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Medical Policy Myocardial Sympathetic Innervation Imaging in Patients with Heart Failure Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 576 BCBSA Reference Number: 6.01.56 (For Plan internal use only) NCD/LCD: NA Related Policies
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Medicare HMO BlueSM and Medicare PPO BlueSM Members

Myocardial sympathetic innervation imaging with 123Iodine meta-iodobenzylguanidine (MIBG) is INVESTIGATIONAL for use in individuals with heart failure.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. Medicare HMO BlueSM This is not a covered service. Medicare PPO BlueSM This is not a covered service.

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CPT Codes / HCPCS Codes / ICD-10 Codes
The following codes are included below for informational purposes. Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable. CPT Codes CPT codes: Code Description 0331T Myocardial sympathetic innervations imaging, planar qualitative and quantitative assessment; 0332T Myocardial sympathetic innervations imaging, planar qualitative and quantitative assessment; with tomographic SPECT HCPCS Codes HCPCS codes:

Code Description A9582 Iodine I-123 iobenguane, diagnostic, per study dose, up to 15 millicuries
Diagnosis Codes Investigational for all diagnoses.

DESCRIPTION
Heart Failure An estimated 6.7 million adults in the U.S. have heart failure. In 2022, heart failure was mentioned on 457,212 death certificates in the U.S.1, According to data in the 2022 Heart and Stroke Statistics Update, 1 in 6 patients with heart failure and reduced ejection fraction developed worsening disease within 18 months of diagnosis and these individuals were more likely to be Black, >80 years of age, and have increased comorbidity burden.2, Black individuals also have the highest risk of developing heart failure in the future, followed by Hispanic, White, and Chinese American individuals, reflecting disparities in the incidence of hypertension, diabetes, and socioeconomic status among these populations. Black individuals also have the highest proportion of incident heart failure not preceded by myocardial infarction (75%). Underlying causes of heart failure include coronary artery disease, hypertension, valvular disorders, and primary cardiomyopathies. These conditions reduce myocardial pump function and decrease left ventricular ejection fraction (LVEF). An early mechanism to compensate for this decreased myocardial function is activation of the sympathetic nervous system. The increased sympathetic activity initially helps compensate for heart failure by increasing heart rate and myocardial contractility to maintain blood pressure and organ perfusion. However, over time, this places additional strain on the myocardium, increasing coronary perfusion requirements, which can lead to worsening of ischemic heart disease and/or myocardial damage. As the ability of the heart to compensate for reduced myocardial function diminishes, clinical symptoms of heart failure develop. Another detrimental effect of heightened sympathetic activity is an increased susceptibility to potentially fatal ventricular arrhythmias.

Overactive sympathetic innervation associated with heart failure involves increased neuronal release of norepinephrine (NE), the main neurotransmitter of the cardiac sympathetic nervous system. In response to sympathetic stimulation, vesicles containing NE are released into the neuronal synaptic cleft. The released NE binds to postsynaptic β1, β2, and α receptors, enhances adenyl cyclase activity, and brings about the desired cardiac stimulatory effects. Norepinephrine is then taken back into the presynaptic space for storage or catabolic disposal, terminating the synaptic response by the uptake-1 pathway. The increased release of NE is usually accompanied by decreased NE reuptake, thereby further increasing circulating NE levels.

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Diagnostic Imaging Guanethidine is a false neurotransmitter that is an analogue of NE; it is also taken up by the uptake-1 pathway. Iodine 123 meta-iodobenzylguanidine (123I-MIBG or MIBG) is chemically-modified guanethidine labeled with radioactive iodine. Iodine 123 meta-iodobenzylguanidine moves into the synaptic cleft and then is taken up and stored in the presynaptic nerve space in a manner similar to NE. However, unlike NE, MIBG is not catabolized and thus concentrates in myocardial sympathetic nerve endings. This concentrated MIBG can be imaged with a conventional gamma camera.3, The concentration of MIBG over several hours after injection is thus a reflection of sympathetic neuronal activity, which in turn may correlate with the severity of heart failure.

