Number:0381
Table Of Contents
Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses cardiovascular disease risk tests.
Medical Necessity
High-Sensitivity C-Reactive Protein (hs-CRP)
Aetna considers high-sensitivity C-reactive protein (hs-CRP) testing medically necessary for members who meetallof the following criteria:- Member has 2 or more coronary heart disease (CHD) major risk factorsFootnote1*,and
- Member has low-density lipoprotein (LDL) cholesterol levels between 100 to 130 mg/dL;and
- Member has been judged to be at an intermediate-risk of cardiovascular disease by global risk assessment (i.e., 10 to 20% risk of CHD per 10 years using Framingham point scoringFootnote2**).
Footnote1*Major risk factors include the following:
- Age (men aged 45 years or older; women aged 55 years or older)
- Current cigarette smoking
- Family history of premature CHD (CHD in male first-degree relative less than 55 years of age; CHD in female first-degree relative less than 65 years of age)
- Hypertension (blood pressure [BP] of 140 mm Hg or higher, or on anti-hypertensive medication)
- Low high-density lipoprotein (HDL) cholesterol (less than 40 mg/dL).
Footnote2**Note: Framingham risk scoring for men and women is presented in theAppendixbelow.
Aetna considers hs-CRP testing experimental and investigational for all other indications, including use as a screening test for the general population and for monitoring response to therapy, because its clinical value for these uses has not been established.
Apolipoprotein B (apo B)
Aetna considers measurement of apolipoprotein B (apoB) medically necessary for use in high-risk persons with hypercholesterolemia to assess whether additional intense interventions are necessary when LDL cholesterol goals are reached (LDL cholesterol less than70 mg/dL and non-HDL cholesterol less than 100 mg/dL in persons with known cardio-vascular disease (CVD) or diabetes mellitus, or LDL-C less than 100 mg/dL and non-HDL cholesterol less than 130 mg/dL in persons with other risk factors). High-risk persons are those withone or more of the following criteria:
- Diabetes mellitus;or
- Known CVD;or
- Two or more of the following CVD risk factors:
- Current cigarette smoking;or
- Family history of premature CVD (CHD in male first-degree relative less than 55 years of age; CHD in female first-degree relative less than 65 years of age);or
- Hypertension (BP of 140 mm Hg or higher, or on anti-hypertensive medication).
Aetna considers measurement of apolipoprotein B (apoB) experimental and investigational for all other indications because its clinical value for other indications has not been established.
hom*ocysteine Testing
Aetna considers hom*ocysteine testing may be medically necessary for the following indications:
- Evaluating persons with hom*ocystinuria (cystathionine beta synthase deficiency);
- Evaluating persons with coagulation disorders (e.g., unexplained thrombotic disorders such as deep venous thrombosis or pulmonary embolism);and
- Evaluating persons with borderline vitamin B12 deficiency.
Experimental and Investigational
hom*ocysteine Testing
Aetna considers hom*ocysteine testing experimental and investigationalfor the following indications:
- Assessing CHD or stroke risk and for evaluating women with recurrent pregnancy loss;
- hom*ocysteine / lipoprotein(a) testing for evaluation of arterial thrombosis in newborns.
Aetna considers hom*ocysteine testing experimental and investigational for all other indications because its effectiveness for indications other than the ones listed in Section I above has not been established.
Measurement of Carotid Intima-Media Thickness
Aetna considers measurement of carotid intima-media thickness experimental and investigational for assessing CHD risk because its effectiveness has not been established.
Noninvasive Measurement of Arterial Elasticity
Aetna considers noninvasive measurements of arterial elasticity by means of blood pressure waveforms (e.g.,CardioVision MS-2000, CVProfilor, Digital Pulse Analyzer (DPA), DSI Pulse Wave Velocity analysis, Max Pulse and HD/PulseWave CR-2000) and noninvasivecalculation and analysisof central arterial pressure waveforms (SphygmoCor) experimental and investigational for assessing CHD risk becausetheir effectiveness has not been established.
Peripheral Arterial Tonometry
Aetna considers peripheral arterial tonometry (e.g., the Endo-PAT2000/EndoPAT device) experimental and investigational for assessing CHD because there is insufficient evidence to support the effectiveness of this approach.
Cardiac Stress Testing and Stress Echocardiography
Aetna considers cardiac stress testing and stress echocardiography experimental and investigational for cardiovascular disease risk assessment in asymptomatic low risk individuals.
Ultrasound of the Upper and Lower Extremity Arteries
Aetna considers ultrasound of the upper and lowerextremity arteriesexperimental and investigational forscreening of persons without signs or symptoms of peripheral arterial disease.
Venous Ultrasound
Aetna considers venous ultrasound experimental and investigational for screening of persons without signs or symptoms of peripheral venous disease. and who are not at high risk for venous thromboembolic disorders.
Experimental CHD Risk Tests
Aetna considers any of the following tests / devicesfor assessing CHD risk experimental and investigational because their clinical value has not been established:
- Acarix CADScor System
- Activated factor VII
- Adiponectin
- Algorithmically scored multi-protein biomarker panels (i.e., HART CADhs, HART CVE, HART KD)
- Angiotensin gene (CardiaRisk AGT)
- Anti-thrombin III
- Apelin
- Apolipoprotein A-I (apo AI) (Boston Heart HDL Map panel)
- Apolipoprotein E (apo E)
- Apolipopritein E genotyping
- ASCVD risk testing (individual or panel) (eg, c-peptide, islet cell antibodies, nonesterified fatty acids (free fatty acids), proinsulin and total insulin)
- B-type natriuretic peptides
- CADence System
- CARDIO inCode-Score
- Carotid ultrasound screening of asymptomatic persons for carotid artery stenosis
- Cathepsin S
- Chromosome 9 polymorphism 9p21
- Circulating microRNAs (e.g., miR-1, miR-16, miR-26a, miR-27a, and miR-29a, miR-133a, and miR-199a-5p; not an all-inclusive list)
- Coenzyme Q10 (CoQ10)
- Coronary artery reactivity test
- Corus CAD Gene Expression Profile
- Cystatin-C
- Endothelin testing
- Factor II (thrombin) (F2 gene)
- Factor V Leiden (F5 gene)
- Fibrinogen
- 4q25 genotype testing (eg, 4q25-AF Risk Genotype Test, Cardio IQ 4q25-AF Risk Genotype Test)
- Galectin-3
- Genetic testing
- GlycA (glycosylated acute phase proteins)
- Growth stimulation expressed gene 2 (ST2)
- HDL subspecies (LpAI, LpAI/AII and/or HDL3 and HDL2)
- Interleukin 6 (IL-6)
- Interleukin 6 -174 g/c promoter polymorphism
- Interleukin 17 gene polymorphism
- Interleukin 18 (IL-18)
- Kinesin-like protein6 (KLP6)
- LDL gradient gel electrophoresis
- LDL subspecies (small and large LDL particles)
- Leptin
- Lipidomic and metabolomic risk markers
- Lipoprotein remnants: intermediate density lipoproteins (IDL) and small density lipoproteins
- Lipoprotein(a) (Lp(a)) enzyme immunoassay
- Lipoprotein-associated phospholipase A2 (Lp-PLA2) (PLAC)
- Liposcale test
- Long chain omega-3 fatty acids composition in red blood cell
- LPA Intron-25 genotype testing (eg, Cardio IQ Intron-25 Genotype Test, LPA Intron-25 Genotype Test)
- MaxPulse testing
- Measurement of free fatty acids
- Methods to determine vascular age
- Mid-regional pro-atrial natriuretic peptide
- MIRISK VP test
- MTHFR genetic testing
- Myeloperoxidase (MPO)
- NMR Lipoprofile
- OmegaCheck Panel
- Osteoprotegerin
- Oxidized low-density lipoprotein as a biomarker for cardiovascular disease stratification
- Oxidized phospholipids
- Peroxisome proliferator-activated receptor
- Plasma ceramide
- Plasma levels of trimethylamine-N-oxide (TMAO)
- Plasminogen activator inhibitor (PAI–1)
- Pregnancy-associated plasma protein-A (PAPP-A)
- Protein C
- Prothrombin gene mutation testing
- QuantaFlo System for evaluation of peripheral arterial disease
- Receptor for advanced glycosylation end products (RAGE) gene Gly82Ser polymorphism testing
- Resistin
- Retinol binding protein 4 (RBP4)
- Serum sterols (eg, Boston Heart Cholesterol Balance Test)
- Singulex SMC testing for risk of cardiac dysfunction and vascular inflammation (eg, SMC Endothelin, SMC IL-6, SMC IL 17A, SMC c TnI and SMC TNF-α)
- Skin cholesterol (eg, PREVU)
- SLCO1B1 (statin induced myopathy genetic testing)
- SNP-based testing (eg, Cardiac Healthy Weight DNA Insight, Healthy Woman DNA Insight Test, Heart Health Genetic Test)
- Soluble cell adhesion molecules (e.g., intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin, and P-selectin)
- Thromboxane metabolite(s) testing
- Tissue plasminogen activator (tPA)
- Toll-like receptor 4 (TLR4) Asp299Gly (rs4986790) polymorphism
- Transforming growth factor beta
- Troponin I (e.g., PATHFAST cTnI-II)
- Tumor necrosis factor-alpha (TNF-a)
- Total cholesterol content in red blood cell membranes
- Vertical Auto Profile(VAP) with or without vertical lipoprotein particle (VLP) technology
- Visfatin
- von Willebrand factor antigen level.
The medical literature does not support the utility of the above tests for screening, diagnosis, or management of CHD.
Related Policies
For coverage criteria for PCSK9 inhibitors (alirocumab (Praluent)), see Pharmacy Clinical Policy Bulletin (PCPB) - PCSK9 Inhibitors.
See also:
- CPB 0140 - Genetic Testing
- CPB 0228 - Cardiac CT, Coronary CT Angiography, Calcium Scoring and CT Fractional Flow Reserve
- CPB 0348 - Recurrent Pregnancy Loss
- CPB 0485 - Autonomic Testing / Sudomotor Tests
- CPB 0525 - Screening for Lipid Disorders
- CPB 0536 - Vitamin B-12 Therapy
- CPB 0618 - Brain Natriuretic Peptide Testing
- CPB 0650 - Polymerase Chain Reaction Testing: Selected Indications
- CPB 0763 - hom*ocysteine Testing.
