mp-567 - Medical Policies - Alabama
Novel Biomarkers in Risk Assessment and Management of Cardiovascular Disease
Policy Number: MP-567
Latest Review Date: December 2020
Policy Grade: B
Measurement of novel lipid and non-lipid risk factors (i.e., apolipoprotein B, apolipoprotein A1, apolipoprotein E, B-type natriuretic peptide, cystatin C, fibrinogen, leptin, low-density lipoprotein subclass, high density lipoprotein subclass, lipoprotein[a]) is considered not medically necessary and investigational as an adjunct to low-density lipoprotein cholesterol in the risk assessment and management of cardiovascular disease.
DESCRIPTION OF PROCEDURE OR SERVICE:
Numerous lipid and non-lipid biomarkers have been proposed as potential risk markers for cardiovascular disease. The biomarkers assessed here are those that have the most evidence in support of their use in clinical care. The biomarkers assessed here are apolipoprotein B, apolipoprotein A1 (apo A1), apolipoprotein E (apo E), B-type natriuretic peptide, cystatin C, fibrinogen, high-density lipoprotein (HDL) subclass, leptin, low-density lipoprotein (LDL) subclass, and lipoprotein A. These biomarkers have been studied as an alternative or addition to standard lipid panels for risk stratification in cardiovascular disease or as treatment targets for lipid-lowering therapy.
Low Density Lipoproteins and Cardiovascular Disease
Low-density lipoproteins (LDLs) have been identified as the major atherogenic lipoproteins and have long been identified by the National Cholesterol Education Project (NCEP) as the primary target of cholesterol- lowering therapy. An LDL particle consists of a surface coat composed of phospholipids, free cholesterol, and apolipoproteins surrounding an inner lipid core composed of cholesterol ester and triglycerides. Traditional lipid risk factors such as LDL-cholesterol (LDL-C), while predictive on a population basis, are weaker markers of risk on an individual basis. Only a minority of subjects with elevated LDL and cholesterol levels will develop clinical disease, and up to 50% of cases of coronary artery disease (CAD) occur in subjects with ‘normal’ levels of total and LDL-C. Thus, there is considerable potential to improve the accuracy of current cardiovascular risk prediction models.
Other non-lipid markers have been identified as having an association with cardiovascular disease (CVD) including B-type natriuretic peptide, cystatin C, fibrinogen and leptin. These biomarkers may have a predictive role in identifying cardiovascular disease risk or in targeting therapy.
Apolipoprotein B (Apo B) is the major protein moiety of all lipoproteins except for high-density lipoprotein (HDL). The most abundant form of apo B, large B or B-100, constitutes the apo B found in LDL and very-low-density lipoproteins (VLDL). Since both LDL and VLDL each contains one molecule of apolipoprotein B, the measurement of apo B reflects the total number of these atherogenic particles, 90% of which are LDL. Since LDL particles can vary both in size and in cholesterol content, for a given concentration of LDL-C, there can be a wide variety of both size and numbers of LDL particles. Thus, it has been postulated that apo B is a better measure of the atherogenic potential of serum LDL than is LDL concentration.
High-density lipoprotein (HDL) contains two associated apolipoproteins (i.e., A1 and A2). High-density lipoprotein (HDL) particles can also be classified by whether they contain apolipoprotein A1 (apo A1) only or whether they contain both apo A1 and apolipoprotein AII (apo A2). All lipoproteins contain apo A1, and some also contain apo A2. Since all HDL particles contain apo A1, this lipid marker can be used as an approximation for HDL number, similar to the way apo B has been proposed as an approximation of the LDL number.
Direct measurement of apo A1 has been proposed as more accurate than the traditional use of HDL level in evaluation of the cardioprotective, or “good,” cholesterol. In addition, the ratio of apolipoprotein B (apo B)/apo A1 has been proposed as a superior measure of the ratio of proatherogenic (i.e., “bad”) cholesterol to anti-atherogenic (i.e., “good”) cholesterol.
Apolipoprotein E (apo E) is the primary apolipoprotein found in VLDLs and chylomicrons. Apolipoprotein E is the primary binding protein for LDL receptors in the liver and is thought to play an important role in lipid metabolism. The apolipoprotein E (APOE) gene is polymorphic, consisting of three epsilon alleles (e2, e3, and e4) that code for three protein isoforms, known as E2, E3, and E4, which differ from one another by one amino acid. These molecules mediate lipid metabolism through their different interactions with the LDL receptors. The genotype of apo E alleles can be assessed by gene amplification techniques, or the apo E phenotype can be assessed by measuring plasma levels of apo E.
