Prior Authorization Review Panel MCO Policy Submission

Prior Authorization Review Panel MCO Policy Submission A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review. Plan: Aetna Better Health Submission Date: 10/01/2018 Policy Number: 0266 Policy Name: Cholecystokinin Cholescintigraphy Effective Date: Revision Date: Type of Submission Check all that apply: New Policy Revised Policy Annual Review No Revisions* *All revisions to the policy must be highlighted using track changes throughout the document. Please provide any clarifying information for the policy below: CPB 0266 Cholecystokinin Cholescintigraphy Clinical content was last revised on 11/08/2013. No additional non-clinical updates were made by Corporate since the last PARP submission, as documented below. Revision and Update History since last PARP submission: 06/21/2018 - This CPB has been reviewed and maintained. 03/14/2019 Tentative next scheduled review date by Corporate. Name of Authorized Individual (Please type or print): Signature of Authorized Individual: Dr. Bernard Lewin, M.D. www.aetnabetterhealth.com/pennsylvania Annual 10/01/2018

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 1 of 10 --> (https://www.aetna.com/) Cholecystokinin Cholescintigraphy Number: 0266 *Please see amendment for Pennsylvania Medicaid at the end of this CPB. Policy Aetna considers cholecystokinin (CCK) administration as an adjunct to cholescintigraphy medically necessary for any of the following indications: 1. After cholescintigraphy, to confirm or exclude chronic calculous cholecystitis; or 2. After cholescintigraphy, to confirm the diagnosis of chronic acalculous cholecystitis; or 3. After cholescintigraphy, to differentiate common duct obstruction from normal hypertonic sphincter of Oddi; or 4. After cholescintigraphy, to exclude acute acalculous cholecystitis; or 5. During cholescintigraphy, as a non-invasive method of diagnosing sphincter of Oddi dysfunction; or 6. Prior to cholescintigraphy, as an alternative to delayed imaging so cholescintigraphy can be completed in 60 minutes (rather than 3 to 4 hours); or Policy His tory Last Review 06/21/2018 Effective: 09/24/1998 Next Review: 03/14/2019 Review History Definitions A dditiona l In form at ion Clinical Policy Bulletin Notes 7. Prior to cholescintigraphy, to empty the gallbladder in members fasting more than 24 hours.

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 2 of 10 Aetna considers cholecystokinin cholescintigraphy experimental and investigational for all other indications (e.g., provocation of pain as a predictor of post-operative relief of symptoms following cholecystectomy for biliary dyskinesia or chronic acalculous gallbladder disease) because its effectiveness for indications other than the ones listed above has not been established. Background This policy is based primarily on a review of indications for cholecystokinin cholescintigraphy by Ziessman (2001). Cholescintigraphy (also known as a hepatobiliary iminodiacetic acid [HIDA] scan or gallbladder scan) is a nuclear medicine test used to diagnose obstruction of the bile ducts (e.g., by a gallstone or a tumor), gallbladder disease, and bile leaks. Cholecystokinin (CCK) is a useful diagnostic adjunct to cholescintigraphy. Recent studies in the medical literature have shown that cholecystokinin cholescintigraphy is clinically reliable in predicting which patients with acalculous cholecystitis or biliary dyskinesia will improve symptomatically following cholecystectomy. Sincalide is the only commercially available form of CCK approved by the U.S. Food and Drug Administration. It may be necessary to administer CCK prior to cholescintigraphy in fasting patients to empty the gallbladder. In this case, CCK is administered to reduce the chance of a false-positive study (i.e., gallbladder non-visualization in a patient who does not have acute cholecystitis).

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 3 of 10 Cholecystokinin may also be administered prior to cholescintigraphy, as an alternative to delayed imaging so cholescintigraphy can be completed in 60 minutes (rather than 3 to 4 hours). This may be important in seriously ill patients who may not be able to complete a delayed imaging study of 3 to 4 hours duration. Patients who would have had delayed visualization usually have gallbladder visualization at 60 minutes if pre-treated with CCK. Cholecystokinin may be used during cholescintigraphy as a noninvasive method of diagnosing sphincter of Oddi dysfunction (i.e., a partial common duct dysfunction at the level of the sphincter of Oddi that is not caused by an obstructing stone or inflammatory fibrosis). Administration of CCK allows noninvasive physiologic assessment of duct drainage. Cholecystokinin may be administered after cholescintigraphy to exclude acute acalculous cholecystitis. If the gallbladder contracts in response to CCK infusion, acute cholecystitis has been ruled out. This response is especially useful where acute acalculous cholecystitis is strongly suspected in a patient with gallbladder filling (potentially false-negative study). It may be necessary to administer CCK after cholescintigraphy to differentiate common duct obstruction from normal hypertonic sphincter of Oddi. Gallbladder contraction in response to CCK occurs in patients with normal hypertonic sphincter of Oddi. Cholecystokinin has also been used after cholescintigraphy to confirm or exclude chronic calculous cholecystitis. Cholecystokinin cholescintigraphy can help confirm or exclude chronic cholecystitis in patients with recurrent abdominal pain and cholelithiasis on ultrasonography. A normal gallbladder ejection fraction makes it very unlikely that chronic cholecystitis is the cause of a patient's symptoms. Alternatively, a low gallbladder ejection fraction is consistent with chronic cholecystitis.