Code | Code Description |
---|---|
High-sensitivity C-reactive protein (hs-CRP): | |
CPT codes covered if selection criteria are met: | |
81400 - 81408 | Molecular pathology |
86141 | C-reactive protein; high sensitivity (hsCRP) [2 or more major risk factors, LDL 100-300 mg/dl, and intermediate risk of CVD by global risk assessment - see criteria] |
ICD-10 codes covered if selection criteria are met: | |
E78.6 | Lipoprotein deficiency [low HDL cholesterol less than 40 mg/dL] |
F17.200 - F17.201, F17.210 - F17.211 F17.220 - F17.221, F17.290 - F17.291 | Nicotine dependence |
I10 - I15.9 | Hypertensive disease [BP 140 mmHg or higher, or on antihypertensive medication] |
Z82.49 | Family history of ischemic heart disease and other diseases of the circulatory system [premature CHD] |
Major risk factors [need at least 2]: | |
Apolipoprotein B (apo B): | |
CPT codes covered if selection criteria are met: | |
82172 | Apolipoprotein, each [covered for apoB - not apoA1 or apoE] |
ICD-10 codes covered if selection criteria are met: | |
E10.10 - E11.9 | Diabetes mellitus [with 2 or more CVD risk factors - see criteria] |
E78.0 | Pure hypercholesterolemia [with 2 or more CVD risk factors - see criteria] |
E78.2 | Mixed hyperlipidemia [with 2 or more CVD risk factors - see criteria] |
F17.200 - F17.201, F17.210 - F17.211F17.220 - F17.221, F17.290 - F17.291 | Nicotine dependence [with 2 or more CVD risk factors - see criteria] |
I10 - I15.9 | Hypertensive disease [with 2 or more CVD risk factors - see criteria] |
I20.0 - I25.9 | Ischemic heart diseases [with 2 or more CVD risk factors - see criteria] |
I25.10 | Atherosclerotic heart disease of native coronary artery without angina pectoris [with 2 or more CVD risk factors - see criteria] |
I50.1 - I50.9 | Heart failure [with 2 or more CVD risk factors - see criteria] |
Z82.49 | Family history of ischemic heart disease and other diseases of the circulatory system [with 2 or more CVD risk factors - see criteria] |
Carotid Ultrasound Screening: | |
CPT codes not covered for indications listed in the CPB: | |
93880 | Duplex scan of extracranial arteries; complete bilateral study |
93882 | unilateral or limited study |
ICD-10 codes covered if selection criteria are met: | |
G04.1 | Tropical spastic paraplegia |
G45.0 – G45.9 | Transient cerebral ischemic attacks and related syndromes |
G46.0 | Middle cerebral artery syndrome |
G46.1 | Anterior cerebral artery syndrome |
G46.2 | Posterior cerebral artery syndrome |
G81.00 – G81.94 | Hemiplegia and hemiparesis |
G82.20 – G82.54 | Paraplegia (paraparesis) and quadriplegia (quadriparesis) |
G83.0 – G83.34 | Other paralytic syndromes |
G83.4 | Cauda equina syndrome |
G83.5 | Locked-in state |
G83.81 – G93.9 | Other specified paralytic syndromes |
G97.31 – G97.32 | Intraoperative hemorrhage and hematoma of a nervous system organ or structure complicating a procedure |
G97.41 – G97.49 | Accidental puncture and laceration of a nervous system organ or structure during a procedure |
G97.51 – G97.52 | Postprocedural hemorrhage of a nervous system organ or structure following a procedure |
H34.00 – H32.8132 | Retinal vascular occlusions |
H34.821 – H34.829 | Venous engorgement |
H34.8310 – H34.9 | Tributary (branch) retinal vein occlusion |
H35.061 – H35.069 | Retinal vasculitis |
H35.81 – H35.9 | Other specified retinal disorders |
H47.011 – H47.019 | Disorders of optic nerve, not elsewhere classified |
H53.10 – H53.11 | Subjective visual disturbances |
H53.121 – H53.129 | Transient visual loss |
H53.131 – H53.139 | Sudden visual loss |
H53.2 | Diplopia |
H53.40 | Unspecified visual field defects |
H53.411 – H53.489 | Scotoma involving central area |
H53.8 | Other visual disturbances |
H53.9 | Unspecified visual disturbance |
H54.7 | Unspecified visual loss |
H59.211 – H59.229 | Accidental puncture and laceration of eye and adnexa during a procedure |
H81.01 – H81.09 | Benign paroxysmal vertigo |
H81.4 | Vertigo of central origin |
H93.11 – H93.19 | Tinnitus |
H93.A1 – A93.A9 | Pulsatile tinnitus |
H95.31 – H95.32 | Accidental puncture and laceration of ear and mastoid process during a procedure |
I25.10 | Atherosclerotic heart disease of native coronary artery without angina pectoris |
I25.110 – I25.119 | Atherosclerotic heart disease of native coronary artery with angina pectoris |
I25.2 | Old myocardial infarction |
I25.5 | Ischemic cardiomyopathy |
I60.00 – I62.9 | Nontraumatic subarachnoid hemorrhage |
I63.00 – I63.9 | Cerebral infarction |
I65.01 – I65.9 | Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction |
I66.01 – I66. 9 | Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction |
I67.0 – I67.9 | Other cerebrovascular diseases |
I68.0 | Cerebral arteritis in other diseases classified elsewhere |
I68.8 | Other cerebrovascular disorders in diseases classified elsewhere |
I69.021 | Dysphasia following nontraumatic subarachnoid hemorrhage |
I69.022 | Dysarthria following nontraumatic subarachnoid hemorrhage |
I69.023 | Fluency disorder following nontraumatic subarachnoid hemorrhage |
I69.028 | Other speech and language deficits following nontraumatic subarachnoid hemorrhage |
I69.090 – I69.098 | Other sequelae of nontraumatic subarachnoid hemorrhage |
I69.120 – I69.128 | Speech and language deficits following nontraumatic intracerebral hemorrhage |
I69.190 – I69.198 | Other sequelae of nontraumatic intracerebral hemorrhage |
I69.220 – I69. 228 | Speech and language deficits following other nontraumatic intracranial hemorrhage |
I69.290 – I69.298 | Other sequelae of other nontraumatic intracranial hemorrhage |
I69.320 – I69.328 | Speech and language deficits following cerebral infarction |
I69.351 – I69.359 | Hemiplegia and hemiparesis following cerebral infarction |
I69.390 – I69.398 | Other sequelae of cerebral infarction |
I69.820 – I69.828 | Speech and language deficits following other cerebrovascular disease |
I69.890 – I69.898 | Other sequelae of other cerebrovascular disease |
I69.920 – I69.928 | Speech and language deficits following unspecified cerebrovascular disease |
I70.0 – I70.1 | Atherosclerosis |
I70.211 – I72.219 | Atherosclerosis of native arteries of extremities with intermittent claudication |
I70.8 | Atherosclerosis of other arteries |
I70.90 – I70.92 | Other and unspecified atherosclerosis |
I72.0 – I72.9 | Other aneurysm |
I75.011 – I75.89 | Atheroembolism |
I77.0 – I77.6 | Other disorders of arteries and arterioles |
I77.70 – I77.79 | Other arterial dissection |
I79.0 – I79.8 | Disorders of arteries, arterioles and capillaries in diseases classified elsewhere |
I97.51 – I97.52 | Accidental puncture and laceration of a circulatory system organ or structure during a procedure |
I97.810 – I97.821 | Other intraoperative and postprocedural complications and disorders of the circulatory system, not elsewhere classified |
J95.71 – J95.72 | Accidental puncture and laceration of a respiratory system organ or structure during a procedure |
K91.71 – K91.72 | Accidental puncture and laceration of a digestive system organ or structure during a procedure |
L76.11 – L76.12 | Accidental puncture and laceration of skin and subcutaneous tissue during a procedure |
M30.0 – M30.8 | Polyarteritis nodosa and related conditions |
M31.10 – M31.19 | Thrombotic microangiopathy |
M31.30 – M31.31 | Wegener's granulomatosis |
M31.4 | Aortic arch syndrome [Takayasu] |
M31.5 | Giant cell arteritis with polymyalgia rheumatica |
M31.6 | Other giant cell arteritis |
M31.7 | Microscopic polyangiitis |
M31.8 | Other specified necrotizing vasculopathies |
M31.9 | Necrotizing vasculopathy, unspecified |
M96.820 – M96.821 | Accidental puncture and laceration of a musculoskeletal structure during a procedure |
N99.71 – N99.72 | Accidental puncture and laceration of a genitourinary system organ or structure during a procedure |
R09.01 – R09.89 | Other symptoms and signs involving the circulatory and respiratory system |
R13.10 – R13.19 | Dysphagia |
R20.0 – R20.9 | Disturbances of skin sensation |
R22.0 - R22.2 | Localized swelling, mass and lump of skin and subcutaneous tissue |
R26.0 – R26.9 | Abnormalities of gait and mobility |
R27.0 – R27.9 | Other lack of coordination |
R29.5 | Transient paralysis |
R29.810 – R29.818 | Other symptoms and signs involving the nervous system |
R42 | Dizziness and giddiness |
R47.01 – R47.89 | Speech disturbances, not elsewhere classified |
R55 | Syncope and collapse |
S09.0XXA – S09.0XXS | Injury of blood vessels of head, not elsewhere classified |
S15.001A – S15.001S | Unspecified injury of right carotid artery |
S15.002A – S15.002S | Unspecified injury of left carotid artery |
S15.009A – S15.009S | Unspecified injury of unspecified carotid artery |
S15.011A – S15.011S | Minor laceration of right carotid artery |
S15.012A – S15.012S | Minor laceration of left carotid artery |
S15.019A – S15.019S | Minor laceration of unspecified carotid artery |
S15.021A – S15.021S | Major laceration of right carotid artery |
S15.022A – S15.022S | Major laceration of left carotid artery |
S15.029A – S15.029S | Major laceration of unspecified carotid artery |
S15.091A – S15.091S | Other specified injury of right carotid artery |
S15.092A – S15.092S | Other specified injury of left carotid artery |
S15.099A – S15.099S | Other specified injury of unspecified carotid artery |
S15.101A – S15.101S | Unspecified injury of right vertebral artery |
S15.102A – S15.102S | Unspecified injury of left vertebral artery |
S15.109A – S15.109S | Unspecified injury of unspecified vertebral artery |
S15.111A – S15.111S | Minor laceration of right vertebral artery |
S15.112A – S15.112S | Minor laceration of left vertebral artery |
S15.122A – S15.122S | Major laceration of left vertebral artery |
S15.191A – S15.191S | Other specified injury of right vertebral artery |
S15.192A – S15.192S | Other specified injury of left vertebral artery |
S15.211A – S15.211S | Minor laceration of right external jugular vein |
S15.212A – S15.212S | Minor laceration of left external jugular vein |
S15.221A – S15.221D | Major laceration of right external jugular vein |
S15.222A – S15.222S | Major laceration of left external jugular vein |
S15.291A – S15.291S | Other specified injury of right external jugular vein |
S15.292A – S15.292D | Other specified injury of left external jugular vein |
S15.311A – S15.311S | Minor laceration of right internal jugular vein |
S15.312A – S15.312S | Minor laceration of left internal jugular vein |
S15.321A – S15.321S | Major laceration of right internal jugular vein |
S15.322A – S15.322D | Major laceration of left internal jugular vein |
S15.391A – S15.391S | Other specified injury of right internal jugular vein |
S15.392A – S15.392S | Other specified injury of left internal jugular vein |
S15.8XXA – S15.8XXS | Injury of other specified blood vessels at neck level |
S25.111A – S25.111S | Minor laceration of right innominate or subclavian artery |
S25.112A – S25.112S | Minor laceration of left innominate or subclavian artery |
S25.119A – S25.119S | Minor laceration of unspecified innominate or subclavian artery |
S25.121A – S25.121S | Major laceration of right innominate or subclavian artery |
S25.122A – S25.122S | Major laceration of left innominate or subclavian artery |
S25.129A – S25.129S | Major laceration of unspecified innominate or subclavian artery |
S25.191A – S25.191S | Other specified injury of right innominate or subclavian artery |
S25.192A – S25.192S | Other specified injury of left innominate or subclavian artery |
S25.199A – S25.199S | Other specified injury of unspecified innominate or subclavian artery |
T82.311A – T82.311S | Breakdown (mechanical) of carotid arterial graft (bypass) |
T82.321A – T82.321S | Displacement of carotid arterial graft (bypass) |
T82.322A – T82.322S | Displacement of femoral arterial graft (bypass) |
T82.328A – T82.328S | Displacement of other vascular grafts |
T82.329A – T82.329S | Displacement of unspecified vascular grafts |
T82.330A – T82.330S | Leakage of aortic (bifurcation) graft (replacement) |
T82.331A – T82.331S | Leakage of carotid arterial graft (bypass) |
T82.391A – T82.392S | Other mechanical complication of carotid arterial graft (bypass) |
Z01.810 | Encounter for preprocedural cardiovascular examination |
Z01.818 | Encounter for other preprocedural examination |
Z09 | Encounter for follow-up examination after completed treatment for conditions other than malignant neoplasm |
Z48.812 | Encounter for surgical aftercare following surgery on the circulatory system |
Z86.711 | Personal history of pulmonary embolism |
Z86.73 | Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits |
ICD-10 codes not covered for indications listed in the CPB: | |
Z00.00 - Z00.01 | Encounter for general adult medical examination without or with abnormal findings |
Z01.810 | Encounter for preprocedural cardiovascular examination |
Z01.818 | Encounter for other preprocedural examination |
Z03.89 | Encounter for observation for other suspected diseases and conditions ruled out |
Z04.9 | Encounter for examination and observation for unspecified reason |
Z09 | Encounter for follow-up examination after completed treatment for conditions other than malignant neoplasm |
Z13.220 | Encounter for screening for lipoid disorders |
Z13.6 | Encounter for screening for cardiovascular disorders |
Z48.812 | Encounter for surgical aftercare following surgery on the circulatory system |
Z82.49 | Family history of ischemic heart disease and other diseases of the circulatory system |
Z86.73 | Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits |
hom*ocysteine testing: | |
CPT codes covered if selection criteria are met: | |
83090 | hom*ocysteine |
CPT codes not covered for indications listed in the CPB: | |
83695 | Lipoprotein (a) |
ICD-10 codes covered if selection criteria are met: | |
E72.11 | hom*ocystinuria |
I26.01 - I26.99 | Pulmonary embolism |
I74.0 - I74.9 | Arterial embolism and thrombosis [unexplained thrombotic disorders] |
I82.0 - I82.91 | Other venous embolism and thrombosis [unexplained thrombotic disorders] |
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive): | |
N96 | Recurrent pregnancy loss |
O03.0 - O03.9 | Spontaneous abortion [recurrent pregnancy loss] |
O09.291 - O09.299 | Supervision of pregnancy with other poor reproductive or obstetric history [recurrent pregnancy loss] |
O26.20 - O26.23 | Pregnancy care for patient with recurrent pregnancy loss |
Z13.6 | Encounter for screening for cardiovascular disorders [assessing coronary heart disease risk] |
Tests considered experimental and investigational for assessing CHD risk: | |
CPT codes not covered for indications listed in the CPB: | |
CADence System, QuantaFlo System - no specific code: | |
0024U | Glycosylated acute phase proteins (GlycA), nuclear magnetic resonance spectroscopy, quantitative |
0052U | 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 |
0119U | Cardiology, ceramides by liquid chromatography–tandem mass spectrometry, plasma, quantitative report with risk score for major cardiovascular events |
0126T | Common carotid intima-media thickness (IMT) study for evaluation of atherosclerotic burden or coronary heart disease risk factor assessment |
0308U | Cardiology (coronary artery disease [CAD]), analysis of 3 proteins (high sensitivity [hs] troponin, adiponectin, and kidney injury molecule-1 [KIM-1]), plasma, algorithm reported as a risk score for obstructive CAD |
0309U | Cardiology (cardiovascular disease), analysis of 4 proteins (NT-proBNP, osteopontin, tissue inhibitor of metalloproteinase-1 [TIMP-1], and kidney injury molecule-1 [KIM-1]), plasma, algorithm reported as a risk score for major adverse cardiac event |
0310U | Pediatrics (vasculitis, Kawasaki disease [KD]), analysis of 3 biomarkers (NT- proBNP, C-reactive protein, and T-uptake), plasma, algorithm reported as a risk score for KD |