Iodine 123 meta-iodobenzylguanidine myocardial imaging has been in use in Europe and Japan, and standardized procedures for imaging have been proposed by European organizations.4, Administration of MIBG is recommended by slow (1 to 2 minute) injection. Planar images of the thorax are acquired 15 minutes (early image) and 4 hours (late image) after injection. In addition, optional single photon emission computed tomography (SPECT) can be performed following the early and late planar images. Iodine 123 meta-iodobenzylguanidine uptake is semi-quantified by determining the average count per pixel in regions of interest drawn over the heart and the upper mediastinum in the planar anterior view. There is no single universally used myocardial MIBG index. The most commonly used myocardial MIBG indices are the early heart to mediastinum (H/M) ratio, late H/M ratio, and the myocardial MIBG washout rate. The H/M ratio is calculated by taking the average count per pixel in the myocardium divided by the average count per pixel in the mediastinum. The myocardial washout rate is expressed as the rate of decrease in myocardial counts over time between early and late imaging (normalized to mediastinal activity).

Iodine 123 meta-iodobenzylguanidine activity is proposed as a prognostic marker in patients with heart failure, to be used in conjunction with established markers or prognostic models to identify heart failure patients at increased risk of short-term mortality. Iodine 123 meta-iodobenzylguanidine activity could also be used to guide treatment decisions or to monitor the effectiveness of heart failure treatments.

Summary
Description In individuals with heart failure, activation of the sympathetic nervous system is an early response to compensate for decreased myocardial function. The concentration of iodine 123 meta- iodobenzylguanidine (MIBG) over several hours after the injection of the agent is a potential marker of sympathetic neuronal activity. Iodine 123 meta-iodobenzylguanidine activity is proposed as a prognostic marker in individuals with heart failure to aid in the identification of individuals at risk of 1- and 2-year mortality. The marker could also be used to guide treatment decisions or to monitor the effectiveness of heart failure treatments.

Summary of Evidence For individuals with heart failure who receive imaging with iodine 123 meta-iodobenzylguanidine (MIBG) for prognosis, the evidence includes numerous studies that MIBG cardiac imaging findings predict outcomes in individuals with heart failure. Relevant outcomes are overall survival, disease-specific survival, functional outcomes, health status measures, quality of life, hospitalizations, and medication use. While the available studies vary in their patient inclusion criteria and methods for analyzing MIBG parameters, the highest quality studies have demonstrated a significant association between MIBG imaging results and adverse cardiac events, including cardiac death. Moreover, MIBG findings have been shown to improve the ability of the Seattle Heart Failure Model (SHFM) and other risk models to predict mortality. However, there is no direct published evidence on the clinical utility of MIBG (ie, whether findings of the test would lead to patient management changes that improve health outcomes) and no chain of evidence can be constructed to support clinical utility. Management changes made as a result of MIBG imaging are uncertain, and it is not possible to determine whether management changes based on MIBG results lead to improved health outcomes compared with management without MIBG imaging. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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Policy History Date Action 11/2025 Annual policy review. Policy updated with literature review through July 28, 2025; no references added. Policy statement unchanged. 11/2024 Annual policy review. Policy updated with literature review through August 5, 2024; no references added. Minor editorial refinement to policy statement; intent unchanged. 11/2023 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 11/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 10/2021 Annual policy review. Policy statements unchanged. 10/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 10/2018 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 10/2017 Annual policy review. New references added. 10/2016 Annual policy review. New references added. 8/2015 Annual policy review. New references added. 9/2014 Annual policy review. New references added. 12/2013 New medical policy describing investigational indications. Effective 12/1/2013.
Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

1. Centers for Disease Control and Prevention (CDC). About heart failure. May 15, 2024; https://www.cdc.gov/heart-disease/about/heart- failure.html?CDCAArefVal=https://www.cdc.gov/heartdisease/heart_failure.htm. Accessed August 5, 2024.
2. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation. Feb 22 2022; 145(8): e153-e639. PMID 35078371
3. Chirumamilla A, Travin MI. Cardiac applications of 123I-mIBG imaging. Semin Nucl Med. Sep 2011; 41(5): 374-87. PMID 21803188
4. Flotats A, Carrió I, Agostini D, et al. Proposal for standardization of 123I-metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging. Aug 2010; 37(9): 1802-12. PMID 20577740
5. Food and Drug Administration (FDA). Approval letter: NDA 22-290. AdreView, (IIobenguane I 123) 2mCi/mL Injection. 2008; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022290s000toc.cfm. Accessed August 5,
7. Food and Drug Administration (FDA). Supplemental Approval letter: NDA 22-290/S-001. AdreView (Iobenguane I 123) Injection. 2013; https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/022290orig1s001ltr.pdf. Accessed August 7, 2024.
8. Food and Drug Administration (FDA). Highlights of Prescribing Information: AdreView (Iobenguane I 123 Injection) for Intravenous Use. 2020; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022290s005lbl.pdf. Accessed August 6, 2024.

