Medical Policy


Subject: Myocardial Sympathetic Innervation Imaging with or without Single-Photon Emission Computed Tomography (SPECT)
Document #: RAD.00064 Publish Date:    10/17/2018
Status: Reviewed Last Review Date:    09/13/2018


This document addresses use of the AdreView injectable tracer agent (iobenguane I 123injection, MIBG) for cardiac imaging to assist with identification of increased risk for short-term mortality associated with heart failure (HF). The radiopharmaceutical tracer, MIBG (123iodine meta-iodobenzylguanidine, known as 123I-MIBG or MIBG) has been proposed for use as a prognostic marker in individuals with heart failure. 

Note: This document addresses cardiac imaging with 123iodine meta-iodobenzylguanidine, (also known as 123I-MIBG or MIBG), and does not address oncologic indications for use of this radiotracer.

Note: For information related to other documents that address cardiac diagnostic imaging, please see the following:

Position Statement

Investigational and Not Medically Necessary:

Myocardial sympathetic innervation imaging with 123iodine meta-iodobenzylguanidine (MIBG) is considered investigational and not medically necessary for all indications, including the evaluation of heart failure.


An estimated 5.7 million adults in the United States have heart failure (HF), which is the main cause of death for approximately 55,000 Americans each year.  An early mechanism to compensate for the decreased myocardial function (seen in HF) is activation of the sympathetic nervous system.  This increase in sympathetic activity initially helps compensate for HF by increasing the heart rate and myocardial contractility, in order to maintain blood pressure and organ perfusion.  Over time, additional strain is placed 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 diminishes, clinical symptoms of HF develop.  Additionally, heightened sympathetic activity increases the presentation of potentially fatal ventricular arrhythmias.

The AdreView (lobenguane I 123 injection, GE Healthcare, General Electric Company, Medi-Physics, Inc., Arlington Heights, IL), is a diagnostic injectable agent which was originally approved for intravenous use by the U.S. Food and Drug Administration (FDA) in 2008.  Updated FDA approval was obtained in 2013 for AdreView as a radiopharmaceutical agent for gamma-scintigraphy indicated for:

It is noted that, while the H/M ratio can purportedly be used as either a dichotomous or continuous variable, the FDA-approved indication is a dichotomous variable with a cutoff in H/M ratio of 1.6.  A ratio less than 1.6 indicates higher risk for cardiac events and early mortality associated with HF, and a ratio of 1.6 or greater indicates lower risk. 

FDA approval of the AdreView injectable agent was based on two studies reported by Jacobson and colleagues (2010), which were known as the AdreView Myocardial Imaging for Risk Evaluation in Heart Failure trial (ADMIRE-HF).  The results indicated that a low MIBG ratio (H/M) was associated with a substantially higher 2-year mortality rate.  Data indicated that the addition of the MIBG score to a known prognostic index, the Seattle Heart Failure Model (SHFM), resulted in improved predictive accuracy.  The analysis presented the combined primary efficacy results of the two studies which included subjects with NYHA functional class II or III HF and an LVEF of 35% or lower.  These clinical parameters were then specified by the FDA as the appropriate criteria for use of the AdreView in individuals with HF who were additionally treated with optimum pharmacotherapy.  Major exclusion criteria were serum creatinine levels above 3.0 mg/dL, the presence of a functioning ventricular pacemaker or cardiac revascularization (history) and a history of myocardial infarction (MI) or implantable cardioverter-defibrillator (ICD) implantation within the past 30 days.

Trial participants received an injection of MIBG (AdreView, GE Healthcare) and then underwent planar and single-photon emission computer tomography (SPECT) imaging of the thorax at 15 minutes after injection (early) and at 3 hours and 50 minutes after injection (late).  The H/M ratio, on a scale from 0 to 4, was determined from both the early and late images.  Study subjects then received standard clinical care and were followed for 2 years.  The primary analysis evaluated the association between the time to first cardiac event occurrence and the late H/M ratio, categorized as < 1.6 or ≥ 1.6.  The authors also evaluated the association between the time to first cardiac event occurrence and late H/M ratio as a continuous variable.  The composite outcome of cardiac events was defined as the occurrence of: (1) HF progression (that is, an increase of 1 or more in NYHA functional class); (2) a potentially life-threatening arrhythmic event (that is, spontaneous ventricular tachyarrhythmia for more than 30 seconds, resuscitated cardiac arrest, or appropriate discharge of an ICD); or (3) cardiac death.