0377U | Cardiovascular disease, quantification of advanced serum or plasma lipoprotein profile, by nuclear magnetic resonance (NMR) spectrometry with report of a lipoprotein profile (including 23 variables) |
0401U | Cardiology (coronary heart disease [CAD]), 9 genes (12 variants), targeted variant genotyping, blood, saliva, or buccal swab, algorithm reported as a genetic risk score for a coronary event |
0423T | Secretory type II phospholipase A2 (sPLA2-IIA) |
0716T | Cardiac acoustic waveform recording with automated analysis and generation of coronary artery disease risk score |
81229 | Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities [not covered for cardiovascular disease risk] |
81240 | F2 (prothrombin, coagulation factor II) (eg, hereditary hypercoagulability) gene analysis, 20210G>A variant |
81241 | F5 (coagulation Factor V) (eg, hereditary hypercoagulability) gene analysis, Leiden variant |
81291 | MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C) |
81328 | SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (eg, adverse drug reaction), gene analysis, common variant(s) (eg, *5) |
81400 | Molecular pathology procedure, Level 1(eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) |
81401 | Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) |
81405 | Molecular pathology procedure, Level 6 |
81406 | Molecular pathology procedure, Level 7 |
81493 | Coronary artery disease, mRNA, gene expression profiling by real-time RT-PCR of 23 genes, utilizing whole peripheral blood, algorithm reported as a risk score |
82163 | Angiotensin II |
82542 | Column chromatography, includes mass spectrometry, if performed (eg, HPLC, LC, LC/MS, LC/MS-MS, GC, GC/MS-MS, GC/MS, HPLC/MS), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen [not covered for cardiovascular disease risk] |
82610 | Cystatin C [not covered for cardiovascular disease risk] |
82725 | Fatty acids, nonesterified [not covered for cardiovascular disease risk] |
82777 | Galectin-3 [not covered for cardiovascular disease risk] |
83006 | Growth stimulation expressed gene 2 (ST2, Interleukin 1 receptor like-1) |
83519 | Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, by radioimmunoassay (eg, RIA) |
83520 | Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [adiponectin] [leptin] [interleukin-6 (IL-6)] [tumor necrosis factor alpha (TNF-a)] [Oxidized phospholipids] [interleukin 17] [toll-like receptor 4 (TLR4)] [Interleukin-18 (IL-18)] [soluble cell adhesion molecules (e.g., intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin, P-selectin)] [transforming growth factor beta] [Oxidized low-density lipoprotein] |
83525 | Insulin, total [not covered for cardiovascular disease risk] |
83695 | Lipoprotein (a) |
83698 | Lipoprotein-associated phospholipase A2 (Lp-PLA2) |
83700 | Lipoprotein, blood; electorophoretic separation and quantitation |
83701 | high resolution fractionation and quantitation of lipoproteins including lipoprotein subclasses when performed (eg, electrophoresis, ultracentrifugation) [VAP cholesterol test] |
83704 | quantitation of lipoprotein particle numbers and lipoprotein particle subclasses (eg, by nuclear magnetic resonance spectroscopy) |
83719 | Lipoprotein, direct measurement; VLDL cholesterol |
83722 | Lipoprotein, direct measurement; small dense LDL cholesterol |
83876 | Myeloperoxidase (MPO) |
83880 | Natriuretic peptide |
83883 | Nephelometry, each analyte not elsewhere specified [retinol binding protein 4 (RBP4)] |
84163 | Pregnancy-associated plasma protein-A (PAPP-A) |
84206 | Proinsulin [not covered for cardiovascular disease risk] |
84431 | Thromboxane metabolite(s), including thromboxane if performed, urine [not covered for cardiovascular disease risk] |
84484 | Troponin, quantitative |
84512 | Troponin, qualitative |
84681 | C-peptide [not covered for cardiovascular disease risk] |
85246 | Factor VIII, VW factor antigen |
85300 | Clotting inhibitors or anticoagulants; antithrombin III, activity |
85301 | Clotting inhibitors or anticoagulants; antithrombin III, antigen assay |
85302 | Clotting inhibitors or anticoagulants; protein c, antigen |
85303 | Clotting inhibitors or anticoagulants; protein c, activity, and Activated Protein C (APC) resistance assay |
85384 | Fibrinogen; activity |
85385 | antigen |
85415 | Fibrinolytic factors and inhibitors; plasminogen activator |
86341 | Islet cell antibody [not covered for cardiovascular disease risk] |
88271 - 88275 | Molecular cytogenetics [genetic testing] [MIRISK VP test] |
93050 | Arterial pressure waveform analysis for assessment of central arterial pressures, includes obtaining waveform(s), digitization and application of nonlinear mathematical transformations to determine central arterial pressures and augmentation index, with interpretation and report, upper extremity artery, non-invasive |
93350 | Echocardiography, transthoracic, real-time with image documentation (2D), includes M-mode recording, when performed, during rest and cardiovascular stress test using treadmill, bicycle exercise and/or pharmacologically induced stress, with interpretation and report |
93351 | including performance of continuous electrocardiographic monitoring, with supervision by a physician or other qualified health care professional |
+93352 | Use of echocardiographic contrast agent during stress echocardiography (List separately in addition to code for primary procedure) |
93895 | Quantitative carotid intima media thickness and carotid atheroma evaluation, bilateral |
93880 | Duplex scan of extracranial arteries; complete bilateral study |
93882 | unilateral or limited study |
93922 | Limited bilateral noninvasive physiologic of upper or lower extremity arteries, (eg, for lower extremity: ankle/brachial indices at distal posterior tibial and anterior tibial/dorsalis pedis arteries plus bidirectional, Doppler waveform recording and analysis at 1-2 levels, or ankle/brachial indices at distal posterior tibial and anterior tibial/dorsalis pedis arteries plus volume plethysmography at 1-2 levels, or ankle/brachial indices at distal posterior tibial and anterior tibial/dorsalis pedis arteries with transcutaneous oxygen tension measurements at 1-2 levels) [Digital Pulse Analyzer (DPA)] [MaxPulse] [DSI Pulse Wave Velocity analysis] |
93923 | Complete bilateral noninvasive physiologic studies of upper or lower extremity arteries, 3 or more levels (eg, for lower extremity: ankle/brachial indices at distal posterior tibial and anterior tibial/dorsalis pedis arteries plus segmental blood pressure measurements with bidirectional Doppler waveform recording and analysis, at 3 or more levels, or ankle/brachial indices at distal posterior tibial and anterior tibial/dorsalis pedis arteries plus segmental volume plethysmography at 3 or more levels, or ankle/brachial indices at distal posterior tibial and anterior tibial/dorsalis pedis arteries plus segmental transcutaneous oxygen tension measurements at 3 or more level(s), or single level study with provocative functional maneuvers (eg, measurements with postural provocative tests, or measurements with reactive hyperemia [Digital Pulse Analyzer (DPA)]) [DSI Pulse Wave Velocity analysis] |
93965 | Noninvasive physiologic studies of extremity veins, complete bilateral study (eg, Doppler waveform analysis with responses to compression and other maneuvers, phleborheography, impedance plethysmography) |
93970 | Duplex scan of extremity veins including responses to compression and other maneuvers; complete bilateral study |
93971 | unilateral or limited study |
Other CPT codes related to the CPB: | |
93454 - 93461, 93563 | Coronary Angiography [coronary artery reactivity test] |
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive): | |
A40.0 - A41.9 | Systemic infections |
E10.10 - E13.9 | Diabetes mellitus |
E75.21 - E75.6, E78.0 - E78.9 | Disorders of lipoid metabolism |
F17.200 - F17.201, F17.210 - F17.211, F17.220 - F17.221, F17.290 - F17.291 | Nicotine dependence |
I10 - I15.9 | Hypertensive disease |
I21.01 - I22.9 | ST elevation (STEMI) and non-ST elevation (STEMI) myocardial infarction |
I25.10 - I25.119, I25.700 - I25.9 | Coronary atherosclerosis |
I25.2 | Old myocardial infarction |
I50.1 - I50.9 | Heart failure |
I73.00 - I73.9 | Other peripheral vascular diseases |
R56.10 - R65.11 | Systemic inflammatory response syndrome (SIRS) of non-infectious origin without/with acute organ dysfunction |
T86.21 | Heart transplant rejection |
T86.22 | Heart transplant failure |
Z13.6 | Encounter for screening for cardiovascular disorders |
Z79.51 - Z79.52 | Long term (current) use of steroids |
Z79.899 | Other long term (current) drug therapy [immunosuppressive agents, chemotherapeutic agents] |
Z82.49 | Family history of ischemic heart disease and other diseases of the circulatory system |
Z87.891 | Personal history of nicotine dependence |
Z94.1 | Heart transplant status |
Z95.1 | Presence of aortocoronary bypass graft |
Cardiac Stress Testing: | |
CPT codes covered if selection criteria are met: | |
93015 | Cardiovascular stress test using maximal or submaximal treadmill or bicycle exercise, continuous electrocardiographic monitoring, and/or pharmacological stress; with supervision, interpretation and report |
93016 | supervision only, without interpretation and report |
93017 | tracing only, without interpretation and report |
93018 | interpretation and report only |
Other CPT codes related to the CPB: | |
93000 | Electrocardiogram, routine ECG with at least 12 leads; with interpretation and report |
93005 | tracing only, without interpretation and report |
93010 | interpretation and report only |
ICD-10 codes covered if selection criteria are met: | |
A18.84 | Tuberculosis of heart |
D86.85 | Sarcoid myocarditis |
E10.10 – E10.9 | Type 1 diabetes mellitus |
E11.00 – E11.9 | Type 2 diabetes mellitus |
E13.00 – E13.9 | Other specified diabetes mellitus |
E78.01 | Familial hypercholesterolemia |
E78.49 | Other hyperlipidemia |
E78.5 | Hyperlipidemia, unspecified |
E85.4 | Organ-limited amyloidosis |
E85.81 | Light chain (AL) amyloidosis |
G45.0 – G45.9 | Transient cerebral ischemic attacks and related syndromes |
G46.4 | Cerebellar stroke syndrome |
G93.3 | Postviral fatigue syndrome |
H35.122 | Retinopathy of prematurity, stage 1, left eye |
I05.0 – 105.9 | Rheumatic mitral valve diseases |
I06.0 – I06.9 | Rheumatic aortic valve diseases |
I07.0 – I07.9 | Rheumatic tricuspid stenosis |
108.0 – I08.9 | Multiple valve diseases |
109.0 | Rheumatic myocarditis |
I09.81 | Rheumatic heart failure |
I09.89 | Other specified rheumatic heart diseases |
I09.9 | Rheumatic heart disease, unspecified |
I11.0 | Hypertensive heart disease with heart failure |
I13.0 | Hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
I13.2 | Hypertensive heart and chronic kidney disease with heart failure and with stage 5 chronic kidney disease, or end stage renal disease |
I16.0 – I16.9 | Hypertensive crisis |
I20.0 -I20.9 | Angina pectoris |
I21.01 – I21.09 | ST elevation (STEMI) myocardial infarction of anterior wall |
I21.11 – I21.29 | ST elevation (STEMI) myocardial infarction of inferior wall |
I21.3 – I21.9 | ST elevation (STEMI) myocardial infarction of other sites |
I21.A1 – I21.A9 | Other type of myocardial infarction |
I22.0 – I22.8 | Subsequent ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction |
I23.1 – I23.8 | Certain current complications following ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction (within the 28 day period) |
I24.1 | Dressler's syndrome |
I24.8 | Other forms of acute ischemic heart disease |
I24.9 | Acute ischemic heart disease, unspecified |
I25.10 | Atherosclerotic heart disease of native coronary artery without angina pectoris |
I25.110 – I25.119 | Atherosclerotic heart disease of native coronary artery with angina pectoris |
I25.2 | Old myocardial infarction |
I25.3 | Aneurysm of heart |
I25.41 – I42.42 | Coronary artery aneurysm and dissection |
I25.5 | Ischemic cardiomyopathy |
I25.6 | Silent myocardial ischemia |
I25.700 – I25.719 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris |
I25.720 – I25.729 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris |
I25.730 – I25.739 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris |
I25.750 – I25.759 | Atherosclerosis of native coronary artery of transplanted heart with angina pectoris |
I25.760 – I25.768 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris |
I25.790 – I25.799 | Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris |
I25.810 – I25.812 | Atherosclerosis of other coronary vessels without angina pectoris |
I25.83 – I25.89 | Other forms of chronic ischemic heart disease |
I25.9 | Chronic ischemic heart disease, unspecified |
I27.0 | Primary pulmonary hypertension |
I27.20 – I27.29 | Other secondary pulmonary hypertension |
I27.81 – I27.9 | Other specified pulmonary heart diseases |
I34.0 – I34.8 | Nonrheumatic mitral valve disorders |
I35.0 – I35.9 | Nonrheumatic aortic valve disorders |
I36.0 – I36.8 | Nonrheumatic tricuspid valve disorders |
I37.0 – I37.8 | Nonrheumatic pulmonary valve disorders |
I42.0 – I42.9 | Cardiomyopathy |
I43 | Cardiomyopathy in diseases classified elsewhere |
I44.0 – I44.2 | Atrioventricular and left bundle-branch block, first degree, second degree |
I44.39 | Other atrioventricular block |
I44.4 | Left anterior fascicular block |
I44.5 | Left posterior fascicular block |
I44.69 | Other fascicular block |
I44.7 | Left bundle-branch block, unspecified |
I45.0 | Right fascicular block |
I45.19 | Other right bundle-branch block |
I45.5 | Other specified heart block |
I45.6 | Pre-excitation syndrome |
I45.81 – I45.89 | Other specified conduction disorders |
I46.2 | Cardiac arrest due to underlying cardiac condition |
I46.8 | Cardiac arrest due to other underlying condition |
I47.0 – I47.2 | Paroxysmal tachycardia |
I48.0 | Paroxysmal atrial fibrillation |
I48.11 | Longstanding persistent atrial fibrillation |
I48.21 | Permanent atrial fibrillation |
I48.3 | Typical atrial flutter |
I48.4 | Atypical atrial flutter |
I48.91 – I48.92 | Unspecified atrial fibrillation and atrial flutter |
I49.01 – I49.02 | Ventricular fibrillation and flutter |
I49.1 | Atrial premature depolarization |
I49.3 | Ventricular premature depolarization |
I49.49 | Other premature depolarization |
I49.5 | Sick sinus syndrome |
I49.8 | Other specified cardiac arrhythmias |
I50.1 | Left ventricular failure, unspecified |
I50.20 – I50.23 | Systolic (congestive) heart failure |
I50.30 – I50.33 | Diastolic (congestive) heart failure |
I50.40 – I50.43 | Combined systolic (congestive) and diastolic (congestive) heart failure |
I50.810 – I50.9 | Other heart failure |
I51.0 – I51.3 | Complications and ill-defined descriptions of heart disease |
I51.5 | Myocardial degeneration |
I51.7 | Cardiomegaly |
I51.89 | Other ill-defined heart diseases |
I63.00 | Cerebral infarction due to thrombosis of unspecified precerebral artery |
I63.011 – I63.019 | Cerebral infarction due to thrombosis of vertebral artery |
I63.02 | Cerebral infarction due to thrombosis of basilar artery |
I63.031 – I63.039 | Cerebral infarction due to thrombosis of carotid artery |
I63.09 | Cerebral infarction due to thrombosis of other precerebral artery |
I63.10 | Cerebral infarction due to embolism of unspecified precerebral artery |
I63.111 – I63.119 | Cerebral infarction due to embolism of vertebral artery |
I16.12 | Cerebral infarction due to embolism of basilar artery |
I63.131 – I63.139 | Cerebral infarction due to embolism of carotid artery |
I63.19 | Cerebral infarction due to embolism of other precerebral artery |
I63.20 | Cerebral infarction due to unspecified occlusion or stenosis of unspecified precerebral arteries |
I63.211 – I63.219 | Cerebral infarction due to unspecified occlusion or stenosis of vertebral arteries |