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 4 of 10 Cholecystokinin may also be administered after cholescintigraphy to confirm the diagnosis of chronic acalculous cholecystitis. Patients with low gallbladder ejection fractions (less than 40 %) determined by cholecystokinin cholescintigraphy have a high positive predictive value for the diagnosis of chronic acalculous cholecystitis. Dibaise (2009) stated that the diagnosis and management of suspected functional biliary pain in patients with an intact gallbladder remains contentious. Major issues include the lack of a clear definition of what constitutes biliary pain, a poor understanding of its natural history and pathophysiology, and the all too common scenario of the patient who has persistent pain despite surgical removal of the gallbladder. As a consequence, symptoms alone have generally been considered to be unreliable in the diagnosis of gallbladder dysfunction, and this has led to a search for a reliable test to help confirm a clinical suspicion of gallbladder dysfunction prior to the definitive treatment, cholecystectomy. At present, CCK with a calculation of the gallbladder ejection fraction is the most commonly used test; however, its utility in predicting symptom outcome after cholecystectomy has been questioned. The use of CCK to determine the appropriateness for cholecystectomy appears to be most useful when performed using a slow infusion of cholecystokinin in a wellselected patient population. Edwards et al (2014) noted that chronic acalculous gallbladder disease (CAGD) falls within the spectrum of diseases associated with gallbladder dysmotility. Cholecystokinincholescintigraphy (CCK-CS) has been used to evaluate for CAGD, with a gallbladder ejection fraction (GBEF) of less than 35 % being indicative of gallbladder dysfunction. The reproduction of biliary colic upon administration of CCK has been cited as indicative of CAGD. These researchers examined if low GBEF or reproduction of pain during CCK-CS was predictor of surgical outcomes related to resolution of symptoms or as a correlate to gallbladder pathology. A

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 5 of 10 retrospective review of patients was performed to evaluate adults with a diagnosis of CAGD who underwent CCK-CS prior to surgical intervention. CPT and ICD-9 coding queries were used to identify the patient population. Patients with cholelithiasis were excluded. A total of 64 patients met inclusion criteria; 2 patients were lost to follow-up and were excluded. During CCK-CS, 41 patients (66 %) reported symptoms similar to their presenting complaint; 21 patients reported no symptoms with CCK-CS. There was no significant relationship between gallbladder pathology and either GBEF or reproduction of symptoms with CCK-CS (p = 0.14). About 81 % of patients (n = 50) had relief of symptoms following cholecystectomy; 66 % of patients (n = 33) with long-term symptom relief after cholecystectomy had reproduction of symptoms with CCK-CS; 19 % of all patients (n = 12) had long-term symptom recurrence despite surgery, 8 of these patients (66 %) had symptom reproduction with CCK-CS. There was no significant correlation with either the GBEF or symptoms reproduction with CCK-CS as a predictor of postoperative outcome (p = 0.12). The authors concluded that provocation of pain by CCK-CS and low GBEF are unreliable predictors of post-operative relief of symptoms following cholecystectomy for biliary dyskinesia or chronic acalculous gallbladder disease. CPT Codes / HCPCS Codes / ICD-10 Codes Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+": Code Code Description CPT codes covered if selection criteria are met: 78226 Hepatobiliary system imaging, including gallbladder when present 78227 with pharmacologic intervention, including quantitative measurement(s) when performed

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 6 of 10 Code Code Description HCPCS codes covered if selection criteria are met: J2805 Injection, sincalide, 5mcg ICD-10 codes covered if selection criteria are met: K80.00 - Cholelithiasis K80.81 K81.0 - Cholecystitis K81.9 K82.0 Obstruction of gallbladder K83.1 Obstruction of bile duct [common] K83.4 Spasm of sphincter of Oddi ICD-10 codes not covered for indications listed in the CPB (not all-inclusive): K82.8 Other specified diseases of gallbladder [predictor of post-operative relief of symptoms following cholecystectomy for biliary dyskinesia or chronic acalculous gallbladder disease] Z98.89 Other specified postprocedural states [predictor of post-operative relief of symptoms following cholecystectomy for biliary dyskinesia or chronic acalculous gallbladder disease] The above policy is based on the following references: 1. Frassinelli P, Werner M, Reed JF 3rd, et al. Laparoscopic cholecystectomy alleviates pain in patients with acalculous biliary disease. Surg Laparosc Endosc. 1998;8(1):30-34.