A total of 985 subjects underwent MIBG imaging (n=435 in the first study and 532 in the second study) and 961 subjects (98%) were available for analysis. There were 760 (79%) subjects with an H/M ratio of less than 1.60 and 201 subjects (21%) with an H/M ratio of at least 1.60.  Study subjects were then followed for a median of 17 months (range 2 days to 30 months).  Cardiac events occurred in 237 of 961 subjects (25%).  The mean late H/M ratio was 1.39 (standard deviation [SD], 0.18) in the group with any of the study’s cardiac events and 1.46 (SD, 0.21) in the group without events.  The study results indicated that the risk of cardiac events was significantly lower in those with an H/M ratio of at least 1.6, as compared to those with an H/M ratio of less than 1.6 (hazard ratio [HR], 0.40; 97.5% confidence interval [CI], 0.25 to 0.64; p<0.001).  In addition, there was a statistically significant association between the cardiac event rate and the H/M ratio as a continuous variable, with lower event rates seen for subjects with higher H/M ratios (HR, 0.22; 95% CI, 0.10 to 0.47; p<0.001).  The estimated 2-year all-cause mortality was 16.1% for subjects with H/M ratios less than 1.60 and 3.0% for those with H/M ratios of at least 1.60 (p<0.001).  The authors also compared the H/M ratios to other prognostic markers.  In a multivariate model including the H/M ratio, b-type natriuretic peptide (BNP), LVEF, and NYHA functional class, all four markers were independently associated with the time to cardiac events.

In 2012, Ketchum and colleagues published an analysis incorporating MIBG imaging findings into the SHFM, using survival data from the trial subjects included in the ADMIRE-HF primary efficacy analysis.  The late H/M ratio from MIBG imaging was divided into 5 categories: less than 1.2, 1.2-1.39, 1.40-1.59, 1.6-1.79 and > 1.8.  In a Cox proportional hazards model, SHFM and H/M ratios were both independent predictors of overall survival.  There was an 82.1% increase in risk for one SD change in the SHFM (p<0.001) and a 60.3% increase in risk for one SD change in the late H/M ratio (p<0.001).  For the outcome of cardiac mortality, each SD increase in SHFM was associated with an 86.1% increase in risk (p<0.001), and each SD increase in the late H/M ratio was associated with a 57.9% increase in risk (p=0.002).  In an area under the curve (AUC) analysis, the addition of H/M ratio to the SHFM significantly improved the prediction of all-cause mortality compared to the SHFM alone.  When the H/M ratio was added to the SHFM, the AUC increased by 0.039 (p=0.026) for 1-year mortality and the AUC increased by 0.028 (p<0.05) for 2-year mortality (Ketchum, 2012).

The results of these and other small trials demonstrate that, although more investigation in larger populations is needed to strengthen previous findings, cardiac (123)I-mIBG imaging shows promise as a new technique for recognizing and following potentially life-threatening cardiac conditions (Doi, 2012; Kasama, 2008; Verberne, 2008).  However, in one systematic review of 33 studies primarily performed in Europe and Japan that compared MIBG imaging results in subjects with HF before and after receiving medication treatment, it was noted that none of the studies used the MIBG imaging results to guide medication treatment choices or compared management strategies that did and did not include MIBG imaging (Treglia, 2013).

In 2011, a working group of the National Heart, Lung, and Blood Institute (NHLBI) published a report on the translation of cardiovascular molecular imaging.  Regarding cardiac MIBG imaging, the report cited the ADMIRE-HF trial and stated that additional clinical trials are needed to determine the efficacy of HF management strategies with MIBG, compared to usual care without MIBG imaging (Buxton, 2011).  Most trial investigators acknowledged that exact protocols for how treatment management changes might be influenced by MIBG imaging are uncertain at this time.  While it is possible that future medical therapy could be guided by the results of MIBG scanning, to date, the evidence is lacking that such management changes will result in improved outcomes.  

The current evidence is insufficient to demonstrate the safety/efficacy or the impact on clinical outcomes for myocardial sympathetic innervation imaging with 123Iodine meta-iodobenzylguanidine (MIBG), with or without SPECT, in the evaluation of HF.  There is no direct published evidence of the clinical utility of MIBG, and there is no indirect evidence of clinical utility.  At the present time, there is insufficient evidence to determine how MIBG results would impact treatment or clinical outcomes, compared to HF management without MIBG imaging.