I63.231 – I63. 239 | Cerebral infarction due to unspecified occlusion or stenosis of carotid arteries |
I63.29 | Cerebral infarction due to unspecified occlusion or stenosis of other precerebral arteries |
I63.30 | Cerebral infarction due to thrombosis of unspecified cerebral artery |
I63.311 – I63.319 | Cerebral infarction due to thrombosis of middle cerebral artery |
I63.321 – I63.329 | Cerebral infarction due to thrombosis of anterior cerebral artery |
I63.331 – I63.339 | Cerebral infarction due to thrombosis of posterior cerebral artery |
I63.341 – I63.349 | Cerebral infarction due to thrombosis of cerebellar artery |
I63.39 | Cerebral infarction due to thrombosis of other cerebral artery |
I63.40 | Cerebral infarction due to embolism of unspecified cerebral artery |
I63.411 – I63.419 | Cerebral infarction due to embolism of middle cerebral artery |
I63.421 – I63.429 | Cerebral infarction due to embolism of anterior cerebral artery |
I63.431 – I63.439 | Cerebral infarction due to embolism of posterior cerebral artery |
I63.441 – I63.449 | Cerebral infarction due to embolism of cerebellar artery |
I63.49 | Cerebral infarction due to embolism of other cerebral artery |
I63.511 – I63.519 | Cerebral infarction due to unspecified occlusion or stenosis of middle cerebral artery |
I63.521 – I63.529 | Cerebral infarction due to unspecified occlusion or stenosis of anterior cerebral artery |
I63.531 – I63.539 | Cerebral infarction due to unspecified occlusion or stenosis of posterior cerebral artery |
I63.541 – I63.549 | Cerebral infarction due to unspecified occlusion or stenosis of cerebellar artery |
I63.59 | Cerebral infarction due to unspecified occlusion or stenosis of other cerebral artery |
I63.6 | Cerebral infarction due to cerebral venous thrombosis, nonpyogenic |
I63.81 – I63.9 | Other cerebral infarction |
I65.01 -I65.09 | Occlusion and stenosis of vertebral artery |
I65.1 | Occlusion and stenosis of basilar artery |
I65.21 – I65.29 | Occlusion and stenosis of carotid artery |
I65.8 | Occlusion and stenosis of other precerebral arteries |
I65.9 | Occlusion and stenosis of unspecified precerebral artery |
I66.01 – I66.9 | Occlusion and stenosis of middle cerebral artery |
I70.0 – I70.1 | Atherosclerosis |
I70.201 – I70.209 | Unspecified atherosclerosis of native arteries of extremities |
I70.211 – I70.219 | Atherosclerosis of native arteries of extremities with intermittent claudication |
I70.221 – I70.229 | Atherosclerosis of native arteries of extremities with rest pain |
I70.231- I70.239 | Atherosclerosis of native arteries of right leg with ulceration of heel and midfoot |
I70.241 – I70.249 | Atherosclerosis of native arteries of left leg with ulceration |
I70.25 | Atherosclerosis of native arteries of other extremities with ulceration |
I70.261 – I70.269 | Atherosclerosis of native arteries of extremities with gangrene |
I70.291 – I70.299 | Other atherosclerosis of native arteries of extremities |
I70.301 – I70.309 | Unspecified atherosclerosis of unspecified type of bypass graft(s) of the extremities |
I70.311 – I70.319 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with intermittent claudication |
I70.321 – I70.329 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with rest pain |
I70.331 – I70.339 | Atherosclerosis of unspecified type of bypass graft(s) of the right leg with ulceration |
I70.341 – I70.349 | Atherosclerosis of unspecified type of bypass graft(s) of the left leg with ulceration |
I70.35 | Atherosclerosis of unspecified type of bypass graft(s) of other extremity with ulceration |
I70.361 – I70.369 | Atherosclerosis of unspecified type of bypass graft(s) of the extremities with gangrene |
I70.391 – I70.399 | Other atherosclerosis of unspecified type of bypass graft(s) of the extremities |
I70.401 – I70.409 | Unspecified atherosclerosis of autologous vein bypass graft(s) of the extremities |
I70.411 – I70.419 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with intermittent claudication |
I70.421 – I70.729 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with rest pain |
I70.431 – I70.439 | Atherosclerosis of autologous vein bypass graft(s) of the right leg with ulceration |
I70.441 – I70.449 | Atherosclerosis of autologous vein bypass graft(s) of the left leg with ulceration |
I70.45 | Atherosclerosis of autologous vein bypass graft(s) of other extremity with ulceration |
I70.461 – I71.469 | Atherosclerosis of autologous vein bypass graft(s) of the extremities with gangrene |
I70.491 - I70.499 | Other atherosclerosis of autologous vein bypass graft(s) of the extremities |
I70.501 – I70.509 | Unspecified atherosclerosis of nonautologous biological bypass graft(s) of the extremities |
I70.511 – I70.519 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities intermittent claudication |
I70.521 - I70.529 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with rest pain |
I70.531 – I70.539 | Atherosclerosis of nonautologous biological bypass graft(s) of the right leg with ulceration |
I70.541 – I70.549 | Atherosclerosis of nonautologous biological bypass graft(s) of the left leg with ulceration |
I70.55 | Atherosclerosis of nonautologous biological bypass graft(s) of other extremity with ulceration |
I70.561 – I70.569 | Atherosclerosis of nonautologous biological bypass graft(s) of the extremities with gangrene |
I70.591 – I70.599 | Other atherosclerosis of nonautologous biological bypass graft(s) of the extremities |
I70.601 – I70.609 | Unspecified atherosclerosis of nonbiological bypass graft(s) of the extremities |
I70.611 – I70.619 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with intermittent claudication |
I70.621 - I70.692 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with rest pain |
I70.631 – I70.639 | Atherosclerosis of nonbiological bypass graft(s) of the right leg with ulceration |
I70.641 - I70.649 | Atherosclerosis of nonbiological bypass graft(s) of the left leg with ulceration |
I70.65 | Atherosclerosis of nonbiological bypass graft(s) of other extremity with ulceration |
I70.661 - I70.669 | Atherosclerosis of nonbiological bypass graft(s) of the extremities with gangrene |
I70.691 – I70.699 | Other atherosclerosis of nonbiological bypass graft(s) of the extremities |
I70.701 – I70.709 | Unspecified atherosclerosis of other type of bypass graft(s) of the extremities |
I70.711 - I70.719 | Atherosclerosis of other type of bypass graft(s) of the extremities with intermittent claudication |
I70.721 - I70.729 | Atherosclerosis of other type of bypass graft(s) of the extremities with rest pain |
I70.731 – I71.739 | Atherosclerosis of other type of bypass graft(s) of the right leg with ulceration |
I70.741 - I70.749 | Atherosclerosis of other type of bypass graft(s) of the left leg with ulceration |
I70.75 | Atherosclerosis of other type of bypass graft(s) of other extremity with ulceration |
I70.767 - I70.769 | Atherosclerosis of other type of bypass graft(s) of the extremities with gangrene |
I70.791 - I70.799 | Other atherosclerosis of other type of bypass graft(s) of the extremities |
I70.8 | Atherosclerosis of other arteries |
I70.90 – I70.92 | Other and unspecified atherosclerosis |
I71.00 – I71.03 | Aortic aneurysm and dissection |
I71.1 | Thoracic aortic aneurysm, ruptured |
I71.2 | Thoracic aortic aneurysm, without rupture |
I71.3 | Abdominal aortic aneurysm, ruptured |
I71.4 | Abdominal aortic aneurysm, without rupture |
I71.5 | Thoracoabdominal aortic aneurysm, ruptured |
I71.6 | Thoracoabdominal aortic aneurysm, without rupture |
I71.8 | Aortic aneurysm of unspecified site, ruptured |
I71.9 | Aortic aneurysm of unspecified site, without rupture |
I73.1 | Thromboangiitis obliterans [Buerger's disease] |
I74.01 - I74.09 | Embolism and thrombosis of abdominal aorta |
I74.10 – I74.9 | Embolism and thrombosis of other and unspecified parts of aorta |
I75.011 – I75.019 | Atheroembolism of upper extremity |
I75.021 – T75.029 | Atheroembolism of lower extremity |
I79.0 | Aneurysm of aorta in diseases classified elsewhere |
I97.0 | Postcardiotomy syndrome |
I97.110 – I97.111 | Postprocedural cardiac insufficiency |
I97.120 – I97.121 | Postprocedural cardiac arrest |
I97.130 – I97.131 | Postprocedural heart failure |
I97.190 – I97.191 | Other postprocedural cardiac functional disturbances |
M79.601 | Pain in right arm |
M79.602 | Pain in left arm |
M79.603 | Pain in arm, unspecified |
Q20.0 – Q20.8 | Congenital malformations of cardiac chambers and connections |
Q21.1 – Q21.8 | Congenital malformations of cardiac septa |
Q22.0 – Q22.8 | Congenital malformations of pulmonary and tricuspid valves |
Q23.0 – Q23.8 | Congenital malformations of aortic and mitral valves |
Q24.0 – Q24.8 | Other congenital malformations of heart |
R00.0 | Tachycardia, unspecified |
R00.1 | Bradycardia, unspecified |
R00.2 | Palpitations |
R06.00 | Dyspnea, unspecified |
R06.01 | Orthopnea |
R06.02 | Shortness of breath |
R06.09 | Other forms of dyspnea |
R06.89 | Other abnormalities of breathing |
R07.2 | Precordial pain |
R07.81 – R07.89 | Other chest pain |
R07.9 | Chest pain, unspecified |
R55 | Syncope and collapse |
R68.84 | Jaw pain |
R93.1 | Abnormal findings on diagnostic imaging of heart and coronary circulation |
R94.30 – R94.39 | Abnormal results of cardiovascular function studies |
T46.991A - T49.994S | Poisoning by other agents primarily affecting the cardiovascular system, accidental (unintentional) |
T82.855A - T82.855S | Stenosis of coronary artery stent |
T82.857A – T82.857S | Stenosis of other cardiac prosthetic devices, implants and grafts |
T82.897A – T82.897S | Other specified complication of cardiac prosthetic devices, implants and grafts |
T86.10 – T86.19 | Complications of kidney transplant |
T86.20 – T86.23 | Complications of heart transplant |
T86.290 – T86.298 | Other complications of heart transplant |
T86.30 – T86.39 | Complications of heart-lung transplant |
T86.40 – T86.49 | Complications of liver transplant |
T86.5 | Complications of stem cell transplant |
T86.810 – T86.819 | Complications of lung transplant |
T86.820 – T86.829 | Complications of skin graft (allograft) (autograft) |
T86.830 – T86.839 | Complications of bone graft |
T86.8401 – T86.8499 | Complications of corneal transplant |
T86.850 – T86.859 | Complication of intestine transplant |
T86.890 – T86.899 | Complications of other transplanted tissue |
T86.90 – T86.99 | Complication of unspecified transplanted organ and tissue |
Z08 | Encounter for follow-up examination after completed treatment for malignant neoplasm |
Z09 | Encounter for follow-up examination after completed treatment for conditions other than malignant neoplasm |
Z48.21 | Encounter for aftercare following heart transplant |
Z48.280 | Encounter for aftercare following heart-lung transplant |
Z79.899 | Other long term (current) drug therapy |
Z94.1 | Heart transplant status |
Z94.3 | Heart and lungs transplant status |
Background
Cardiovascular disease (CVD) risk testing is utilized to indicate the chances of having a coronary event. The most common tests to determine cardiac risk are high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol and triglycerides (often referred to as a basic or standard lipid panel).
Non-traditional risk factors for coronary heart disease (CHD) are used increasingly to determine patient risk, in part because of an assumption that many patients with CHD lack traditional risk factors (e.g., cigarette smoking, diabetes, hyperlipidemia, and hypertension).
Hackman and Anand (2003) summarized existing evidence about the connection between atherosclerotic vascular disease and certain nontraditionalCHDrisk factors (abnormal levels of C-reactive protein [CRP], fibrinogen, lipoprotein(a), and hom*ocysteine [Hcy]). The authors conclude that current evidence does not support the notion that non-traditional risk assessment adds overall value to traditional risk assessment. The authors explained that “for each putative risk factor, there must be prospective controlled trials demonstrating that targeting individuals with elevated levels of these risk factors for proven risk-reducing interventions offers advantages over current methods of targeting therapy (e.g., by cholesterol, diabetes, and blood pressure screening); or selectively and specifically reducing the risk factor reduces hard cardiovascular end points, such as mortality, nonfatal myocardial infarction, and stroke.”
Large prospective studies support screening for traditional risk factors. In one study, Greenland et al (2003) assessed major antecedent risk factors among patients who suffered fatal CHD or non-fatal myocardial infarction (MI) while enrolled in 3 prospective cohort studies involving nearly 400,000 patients (age range of18 to 59). Follow-up ranged from 21 to 30 years. Major risk factors were defined as total cholesterol greater than or equal to 240 mg/dL (greater than or equal to 6.22 mmol/L), systolic blood pressure (BP)greater than or equal to 140 mm Hg, diastolic BP greater than or equal to 90 mm Hg, current cigarette smoking, and diabetes. Of patients age 40 to 59 at baseline who died of CHD during the 3 studies, 90 % to 94 % of women and 87 % to 93 % of men had at least 1 major CHD risk factor. In the 1 study that assessed non-fatal MI, at least 1 major risk factor was present in 87 % of women and 92 % of men age 40 to 59.
In another large study (Khot et al, 2003), researchers analyzed data from more than 120,000 patients enrolled in 14 randomizedcontrolled trials (RCTs) to determine the prevalence of baseline conventional risk factors among CHD patients. Of patients with CHD, 85 % of women and 81 % of men had at least 1 conventional risk factor.
As Cantoand Iskandrian (2003) notes, these data challenge the assumption that "only 50 %" of CHD is attributable to conventional risk factors and emphasize the importance of screening for these risk factors and aggressively treating patients who have them.
An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2005) provided a framework for the evaluation of the potential clinical utility of putative risk factors for cardiovascular disease. The assessment explained that the strongest evidence of the value of such a test is direct evidence that its measurement to assess cardiovascular disease risk results in improved patient outcomes. In the absence of such evidence, the assessment of the potential clinical utility of a test lies in understanding a chain of logic and the evidence supporting those links in the chain. The potential for clinical utility of a test for assessing cardiovascular disease risk lies in following a chain of logic that relies on evidence regarding the ability of a measurement to predict cardiovascular disease beyond that of current risk prediction methods or models, and evidence regarding the utility of risk prediction to treatment of cardiovascular disease. In order to assess the utility of a test in risk prediction, specific recommendations regarding patient management based on the test results should be stated. he assessment notes that another factor that would be important to consider is the availability and reliability of laboratory measurements.
In a report on the use of non-traditional risk factors in CHD risk assessment, the U.S. Preventive Services Task Force (USPSTF, 2009) stated thatthere is insufficient evidence to recommend the use of non-traditional risk factors to screen asymptomatic individuals with no history of CHD to prevent CHD events. Treatment to prevent CHD events by modifying risk factors is currently based on the Framingham risk model. Risk factors not currently part of the Framingham model (i.e., non-traditional risk factors) include high sensitivity CRP (hs-CRP), ankle-brachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness, electron beam computed tomography,Hcy level, and lipoprotein(a) level.
