Laxative change 56.2% vs 39.6% 0.18 Same Transit-retardant change 3.1% vs 1.9% 1.00 Same CTT, colon transit time; GES, gastric emptying scintigraphy; SBTT, small bowel transit time; WMC, wireless motility time. Diet recommendations were influenced by transit results. suggested that marker retention profiles may be different in slow Gastroparesis diets were preferentially advocated for delayed transit constipation than with outlet obstruction, although this was gastric emptying, supporting a controlled diabetic gastroparesis not subsequently confirmed (36). It is possible that some site trial reporting benefits of small particle diets (32). Antidumping investigators wished to measure regional colon transit delays in diets were advocated more for rapid gastric emptying, again some of their study patients. reflecting a physiologic basis for treatment (33). Although rapid This investigation had limitations. Each center had different emptying can be found in functional dyspepsia, diabetes, and resources and practice standards, which influenced local man- cyclic vomiting, the pathophysiologic relevance of rapid transit agement options. We considered this a strength of this study, as it remains unproved (15,16,34). reflected real-life practice patterns across diverse settings. Site Recommendations for additional testing differed based on investigators were afforded leeway in making decisions, which did transit. Multiple motility tests were more often advised based on not consider medication affordability, insurance coverage, or GES vs WMCs regardless of delays probably because GES provides acceptance of invasive testing. It was beyond the scope of this no extragastric information. More additional motility tests were investigation to determine whether differences in the impact of recommended for delayed vs normal small bowel and colon transit; WMC vs GES findings on management decisions translated into differences trended higher when colon delays were isolated. WMC different symptom and quality of life outcomes. Furthermore, it testing did not eliminate decisions to perform anorectal manom- was not possible to quantify longitudinal outcomes relating to etry to exclude dyssynergia as a cause of constipation (35). Ano- management decisions that were made based on findings of either rectal manometry was similarly advocated for 39 patients after WMCs or GES as individual tests; rather, any outcome would be obtaining GES results vs 42 patients after obtaining WMC results. influenced by clinical decisions that were made by site inves- However, anorectal manometry was not ordered significantly more tigators based on knowledge of both the WMC and GES results often in those with delayed WMC CTT (17/45, 37.8%) than with taken together. We plan to correlate transit findings with symp- normal CTT (25/101, 24.8%) (P5 0.12), indicating that the WMC tom profiles at baseline and follow-up in future reports. Never- colon transit interpretation was not the sole determining factor in theless, our detailed findings provide unique insights into how ordering this test. By contrast, radiopaque marker studies were clinicians approach management decisions in patients with pre- ordered more often after GES reflecting the inability of gastric test possibilities of having gastroparesis. scintigraphy to measure colon transit. Curiously, small numbers of In conclusion, gastric emptying and gut transit testing influ- radiopaque marker tests were ordered on the basis of WMC enced management decisions in suspected gastroparesis. WMC findings, although WMC CTT results were available. Older studies findings led to greater medication changes and fewer Clinical and Translational Gastroenterology VOLUME 10 | OCTOBER 2019 www.clintranslgastro.com MOTILITY Impact on Management Decisions 9 Table 5. Impact of gastric emptying scintigraphy and WMC testing on additional diagnostic test recommendations in relation to extragastric transit delays Recommended for additional diagnostic testing Extragastric transit comparison Additional test recommended Percent of subjects P value Test with greater impact on management Delayed SBTT (n 5 33) vs normal SBTT Endoscopy/imaging tests 9.1% vs 9.1% 1.00 Same (n 5 110) Any motility tests 48.5% vs 27.3% 0.03 Delayed > normal SBTT Multiple ($2) motility tests 6.1% vs 3.6% 0.62 Same Other tests 36.4% vs 25.5% 0.27 Same Delayed SBTT as isolated WMC abnormality Endoscopy/imaging tests 9.1% vs 9.1% 1.00 Same Any motility tests 45.5% vs 27.3% 0.29 Same (n 5 11) vs normal SBTT (n 5 110) Multiple ($2) motility tests 0% vs 3.6% 1.00 Same Other tests 36.4% vs 