It has been proposed that various APOE genotypes are more atherogenic than others and that apo E measurement may provide information on the risk of coronary artery disease (CAD) above traditional risk factor measurement. It has also been proposed that the apo E genotype may be useful in the selection of specific components of lipid-lowering therapy, such as drug selection. In the major lipid-lowering intervention trials, including trials of statin therapy, there is considerable variability in response to therapy that cannot be explained by factors such as compliance. The APOE genotype may be one factor that determines an individual’s degree of response to interventions such as statin therapy.
High-Density Lipoprotein Subclass
High-density lipoprotein (HDL) particles exhibit considerable heterogeneity, and it has been proposed that various subclasses of HDL may have a greater role in protection from atherosclerosis. Particles of HDL can be characterized based on size/density and/or on the apolipoprotein composition. Using size/density, HDL can be classified into HDL2, the larger, less dense particles that may have the greatest degree of cardioprotection, and HDL3, which are smaller, denser particles.
An alternative to measuring the concentration of subclasses of HDL (e.g. HDL 2 and HDL3) is a direct measurement of HDL particle size and/or number. Particle size can be measured by nuclear magnetic resonance spectroscopy (NMR) or by gradient-gel electrophoresis. High-density lipoprotein particle numbers can be measured by NMR spectroscopy. Several commercial labs offer these measurements of HDL particle size and number. Measurement of apo A-1 has used measurement of HDL particle number as a surrogate, based on the premise that each HDL particle contains one apo A1 molecule.
Low-Density Lipoprotein Subclass
Two main subclass patterns of LDL, called A and B, have been described. In subclass pattern A, the particles have a diameter larger than 25 nm and are less dense, while in subclass pattern B, the particles have a diameter less than 25 nm and a higher density. Subclass pattern B is a commonly inherited disorder associated with a more atherogenic lipoprotein profile, also termed “atherogenic dyslipidemia.” In addition to small, dense LDL, this pattern includes elevated levels of triglycerides, elevated levels of apolipoprotein B, and low levels of HDL. This lipid profile is commonly seen in Type II diabetes and is one component of the “metabolic syndrome,” defined by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel 3; ATP 3) to also include high normal blood pressure, insulin resistance, increased levels of inflammatory markers such as C-reactive protein (CRP), and a prothrombotic state. The presence of the metabolic syndrome is considered by Adult Treatment Panel 3 to be a substantial risk-enhancing factor for CAD.
Low-density lipoprotein size has also been proposed as a potentially useful measure of treatment response. Lipid-lowering treatment decreases total LDL and may also induce a shift in the type of LDL, from smaller, dense particles to larger particles. It has been proposed that this shift in lipid profile may be beneficial in reducing the risk for CAD independent of the total LDL level. Also, some drugs may cause a greater shift in lipid profile than others. Niacin and/or fibrates may cause a greater shift from small to large LDL size than statins. Therefore, measurement of LDL size may potentially play a role in drug selection or may be useful in deciding to use a combination of two or more drugs rather than a statin alone.
In addition to the size of LDL particles, interest has been shown in assessing the concentration of LDL particles as a distinct cardiac risk factor. For example, the commonly performed test, LDL-C is not a direct measure of LDL but, chosen for its convenience, measures the amount of cholesterol incorporated into LDL particles. Since LDL particles carry much of the cholesterol in the bloodstream, the concentration of cholesterol in LDL correlates reasonably well with the number of LDL particles when examined in large populations. However, for an individual patient, the LDL-C level may not reflect the number of particles due to varying levels of cholesterol in different sized particles. It is proposed that the discrepancy between the number of LDL particles and the serum level of LDL-C represents a significant source of unrecognized atherogenic risk. The size and number of particles are interrelated. For example, all LDL particles can invade the arterial wall and initiate atherosclerosis. However, small, dense particles are thought to be more atherogenic compared to larger particles. Therefore, for patients with elevated numbers of LDL particles, the cardiac risk may be further enhanced when the particles are smaller versus larger.