To determine if non-traditional risk factors could play a role in determining those at high- risk for CHD, the USPSTF reviewed the published literature and found the availability and validity of the evidence varied considerably (USPSTF, 2009). They said there is insufficient evidence to determine the percentage of intermediate-risk individuals who would be re-classified by screening with non-traditional risk factors, other than hs-CRP and ABI. For individuals re-classified as high-risk on the basis of hs-CRP or ABI scores, data are not available to determine whether they benefit from additional treatments. In addition, there is not enough information available about the benefits and harms of using non-traditional risk factors in screening. Potential harms include lifelong use of medications without proven benefit and psychological and other harms from being mis-classified in a higher risk category. The USPSTF stated that clinicians should continue to use the Framingham model to assess CHD risk and guide risk-based preventive therapy (USPSTF, 2009).
High Sensitivity C-Reactive Protein (hs-CRP)
C-reactive protein (CRP) is produced by the liver. An elevated CRP level may be indicative of inflammation (nonspecific location). hs-CRP can detect the slight elevations in serum CRP that are associated with coronary artery disease (CAD), which can be within the normal range.
It has been theorized that certain markers of inflammation –both systemic and local – may play a role in the development of atherosclerosis. High sensitivityCRP (hs-CRP) is one systemic marker of inflammation that has been intensively studied and identified as an independent risk factor for coronary artery disease (CAD). Of current inflammatory markers identified, hs-CRP has the analyte and assay characteristics most conducive for use in practice. A Writing Group convened by the American Heart Association and the Centers for Disease Control and Prevention (Pearson et al, 2003) endorsed the optional use of hs-CRP to identify persons without known cardiovascular disease who are at intermediate risk (10 to 20% risk of coronary heart disease over the next 10 years). For these patients, the results of hs-CRP testing may help guide considerations of further evaluation (e.g., imaging, exercise testing) or therapy (e.g., drug therapies with lipid-lowering, anti-platelet, or cardio-protective agents). The Writing Group noted, however, that the benefits of such therapy based on this strategy remain uncertain. High-sensitivity CRP testing is not necessary in high-risk patients who have a 10-year risk of greater than 20 %, as these patients already qualify for intensive medical interventions. Individuals at low-risk (less than 10% per 10 years) will be unlikely to have a high-risk (greater than 20 %) identified through hs-CRP testing. The Writing group recommended screening average risk (10-year risk less than 10 %) for hs-CRP for purposes of cardiovascular risk assessment. The Writing Group stated that hs-CRP also may be useful in estimating prognosis in patients who need secondary preventive care, such as those with stable coronary disease or acute coronary syndromes and those who have underdone percutaneous coronary interventions. The Writing Group posited that this information may be useful in patient counseling because it offers motivation to comply with proven secondary preventive interventions. However, the Writing Group noted that the utility of hs-CRP in secondary prevention is more limited because current guidelines for secondary prevention generally recommend, without measuring hs-CRP, the aggressive application of secondary preventive interventions. The Writing Group recommends measurement of hs-CRP be performed twice (averaging results), optimally2 weeks apart, fasting or non-fasting in metabolically stable patients. Patients with an average hs-CRP level greater than 3.0 mg/dL are considered to be at high relative risk of CHD. Patients with an average hs-CRP level less than 1 mg/L are at low relative risk, and patients with an hs-CRP level between 1.0 and 3.0 mg/L are at average relative risk. If hs-CRP level is greater than 10 mg/dL, the Writing Group recommends that testing should be repeated and the patient examined for sources of infections or inflammation. The Writing group recommended against the measurement of inflammatory markers other than hs-CRP (cytokines, other acute-phase reactants) for determination of coronary risk in addition to hs-CRP.
In an analysis of Women’s Health Study participants, including hs-CRP in cardiovascular disease (CVD)-risk prediction improved the predictive accuracy in non-diabetic women whose traditional 10-year CVD risk was at least 5 %. Cook et al (2006) compared risk-prediction models that include or do not include hs-CRP. The models were applied to 15,048 Women’s Health Study participants who were age 45 or older and free of cardiovascular disease and cancer at baseline. During a mean follow-up of 10 years, 390 women developed CVD. For accurately predicting CVD events, hs-CRP was out-matched only by older age, current smoking, and high blood pressure among traditional Framingham variables. Non-diabetic women were classified according to their 10-year risk for CVD in a model without CRP. Adding CRP to the model substantially improved predictive accuracy for women with an initial 10-year CVD risk of at least 5 %. The gain in accuracy was greatest among women initially classified in the 5 % to 9.9 % risk range: 21.3 % of those women were re-classified in a more accurate risk category when CRP was included in the risk-prediction model (11.9 % moved down a risk category (toless than5 %) and 9.5 % moved up a risk category (to 10 % to 19.9 %)). Accounting for the predictive value of older age, smoking, and high BP lessened the predictive contribution of CRP but still left CRP ahead of any cholesterol parameter (total, LDL, or HDL).
In a nested, case-control study of 122 cases and 244 controls drawn from a cohort of Women's Health Study participants, Ridker et al (2000) assessed the risk for CVD according to levels of4 inflammatory markers:hs-CRP, serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type-1 (sICAM-1). hom*ocysteine and several lipid and lipoprotein fractions (including apolipoprotein A-I, apolipoprotein B-100, lipoprotein(a), total cholesterol and HDL cholesterol) were measured. Outcomes included fatal CHD, non-fatal MI, stroke, or coronary re-vascularization procedures. Overall, hs-CRP showed the strongest univariate association with all markers studied. Although several other markers studies were univariate predictors of CVD, hs-CRP was the only novel plasma marker that predicted risk in multi-variate analysis. Total cholesterol-to-HDL ratio also predicted risk in multi-variate analysis.
Yeh (2005) noted that as a clinical tool for assessment of cardiovascular risk, hs-CRP testing enhances information provided by lipid screening or global risk assessment. While statin therapy and other interventions can reduce hs-CRP, whether or not such reductions can actually prevent cardiovascular events is being investigated. This is in agreement with the observation of Nambi and Ballantyne (2005) who stated that studies are now under way to evaluate if targeting patients with high CRP and low LDL cholesterol will have any impact on future cardiovascular events and survival and whether changes in CRP correlate to event reduction.
Evidence from the JUPITER trial suggests that, for people choosing to start statin therapy, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with statins (Ridker et al, 2009). In an analysis of 15,548 initially healthy men and women participating in the JUPITER trial (87 % of full cohort),investigators prospectively assessed the effects of rosuvastatin versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial re-vascularisation, or cardiovascular deathduring a maximum follow-up of 5 years (median of1.9 years). Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1.8 mmol/L had a 55 % reduction in vascular events, and those achieving hsCRP less than 2 mg/L a 62 % reduction. Although LDL cholesterol and hs-CRP reductions were only weakly correlated in individual patients (r values < 0.15),the investigators reported a 65 % reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/L and hs-CRP less than 2 mg/L, versus a 33 % reduction in those who achieved1 or neither target. In participants who achieved LDL cholesterol less than 1.8 mmol/L and hs-CRP less than 1 mg/L,the investigators founda 79 % reduction. The investigators reported that achieved hs-CRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio (Ridker et al, 2009).
A meta-analysis found that hsCRP concentration has continuous associations with the risk of coronary heart disease, ischemic stroke, and vascular mortality (Emerging Risk Factors Collaboration, 2010). Investigators assessed the associations of hs-CRP concentration with risk of vascular and non-vascular outcomes under different circ*mstances. Investigators meta-analyzed individual records of 160,309 people without a history of vascular disease (i.e., 1.31 million person-years at risk, 27,769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels. The investigators found thatlog(e) hs-CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1 standard deviationhigher log(e) hs-CRP concentration (3-fold higher) were 1.63 (95 % confidence interval (CI): 1.51 to 1.76) when initially adjusted for age and sex only, and 1.37 (1.27 to 1.48) when adjusted further for conventional risk factors; 1.44 (1.32 to 1.57) and 1.27 (1.15 to 1.40) for ischemic stroke; 1.71 (1.53 to 1.91) and 1.55 (1.37 to 1.76) for vascular mortality; and 1.55 (1.41 to 1.69) and 1.54 (1.40 to 1.68) for non-vascular mortality. The investigatorsnoted that RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07 to 1.42) for coronary heart disease; 1.32 (1.18 to 1.49) for ischemic stroke; 1.34 (1.18 to 1.52) for vascular mortality; and 1.34 (1.20 to 1.50) for non-vascular mortality. The investigators concluded that hs-CRP concentration has continuous associations with the risk of coronary heart disease, ischemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The investigators noted that therelevance of hs-CRP to such a range of disorders is unclear. The investigators found that associations with ischemic vascular disease depend considerably on conventional risk factors and other markers of inflammation.
According to guidelines from the National Academy of Clinical Biochemistry (2009), if global risk is intermediate and uncertainty remains as to the use of preventive therapies, hs-CRP measurement might be useful for further stratification into a higher or lower risk category.Guidelines from the American College of Cardiology/American Heart Association (2010) also addressthe selection of patients for statin therapy, stating it can be useful in men 50 years or olderand women 60 years of age or olderwith LDL-C less than 130 mg/dL; not on lipid-lowering, hormone replacement, or immunosuppressant therapy; without clinical coronary heart disease, diabetes, chronic kidney disease, severe inflammatory conditions, or contraindications to statins.
Guidelines from the Canadian Cardiovascular Society (2009, 2013) state that the measurement of hs-CRP is being recommended in men older than 50 years and women older than 60 years of age who are at intermediate risk (10% to 19%) according to their Framinghamrisk score and who do not otherwise qualify for lipid-lowering therapy (i.e., if their LDL-C is less than 3.5 mmol/L). The guidelines explain that the rationale for measuring hs-CRP specifically in these individuals is that we now have class I evidence for the benefit of statin therapy in such individuals, if their hs-CRP is greater than 2.0 mg/L. The guidelinesfound that data from theJUPITER studyshow that statin therapy reduces cardiovascular events (hazard ratio 0.56 [95% CI 0.46 to 0.69]; P<0.00001). The guidelines note, because hs-CRP can be elevated during acute illness, clinical judgment should be exercised in the interpretation of any single measurement of hs-CRP. Canadian Cardiovascular Society guidelines (2013) state that those subjects who meet JUPITER criteria (men greater than50 years andwomen greater than60 years of age and CRP greater than or equal to2 mg/L and LDL greater than 3.5 mmol/L) could be considered for treatment based on the results of that study.
An American Heart Association statement on nontraditional risk factors and biomarkers in cardiovascular disease in youth (Balagopal, et al., 2011) stated: "There currently is no clinical role for measuring CRP routinely in children when assessing or considering therapy for CVD risk factors." The AHA statement explains that, although numerous studies suggest that CRP is elevated in children with higher CVD risk, correlates with the progression of atherosclerotic changes, and tracks, albeit weakly, over 21 years from childhood to adulthood independently of other metabolic and conventional cardiovascular risk factors, it is not yet clear whether high CRP levels during childhood and adolescence lead to an increased risk of CVD in later life. The AHA stated that lifestyle interventions have been shown to decrease CRP in children, and statins reduce CRP in adults. "However, minimal information is available on the effect of statins on CRP in children and youth and, importantly whether lowering CRP in children per se would modify preclinical disease or CVD outcomes."
An assessmentprepared for the Agency for Healthcare Research and Quality (Helfand, et al., 2009) found that, "across all of the criteria listed in the table, C-reactive and electron beam computed tomography scan had the strongest evidence for an independent effect in intermediate-risk individuals, and both reclassify some individuals as high-risk."
An National Heart Lung and Blood Institute (2012) guideline on cardiovascular disease risk in children and adolescentsfound insufficient evidence to recommend the measurement of inflammatory markers in youths.
The American Association of Clinical Endocrinologists (2012) have a 2b recommendation for the use ofhs-CRP to stratify CVD risk in patients with a standard risk assessment that is borderline, or in those with an LDL-C concentration less than 130 mg/dL.
A European consensus guideline (2012)included a strong recommendation thaths-CRP should not be measured in asymptomatic low-risk individuals and high-risk patients to assess 10-year risk of CVD. The guideline included a weak recommendation that high-sensitivity CRP may be measured as part of refined risk assessment in patients with an unusual or moderate CVD risk profile.
Lipoprotein (a) Enzyme Immunoassay
Lipoprotein(a) testing (Lp[a])is an LDL cholesterol particle that is attached to a special protein called apo A. Elevated levels in the blood are purportedly linked to a greater likelihood of atherosclerosis and heart attacks.
The lipoprotein(a) (Lp(a)) enzyme immunoassay have been promoted as an important determinantof CHD risk, and as a guide to drug and diet therapy in patients with established CAD.
Although there is evidence for an association ofLp(a) with cardiovascular disease, there are no data to suggest that more aggressive risk factor modification would improve patient-oriented health outcomes (Pejicand Jamieson, 2007). Furthermore,it is very difficult to modifyLp(a). Some studies suggest that it can be lowered using high doses of niacin, neomycin, or estrogen in women (e.g., Gurakar et al, 1985).
Braunwald et al states “because Lp(a) measurement is not a widely available laboratory determination and the clinical significance of alterations in Lp(a) is not known, the NCEP [National Cholesterol Education Program] does not recommend the routine measurement of this lipoprotein at this time.”
Prospective studies that evaluated Lp(a) as a predictor of cardiovascular events have had conflicting results. Some studies suggested that Lp(a) was an independent risk factor for CHD (Bostom et al, 1994; Bostom et al, 1996; Schaefer et al, 1994; Nguyen et al, 1997; Wald et al, 1994; Cremer et al, 1994; Schwartzman et al, 1998; Ariyo et al, 2003; Shai et al, 2003), while others showed no significant association (Coleman et al, 1992; Ridker et al, 1993; Jauhiainen et al, 1991; Cantin et al, 1998; Nishino et al, 2000). A meta-analysis of 5,436 patients followed for at least1 year concluded that elevated Lp(a) is associated with increased cardiovascular risk (relative risk 1.6; 95 % CI: 1.4 to 1.8) (Danesh et al, 2000).
Hackam and Anand (2003) systematically reviewed the evidence for Lp(a) and concluded that “the use of Lp(a) as a screening tool has some limitations.” Although they identified moderate evidence for its role as an independent risk factor, they found minimal information on its incremental risk, and no prospective clinical outcome studies evaluating its role in management.
