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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. 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.

05-86000-24

Original Effective Date: 03/15/05

Reviewed: 06/23/16

Revised: 07/15/16

Subject: Laboratory Tests for Heart Transplant Rejection

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CEbRTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Position Statement Billing/Coding Reimbursement Program Exceptions Definitions Related Guidelines
           
Other References Updates    
           

DESCRIPTION:

The majority of cardiac transplant recipients experience at least one episode of rejection in the first year after transplantation. Acute cellular rejection is most likely to occur in the first six months, with a significant decline in the incidence of rejection after this time. Although immunosuppressants are required on a life-long basis, dosing is adjusted based on graft function and the grade of acute cellular rejection determined by histopathology. Endomyocardial biopsies are typically taken from the right ventricle via the jugular vein on a weekly basis for the first month, and once or twice monthly for the following 6 months. Surveillance biopsies may also be taken on a yearly basis following stabilization.

While endomyocardial biopsy is the gold standard for assessing heart transplant rejection, biopsy may be limited by a high degree of interobserver variability in grading of results and the significant morbidity and even mortality that can occur with the biopsy procedure. Also, the severity of rejection may not always coincide with the grading of the rejection by biopsy. Finally, biopsy cannot be used to identify patients at risk of rejection, limiting the ability to initiate therapy to interrupt the development of rejection. For these reasons, many consider endomyocardial biopsy a flawed gold standard. Therefore, noninvasive methods of detecting cellular rejection have been explored. It is hoped that non-invasive tests will assist in determining appropriate patient management and avoid overuse or underuse of treatment with steroids and other immunosuppressants that can occur with false negative and false positive biopsy reports.

POSITION STATEMENT:

The measurement of volatile organic compounds (i.e. Heartsbreath® test) to assist in the detection of moderate grade 2R/grade 3 heart transplant rejection is considered experimental or investigational.

The evaluation of genetic expression in the peripheral blood, including, but not limited to the detection of acute heart transplant rejection or graft dysfunction (i.e. AlloMap®) is considered experimental or investigational.

The use of the Presage® ST2 assay is considered experimental or investigational for all indications including, but not limited to, predicting prognosis and predicting acute cellular rejection in the post cardiac transplantation period.

Although there are ongoing clinical studies on the use of these tests, the current data are inadequate to permit scientific conclusions regarding the impact of these tests on management decisions and health outcomes.

BILLING/CODING INFORMATION:

CPT Coding:

81595

Cardiology (heart transplant), mRNA, gene expression profiling by real-time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing subfraction of peripheral blood, algorithm reported as a rejection risk score (investigational)

83006

Growth stimulation expressed gene 2 (ST2, Interleukin 1 receptor like-1) (investigational)

0085T

Breath test for heart transplant rejection (investigational)

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products:

The following National Coverage Determination (NCD) was reviewed on the last guideline reviewed date: Heartsbreath Test for Heart Transplant Rejection (260.10) located at cms.gov.

The following were reviewed on the last guideline reviewed date and are located at palmettogba.com:

• Local Coverage Determination (LCD): Molecular Diagnostic Tests (MDT) (L35025)

• MolDx: AlloMap Billing and Coding Guidelines Update (A53099)

DEFINITIONS:

No guideline specific definitions apply.

RELATED GUIDELINES:

None applicable.

OTHER:

None applicable.

REFERENCES:

  1. Blue Cross Blue Shield Association Medical Policy Reference Manual. 2.01.68 Laboratory Tests for Heart Transplant Rejection, 05/16.
  2. Blue Cross Blue Shield Association Medical Policy Reference Manual. 2.04.130 ST2 Assay for Chronic Heart Failure and Heart Transplant Rejection, 05/16.
  3. Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Gene expression profiling as a noninvasive method to monitor for cardiac allograft rejection. TEC Assessments 2011; volume 26, tab 8.
  4. Centers for Medicare & Medicaid Services (CMS), Decision Memo for Heartsbreath Test for Heart Transplant Rejection (CAG-00394N), 12/08/08.
  5. Centers for Medicare & Medicaid Services (CMS), NCD for Heartsbreath Test for Heart Transplant Rejection (260.10), 04/09, accessed at cms.org 05/25/16.
  6. ClinicalTrials.gov, Acute Cardiac Allograft Cellular Rejection and Cardiac Allograft Vasculopathy: Identification of Diagnostic Biomarkers and Target Pathways for Preventive Therapy, sponsored by National Institutes of Health Clinical Center, accessed 12/06/07.
  7. ClinicalTrials.gov, Bridging Pediatric and Adult Biomarkers in Graft-Versus-Host Disease, sponsored by Indiana University, accessed 05/25/16.
  8. ClinicalTrials.gov, Cardiac allograft Rejection Gene Expression Observational (CARGO) II Study (CARGOII), sponsored by XDx, accessed 01/12/09.
  9. ClinicalTrials.gov, A Comparison of AlloMap Molecular Testing and Traditional Biopsy-based Surveillance for Heart Transplant Rejection Early Post-transplantation (EIMAGE), sponsored by XDx, accessed 04/23/13.
  10. ClinicalTrials.gov, Early Invasive Monitoring Attenuation Through Gene Expression (EIMAGE) Trial, sponsored by XDx, accessed 07/18/12.
  11. ClinicalTrials.gov, Invasive Monitoring Attenuation Through Gene Expression (IMAGE) Trial, Sponsored by XDx, accessed 01/12/09.
  12. ClinicalTrials.gov. Evaluation of Magnetocardiography as a Tool for Non-Invasive Detection of Tissue Rejection in Cardiac Transplant Recipients, sponsored by Mayo Clinic & CardioMag Imaging. Accessed 12/06/07.
  13. ClinicalTrials.gov, Outcomes AlloMap Registry: the Long-term Management and Outcomes of Heart Transplant Recipients With AlloMap Testing (OAR), sponsored by XDx, accessed 05/25/16.
  14. ClinicalTrials.gov. Study of Heart Transplant Rejection, sponsored by National Institutes of Health Clinical Center (CC). Accessed 02/09/07.
  15. ClinicalTrials.gov. Utility of Donor-Derived Cell-free DNA in Association With Gene-Expression Profiling (AlloMap®) in Heart Transplant Recipients (D-OAR), sponsored by XDx, accessed 05/25/16.
  16. ClinicalTrials.gov, Validation of Heartsbreath Test for Heart Transplant Rejection, sponsored by Menssana Research, Inc. accessed 05/25/16.
  17. Conrad, S. A. (2004). Transplants, Heart.
  18. Costanzo MR, Dipchand A, Starling R et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29(8):914-56 accessed at ishlt.org 04/15/14.
  19. Crespo-Leiro MG, Stypmann J, Schulz U, et al. Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. Eur Heart J. Jan 7 2016.
  20. Deng MC, Eisen HJ, Mehra MR, et al., Noninvasive Discrimination of Rejection in Cardiac Allograft Recipients Using Gene Expression Profiling, American Journal of Transplantation, Vol 6, Issue 1, page 150-160, January 2006.
  21. Deng MC, Elashoff B, Pham MX et al. Utility of Gene Expression Profiling Score Variability to Predict Clinical Events in Heart Transplant Recipients. Transplantation 2014.
  22. ECRI Institute. Gene Expression Profiling to Monitor Acute Heart Transplant Rejection, Emerging Technology Evidence Report, 12/11. Accessed at ecri.org 07/18/12.
  23. ECRI Institute, Health Technology Assessment: Gene Expression Profiling to Monitor Heart Transplant Rejection, 2011, accessed at ecri.org 04/25/13.
  24. Executive Healthcare Management, When New Technology Revolutionizes Patient Care, accessed 09/24/07.