Lipoprotein (a) [Lp (a)] is a lipid-rich particle similar to LDL. The major apolipoprotein associated with LDL is apo B; in Lp (a), however, there is an additional apo A covalently linked to the apo B. The apo A molecule is structurally similar to plasminogen, suggesting that Lp (a) may contribute to the thrombotic and atherogenic basis of cardiovascular disease. Levels of Lp (a) are relatively stable in individuals over time but vary up to 1,000-fold between individuals, presumably on a genetic basis. The similarity between Lp (a) and fibrinogen has stimulated intense interest in Lp (a) as a link between atherosclerosis and thrombosis. In addition, approximately 20% of patients with CAD have elevated levels of Lp (a). Therefore, it has been proposed that levels of Lp (a) may be an independent risk factor for CAD.
Brain Natriuretic Peptide
Brain Natriuretic Peptide (BNP) is an amino acid polypeptide that is secreted primarily by the ventricles of the heart when the pressure to the cardiac muscles increases or there is myocardial ischemia. Elevations in BNP levels reflect deterioration in cardiac loading levels and may predict adverse events. BNP has been studied as a biomarker for managing heart failure and predicting cardiovascular and heart failure risk.
Cystatin C is a small serine protease inhibitor protein that is secreted from all functional cells in the body. It has primarily been used as a biomarker of kidney function. Cystatin C has also been studied to determine whether it may serve as a biomarker for predicting cardiovascular risk. Cystatin C is encoded by the CST3 gene.
Fibrinogen is a circulating clotting factor and precursor of fibrin. It is important in platelet aggregation and a determinant of blood viscosity. Fibrinogen levels have been shown to be associated with future risk of cardiovascular risk and all-cause mortality.
Leptin is a protein secreted by fat cells that have been found to be elevated in heart disease. Leptin has been studied to determine if it has any relationship with the development of cardiovascular disease.
The most recent literature review was updated through October 30, 2020.
Summary of Evidence
For individuals who are asymptomatic with risk of cardiovascular disease who receive novel cardiac biomarker testing (e.g., apo B, apo A1, apo E, HDL subclass, LDL subclass, lipoprotein a, B-type natriuretic peptide, cystatin C, fibrinogen, leptin), the evidence includes systematic reviews, meta-analyses, and large, prospective cohort studies. Relevant outcomes are overall survival, other test performance measures, change in disease status, morbid events, and medication use. The evidence from cohort studies and meta-analyses of these studies has suggested that some of these markers are associated with increased cardiovascular risk and may provide incremental accuracy in risk prediction. In particular, apo B and apo A1 have been identified as adding some incremental predictive value. However, it has not been established whether the incremental accuracy provides clinically important information beyond that of traditional lipid measures. Furthermore, no study has provided high-quality evidence that measurement of markers leads to changes in management that improve health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with hyperlipidemia managed with lipid-lowering therapy who receive novel cardiac biomarker testing (e.g., apo B, apo A1, apo E, apo E, HDL subclass, LDL subclass, lipoprotein a, B-type natriuretic peptide, cystatin C, fibrinogen, leptin), the evidence includes analyses of the intervention arm(s) of lipid-lowering medication trials. Relevant outcomes are overall survival, change in disease status, morbid events, and medication use. In particular, apo B, apo A1, and apo E have been evaluated as markers of lipid-lowering treatment success, and evidence from the intervention arms of several randomized controlled trials has suggested that these markers are associated with treatment success. However, there is no direct evidence that using markers other than LDL and HDL as a lipid-lowering treatment target leads to improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
National Heart, Lung, and Blood Institute
The National Heart, Lung, and Blood Institute’s (NHLBI’s) National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel 3) issued a position statement in 2001. Apo B, apo A-1, lipid subclass, and lipoprotein (a) were listed as “emerging risk factors” for cardiovascular risk assessment, without specific recommendations for how these measures should be used in clinical practice. A 2004 update to these guidelines discussed the result of clinical trials of statin therapy.
In 2013, the institute published a systematic evidence review on managing blood cholesterol in adults. The review was used to develop joint guidelines by the American College of Cardiology and American Heart Association (ACC/AHA) on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults.
American College of Cardiology and American Heart Association (ACC and AHA)
ACC/AHA published guidelines in 2013 for the assessment of cardiovascular risk. Pooled cohort equations for estimating arteriosclerotic cardiovascular disease (ASCVD) were developed from sex- and race-specific proportional hazards models that included covariates of age, treated or untreated systolic blood pressure level, total cholesterol and high-density lipoprotein (HDL) cholesterol levels, current smoking status, and history of diabetes. Additional risk factors evaluated included diastolic blood pressure, family history of ASCVD, moderate or severe chronic kidney disease, and body mass index. None of these variables significantly improved discrimination for ten-year hard ASCVD risk prediction. The ACC and AHA recommended that further research using state of the art statistical techniques (including net reclassification improvement and integrative discrimination index) examine the utility of novel biomarkers when added to these new pooled cohort equations in different populations and patient subgroups. The guidelines state that future updates might include guidance on whether on-treatment markers such as apo B, Lp (a), or low-density lipoprotein (LDL) particles are useful for guiding treatment decisions.