Although some studies have linked elevated serum levels ofLp(a) to cardiovascular risk, the clinical utility of this marker has not been established. Suk Danik et al (2006) analyzed data available from a cohort of about 28,000 participants followed for 10 years in the Women’s Health Study. Blood samples that had been frozen at study entry were tested for lipoprotein(a), and incident cardiovascular events were documented during the follow-up period. A total of 26 % of the women had lipoprotein(a) levels greater than 30 mg/dL, which is the level currently considered to confer increased cardiovascular risk. However, only the women in the highest quintile with respect to lipoprotein(a) level (greater than or equal to 44 mg/dL) were more likely to experience cardiovascular events than women in the lowest quintile (hazard ratio [HR], 1.47); thus, a threshold effect was seen. Overall, women with the highest rates of cardiovascular disease were those who had lipoprotein(a) levels at or above the 90th percentile and LDL-C levels at or above the median. These findings indicate that routinely measuring lipoprotein(a) is of little benefit for most women. However, lipoprotein(a) testing might be helpful in the clinical management of women who are at particularly high-risk or who have already experienced a cardiovascular event despite having few or no traditional risk factors. Since lipoprotein(a) is not decreased by lipid-lowering therapies, the mainstay of therapy for cardiovascular risk is still aggressive control of LDL-C levels with a statin or niacin, regardless of a woman’s lipoprotein(a) level.
A study by Ariyo et al (2003) of the predictive value of Lp(a) in the elderly (age greater than 65 years) found that lipoprotein(a) levels have prognostic value for stroke and death in men, but not for CHD in men or for any major vascular outcome in women. However, even the links for stroke and death in men were evident only in the highest compared with the lowest quintile, not in intermediate quintiles. Ariyo et al (2003) prospectively studied 3,972 Cardiovascular Health Study participants (minimum age of 65) who had Lp(a) measurements taken at baseline and did not have vascular disease. Overall, mean baseline Lp(a) levels were slightly higher among women (4.4 mg/dL) than among men (3.9 mg/dL). Median follow-up was 7.4 years. Study participants were placed into quintiles of Lp(a) level (lowest, 0.1 to 1.2 mg/dL; highest, 8.2 to 47.5 mg/dL). In analyses adjusted for other vascular-disease risk factors, elderly women in the highest Lp(a) quintile were no more likely to experience stroke,CHD, death from vascular causes, or death from any cause than were elderly women in the lowest quintile. However, compared with elderly men in the lowest Lp(a) quintile, elderly men in the highest quintile were significantly more likely to experience stroke (HR, 2.92), death from vascular causes (HR, 2.09), and death from any cause (HR, 1.60), but not CHD. The authors concluded that, overall, these results do not appear to support routine measurement of Lp(a) levels in elderly persons.
A meta-analysis found independent but modest associations of Lp(a) concentration with risk of CHD and stroke (Emerging Risk Factors Collaboration, 2009). To assess the relationship of Lp(a) concentration with risk of major vascular and non-vascular outcomes, the investigators examined long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009. Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or non-fatal vascular disease outcomes or non-vascular deaths were recorded, including 9,336 CHD outcomes, 1,903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1,091 other vascular deaths, 8,114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known pre-existing CHD or stroke at baseline. The investigators reported thatLp(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. The investigators also found that associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95 % CI: 5.4 to 5.9) per 1,000 person-years and 4.4 (95 % CI: 4.2 to 4.6) per 1,000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95 % CI: 1.11 to 1.22) per 3.5-fold higher usual Lp(a) concentration (i.e., per 1 standard deviation), and it was 1.13 (95 % CI: 1.09 to 1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95 % CI: 1.02 to 1.18) for ischemic stroke, 1.01 (95 % CI: 0.98 to 1.05) for the aggregate of non-vascular mortality, 1.00 (95 % CI: 0.97 to 1.04) for cancer deaths, and 1.00 (95 % CI: 0.95 to 1.06) for non-vascular deaths other than cancer.
A genetic association study identified2 single nucleotide polymorphisms that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk for coronary artery disease, providingsupport for a causal role of Lp(a) lipoprotein in CAD (Clarke et al, 2009). Investigators assessed 2,100 candidate genes in 3,145 case patients with CAD and 3,352 controls. Single-nucleotide polymorphisms (SNPs) mapped to3 chromosomal regions (6q26-27, 9p21, and 1p13) associated with Lp(a) lipoprotein weresignificantly associated with CAD risk. An accompanying editorial (Katherisan, 2009) stated: "Although the appropriate role of plasma Lp(a) lipoprotein in risk assessment remains a subject of debate, there is likely to be increased enthusiasm for measuring plasma Lp(a) lipoprotein levels (and possibly LPA genetic variants) to assess the risk of coronary disease. Additional studies are needed to determine whether knowledge regarding Lp(a) lipoprotein will prove to be clinically useful with respect to risk discrimination, calibration, or reclassification." In particular, the editorialist stated: "To close the loop for plasma Lp(a) lipoprotein from a curiosity to a causal risk factor, a therapeutic intervention that selectively lowers the plasma Lp(a) lipoprotein level will need to be tested in a randomized clinical trial" (Katherisan, 2009).
In a nested case-control study, lipoprotein(a) was found to add little to standard lipid measures and CRP in predicting development of peripheral arterial disease. Ridker et al (2001) had access to baseline plasma samples from 14,916 healthy men from the Physicians' Health Study. Samples from 140 cases who developed symptomatic peripheral arterial disease (PAD) during 9-year follow-up were compared with samples from 140 controls (matched by age, smoking status, and length of follow-up) who did not develop PAD. Eleven standard and novel biomarkers were analyzed. Most biomarkers were significant independent predictors of PAD. Ratio of total cholesterol (TC) to HDL cholesterol was the strongest lipid predictor (adjusted relative risk, 3.9; 95% CI: 1.7 to 8.6); CRP was the strongest non-lipid predictor (adjusted RR, 2.8; 95 % CI: 1.3 to 5.9). In a separate analysis of which novel biomarkers would enhance the predictive power of standard lipid measures (TC and TC/HDL ratio), the inflammatory markers (fibrinogen and CRP) were the only ones to add to it significantly (CRP even more than fibrinogen). As expected, lipoprotein(a) andHcy added little, asdid LDL cholesterol, apolipoprotein A-1, and apolipoprotein B-100.
No universally accepted, standardized method for determination for Lp(a) exists, althougha working group of the International Federation of Clinical Chemistry demonstrated the inaccuracy of Lp(a) values determined by methods sensitive to apo(a) size and recommended the widespread implementation of a proposed reference material for those Lp(a) assays that are validated to be unaffected by apo(a) size heterogeneity (Tate et al, 1998; Tate et al, 1999; Marcovina et al, 2000). Lipoprotein(a) concentrations are unaffected by most available lipid-lowering therapies, with the exception of high-dose nicotinic acid, which is often poorly tolerated. This has made it difficult to demonstrate that Lp(a) plays a direct role in vascular disease, since large-scale controlled intervention studies examining the reduction of Lp(a) and hard cardiovascular end points have not been performed. Lastly, the incremental predictive value of Lp(a) measurement additive to that of traditional screening methods for global risk assessment has not been formally studied.
There is no uniform guideline recommendation for the use of Lp(a) in assessment of cardiovascular disease risk. The U.S. Preventive Services Task Force (USPSTF, 2009)does not recommend the use ofLp(a) for cardiovascular screening. The USPSTF (2009)concluded that there is insufficient evidence to recommend the use of lipoprotein(a) level to screen asymptomatic individuals with no history of CHD to prevent CHD events.
An assessment prepared for the Agency for Healthcare Quality and Research (Helfand, et al., 2009) concluded that "lipoprotein(a) probably provides independent information about coronary heart disease risk, but data about their prevalence and impact when added to Framingham risk score in intermediate-risk individuals are limited."
An assessment by the National Academy of Clinical Biochemistry (Cooper et al, 2009) stated that lipoprotein (a) screening is not warranted for primary prevention and assessment of cardiovascular risk. However, if risk is intermediate (10 % to 20 %) and uncertainty remains as to the use of preventive therapies such as statins or aspirin, then lipoprotein (a) measurement "may be done at the physician’s discretion." The assessment also stated that, after global risk assessment, lipoprotein (a) measurements in patients with a strong family history of premature CVD "may be useful" for identifying individuals having a genetic predisposition of CVD. The assessment stated, however, thatbenefits of therapies based on lipoprotein (a) concentrations are uncertain. If both lipoprotein (a) and LDL-C are highly increased, "an attempt can be made at the physician’s discretion to lower lipoprotein (a) level by lowering the elevated LDL-C." The assessment stated that there is insufficient evidence to support therapeutic monitoring of lipoprotein (a) levels for evaluating the effects of treatment. The assessment also stated that population routine testing for small size apolipoprotein (a) is not warranted.
A consensus statement by the American College of Cardiology (ACC) and the American Diabetes Association (ADA) (Brunzell et al, 2008) concluded that the clinical utility of routine measurement of Lp(a) is unclear, although more aggressive control of other lipoprotein paramters may be warranted in those with high concentrations of Lp(a).
A European consensus statement (2012) found thathigh concentrations of Lp(a) are associated with increased risk of CHD and ischemic stroke, although there is no randomized intervention showing that reducing Lp(a) decreases CVD risk. The guidelines concluded that there is no justification for screening the general population for Lp(a) at present, and no evidence that any value should be considered as a target.
Canadian Cardiovascular Society guidelines (2013) state that measurement of Lp(a) might be of value in additional risk assessment particularly in individuals with a family history of premature vascular disease and familial hypercholesterolemia. The guidelines, however, make no recommendation for use of Lp(a) in cardioavascular disease risk assessment.
Guidelines from the American Academy of Clinical Endocrinology (2012) state that testing for lipoprotein (a) isnot generally recommended, although it may provide useful information to ascribe risk in white patients with CAD or in those with an unexplained family history of early CAD.
Guidelines from the National Heart Lung and Blood Institute (2012) on cardiovascular disease in children and adolescents states thatthere is currently no medication therapy specific for elevated Lp(a), and similar to isolated low HDL–C levels, management may focus on addressing other risk factors and on more aggressively managing concomitant elevations of LDL–C, TG, and non-HDL–C. In adults, niacin will lower Lp(a) approximately 15 percent, but this has not been studied in children.
The Emerging Risk Factors Collaboration (Di Angelantonio, et al., 2012) found, in a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction. Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). The investigators assessed discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk. The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors.The investigatorsestimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.
O'Donoghue et al (2014) evaluated the prognostic utility of Lp(a) in individuals with CAD. Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95 % CI: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95 % CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95 % CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of LDL cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was greater than or equal to 130 mg/dl (OR: 1.46, 95 % CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol less than 130 mg/dl (OR: 1.20, 95 % CI: 0.90 to 1.60, p = 0.21). The authors concluded that Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear. The authors stated that “although the current study demonstrates that patients with established CAD who have a high level of Lp(a) are at an increased risk of subsequent major adverse cardiovascular events (MACE), the marked heterogeneity between studies raises questions regarding the value of Lp(a) as a clinically useful biomarker for risk assessment, particularly among patients with well-controlled LDL cholesterol. Moreover, although Lp(a) may directly contribute to CHD, there is currently insufficient evidence to suggest that Lp(a) levels above a discrete cut point should be used to guide therapy or that treatment will translate into improved clinical outcomes”.
Apo [Apolipoprotein] B Testing
An apolipoprotein is any of various proteins that combines with a lipid to form a lipoprotein, such as HDL or LDL. Apolipoproteins are important in the transport of cholesterol in the body and the regulation of the level of cholesterol in cells and blood. Apolipoprotein B (apo B)is the primary apolipoprotein of LDL, which is responsible for carrying cholesterol to tissues.
Each LDL particle has one molecule of apo B per particle. Therefore, the apo B concentration is an indirect measurement of the number of LDL particles, in contrast to LDL cholesterol, which is simply a measure of the cholesterol contained within the LDL. Because apo B is a marker for LDL particle number, the greater or higher the apo B level suggests an increased level of small, dense LDL particles which are thought to be especially atherogenic.
Guidelines from the ACC and the ADA recommend the use of apoB in persons at elevated cardiometabolic risk to assess whether additional intense interventions are necessary when LDL cholesterol goals are reached (Brunzell et al, 2008). According to these guidelines, high-risk persons are those with known CVD, diabetes, or multiple CVD risk factors (i.e., smoking, hypertension, family history of premature CVD). The American Association of Clinical Chemistry has issued similar recommendations regarding the use of apoB (Contois et al, 2009).
The INTERHEART study found the apo B:apo A-1 to be a stronger predictor of MIthan their cholesterol counterparts (McQueen et al, 2008). In this study, 12,461 patients with acuteMI from the world’s major regions and ethnic groups were compared with 14,637 age- and sex-matched controls to assess the contributions of various cardiovascular risk factors. Investigators obtained non-fasting blood samples from 9,345 cases and 12,120 controls and measured cholesterol fractions and apolipoproteins to determine their respective predictive values. Ratios were stronger predictors of MI than were individual components, and apolipoproteins were better predictors than their cholesterol counterparts. Theapo B:apo A-1 ratio was the strongest predictor, with a population-attributable risk of 54 %, compared with risks of 37 % for LDL/HDL and 32 % for total cholesterol/HDL. A 1-standard-deviation increase inapo B:apo A-1was associated with an odds ratio of 1.59 for MI, compared with 1.17 for an equivalent increase in total cholesterol/HDL. The results were similar for both sexes and across all ethnic groups and ages.
Apo B testing has not been validated as a tool for risk assessment in the general population. Astudy found that measuring apo B and apo A-I, the main structural proteins of atherogenic and antiatherogenic lipoproteins and particles, adds little to existing measures ofCADrisk assessment and discrimination in the general population. van der Steeg et al (2007) measured apolipoprotein and lipid levels for 869 cases (individuals who developed fatal or nonfatal CAD) and 1,511 matched controls (individuals who remained CAD-free) over a mean follow-up of 6 years. Upon enrollment, participants were 45 to 79 years old and apparently healthy. Occurrence of CAD during follow-up was determined using a regional health authority database (hospitalizations) and U.K. Office of National Statistics records (deaths). The apo B:apo A-I ratio was associated with future CAD events independent of traditional lipid values, including total cholesterol:HDL cholesterol ratio (adjusted odds ratio, 1.85), and independent of the Framingham risk score (OR, 1.77). However, the apo B:apo A-I ratio did no better than lipid values in discriminating between individuals who would and would not develop CAD, and it added little to the predictive value of the Framingham risk score. In addition, this ratio incorrectly classified 41 % of cases and 50 % of controls.
