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Homocysteine Testing in the Screening, Diagnosis, and Management of Cardiovascular Disease and Venous Thromboembolic Disease

Policy Number: MP-341

Latest Review Date:  January 2024

Category:  Laboratory  

POLICY:

Measurement of plasma levels of homocysteine for the screening, evaluation, and management of individuals for cardiovascular disease is considered investigational.

Measurement of plasma levels of homocysteine for the screening, evaluation, and management of individuals with venous thromboembolism or risk of venous thromboembolism is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Homocysteine is an amino acid that has been evaluated as a potential marker of cardiovascular disease (CVD) and as a potential risk marker for people with CVD and thrombotic disorders; the presence of this amino acid raises one’s risk of developing a blood clot. The association between homocysteine-lowering interventions and the risk of CVD or thrombotic events has been examined.

Homocysteine is a sulfur-containing amino acid that is rapidly oxidized in plasma into homocysteine and cysteine-homocysteine disulfide. Measurement of total plasma homocysteine is the sum of homocysteine and its oxidized forms.

Plasma levels of homocysteine have been actively researched as a risk factor for cardiovascular disease (CVD), initially based on the observation that patients with hereditary homocystinuria, an inborn error of metabolism associated with high plasma levels of homocysteine, had a markedly increased risk of CVD. Subsequently, prospective epidemiologic studies were conducted to determine if an elevated plasma level of homocysteine was an independent risk factor for CVD and could be used to improve current risk prediction models. Several case-control studies have also suggested that elevated homocysteine is a risk factor for venous thromboembolism (VTE; pulmonary embolism, deep vein thrombosis).

Interest in homocysteine as a potentially modifiable risk factor has been stimulated by the epidemiologic finding that levels of homocysteine are inversely correlated with levels of folate. This finding has raised the possibility that treatment with folic acid might lower homocysteine levels and, in turn, reduce the risk of cardiovascular disease. Therefore, homocysteine has a potential utility both as a risk predictor and as a target of treatment.

Determination of homocysteine concentration may be offered as a component of a comprehensive cardiovascular risk assessment that may include evaluation of small-density lipoproteins, subclassification of high-density lipoproteins, evaluation of lipoprotein (a), high-sensitivity C-reactive protein, and genotyping of apolipoprotein E. Determination of homocysteine concentration may also be offered as part of the risk assessment for patients at high risk of VTE events or who have experienced idiopathic VTE, recurrent VTE, thrombosis occurring at a young age, or thrombosis at an unusual site.

KEY POINTS:

The most recent literature update was performed through October 11, 2023. 

Summary of Evidence

For individuals who are asymptomatic with the risk of cardiovascular disease (CVD) or individuals with CVD who receive homocysteine testing, the evidence includes observational studies and randomized controlled trials (RCTs) of homocysteine-lowering interventions. Relevant outcomes are changes in disease status and morbid events such as cardiovascular (CV) events, including myocardial infarction (MI), stroke, and CV death. Evidence from RCTs evaluating homocysteine-lowering interventions does not support the hypothesis that lowering homocysteine levels with folate and/or B vitamins improves CV outcomes. Numerous large RCTs and meta-analyses of these trials have consistently reported that homocysteine-lowering treatment is ineffective in reducing major CV events. A Cochrane systematic review found that homocysteine-lowering treatment reduced the risk of stroke. However, the investigators considered the results weak, and the clinical significance of this reduction is still unknown. Given a large amount of evidence from placebo-controlled, randomized trials that homocysteine-lowering interventions do not improve health outcomes, it is unlikely that routine homocysteine testing has the potential to change management that improves health outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with the risk of venous thromboembolism (VTE) or individuals who have experienced VTE events who receive homocysteine testing, the evidence includes observational studies and RCTs of homocysteine-lowering interventions. Relevant outcomes are change in disease status and morbid events such as VTE occurrence. Evidence from RCTs evaluating homocysteine-lowering interventions does not support the hypothesis that lowering homocysteine levels with folate and/or B vitamins reduces the risk of VTE. Only a single RCT was designed to test for VTE as a primary outcome. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

Cardiovascular Disease

National Institute for Health and Care Excellence

In 2023, NICE updated its guidance on risk assessment and reduction of cardiovascular disease (CVD), including lipid modification. The guidance asserted that full formal risk assessments should use a combination of risk assessment tools as well as informed clinical judgment. Homocysteine testing was not mentioned.