The ACC/AHA (2019) guideline on primary prevention of cardiovascular disease state regarding elevated Lp (a) that “a relative indication for its measurement is family history of premature ASCVD. An Lp (a) ≥50 mg/dL or ≥125 nmol/L constitutes a risk-enhancing factor, especially at higher levels of Lp (a).” The guideline further states regarding elevated apo B (≥130 mg/dL) that “a relative indication for its measurement would be triglyceride ≥200 mg/dL. A level ≥130 mg/dL corresponds to an LDL-C >160 mg/dL and constitutes a risk-enhancing factor.”
American Diabetes Association and American College of Cardiology (ACC) Foundation
In 2008, a publication from a consensus conference of the American Diabetes Association and the American College of Cardiology Foundation addressed lipoprotein management in patients with cardiometabolic risk. This statement included specific recommendations for incorporating apo B testing into clinical care for high-risk patients and recommended that, for patients with metabolic syndrome who are being treated with statins, both LDL-C and apo B should be used as treatment targets, with an apo B target of less than 90 mg/dL, even if target LDL has been achieved.
This consensus statement also commented on the use of LDL particle number in patients with cardiometabolic risk. They commented on the limitations of the clinical utility of nuclear magnetic resonance measurement of LDL particle number or size, including lack of widespread availability. The statement also noted that there is a need for more independent data confirming the accuracy of the method and whether its predictive power is consistent across various patient populations.
The American Diabetes Association 2020 Standards of Care do not discuss the use of novel biomarkers for cardiovascular disease and risk management.
American Association of Clinical Endocrinologists and the American College of Endocrinology
In 2017, American Association of Clinical Endocrinologists and the American College of Endocrinology published joint guidelines on the management of dyslipidemia and the prevention of cardiovascular diseases. The guidelines recommended that, among patients with “triglyceride (TG) concentration of greater than 150 mg/dL or HDL-C concentration of less than 40 mg/dL, the apo B or the apo B to apo AI ratio may be useful in assessing residual risk in individuals at risk for ASCVD (even when the LDL-C levels are controlled).”
National Lipid Association
The National Lipid Association (NLA) recommendations for patient-centered management of dyslipidemia were published in 2015. These recommendations stated that non-HDL-C and LDL-C should be the primary targets for therapy and that apo B is an optional, secondary target for therapy. NLA favored non-HDL-C over apo B because it is universally available and because apo B has not consistently shown superiority in predicting atherosclerotic cardiovascular disease (ASCVD) risk.
In 2018, the NLA published a guideline on the management of blood cholesterol in conjunction with 11 other organizations, which discussed the measurement of apo B and Lp (a). A triglyceride level ≥200 mg/dL was mentioned as a relative indication of apo B measurement. Relative indications for measurement of Lp (a) include family history of premature ASCVD or ASCVD without traditional risk factors.
In 2019, the NLA issued a scientific statement on the use of Lp(a), which notes that Lp(a) measurement "is reasonable" to refine risk assessment for ASCVD events in the following populations: patients with first-degree relatives with premature ASCVD (<55 years of age for men; <65 years of age for women), patients with premature ASCVD without traditional risk factors, patients with severe hypercholesterolemia (LDL-C ≥190 mg/dL) or familial hypercholesterolemia, and patients with very-high risk of ASCVD that may be candidates for PCSK9 inhibitor therapy. Additionally Lp (a) "may be reasonable" to measure in patients with the following: intermediate (7.5 to 19.9%) or borderline (5 to 7.4%) ASCVD risk when statin initiation is uncertain for primary prevention, inadequate response to LDL-C lowering therapy despite adherence, family history of elevated Lp (a), calcific valvular aortic stenosis, or recurrent or progressive ASCVD despite lipid-lowering therapy.