A large, population-based, cohort study suggests that the apo B:apo A-1 ratio has little clinical utility in predicting incidentCHD in the general population, and that measuring total cholesterol and HDL appears to suffice to determine heart disease risk (Ingelsson et al, 2007). Investigators used a variety of techniques to evaluate the relative utility of apo B, apolipoprotein A-1 (apo A-1), serum total cholesterol, HDL cholesterol, LDL cholesterol, non-HDL cholesterol, and3 lipid ratios in determining risk for CHD, as well as the relative ability of these measures to reclassify CHD risk. More than 3,300 middle-aged, white participants in the Framingham Offspring Study withoutCVD were followed for a median of 15 years. A total of 291 first CHD events occurred, 198 of them in men. In men, elevations in non-HDL cholesterol, apo B, total cholesterol:HDL ratio, LDL:HDL ratio, and apo B:apo A-1 ratio were all significantly associated with increased CHD risk to a similar degree. Elevated apo A-1 and HDL were likewise associated with reduced CHD risk. Women had results similar to those in men except that decreased apo A-1 was not significantly associated with incident CHD. In sex-specific analyses, elevated LDL and total cholesterol were not significantly associated with increased CHD risk in either men or women, perhaps owing to the lack of statistical power of these substudies. In men, total cholesterol:HDL and apo B:apo A-1 ratios both improved reclassification of 10-year risk for CHD; however, the difference between the two was not significant. In women, neither lipid ratio improved CHD risk reclassification.
Canadian Cardiovascular Society guidelines (2009, 2013) recommend apoB as the primary alternate target to LDL-C. The guidelines explain that, based on the available evidence, many experts have concluded that apoB is a better marker than LDL-C for the risk of vascular disease and a better index of the adequacy of LDL-lowering therapy than LDL-C.The guidelines also note that there now appears to be less laboratory error in the determination of apoB than LDL-C, particularly in patients with hypertriglyceridemia, and all clinical laboratories could easily and inexpensively provide standardized measurements of apoB. The guidelines state, however, that not all experts are fully convinced that apoB should be measured routinely and, in any case, apoB is not presently being measured in most clinical laboratories. Consequently, a substantial educational effort for patients and physicians would be required for the most effective introduction of apoB into widespread clinical practice. The guidelines conclude that, despite these reservations, all would agree that physicians who wish to use apoB in their clinical care should be encouraged to do so. Furthermore, the present compromise approach represents a positive transitional phase in the assessment of lipid parameters to improve the prevention of CVD through the clinical measurement of apoB. The guidelines state that apoB target for high-risk subjects is less than 0.80 g/L.
Guidelines from the British Columbia Medical Services Commission (2008)states thatapolipoprotein B (apoB) should be considered for follow-up testing in high-risk patients who are undergoing treatment for hypercholesterolemia (but not for other dyslipidemias). The guidelines state that other lipid tests are not required if using apoB for follow-up.
Guidelines from the American Association of Clinical Endocrinologists (2012) recommend apo B measurements to assess the success of LDL-C–lowering therapy. The guidelines note that LDL particle number as reflected by apo B is a more potent measure of cardiovascular disease (CVD) risk than LDL-C and LDL particle size (e.g., small, dense LDL).
A European consensus statement (2012)reported that, because apoB levels have so frequently been measured in outcome studies in parallel with LDL cholesterol, apoB can be substituted for LDL cholesterol, but it does not add further to the risk assessment.The guidelines found that, based on the available evidence, it appears that apoB is a similar risk marker to LDL cholesterol and a better index of the adequacy of LDL-lowering therapy. Also, there appears to be less laboratory error in the determination of apoB than LDL cholesterol, particularly in patients with hypertriglyceridemia, and laboratories could easily and inexpensively provide standardized measurements of apoB. The guideline stated, however, that apoB is not presently being measured in most laboratories but, if measured, it should be less than 80 and less than100 mg/dL for subjects with very high or high CVD risk, respectively.
Further study is needed to determine the usefulness of apolipoprotein B measurement as an adjunct to risk evaluation by routine lipid measurements in the general population. An assessment prepared for the Agency for Healthcare Research and Quality (Helfand, et al., 2009) concluded that "the contribution of ApoB ...to risk assessment for a first ASCVD event is uncertain at present."
There is emerging evidence of a relationship between apo B and stroke risk. Bhatia et al (2006) assessed the relationships between various lipid subfractions andischemic strokerisk in a cohort of 261 patients after transient ischemic attack (TIA). During 10 years of follow-up, 45 patients experienced ischemic stroke. Apolipoprotein B (Apo B) and Apo B/Apo A1 ratio were the only predictors of stroke.
Standards of Care from the American Diabetes Association (2014) state that some experts recommend a greater focus on non– HDL cholesterol, apolipoprotein B (apoB), or lipoprotein particle measurements to assess residual CVD risk in statin-treated patients who are likely to have small LDL particles, such as people with diabetes, but it is unclear whether clinical management would change with these measurements.
A Working Group of the American Association for Clinical Chemistry (Cole, et al., 2013)found that, in most studies, both apoB and LDL particle number were comparable in association with clinical outcomes, and nearly equivalent in their ability to assess risk for cardiovascular disease. The Working Group stated thatapo B appears to be the preferable biomarker for guideline adoption because of its availability, scalability, standardization, and relatively low cost.
The National Heart, Lung, and Blood Institute’s expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents (2011) stated that “In terms of other lipid measurements:
- at this time, most but not all studies indicate that measurement of apolipoprotein B (apoB) and apolipoprotein A-1 (apoA–1) for universal screening provides no additional advantage over measuring non-HDL–C, LDL–C, and HDL–C;
- measurement of lipoprotein(a) (Lp[a]) is useful in the assessment of children with both hemorrhagic and ischemic stroke;
- in offspring of a parent with premature CVD and no other identifiable risk factors, elevations of apoB, apoA–1, and Lp(a) have been noted; and
- measurement of lipoprotein subclasses and their sizes by advanced lipoprotein testing has not been shown to have sufficient clinical utility in children at this time (Grade B)”.
Also, UpToDate reviews on “Overview of the possible risk factors for cardiovascular disease” (Wilson, 2014a) and “Estimation of cardiovascular risk in an individual patient without known cardiovascular disease” (Wilson 2014b) do not mention the use of apolipoprotein A-1 (apoA-1) as a management tool.
The Institute for Clinical Systems Improvement’s clinical practice guideline on “Diagnosis and initial treatment of ischemic stroke” (Anderson et al, 2012) did not mention the measurements of markers of cholesterol production (lathosterol and desmosterol) and absorption (beta-sitosterol, campesterol, and cholestanol).
Also, UpToDate reviews on “Overview of the possible risk factors for cardiovascular disease” (Wilson, 2014a) and “Estimation of cardiovascular risk in an individual patient without known cardiovascular disease” (Wilson 2014b) do not mention measurements of markers of cholesterol production (lathosterol and desmosterol) and absorption (beta-sitosterol, campesterol, and cholestanol) as a management tools.
An Endocrine Society practice guideline (Berglund, et al., 2012) states that "The Task Force suggests that measurement of apolipoprotein B (apoB) or lipoprotein(a) [Lp(a)] levels can be of value, whereas measurement of other apolipoprotein levels has little clinical value."
The Emerging Risk Factors Collaboration (Di Angelantonio, et al., 2012) found, in a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.The investigators estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone..The investigators estimated that additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.
Guidelines from the American College of Cardiology and the American Heart Association (Goff, et al., 2014) state that "the contribution of ApoB ...to risk assessment for a first ASCVD event is uncertain at present."
Apolipoprotein E (apo E) Testing
Apolipoprotein E (apo E)is atype of lipoprotein that is a major component of very low density lipoproteins (VLDL). Apo E is essential for the normal catabolism (breaking down) of triglyceride-rich lipoprotein constituents (components). A major function of VLDL is to remove excess cholesterol from the blood and carry it to the liver for processing.
Apo E is essential in the metabolism of cholesterol and triglycerides and helps to clear chyomicrons and very-low-density lipoproteins. Apo E has been studied for many years for its involvement in CVD. Apo E polymorphisms have functional effects on lipoprotein metabolism, and has been studied in disorders associated with elevated cholesterol levels and lipid derangements. The common isoforms of apolipoprotein E (apoE), E2, E3, and E4,have been found tobedeterminants of plasma lipid concentrations, and1 allele of the apoE gene,the epsilon4 (E4)allele is associated withan increasedrisk of coronary heart disease. In addition,the apoE4allele is being investigated as a potential risk factor for Alzheimer's disease and stroke.
Several small studies and an earlier review have demonstrated variation in cholesterol levels and coronary disease risk associated with apo E isoforms. The literature on apo E and CVDwas reviewed by Eichner et al (2002); the investigators concluded that the apo E genotype yields poor predictive values when screening for clinically defined atherosclerosis despite positive, but modest associations with plaque and coronary heart disease outcomes. The value of apo E testing in the diagnosis and management of CHD needs further evaluation.
One study found that smoking increases the risk of coronary heart disease in men of all apo E genotypes, but particularly in men carrying the epsilon4 allele. Humphries et al (2001)investigated whether the effect of smoking on coronary heart disease risk is affected by APOE genotype. The investigatorsenrolled 3,052 middle-aged men who were free of coronary heart disease for prospective cardiovascular surveillance in the second Northwick Park Heart Study (NPHSII). Compared with never-smokers, risk of coronary heart disease in ex-smokers was 1.34 (95 % CI: 0.86 to 2.08) and in smokers it was 1.94 (1.25 to 3.01). This risk was independent of other classic risk factors. In never-smokers, risk was closely similar in men with different genotypes. Risk in men hom*ozygous for the epsilon3 allele was 1.74 (1.10 to 2.77) in ex-smokers and 1.68 (1.01 to 2.83) in smokers, whereas in men carrying the epsilon4 allele risk was 0.84 (0.40 to 1.75) and 3.17 (1.82 to 5.50), respectively, with no significant differences in risk in the epsilon2 carriers. For the epsilon3 group, the genotype effect on risk was no longer significant after adjustment for classic risk factors (including plasma lipids). However, even after adjustment, smokers who were carriers of the epsilon4 allele, showed significantly raised risk of coronary heart disease compared with the non-smoking group (2.79, 1.59 to 4.91, epsilon4-smoking interaction p = 0.007). An accompanying editorial pointed out that it is important to determine how much of the variation in risk for CHD is attributable to the effects of apoE, in order to evaluate the importance of screening forapoE genotype (Wangand Mahaney, 2001).
Bennett et al (2007)conducted a meta-analysis to assess the relation of apo E genotypes to LDL cholesterol (LDL-C) and coronary disease risk. The researchers identified 82 studies of lipid levels (involving data on some 86,000 healthy participants) and 121 studies of coronary outcomes (involving data on some 38,000 cases and 83,000 controls) from both published and unreported sources. Pooling the lipid studies, researchers found a roughly linear relation toward increasing LDL-C levels when apo E genotypes were ordered 2/2, 2/3, 2/4, 3/3, 3/4, 4/4. Participants with the 2/2 genotype had LDL-C levels that were 31 % lower than those with the 4/4 genotype. The associations were weaker between apo E alleles and triglyceride levels or HDL cholesterol levels. Turning to the coronary outcome studies, when the researchers used patients with the most common allele– 3/3– as a reference, they found that carriers of the 2 allele had a 20 % lower risk for coronary disease, while those with the 4 allele had a 6 % increase in risk. Compared with individuals with the most common allele, those with the 2/2 genotype appear to have a 20 % lower risk for coronary heart disease, while those with the 4/4 genotype appear to have a slightly higher risk. A commentator stated that these results are interesting, but the low prevalence of the 2 allele (about 7 % in Western populations) and its association with the development of Parkinson disease make the consequences of these results– and the utility and feasibility of routine screening– uncertain (Foody, 2007).
Available evidence indicates that apo E genotype is a poor predictor of ischemic stoke. Sturgeon and colleagues examined whether apo E genotype alters the risk for ischemic stroke, as previous studies examining whether apo E genotype alters the risk for stroke have yielded conflicting results. In this study, 14,679 individuals in the Atherosclerosis Risk in Communities (ARIC) study were genotyped for apo E. During more than 183,569 person-years of follow-up, 498 participants had an ischemic stroke. After stratifications by sex and race and adjustments for non-lipid risk factors for stroke, no significant relation between apo E genotype and stroke was identified, except for a lower risk associated with APOE-epsilon-2 compared with APOE-epsilon -3 in black women only. The investigators concluded that the apo E genotype is at most a weak factor for ischemic stroke.
The American Association of Clinical Chemistry (AACC, 2009) has stated that the test for apo E is not widely used and it's clinical usefulness is still being researched. Guidelines from the American Association of Clinical Endocrinologists (2012)has a grade 2B recommendationthat assessment of apo AI "may be useful in certain cases."The AACE guidelines state thata normal apo AI level in a patient with low HDL-C suggests the existence of an adequate number of HDL-C particles that contain less cholesterol and may be an indication of less risk.
hom*ocysteine Testing
hom*ocysteine (Hcy) is an amino acid that is found normally in the body. hom*ocysteine is used by the bodyto make protein and to build and maintain tissue.Studies suggest that high blood levels of this substance may increase a person's chance of developing heart disease, stroke, and peripheral artery disease (PAD). It is believed that high levels ofHcy may damage arteries, may make blood more likely to clot, and may make blood vessels less flexible. It is also suggested that treatment consisting of high doses of folic acid, vitamins B6 and B12 decreases a patient'sHcy levels and thus decreases their risk of CVD. However, published study results in the medical literature are conflicting; therefore the usefulness of Hcy testing in reducing CVDrisk and improving patient outcomes has not been demonstrated. ATP III noted the uncertainty about the strength of the relation betweenHcy and CHD, a lack of clinical trials showing that supplemental B vitamins will reduce risk for CHD, and the relatively low prevalence of elevatedHcy in the U.S. population.
In a structured evidence review, Hackam and Anand (2003) found moderate evidence thatHcy is an independent risk predictor of coronary heart, cerebrovascular and peripheral vascular disease. However, the authors found only minimal evidence that Hcy contributes incrementally to risk prediction. The authors also stated that it is unclear whether elevatedHcy is causal or simply a marker of atherosclerotic vascular disease. The authors found few, if any, controlled studies to evaluate risk-reduction strategies for these4 factors. Hackman and Anand (2003) stated “[w]hether hom*ocysteine is causative in the pathogenesis of atherosclerosis, is related to other confounding cardiovascular risk factors, or is a marker of existing vascular disease will have to await the completion of a number of large, randomized controlled trials studying the effect of hom*ocysteine-lowering vitamins on cardiovascular end points.”