American Heart Association and the American Stroke Association

In 2014, The American Heart Association (AHA) and the American Stroke Association (ASA) issued joint guidelines on the primary prevention of stroke. These guidelines were endorsed by the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the Preventive Cardiovascular Nurses Association. The guidelines stated that patients with hyperhomocysteinemia may be treated with B-complex vitamins to prevent ischemic stroke, but that the effectiveness was not clearly established (class IIb; level of evidence B). In 2021, the AHA/ASA released a joint guideline on the prevention of stroke in patients with stroke and transient ischemic attack (TIA). The guideline stated that "in patients with ischemic stroke or TIA with hyperhomocysteinemia, supplementation with folate, vitamin B6, and vitamin B12 is not effective for preventing subsequent stroke."

American College of Cardiology and American Heart Association

In 2019, the American College of Cardiology (ACC) and the AHA issued a joint guideline on the primary prevention of CVD. The use of homocysteine was not mentioned as a marker to guide prevention strategy.

In 2016, the ACC and AHA issued a joint guideline for the management of patients with lower extremity peripheral disease. The guideline recommended against the use of B-complex vitamin supplementation to lower homocysteine, since it did not show benefit in the HOPE-2 trial.

In 2013, the ACC and AHA issued joint guidelines on the assessment of atherosclerotic cardiovascular risk. These guidelines were endorsed by 6 medical specialty associations. The guidelines developed multivariable equations to estimate age- and race-specific arteriosclerotic cardiovascular risk. The equations included age, total and high-density cholesterol levels, systolic blood pressure, antihypertensive treatment use, diabetes history, and current smoking status. The use of homocysteine screening for assessing the atherosclerotic cardiovascular risk was not considered in these guidelines.

National Academy of Clinical Biochemistry

In 2009, the National Academy of Clinical Biochemistry published guidelines on biomarkers for primary prevention of CVD. The Academy concluded that while homocysteine is a modest independent CVD risk factor, homocysteine screening for primary prevention and assessment in healthy individuals was unwarranted.

Venous Thromboembolism

Agency for Healthcare Research and Quality

In 2016, the Agency for Healthcare Research and Quality issued guidelines for effective quality improvement in preventing hospital-associated venous thromboembolism. Content for this guidance was last reviewed in March 2023. The venous thromboembolism prevention protocol recommended a venous thromboembolism risk assessment, a bleeding risk assessment, and clinical decision support on prophylactic choices. Homocysteine testing was not mentioned in these guidelines.

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (2018, updated 2019) issued guidance on reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. Homocysteine testing was not mentioned in this guidance.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (2018) issued a recommendation on the assessment of CVD risk with nontraditional risk factors. Homocysteine levels were not mentioned in this recommendation.

KEY WORDS:

Homocysteine, homocysteine, hyperhomocysteinemia, cardiovascular disease, CVD, venous thromboembolic disease

APPROVED BY GOVERNING BODIES:

Several of the homocysteine test systems have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. FDA product code: LPS. Examples are listed in Table 1.

Table 1. Homocysteine Test Systems

Assay

Laboratory

Approval Date

Homocysteine Enzymatic Assay

Roche Diagnostics

2012

Diazyme Enzymatic Homocysteine Assay

Diazyme Laboratories

2012

A/C Automatic Enzymatic Hcy [Homocysteine] Assay

AntiCancer Inc.

2008

Teco Enzymatic Homocysteine Assay

Teco Diagnostics

2007

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

83090

Homocysteine

REFERENCES:

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  2. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. Sep 10 2019; 140(11): e596-e646.
  3. Bazzano LA, Reynolds K, Holder KN, et al.  Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials.  JAMA 2006; 296(22); 2720-6.
  4. Bonaa KH, Njolstad I, Ueland PM, et al.  Homocysteine lowering and cardiovascular events after acute myocardial infarction.  NEJM 2006; 354(15):157-88.
  5. Catena C, Colussi G, Nait F, et al. Elevated Homocysteine Levels Are Associated With the Metabolic Syndrome and Cardiovascular Events in Hypertensive Patients. Am J Hypertens. Jul 2015; 28(7):943-950.
  6. Clarke R, Halsey J, Bennett D et al. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis 2011; 34(1):83-91.
  7. Clarke R, Halsey J, Lewington S et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer and cause-specific mortality. Arch Intern Med 2010; 170(18):1622-31.
  8. Den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost. Feb 2005; 3(2): 292-9.
  9. den Heijer M, Rosendaal FR, Blom HJ, et al. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost. Dec 1998; 80(6): 874-7. 
  10. den Heijer M, Willems HP, Blom HJ, et al. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial. Blood. Jan 01 2007; 109(1): 139-44.
  11. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. Mar 21 2017; 135(12): e726-e779.
  12. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Jul 1 2014; 63(25 Pt B):2935-2959.
  13. Greenland P, Alpert JS, Beller GA et al. American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. 2010 ACCF/AHA guideline for assessment of cardiovascular risk on asymptomatic adults. Circulation 2010; 21: 122(25):e584-636.
  14. Han L, Wu Q, Wang C, et al. Homocysteine, Ischemic Stroke, and Coronary Heart Disease in Hypertensive Patients: A Population-Based, Prospective Cohort Study. Stroke. Jul 2015; 46(7):1777-1786.
  15. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. Oct 2002; 288(16): 2015-22.
  16. Huang T, Chen Y, Yang B et al. Meta-analysis of B vitamin supplementation on plasma homocysteine, cardiovascular and all-cause mortality. Clin Nutr 2012; 31(4):448-54.
  17. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  18. Jacques PF, Selhub J, Bostom AG, et al.  The effect of folic acid fortification on plasma folate and total homocysteine concentrations.  NEJM 1999; 3409(19):1449-54.
  19. Kaul S, Zadeh AA, Shah PK.  Homocysteine hypothesis for atherothrombotic cardiovascular disease: non-validated.  J Am Coll Cardiol 2006; 48(5):94-23.
  20. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. Jul 2021; 52(7): e364-e467. 
  21. Liu Y, Tian T, Zhang H, et al. The effect of homocysteine-lowering therapy with folic acid on flow-mediated vasodilation in patients with coronary artery disease: a meta-analysis of randomized controlled trials. Atherosclerosis. Jul 2014; 235(1):31-35.
  22. Lonn E, Yusuf S, Arnold MJ, et al.  Homocysteine lowering with folic acid and B vitamins in vascular disease.  NEJM 2006; 354(15):1567-77.
  23. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. Aug 17 2017; 8(8): CD006612. 
  24. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. Jan 31 2013; (1): CD006612
  25. Martí-Carvajal AJ, Solà I, Lathyris D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. Jan 15 2015; 1: CD006612.
  26. Maynard G. Preventing hospital-associated venous thromboembolism: a guide for effective quality improvement. 2nd ed. Rockville, MD: Agency for Healthcare Research and Quality; 2016
  27. McMahaon JA, Green TJ, Skeaff CM, et al.  A controlled trial of homocysteine lowering and cognitive performance.  NEJM 2006; 354(26):2764-72. 
  28. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. Dec 2014; 45(12): 3754-832.
  29. Myers GL, Christenson RH, Cushman M, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. Feb 2009; 55(2): 378-84.
  30. Naess IA, Christiansen SC, Romundstad PR, et al. Prospective study of homocysteine and MTHFR 677TT genotype and risk for venous thrombosis in a general population--results from the HUNT 2 study. Br J Haematol. May 2008; 141(4): 529-35.
  31. National Institute for Health and Care Excellence (NICE). Cardiovascular disease: risk assessment and reduction, including lipid modification [CG181]. Updated October 2021; https://www.nice.org.uk/guidance/cg181/chapter/1- Recommendations#identifying-and-assessing-cardiovascular-disease-cvd-risk-2.
  32. National Institute for Health and Care Excellence (NICE). Venous thromboembolism in over 16s: reducing the risk of hospita-acquired deep vein thrombosis or pulmonary embolism. [NG89]. 2018; https://www.nice.org.uk/guidance/ng89.
  33. Park CS, Ihm SH, Yoo KD et al. Relation between C-reactive protein, homocysteine levels, fibrinogen and lipoprotein levels and leukocyte and platelet counts, and 10-year risk for cardiovascular disease among healthy adults in the USA. Am J Cardiol 2010; 105(9):1284-88.
  34. Park JH, Saposnik G, Ovbiagele B, et al. Effect of B-vitamins on stroke risk among individuals with vascular disease who are not on antiplatelets: A meta-analysis. Int J Stroke. Feb 2016; 11(2): 206-11.
  35. Peng HY, Man CF, Xu J, et al. Elevated homocysteine levels and risk of cardiovascular and all-cause mortality: a meta-analysis of prospective studies. J Zhejiang Univ Sci B. Jan 2015; 16(1):78-86.
  36. Rasouli ML, Nasir K, Blumenthal RS, et al.  Plasma homocysteine predicts progression of atherosclerosis.  Atherosclerosos 2005; 181(10:159-65.
  37. Ray JG, Kearon C, Yi Q, et al. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Ann Intern Med. Jun 05 2007; 146(11): 761-7.
  38. Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med. Oct 26 1998; 158(19): 2101-6.
  39. Sheng L, Wu C, Bai YY, et al. Plasma homocysteine levels are independently associated with alterations of large artery stiffness in men but not in women. J Geriatr Cardiol. May 2015; 12(3):251-256.
  40. Shi Z, Guan Y, Huo YR, et al. Elevated Total Homocysteine Levels in Acute Ischemic Stroke Are Associated With Long-Term Mortality. Stroke. Sep 2015; 46(9):2419-2425.
  41. Shoamanesh A, Preis SR, Beiser AS, et al. Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study. Neurology. Sep 20 2016; 87(12): 1206-11.
  42. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010; 303(24-Jan):2486-2494.
  43. Syvanne M, Whittall RA, Turpeinen U et al.  Serum homocysteine concentrations, gemfibrozil treatment, and progression of coronary atherosclerosis.  Atherosclerosis 2004; 172(2):267-72.
  44. The Homocysteine Studies collaboration.  Homocysteine and risk of ischemic heart disease and stroke; a meta-analysis.  JAMA 2002; 288(16); 2015-22. 
  45. U.S. Preventive Services Task Force. Cardiovascular Disease: Risk Assessment Using Nontraditional Risk Factors. 2018; https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/cardiovascular-disease-screening-using-nontraditional-risk-assessment.
  46. van Dijk SC, Enneman AW, Swart KM, et al. Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial. J Hypertens. Sep 2015; 33(9):1897-1906; discussion 1906.
  47. Veeranna V, Zalawadiya SK, Niraj A et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol 2011; 58(10):1025-33.
  48. Wald DS, Wald NJ, Morris JK, et al.  Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence.  BMJ 2006; 333(7578):1114-7. 
  49. Wang C, Han L, Wu Q, et al. Association between homocysteine and incidence of ischemic stroke in subjects with essential hypertension: A matched case-control study. Clin Exp Hypertens. Nov 2015; 37(7):557-562.
  50. Wang CY, Chen ZW, Zhang T, et al. Elevated plasma homocysteine level is associated with ischemic stroke in Chinese hypertensive patients. Eur J Intern Med. Jul 2014; 25(6):538-544.
  51. Yi X, Zhou Y, Jiang D, et al. Efficacy of folic acid supplementation on endothelial function and plasma homocysteine concentration in coronary artery disease: A meta-analysis of randomized controlled trials. Exp Ther Med. May 2014; 7(5):1100-1110.
  52. Zhou K, Zhao R, Geng Z, et al. Association between B-group vitamins and venous thrombosis: systematic review and meta-analysis of epidemiological studies. J Thromb Thrombolysis. Nov 2012; 34(4): 459-67.
  53. Zhou YH, Tang JY, Wu MJ et al. Effect of folic acid supplementation on cardiovascular outcomes: A systematic review and meta-analysis. PLoS ONE 2011; 6(9):e25142.