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence (2016) updated its guidance on risk assessment and reduction including lipid modification of cardiovascular disease (CVD). The guidelines recommend measuring a full lipid profile including total cholesterol, HDL, non-HDL, and triglycerides before starting lipid lowering therapy for primary prevention of CVD. The guidelines also recommend measurement of total cholesterol, HDL, non-HDL, and triglycerides for primary and secondary prevention in people who have been started on high intensity statins at three months of treatment aiming for a 40% reduction in non-HDL. Nontraditional risk factors, including ApoB, were not discussed as part of risk assessment or treatment targets.
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (2009) issued recommendations on the use of nontraditional risk factors for the assessment of coronary heart disease. They included lipoprotein (a) in their summary statement that stated “The evidence is insufficient to assess the balance of benefits and harms of using the nontraditional risk factors discussed in this statement to screen asymptomatic men and women with no history of CHD to prevent CHD events”.
The recommendation was updated in 2019 and came to the same conclusion: evidence is insufficient to assess the benefits and harms of novel testing methods to diagnose CVD. However, the nontraditional risk factors included in this recommendation were different than those in this evidence review.
Apolipoprotein A-1, apo A-1, apolipoprotein B, apo B. apolipoprotein E, apo E, B-type natriuretic peptide, cardiac risk factors, novel cardiovascular risk assessment, cystatin C, fibrinogen, HDL subclass testing, HDL subclassification, high density lipoprotein subclassification, LDL subclass, leptin, lipoprotein A., lipoprotein, small-density, management of cardiovascular disease, small-density lipoproteins, small-diameter lipoproteins, lp(a), VAP, VAP diagnostics
APPROVED BY GOVERNING BODIES:
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Lipid and non‒lipid biomarker tests are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply.
FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
Electrophoretic technique, not elsewhere specified
Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
Lipoprotein, blood; electrophoretic separation and quantitation
Lipoprotein, blood; high resolution fractionation and quantitation of lipoproteins including lipoprotein subclasses when performed (e.g., electrophoresis, ultracentrifugation)
Lipoprotein, blood; quantitation of lipoprotein particle number(s) (e.g., by nuclear magnetic resonance spectroscopy), includes lipoprotein particle subclass(es), when performed
Protein; Western Blot, with interpretation and report, blood or other body fluid
Unlisted chemistry procedure
Secretory type II phospholipase A2 (sPLA2-IIA)
Lipoprotein, blood, high resolution fractionation and quantitation of lipoproteins, including all five major lipoprotein classes and subclasses of HDL, LDL, and VLDL by vertical auto profile ultracentrifugation (Effective 07/01/2018)
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Medical Policy Panel, September 2014
Medical Policy Group, November 2014 (1): Creation of new policy by combining medical policies # 054, 340, 343 and 344, which will be archived upon implementation of this policy; reversal of coverage to non-covered for measurement of Small Low Density Lipoprotein (LDL) Particles, Lipoprotein (a) [lp (a)] Enzyme Immunoassay and apolipoprotein B (apo B) related to management of CVD risk in certain patient populations
Medical Policy Administration Committee, November 2014
Available for comment November 25, 2014 through January 8, 2015
Medical Policy Panel, September 2015
Medical Policy Group, September 2015 (3): 2015 Updates to Key Points & References; no change in policy statement.
Medical Policy Group, November 2015: 2016 Annual Coding Update. Added CPT code 0423T to current coding
Medical Policy Panel, December 2016
Medical Policy Group, December 2016 (3): Updates to Key Points, Approved by Governing Bodies, Coding (2017 Annual Coding Update) & References; no change in policy statement
Medical Policy Panel, February 2018
Medical Policy Group, March 2018 (4): Updates to Description, Key Points, and References. Removed policy section for dates of service prior to January 9, 2015. No change to policy statement.
Medical Policy Group, June 2018: Quarterly coding update, July 2018. Added new CPT code 0052U to Current Coding. Added new Key Words: VAP and VAP diagnostics.
Medical Policy Panel, December 2018
Medical Policy Group, January 2019 (9): 2018 updates to Description, Key Points; no change to policy statement.
Medical Policy Panel, December 2019
Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.
Medical Policy Group, January 2020 (9): Removed CPT code 81401, this code is not applicable to this policy.
Medical Policy Panel, December 2020
Medical Policy Group, December 2020 (9): 2020 Updates to Description, Key Points, References. Removed note “For testing performed as a panel, see medical policy #538-Cardiovascular Risk Panels” from policy statement, as MP #538 is now archived and managed by genetic testing vendor program. Replaced abbreviations LDL and HDL with “low density lipoprotein” and “high density lipoprotein” for clarity within policy statement. No change to intent of 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.