**History/Background and/or General Information**

Recent studies have shown that chronic, low-grade inflammation contributes to
atherogenesis and the development of coronary artery disease (CAD).
Inflammatory changes lead to progressive disease, which culminates in plaque
instability, rupture, thrombosis, and myocardial infarction (MI). Increasing
recognition of the inflammatory component of atherogenesis provides the
biological plausibility for the use of inflammatory markers as prognostic
indicators of atherosclerotic complications.

Increased serum levels of C-reactive protein (CRP), an inflammatory biomarker,
have been linked to an increased risk of myocardial infarction, stroke,
peripheral arterial disease, and sudden cardiac death even in the absence of
hyperlipidemia. CRP is a nonspecific, acute-phase reactant produced in
response to tissue injury, inflammation or infection. CRP is secreted by
hepatocytes, where its synthesis is regulated by cytokines. A high sensitivity
C-reactive protein (hsCRP) assay measures low levels of CRP, which allows for
measurement of conditions indicative of chronic, low-grade inflammation. The
stimulus for the rise in serum CRP in CAD remains undetermined, although it
may result from local inflammation within atheromatous plaques, from a
systemic or local inflammation or infection elsewhere in the body that
contributes to atherogenesis, or to unrelated conditions. Increased CRP may
reflect plaque instability and an increased risk for a CAD event.

The standard CRP assays have limits of measuring acute-phase detection of
3.0-5.0 mg/L and lack the sensitivity required to detect slight elevations
that occur in CAD. High-sensitivity assays can measure levels as low as 0.175
mg/L, which may be associated with CAD. hsCRP assays are based on
nephelometric analysis of antigen-antibody complexes using monoclonal
antibodies with sufficient sensitivity to detect low levels of CRP.

The hsCRP results, along with The Framingham Heart Study Risk Assessment (a
tool which considers gender, age, total cholesterol, HDL cholesterol, systolic
blood pressure, antihypertensive medications, family history and smoking
risks) provides cardiac prognostic information. However, hsCRP and LDL
cholesterol levels are minimally correlated.

**Covered Indications**

High-sensitivity C-reactive protein (hsCRP) testing will be considered
medically reasonable and necessary for the assessment of CAD risk when **ALL**
of the following criteria are met:

  * When the hsCRP would add substantial incremental information in the decision making process to optimize/maximize current lipid lowering pharmacologic therapy in a patient who has been identified as being at intermediate risk for CAD (10-year risk of coronary heart disease between 10-20% per the ATPIII Guidelines). This is to be used for a one time decision point and is not intended to monitor therapy.
  * The test is performed in patients considered to be metabolically stable and without obvious inflammatory or infectious conditions.

The American Heart Association (AHA) recommends the following cutpoints for
hsCRP corresponding to three levels of risk:

  * Low risk < 1.0 mg/L
  * Average risk > 1.0 to < 3.0 mg/L
  * High risk > 3.0 mg/L

Generally, the measurement of hsCRP markers may be performed twice (averaging
results), optimally two weeks apart and fasting or nonfasting, with the
average expressed in mg/L, in metabolically stable patients. If an average CRP
level of >10.0 mg/L is found on two tests performed 2 weeks apart, a third
test may be performed after ruling out possible infectious or inflammatory
causes for the increase (AHA/CDC Recommendation).

**_Limitations_**

Routine screening performed without a relationship to the evaluation or
treatment of a symptom, sign, illness or injury is not covered. If high
sensitivity C-reactive protein (hsCRP) testing is performed for cardiovascular
risk assessment, in the absence of signs or symptoms of illness or injury,
then the service will be denied as not reasonable or medically necessary.

Testing for hsCRP as a screening test for the general population or for
monitoring response to therapy is not covered.

Commonly, hsCRP is elevated in inflammatory conditions (e.g., rheumatic fever,
rheumatoid arthritis, systemic vasculitis, myocardial infarction, acute
pancreatitis) and are not considered medically reasonable and necessary for
purposes of this LCD.

As published in the CMS IOM Publication 100-08, _Medicare Program Integrity
Manual_ , Chapter 13, Section 13.5.4, an item or service may be covered by a
contractor LCD if it is reasonable and necessary under the Social Security Act
Section 1862 (a)(1)(A). Contractors shall determine and describe the
circumstances under which the item or service is considered reasonable and
necessary.