Overactive sympathetic innervation associated with HF involves increased neuronal release of norepinephrine (NE), which is 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 post-synaptic beta-1, beta-2 and alpha receptors, enhances adenyl cyclase activity and brings about the desired cardiac stimulatory effects.  NE is then taken back into the presynaptic space for storage or catabolic disposal that terminates the synaptic response by the uptake-1 pathway.  The increased release of NE is usually accompanied by decreased NE reuptake, which increases circulating NE levels.

Guanethidine (an antihypertensive drug) is a false neurotransmitter that is an analogue of NE; it is also taken up by the uptake-1 pathway.  123Iodine meta-iodobenzylguanidine (known as 123I-MIBG or MIBG) is guanethidine that has been chemically modified and labeled with radioactive iodine.  MIBG moves into the synaptic cleft and is taken up and stored in the presynaptic nerve space similar to NE.  However, unlike NE, MIBG is not catabolized and concentrates in myocardial sympathetic nerve endings.  This concentrated MIBG can be imaged with a conventional gamma camera (Chirumamilla, 2011).  MIBG myocardial imaging is conducted by an injection of MIBG and planar images are then acquired 15 minutes (early image) and 4 hours (late image) after injection.  Optional single-photon emission computed tomography (SPECT) imaging can be performed following the early and late planar images.  MIBG uptake is semi-quantified by determining the average count per pixel in regions of interest (ROI) drawn over the heart and the upper mediastinum in the planar anterior view.  The concentration of MIBG over several hours after injection of the agent is a reflection of sympathetic neuronal activity, which may correlate with HF severity.  MIBG activity has also been suggested for potential use in guiding treatment decisions or in the monitoring of HF treatment effectiveness.                    

According to the FDA prescribing information, limitations of use state:

AdreView utility has not been established for:

Hypersensitivity reactions have uncommonly been reported during the postmarketing use of AdreView.
The following drugs have the potential to decrease the uptake of NE and cause false negative imaging results:

Clinical studies have not determined which specific drugs may cause false negative imaging results nor whether all drugs in any specific pharmacologic class have the same potential to produce negative imaging results.  Increasing the dose of AdreView will not overcome any potential uptake limiting effect of these drugs.  Before AdreView administration, drugs known or expected to reduce NE uptake must be discontinued for at least 5 biological half-lives, as clinically tolerated.  Many commonly used cardiovascular, pulmonary, and neuropsychiatric medications interfere with AdreView imaging.  AdreView imaging should not be performed if discontinuation of these medications would involve risks which outweigh the value of AdreView imaging (FDA, 2013).


Heart failure (HF), also referred to as Congestive Heart Failure (CHF): A condition in which the heart no longer adequately functions as a pump. As blood flow out of the heart slows, blood returning to the heart through the veins backs up, causing congestion in the lungs and other organs.

Heart-to-mediastinum (H/M) ratio: This refers to a cardiac measure which is calculated by taking the average count per pixel in the myocardium divided by the average count per pixel in the mediastinum. The H/M ratio is proposed as an independent predictor of risk for cardiac events and early mortality associated with HF.

123Iodine meta-iodobenzylguanidine (known as 123I-MIBG or MIBG) Imaging: This radiopharmaceutical imaging agent (known by the branded name, AdreView) is used with standard or SPECT scanning to measure the heart-to-mediastinum (H/M) ratio, in order to predict risk for cardiac events and death associated with HF.

Myocardial sympathetic innervation imaging: This technology involves use of the AdreView (MIBG) tracer injectable with scintigraphic scanning, in order to image the myocardium and measure myocardial sympathetic innervations. This imaging technique can determine certain cardiac variables, including the H/M ratio, which is proposed as a prognostic marker of HF symptom progression and risk for cardiac arrhythmias and death, associated with HF.