POLICY HISTORY:

Medical Policy Group, January 2009 (2)

Medical Policy Administration Committee, February 2009

Available for comment January 22-March 8, 2009

Medical Policy Group, May 2009 (2)

Medical Policy Administration Committee, June 2009

Medical Policy Group, April 2011 (1): Update to Description, Key Points and References

Medical Policy Group, November 2012 (1): 2012 Updates to Key Points and

References. Policy statement remains unchanged

Medical Policy Group, February 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, April 2014

Medical Policy Group, April 2014 (1): Policy updated with literature review through

February 2014; no references added; no change to policy statement

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3): 2015 Updates to Key Points & References; no change in policy statement.

Medical Policy Panel, December 2015

Medical Policy Group, January 2016 (3):  2015 Updates to Key Points & References; no change in policy statement

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): Annual updates to Key Points & Description. Scope of review broadened to include venous thromboembolism. Investigational policy statement added for homocysteine measurement in the evaluation of venous thromboembolism disease. Title of policy updated to include addition “and Venous Thromboembolic Disease”.

Available for comment January 30, 2019 through March 16, 2019

Medical Policy Administration Committee, February 2019

Medical Policy Panel, December 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Key Points, Description. Added key words: cardiovascular disease, CVD, venous thromboembolic disease. No change to intent of policy statement.

Medical Policy Panel, December 2020

Medical Policy Group, December 2020 (9): 2020 Updates to Key Points, Description, References. No change to policy statement.

Medical Policy Panel, December 2021

Medical Policy Group, December 2021 (9): 2021 Updates to Key Points, Description, References. Policy statement portion speaking to VTE updated to remove “not medically necessary,” policy statement portion speaking to CVD updated to remove “investigational,” no change to policy intent.

Medical Policy Panel, December 2022

Medical Policy Group, December 2022 (9): 2022 Updates to Key Points, Description, References. Replaced word "patient" with "individual" in policy statement; "Effective for dates of service March 9, 2009 through March 16, 2019" information removed from policy statement; no change to policy intent.

Medical Policy Panel, December 2023

Medical Policy Group, January 2024 (5): Updates to Description, Key Points; Practice Guidelines and Position Statements, Benefit Application, and References. No change to Policy Statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.