  25. Fang, K, Clinical Utilities of Peripheral blood Gene Expression Profiling in the Management of Cardiac Transplant Patients, Journal of Immunotoxicology, Vol 4, July 2007, pages 209-217.
  26. Hayes, Inc; Hayes Brief: Allomap Molecular Expression Testing (XDx Inc. [Expression Diagnostics] for Detection of Heart Transplant Rejection, August 10, 2006 (update 08/07).
  27. JA T. Gene Expression Profiling for the Diagnosis of Heart Transplant Rejection. California Technology Assessment Forum. 2010, accessed at ctaf.org 07/18/12.
  28. Mehra MR, Uber PA, Genomic Biomarkers and Heart Transplantation, Heart Fail Clin. 2007 Jan; 3(1): 83-6.
  29. Nikolaidis LA, Borzognia B, Bove AA, Limitations of Molecular Expression Profiling (Allomap Score) in Predicting Endomyocardial biopsy Findings in Cardiac Allograft Recipients: Two Year Follow-Up Surveillance Study, Circulation. October 2007; 116:II_505.
  30. Palmetto GBA, Local Coverage Determination (LCD): Molecular Diagnostic Tests (MDT) (L35025), accessed at palmettogba.com 05/26/16.
  31. Palmetto GBA Medicare, MOLDX: AlloMap Billing and Coding Guidelines Update (A53099), 12/31/15; accessed at palmettogba.com 05/25/16.
  32. Pham MX, Deng MC, Kfoury AG, et al, Molecular Testing for Long-Term Rejection surveillance in Heart Transplant Recipients: Design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial, J Heart Lung Transplant. 2007 Aug; 26(8): 808-14.
  33. Phillips, M., Boehmer, J. P., Cataneo, R. N., Cheema, T., Eisen, H. J., Fallon, J. T., Fisher, P. E., Gass, A., Greenberg, J., Kobashigawa, J., Mancini, D., Rayburn, B., & Zucker, M. J. (2004). Heart allograft rejection: detection with breath alkanes in low levels (the HARDBALL study). Journal of Heart Lung Transplant, 23(6), 701-708. (Abstract).
  34. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. Nov 2005;24(11):1710-1720.
  35. U.S. Food and Drug Administration (FDA), 510(k) Substantial Equivalence Determination, AlloMap Molecular Expression Testing, 08/08.
  36. U.S. Food and Drug Administration (FDA), 510(k) Summary, Presage® ST2 Assay, 12/11.
  37. U.S. Food and Drug Administration (FDA), New Humanitarian Device Approval, Heartsbreath, H03004, 02/24/04.
  38. Yamani MH, Taylor DO, Haire C, Smedira N, Starling RC, Post-Transplant Ischemic Injury is Associated With Up-regulated AlloMap Gene Expression, Clin Transplant. 2007 Jul-Aug; 21(4): 523-5.
  39. Yamani MH, Taylor DO, Rodriguez ER, et al, Transplant Vasculopathy is Associated with Increased AlloMap Gene Expression Score, J Heart Lung Transplant. 2007 Apr; 26(4): 403-6.
  40. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Oct 15 2013;62(16):e147-239.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Medical Policy & Coverage Committee on 06/23/16.

GUIDELINE UPDATE INFORMATION:

03/15/04

New Medical Coverage Guideline.

03/15/06

Annual review; continue investigational status.

03/15/07

Scheduled review; no change in coverage statement; references.

06/15/07

Reformatted guideline.

11/15/07

Revision: title changed, description section updated, position statement updated, Medicare Advantage section updated, references updated.

02/15/08

Annual review: position statements maintained; description section updated; references updated.

02/15/09

Annual review: position statements maintained; description section and references updated.

12/15/09

Annual review: position statements maintained; description section and references updated.

09/15/12

Review; position statements maintained; program exceptions section and references updated.

06/15/13

Annual review; position statements maintained and references updated.

06/15/14

Annual review; position statements maintained, program exception and reference updated.

06/15/15

Annual review; position statements maintained and references updated.

01/01/16

Annual HCPCS/CPT update; code 81595 added.

07/15/16

Annual review; revise the position statement section, coding, program exception, and references.

Date Printed: October 20, 2017: 08:41 AM