An assessment by the Institute for Clinical Systems Improvement (ICSI, 2003) concluded that “[t]he relevance of studies of [plasma hom*ocysteine] as a risk factor for cardiovascular disease is unclear given the decreasing [plasma hom*ocysteine] levels as a result of mandatory folic acid supplementation. It remains unproven whether lowered [plasma hom*ocysteine] levels will result in reduced morbidity and mortality from cardiovascular disease.”
Prospective clinical studies have failed to demonstrate beneficial effects ofHcy- lowering therapy on CVD. An international randomized trial involved 5,522 patients with histories of documented vascular disease (coronary, cerebrovascular, or peripheral) or with diabetes plus another risk factor. Patients received either a combination pill (containing folic acid, vitamin B6, and vitamin B12 or placebo daily (HOPE 2 Investigators, 2006). After 5 years, meanHcy levels were about 25 % lower in the vitamin group than in the placebo group. However, no significant difference was found between groups in the primary endpoint of MI, stroke, or cardiovascular death (18.8% versus 19.8 %; p = 0.41) or in various secondary outcomes. Importantly, vitamin B supplementation did not benefit patients with the highest baselineHcy levels or patients from countries without mandatory folate fortification of food.
In a secondary prevention randomized trial from Norway (Bonaa et al, 2006), 3,749 patients with MI during the preceding 7 days received vitamin B supplements or placebo. During an average follow-up of 3 years, vitamin supplementation conferred no benefit for any clinical outcome.
A randomized controlled clinical trialfound noeffect of treatment with folic acid, vitamin B12 and vitamin B6 for secondary prevention in patients with coronary artery disease or aortic valve stenosis (Ebbing et al, 2008). The researchers reported on a randomized, double-blind controlled trial conducted in the2 university hospitals in western Norway in between 1999 and 2006. A total of 3,096 adult participants undergoing coronary angiographywere randomized. At baseline, 59.3 % had double- or triple-vessel disease, 83.7 % had stable angina pectoris, and 14.9 % had acute coronary syndromes. Study participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid plus vitamin B12 andvitamin B6; folic acid plus vitamin B12; vitamin B6 alone; or placebo (n = 780). The primary end point of this study was a composite of all-cause death, non-fatal acute MI, acute hospitalization for unstable angina pectoris, and non-fatal thromboembolic stroke. Mean plasma totalHcy concentration was reduced by 30 % after 1 year of treatment in the groups receiving folic acid and vitamin B12. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7 %): 219 participants (14.2 %) receiving folic acid/vitamin B12versus 203 (13.1 %) not receiving such treatment (HR, 1.09; 95 %CI: 0.90 to 1.32;p = 0.36) and 200 participants (13.0 %) receiving vitamin B6versus 222 (14.3 %) not receiving vitamin B6 (HR, 0.90; 95 %CI: 0.74 to 1.09;p = 0.28). The investigators concluded that this trial did not find an effect of treatment with folic acid, vitamin B12 or vitamin B6 on total mortality or cardiovascular events. The researchers concluded that "[o]ur findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease."
A randomized trials amongwomenwith and withoutpre-existing CVD failed to support benefits of B-vitamin supplementation on cardiovascular risk (Albert et al, 2008). Within an ongoing RCT of antioxidant vitamins, 5,442 women who were U.S. health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005. The primary endpoint of the study was acomposite outcome of MI, stroke, coronary re-vascularization, or CVD mortality. Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-yearsversus 219.2/10,000 person-years for the activeversus placebo group; relative risk (RR), 1.03; 95 % CI: 0.90 to 1.19;p = 0.65), as well as for the secondary outcomes including MI (34.5/10,000 person-years versus 39.5/10,000 person-years; RR, 0.87; 95 % CI: 0.63 to 1.22;p = 0.42), stroke (41.9/10,000 person-yearsversus 36.8/10,000 person-years; RR, 1.14; 95 % CI: 0.82 to 1.57;p = 0.44), and CVD mortality (50.3/10,000 person-yearsversus 49.6/10,000 person-years; RR, 1.01; 95 % CI: 0.76 to 1.35;p = 0.93). In a blood substudy, geometric mean plasmaHcy level was decreased by 18.5 % (95 % CI: 12.5 % to 24.1 %;p < 0.001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95 % CI: 1.54 to 2.96 micromol/L). The researchers concluded that, after 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant Hcy lowering.
Despite the biological plausibility of lower plasma Hcy levels improving endothelial function,a RCT showed no benefit, and actual harm, from B-vitamin supplementation in patients with diabetic nephropathy (House et al, 2010). Hyper-hom*ocysteinemia is frequently observed in patients with diabetic nephropathy. B-vitamin therapy (folic acid, vitamin B(6), and vitamin B(12)) has been shown to lower the plasma concentration of Hcy. In order to determine whether B-vitamin therapy can slow progression of diabetic nephropathy and prevent vascular complications, investigators conducteda multi-center, randomized, double-blind, placebo-controlled trial (Diabetic Intervention with Vitamins to Improve Nephropathy [DIVINe]) at 5 university medical centers in Canada between May 2001 and July 2007 (House et al, 2010). The study involved 238 participants who had type 1 or 2 diabetes and a clinical diagnosis of diabetic nephropathy. Subjects were randomly assigned to receiveB vitamins containing folic acid, vitamin B6, and vitamin B12, or matching placebo. The main outcome measure was a change in radionuclide glomerular filtration rate (GFR) between baseline and 36 months. Secondary outcomes were dialysis and a composite of MI, stroke, re-vascularization, and all-cause mortality. Plasma totalHcy was also measured. The mean (SD) follow-up during the trial was 31.9 (14.4) months; enrollment was ended early by the data and safety monitoring board. At 36 months, the mean decrease in GFR was significantly greater in B-vitamin recipients than in non-recipients, even though plasmaHcy levels declined substantially in treated patients and rose in controls. Treated patients also incurred roughly double the risk for adversecardiovascular events as did controls. At 36 months, radionuclide GFR decreased by a mean (SE) of 16.5 (1.7) mL/min/1.73 m(2) in the B-vitamin group compared with 10.7 (1.7) mL/min/1.73 m(2) in the placebo group (mean difference, -5.8; 95 % CI: -10.6 to -1.1; P = .02). There was no difference in requirement of dialysis (HR, 1.1; 95 % CI: 0.4 to 2.6;p = 0.88). The composite outcome occurred more often in the B-vitamin group (HR, 2.0; 95 % CI: 1.0 to 4.0;p = 0.04). Plasma total Hcy decreased by a mean (SE) of 2.2 (0.4) micromol/L at 36 months in the B-vitamin group compared with a mean (SE) increase of 2.6 (0.4) micromol/L in the placebo group (mean difference, -4.8; 95 % CI: -6.1 to -3.7;p < 0.001, in favor of B vitamins). The authors concluded that, among patients with diabetic nephropathy, high doses of B vitamins compared with placebo resulted in a greater decrease in GFR and an increase in vascular events. Commenting on this study, Schwenk (2010) stated, "[g]iven that most other trials also have shown that B-vitamin supplementation does not prevent stroke and CV disease, such supplements should be avoided unless patient subgroups that derive benefit are identified in future clinical trials."
A long-term RCT involving survivors of MI found that substantial long-term reductions in bloodHcy levels with folic acid and vitamin B12 supplementation did not have beneficial effects on vascular outcomes (Study of the Effectiveness of Additional Reductions in Cholesterol and hom*ocysteine (SEARCH) Collaborative Group, 2010). In this double-blind RCT of 12,064 survivors of MI in secondary care hospitals in the United Kingdom between 1998 and 2008, subjects were randomized to2 mg folic acid plus 1 mg vitamin B12 dailyor tomatching placebo. Study endpoints were first major vascular event, defined as major coronary event (coronary death, MI, or coronary re-vascularization), fatal or non-fatal stroke, or non-coronary re-vascularization. The investigators reported that allocation to the study vitamins reducedHcy by a mean of 3.8 µmol/L (28 %). During 6.7 years of follow-up, major vascular events occurred in 1,537 of 6,033 participants (25.5 %) allocated folic acid plus vitamin B12versus 1,493 of 6,031 participants (24.8 %) allocated placebo (risk ratio [RR], 1.04; 95 % CI: 0.97 to 1.12;p = 0.28). The investigators foundno apparent effects on major coronary events (vitamins, 1,229 [20.4 %],versus placebo, 1,185 [19.6 %]; RR, 1.05; 95 % CI: 0.97 to 1.13), stroke (vitamins, 269 [4.5 %],versus placebo, 265 [4.4 %]; RR, 1.02; 95 % CI: 0.86 to 1.21), or non-coronary revascularizations (vitamins, 178 [3.0 %],versus placebo, 152 [2.5 %]; RR, 1.18; 95 % CI: 0.95 to 1.46). The investigators did not findsignificant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6 %],versus placebo, 559 [9.3 %]) or non-vascular causes (vitamins, 405 [6.7 %],versus placebo, 392 [6.5 %]). An accompanying commentary by Schwenk (2010) stated: "These results, and those of the seven prior major trials, should end what seems to be an unjustified persistence by many clinicians to recommend folate supplementation to prevent CV disease. Clinical efforts should focus on modification of CV risk factors, for which evidence supports improved outcomes."
These results are consistent with earlier RCTs ofHcy lowering therapy forCVD. In a multi-center double-blind randomized study, Toole et al (2004) enrolled 3,680 patients with non-disabling, non-embolic ischemic strokes and totalHcy levels above the 25th percentile for the North American stroke population. Patients received either high- doses of Hcy-lowering vitamins (2.5 mg folic acid, 25 mg pyridoxine, and 0.4 mg cobalamin) or low doses that would not be expected to lowerHcy significantly (20 µg, 200 µg, and 6 µg, respectively). During 2 years of follow-up, mean total Hcy decreased from 13.4 µmol/L to about 11 µmol/L in the high-dose group and changed only minimally in the control group. However, no reductions were noted in rates of recurrent stroke, coronary events, or death. Even in the subgroup with the highest Hcy levels, high-dose therapy was ineffective.
In an open-label, prospective trial from the Netherlands, Liem et al (2003) randomized 593 consecutive outpatients with CADto folic acid or to standard care. All had been taking statins for at least 3 months. The2 groups had similar baseline characteristics, including mean plasmaHcy levels of 12 µmol/L. By 3 months,Hcy levels had decreased among folic-acid recipients (by 18 %) but not among controls. By a mean follow-up of 24 months, clinical vascular events (i.e., death, MI, stroke, invasive coronary procedures, vascular surgery) had occurred at similar rates in folic-acid (12.3 %) and standard-care (11.2 %) recipients; the similarity also was evident among patients in the highest quartile of baselineHcy level (greater than 13.7 µmol/L). In multi-variate analysis, poor creatinine clearance was a more important cardiovascular risk factor than elevatedHcy level was.
Routine testing forHcy is also not supported in persons with venous thromboembolism. In a secondary analysis of a previously published multi-national RCT designed to assess the effect of Hcy-lowering therapy on the risk for arterial disease (Ray et al, 2007), investigators studied whether daily folate (2.5 mg) and vitamins B6 (50 mg) and B12 (1 mg) affected the risk for symptomatic deep venous thrombosis or pulmonary embolism. Subjects were 5,522 adults (age 55 years and older) with arterial vascular disease, diabetes, and at least1 other CVD risk factor. During a mean follow-up of 5 years,Hcy levels decreased more in the vitamin-therapy group than in the placebo group. However, the incidence of venous thromboembolism did not differ between the vitamin-therapy and placebo groups, both overall and among the quartile with the highestHcy levels (i.e., greater than 13.8 µmol /L) at baseline.
These results were similar to an earlier secondary prevention trial ofHcy for venous thromboembolism (VTE). In the first randomized trial ofHcy therapy to prevent recurrent VTE, den Heijer et al (2007) enrolled 701 patients with recent VTE (either proximal deep-vein thrombosis or pulmonary embolism), but without major predisposing risk factors such as recent surgery or immobilization. At baseline, 50 % the patients had hyper-hom*ocysteinemia (mean, 15.5 µmol/L), and50 %had normal levels (mean, 9.0 µmol/L). Patients were randomized to receive a B-vitamin supplement (5 mg folic acid, 0.4 mg B12, and 50 mg B6) or placebo, in addition to standard anti-coagulation. During 2.5 years of follow-up, the overall incidence of recurrent VTE was not significantly different in the B-vitamin and placebo groups (5.4% versus. 6.4 %). In hyper-hom*ocysteinemic patients, the incidence of recurrent venous thromboembolism was non-significantly higher in B-vitamin recipients than in placebo recipients (6.7% versus 6.0 %); in those with normal Hcy, the incidence of recurrent VTE was non-significantly lower in B-vitamin recipients (4.1 % versus 7.0 %). The authors noted that their study might have been under-powered to detect a small beneficial effect. However, they also speculate that Hcy's observed epidemiologic association with venous thromboembolism might in fact be mediated by some other thrombophilic factor that is correlated with Hcy.
An American Heart Association Science Advisory (Malinow et al, 1999) has concluded: "Although there is considerable epidemiological evidence for a relationship between plasma hom*ocyst(e)ine and cardiovascular disease, not all prospective studies have supported such a relationship …. Until results of controlled clinical trials become available, population-wide screening is not recommended…. Such treatment (supplemental vitamins) is still considered experimental, pending results from intervention trials showing that hom*ocyst(e)ine lowering favorably affects the evolution of arterial occlusive diseases."
A consensus statement from the ACC and the ADA (Brunzell et al, 2008) reported that Hcy testing has been evaluated to determine its prognostic significance in CVD. However, the independent predictive value ofHcy testing and its clinical utility are unclear.
The National Academy of Clinical Biochemistry (Cooperand Pfeiffer, 2009) stated that "we conclude that the clinical application of Hcy measurement for risk assessment of primary prevention of CVD is currently uncertain."
An assessment prepared for the Agency for Healthcare Research and Quality (Helfand, et al., 2009) found that "hom*ocysteine ...probably provide[s] independent information about coronary heart disease risk, but data about their prevalence and impact when added to Framingham risk score in intermediate-risk individuals are limited."
The U.S. Preventive Services Task Force (USPSTF, 2009) stated that there is insufficient evidence to recommend the use