25.5% 0.48 Same Delayed CTT (n 5 45) vs normal CTT Endoscopy/imaging tests 6.7% vs 9.9% 0.75 Same Any motility tests 46.7% vs 26.7% 0.02 Delayed > normal CTT (n 5 101) Multiple ($2) motility tests 4.4% vs 4.0% 1.00 Same Other tests 28.9% vs 28.7% 1.00 Same Delayed CTT as isolated WMC abnormality Endoscopy/imaging tests 5.0% vs 9.9% 0.69 Same Any motility tests 50.0% vs 26.7% 0.06 Same (n 5 20) vs normal CTT (n 5 101) Multiple ($2) motility tests 5.0% vs 4.0% 1.00 Same Other tests 15.0% vs 28.7% 0.27 Same Generalized delay (n 5 32) vs isolated Endoscopy/imaging tests 9.4% vs 3.8% 0.36 Same Any motility tests 46.9% vs 37.7% 0.50 Same delay (n 5 53) Multiple ($2) motility tests 6.2% vs 1.9% 0.55 Same Other tests 34.4% vs 22.6% 0.31 Same CTT, colon transit time; SBTT, small bowel transit time; WMC, wireless motility capsule. recommendations for additional motility testing compared with MA501). Matilde Lourd, a Medtronic employee, provided some GES. Recommendations for prokinetics, neuromodulators, and initial data analyses for the primary endpoints of this study before its gastroparesis diets were influenced by gastric emptying delays, presentation at the 2017 World Congress of Gastroenterology whereas laxative recommendations and ordering of additional meeting; statistical analyses of these data were verified by Gregory E. coloanal motility tests were influenced by extragastric delays. Wilding, and all additional statistical analyses relating to specific management decisions and decisions related to gut transit abnormalities were conducted by Gregory E. Wilding, a consultant CONFLICTS OF INTEREST for Medtronic as described below. All initial data collection was Guarantor of the article: William L. Hasler, MD. performed by site investigators. Data were transferred to a central Specific author contributions: W.L.H.: Study design, experimental database supervised by Medtronic. Medtronic did not participate in conduct, data collection, data analysis, manuscript preparation, and study design, data interpretation, writing support, or other approval of the final manuscript version. S.S.C.R: Experimental preparation assistance for this article. conduct, data collection, manuscript preparation, and approval of the Potential competing interests: W.L.H.: Received grant funding from final manuscript version. R.W.M.: Experimental conduct, data Medtronic for conduct of research as site principal investigator at collection, and approval of the final manuscript version. R.A.K.: University of Michigan, Ann Arbor, MI. S.S.C.R.: Received grant Experimental conduct, data collection, and approval of the final funding from Medtronic for conduct of research as site principal manuscript version. L.A.N.: Experimental conduct, data collection, and investigator at Medical College of Georgia, Augusta, GA. R.W.M.: approval of the final manuscript version. M.I.S.: Experimental conduct, Received grant funding from Medtronic for conduct of research as data collection, and approval of the final manuscript version. A.A.L.: site co-principal investigator at Texas Tech University, El Paso, TX. Experimental conduct, data collection, manuscript preparation, and R.A.K.: Received grant funding from Medtronic for conduct of re- approval of the final manuscript version. B.M.: Experimental conduct, search as site principal investigator at ClinSearch, Chattanooga, TN. data collection, and approval of the final manuscript version. J.M.W.: L.A.N.: Received grant funding from Medtronic for conduct of re- Experimental conduct, data collection, and approval of the final search as site principal investigator at Stanford University, Palo Alto, manuscript version. H.P.P.: Experimental conduct, data collection, and CA. M.I.S.: Received grant funding from Medtronic for conduct of approval of the final manuscript version. I.S.: Experimental conduct, research as site principal investigator at Florida Digestive Health data collection, and approval of the final manuscript version. G.E.W.: Associates, Largo, FL. A.A.L.: Received grant funding from Med- Study design and statistical analysis of data. B.K.: Study design, tronic for conduct of research as site principal investigator at the experimental conduct, data collection, data analysis, manuscript University of Vermont, Burlington, VT (he has since moved to the preparation, and approval of the final manuscript version. University of Michigan, Ann Arbor, MI). B.M.: Received grant Financial support: The parent study supporting the data and funding from Medtronic for conduct of research as site principal analyses included in this article