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8. Verschure DO, Veltman CE, Manrique A, et al. For what endpoint does myocardial 123I-MIBG scintigraphy have the greatest prognostic value in patients with chronic heart failure? Results of a pooled individual patient data meta-analysis. Eur Heart J Cardiovasc Imaging. Sep 2014; 15(9): 996-
9. PMID 24686260
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11. Jacobson AF, Senior R, Cerqueira MD, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. May 18 2010; 55(20): 2212-21. PMID 20188504
12. Ketchum ES, Jacobson AF, Caldwell JH, et al. Selective improvement in Seattle Heart Failure Model risk stratification using iodine-123 meta-iodobenzylguanidine imaging. J Nucl Cardiol. Oct 2012; 19(5): 1007-16. PMID 22949270
13. Al Badarin FJ, Wimmer AP, Kennedy KF, et al. The utility of ADMIRE-HF risk score in predicting serious arrhythmic events in heart failure patients: incremental prognostic benefit of cardiac 123I- mIBG scintigraphy. J Nucl Cardiol. Aug 2014; 21(4): 756-62; quiz 753-55, 763-5. PMID 25015681
14. Jain KK, Hauptman PJ, Spertus JA, et al. Incremental utility of iodine-123 meta-iodobenzylguanidine imaging beyond established heart failure risk models. J Card Fail. Aug 2014; 20(8): 577-83. PMID 24951931
15. Narula J, Gerson M, Thomas GS, et al. ¹²³I-MIBG Imaging for Prediction of Mortality and Potentially Fatal Events in Heart Failure: The ADMIRE-HFX Study. J Nucl Med. Jul 2015; 56(7): 1011-8. PMID 26069309
16. Agostini D, Ananthasubramaniam K, Chandna H, et al. Prognostic usefulness of planar 123 I-MIBG scintigraphic images of myocardial sympathetic innervation in congestive heart failure: Follow-Up data from ADMIRE-HF. J Nucl Cardiol. Aug 2021; 28(4): 1490-1503. PMID 31468379
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19. Katoh S, Shishido T, Kutsuzawa D, et al. Iodine-123-metaiodobenzylguanidine imaging can predict future cardiac events in heart failure patients with preserved ejection fraction. Ann Nucl Med. Nov 2010; 24(9): 679-86. PMID 20824398
20. Minamisawa M, Izawa A, Motoki H, et al. Prognostic Significance of Neuroadrenergic Dysfunction for Cardiovascular Events in Patients With Acute Myocardial Infarction. Circ J. 2015; 79(10): 2238-45. PMID 26155851
21. Scala O, Paolillo S, Formisano R, et al. Sleep-disordered breathing, impaired cardiac adrenergic innervation and prognosis in heart failure. Heart. Nov 15 2016; 102(22): 1813-1819. PMID 27340199
22. Nakata T, Nakajima K, Yamashina S, et al. A pooled analysis of multicenter cohort studies of (123)I- mIBG imaging of sympathetic innervation for assessment of long-term prognosis in heart failure. JACC Cardiovasc Imaging. Jul 2013; 6(7): 772-84. PMID 23845574
23. Treglia G, Stefanelli A, Bruno I, et al. Clinical usefulness of myocardial innervation imaging using Iodine-123-meta-iodobenzylguanidine scintigraphy in evaluating the effectiveness of pharmacological treatments in patients with heart failure: an overview. Eur Rev Med Pharmacol Sci. Jan 2013; 17(1): 56-68. PMID 23329524
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25. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. May 03 2022; 79(17): e263-e421. PMID 35379503