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 7 of 10 2. Klieger PS, O'Mara RE. The clinical utility of quantitative cholescintigraphy: The significance of gallbladder dysfunction. Clin Nucl Med. 1998;23(5):278-282. 3. Khosla R, Singh A, Miedema BW, et al. Cholecystectomy alleviates acalculous biliary pain in patients with a reduced gallbladder ejection fraction. South Med J. 1997;90(11):1087-1090. 4. Barr RG, Agnesi JN, Schaub CR. Acalculous gallbladder disease: US evaluation after slow-infusion cholecystokinin stimulation in symptomatic and asymptomatic adults. Radiology. 1997;204(1):105-111. 5. Mishkind MT, Pruitt RF, Bambini DA, et al. Effectiveness of cholecystokinin-stimulated cholescintigraphy in the diagnosis and treatment of acalculous gallbladder disease. Am Surg. 1997;63(9):769-774. 6. Reed DN Jr, Fernandez M, Hicks RD. Kinevac-assisted cholescintigraphy as an accurate predictor of chronic acalculus gallbladder disease and the likelihood of symptom relief with cholecystectomy. Am Surg. 1993;59(5):273-277. 7. Sorenson MK, Fancher S, Lang NP, et al. Abnormal gallbladder nuclear ejection fraction predicts success of cholecystectomy in patients with biliary dyskinesia. Am J Surg. 1993;166(6):672-674. 8. Kloiber R, Molnar CP, Shaffer EA. Chronic biliary-type pain in the absence of gallstones: The value of cholecystokinin in cholescintigraphy. AJR Am J Roentgenol. 1992;159(3):509-513. 9. Yap L, Wycherley AG, Morphett AD, et al. Acalculous biliary pain: Cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology. 1991;101(3):786-793. 10. Westlake PJ, Hershfield NB, Kelly JK, et al. Chronic right upper quadrant pain without gallstones: Does HIDA scan predict outcome after cholecystectomy. Am J Gastroenterol. 1990;85(8):986-990.

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 8 of 10 11. Pickleman J, Peiss RL, Henkin R, et al. The role of sincalide cholescintigraphy in the evaluation of patients with acalculous gallbladder disease. Arch Surg. 1985;120(6):693-697. 12. Ziessman HA. Cholecystokinin cholescintigraphy: Victim of its own success? J Nucl Med. 1999;40 (12):2038-2042. 13. Ziessman HA. Cholecystokinin cholescintigraphy: Clinical indications and proper methodology. Radiol Clin North Am. 2001;39(5):997-1006, ix. 14. Poynter MT, Saba AK, Evans RA, et al. Chronic acalculous biliary disease: Cholecystokinin cholescintigraphy is useful in formulating treatment strategy and predicting success after cholecystectomy. Am Surg. 2002;68(4):382-384. 15. Delgado-Aros S, Cremonini F, Bredenoord AJ, Camilleri M. Systematic review and meta-analysis: Does gallbladder ejection fraction on cholecystokinin cholescintigraphy predict outcome after cholecystectomy in suspected functional biliary pain? Aliment Pharmacol Therapeut. 2003;18(2):167-174. 16. Krishnamurthy GT, Krishnamurthy S, Watson RD. Characterization of basal hepatic bile flow and the effects of intravenous cholecystokinin on the liver, sphincter, and gallbladder in patients with sphincter of Oddi spasm. Eur J Nucl Med Mol Imaging. 2004;31 (1):85-93. 17. Bingener J, Richards ML, Schwesinger WH, Sirinek KR. Laparoscopic cholecystectomy for biliary dyskinesia: Correlation of preoperative cholecystokinin cholescintigraphy results with postoperative outcome. Surg Endosc. 2004;18(5):802-806. 18. Behar J, Corazziari E, Guelrud M, et al. Functional gallbladder and sphincter of oddi disorders. Gastroenterology. 2006;130(5):1498-1509.

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 9 of 10 19. Ziessman HA. Functional hepatobiliary disease: Chronic acalculous gallbladder and chronic acalculous biliary disease. Semin Nucl Med. 2006;36(2):119-132. 20. Dibaise JK. Evaluation and management of functional biliary pain in patients with an intact gallbladder. Expert Rev Gastroenterol Hepatol. 2009;3(3):305-313. 21. Krishnamurthy GT, Krishnamurthy S. Extended application of 99mTc-mebrofenin cholescintigraphy with cholecystokinin in the evaluation of abdominal pain of hepatobiliary and gastrointestinal origin. Nucl Med Commun. 2010;31(5):346-354. 22. DiBaise JK, Richmond BK, Ziessman HA, et al. Cholecystokinin-cholescintigraphy in adults: Consensus recommendations of an interdisciplinary panel. Clin Nucl Med. 2012;37(1):63-70. 23. Ziessman HA. Sincalide cholescintigraphy -- 32 years later: Evidence-based data on its clinical utility and infusion methodology. Semin Nucl Med. 2012;42(2):79-83. 24. Edwards MA, Mullenbach B, Chamberlain SM. Pain provocation and low gallbladder ejection fraction with CCK cholescintigraphy are not predictive of chronic acalculous gallbladder disease symptom relief after cholecystectomy. Dig Dis Sci. 2014;59(11):2773-2778.

Cholecystokinin Cholescintigraphy - Medical Clinical Policy Bulletins Aetna Page 10 of 10 Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change. Copyright 2001-2018 Aetna Inc.

AETNA BETTER HEALTH OF PENNSYLVANIA Amendment to Aetna Clinical Policy Bulletin Number: 0266 Cholecystokinin Cholescintigraphy There are no amendments for Medicaid. www.aetnabetterhealth.com/pennsylvania Annual 10/01/2018