New York Heart Association (NYHA) Definitions:
The NYHA classification of HF is a 4-tier system that categorizes subjects based on subjective impression of the degree of functional compromise; the four NYHA functional classes are as follows:


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:




Myocardial sympathetic innervation imaging, planar qualitative and quantitative assessment;


Myocardial sympathetic innervation imaging, planar qualitative and quantitative assessment; with tomographic SPECT







Iodine I-123 iobenguane, diagnostic, per study dose, up to 15 millicuries [AdreView; when specified for use in myocardial imaging]



ICD-10 Diagnosis



All diagnoses


Peer Reviewed Publications:

  1. Akutsu Y, Kaneko K, Kodama Y, et al. Iodine-123 mIBG imaging for predicting the development of atrial fibrillation. JACC Cardiovasc Imaging. 2011; 4(1):78-86.
  2. 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. 2014; 21(4):756-762.
  3. Chirumamilla A, Travin MI. Cardiac applications of 123I-mIBG imaging. Semin Nucl Med. 2011; 41(5):374-387.
  4. Doi T, Nakata T, Hashimoto A, et al. Synergistic prognostic values of cardiac sympathetic innervation with left ventricular hypertrophy and left atrial size in heart failure patients without reduced left ventricular ejection fraction: a cohort study. BMJ Open. 2012; 2(6).
  5. Hachamovitch R, Nutter B, Menon V, Cerqueira MD. Predicting risk versus predicting potential survival benefit using 123I-mIBG imaging in patients with systolic dysfunction eligible for implantable cardiac defibrillator implantation: analysis of data from the prospective ADMIRE-HF study. Circ Cardiovasc Imaging. 2015; 8(12).
  6. 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. 2010; 55(20):2212-2221.
  7. 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. 2014; 20(8):577-583.
  8. Kasama S, Toyama T, Sumino H, et al. Prognostic value of serial cardiac 123I-MIBG imaging in patients with stabilized chronic heart failure and reduced left ventricular ejection fraction. J Nucl Med. 2008; 49(6):907-914.
  9. 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. 2012; 19(5):1007-1016.
  10. Klein T, Abdulghani M, Smith M, et al. Three-dimensional 123I-meta-iodobenzylguanidine cardiac innervation maps to assess substrate and successful ablation sites for ventricular tachycardia: a feasibility study for a novel paradigm of innervation imaging. Circ Arrhythm Electrophysiol. 2015; 8(3):583-591.
  11. Marshall A, Cheetham A, George RS, et al. Cardiac iodine-123 metaiodobenzylguanidine imaging predicts ventricular arrhythmia in heart failure patients receiving an implantable cardioverter-defibrillator for primary prevention. Heart. 2012; 98(18):1359-1365.
  12. 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. 2013; 6(7):772-784.
  13. 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. 2015; 56(7):1011-1018.
  14. Sood N, Al Badarin F, Parker M, et al. Resting perfusion MPI-SPECT combined with cardiac 123I-mIBG sympathetic innervation imaging improves prediction of arrhythmic events in non-ischemic cardiomyopathy patients: sub-study from the ADMIRE-HF trial. J Nucl Cardiol. 2013; 20(5):813-820.
  15. 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. 2013; 17(1):56-68.
  16. Verberne HJ, Brewster LM, Somsen GA, et al. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. 2008; 29(9):1147-1159.
  17. 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. 2014; 15(9):996-1003.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. BlueCross BlueShield Association TEC Assessment. Myocardial Sympathetic Innervation Imaging in Heart Failure. 2014; (28)12.
  2. Buxton DB, Antman M, Danthi N, et al. Report of the National Heart, Lung, and Blood Institute (NHLBI) Working Group on the Translation of Cardiovascular Molecular Imaging. Circulation. 2011; 123(19):2157-2163. Executive summary available at: Accessed on August 20, 2018.
  3. U.S. Food and Drug Administration (FDA). Center for Drug Evaluation and Research. AdreView (Iobenguane I 123 Injection). NDA: 3279800. Product approval information.  Rockville, MD: FDA; March 3, 2013. Available at: Accessed on August 20, 2018.
Websites for Additional Information
  1. Heart failure. Available at: Accessed on August 20, 2018.
  2. National Heart, Lung and Blood Institute. What is heart failure? Available at: Accessed on August 20, 2018.

Heart Failure, Congestive Heart Failure (CHF)
123iodine meta-iodobenzylguanidine
lobenguane I 123 injection
Sympathetic Innervation Imaging, Myocardial

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History






Medical Policy & Technology Assessment Committee (MPTAC) review. References were updated.



MPTAC review. The document header wording was updated from “Current Effective Date” to “Publish Date.” References were updated.



MPTAC review. References were updated.



MPTAC review. References were updated. Removed ICD-9 codes from Coding section.



MPTAC review. The Rationale, Background, and References sections were updated.



MPTAC review. Initial document development.