were funded by Medtronic (grant investigator at the University of Miami, Miami, FL (she has since American College of Gastroenterology Clinical and Translational Gastroenterology MOTILITY 10 Hasler et al. with suspected gastroparesis. Clin Gastroenterol Hepatol 2019;17: moved to Carolinas HealthCare System, Charlotte, NC). J.M.W.: 1770–9.e2. Received grant funding from Medtronic for conduct of research as 8. Stein E, Berger Z, Hutfless S, et al. Wireless Motility Capsule Versus Other site principal investigator at Indiana University, Indianapolis, IN. Diagnostic Technologies for Evaluating Gastroparesis and Constipation: H.P.P.: Received grant funding from Medtronic for conduct of re- A Comparative Effectiveness Review. Agency for Healthcare Research search as site principal investigator at Temple University, Phila- and Quality; 2013. 9. Parkman HP, Yates K, Hasler WL, et al. Clinical features of idiopathic delphia, PA. I.S.: Received grant funding from Medtronic for conduct gastroparesis vary with sex, body mass, symptom onset, delay in gastric of research as site co-principal investigator at Texas Tech University, emptying, and gastroparesis severity. Gastroenterology 2011;140:101–15. El Paso, TX. G.E.W.: Received compensation as a consultant by 10. Parkman HP, Yates K, Hasler WL, et al. Similarities and differences Medtronic for statistical analyses of study data. B.K.: Received grant between diabetic and idiopathic gastroparesis. Clin Gastroenterol funding from Medtronic for conduct of research as site principal Hepatol 2011;9:1056–64. investigator at Massachusetts General Hospital, Boston, MA. None of 11. Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal disorders. Gastroenterology 2016;150:1380–92. the investigators is an employee of Medtronic, none owns stocks or 12. Arora Z, Parungao JM, Lopez R, et al. Clinical utility of wireless motility shares in Medtronic, and none owns patents with Medtronic. capsule in patients with suspected multiregional gastrointestinal Clinical trial registry: Analyses included in this article were dysmotility. Dig Dis Sci 2015;60:1350–7. conducted according to a priori planned secondary study endpoints 13. Hasler WL, May KP, Wilson LA, et al. Relating gastric scintigraphy and of a registered clinical trial (ClinicalTrials.gov NCT02022826). symptoms to motility capsule transit and pressure findings in suspected gastroparesis. Neurogastroenterol Motil 2018;30. 14. Delgado-Aros S, Camilleri M, Cremonini F, et al. Contributions of gastric Study Highlights volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia. Gastroenterology 2004;127:1685–94. WHAT IS KNOWN 15. Bharucha AE, Camilleri M, Forstrom LA, et al. Relationship between clinical features and gastric emptying disturbances in diabetes mellitus. 3 Gastric emptying is measured by GES or WMCs; the latter also Clin Endocrinol (Oxf) 2009;70:415–20. 16. Rao SS, Camilleri M, Hasler WL, et al. Evaluation of gastrointestinal assesses extragastric transit. transit in clinical practice: Position paper of the American and European 3 Patients with suspected gastroparesis report diffuse Neurogastroenterology and Motility Societies. Neurogastroenterol Motil symptoms suggesting possible generalized dysmotility. 2011;23:8–23. 3 Impacts of GES and WMCs on management decisions are 17. Galil MA, Critchley M, Mackie CR. Isotope gastric emptying tests in poorly defined. clinical practice: Expectation, outcome, and utility. Gut 1993;34:916–9. 18. Kuo B, Maneerattanaporn M, Lee AA, et al. Generalized transit delay on WHAT IS NEW HERE wireless motility capsule testing in patients with clinical suspicion of gastroparesis, small intestinal dysmotility, or slow transit constipation. 3 More treatment changes were recommended, and ordering Dig Dis Sci 2011;56:2928–38. of additional motility tests was eliminated more based on 19. Rao SS, Mysore K, Attaluri A, et al. Diagnostic utility of wireless motility WMCs—testing which detected more gastric and extragastric capsule in gastrointestinal dysmotility. J Clin Gastroenterol 2011;45: 684–90. abnormalities. 20. Tseng AS, Crowell MD, DiBaise JK. Clinical utility of gastric emptying 3 These tests provided information that differentially influenced scintigraphy: Patient and physician perspectives. Neurogastroenterol clinical decisions in suspected gastroparesis. Motil 2018;30:e13279. 21. Wang YT, Mohammed SD, Farmer AD, et al. 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Clinical and Translational GastroenterologyWolters Kluwer Health

Published: Oct 1, 2019

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