Description
Cardiac biomarkers are the biochemical markers released in blood from the injured myocardial tissue. They become elevated in blood after a certain period and can be measured. Examples of cardiac biomarkers commonly used in the clinical setting include Troponin and Creatine Kinase MB isoenzyme (CKMB) (Thygesen, Alpert, & White, 2007).

Regulatory Status
There is a multitude of FDA-approved cardiac biomarkers tests for Troponin and CKMB currently available in high and moderate complexity formats. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy  

1. Measurement of cardiac troponin (troponin T or I) for the diagnosis of myocardial infarction (MI) is considered MEDICALLY NECESSARY in all patients presenting with signs and symptoms of acute coronary syndrome.* (Please see Note 1.)
2. Measurement of following cardiac biomarkers for the diagnosis and/or prognosis of MI is NOT MEDICALLY NECESSARY in patients presenting with signs and symptoms of acute coronary syndrome*:
   • Aspartate aminotransferase (AST/SGOT)
   • Cardiac creatine kinase isoenzyme MB (CKMB)
   • Creatine kinase (CK)
   • Creatine kinase Isoenzymes
   • Lactate Dehydrogenase (LD, LDH)
   • Myoglobin
3. Measurement of cardiac biomarkers in patients presenting with signs and symptoms of acute coronary syndrome* in an outpatient setting which is not capable of performing adequate clinical MI evaluation (e.g. independent lab or physician’s office) is NOT MEDICALLY NECESSARY 
4. Measurement of the following cardiac biomarkers for the diagnosis and/or prognosis of MI is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in patients presenting with signs and symptoms of acute coronary syndrome*:
   • Copeptin
   • Troponin C
   • C-reactive protein
   • Heart-type fatty acid binding protein (H-FABP)
   • any other cardiac biomarkers not listed above

*Note 1:

Acute Coronary Syndrome/Myocardial Infarction Common Signs and Symptoms (Reeder, 2020):

• Ischemic chest pain with radiation to an upper extremity, radiation to both arms, and pain associated with diaphoresis or with nausea and vomiting.
• Squeezing, tightness, pressure, constriction, crushing, strangling, burning, heartburn, fullness in the chest, band-like sensation, knot in the center of the chest, lump in throat, ache, heavy weight on chest and toothache (when there is radiation to the lower jaw).
• Ischemic pain often radiates to other parts of the body including the upper abdomen (epigastrium), shoulders, arms (upper and forearm), wrist, fingers, neck and throat, lower jaw and teeth (but not upper jaw), and not infrequently to the back (specifically the interscapular region).
• Shortness of breath, belching, nausea, indigestion, vomiting, diaphoresis, dizziness, lightheadedness, clamminess, and fatigue.

Atypical Signs and Symptoms (Reeder, 2020):

Dyspnea alone, weakness, nausea and/or vomiting, epigastric pain or discomfort, palpitations, syncope, or cardiac arrest

Reimbursement Limitations:

Maximum of 4 serial troponin tests will be reimbursed (e.g. Repeat troponin measurements) in the first 24 – 72 hours after presentation

Rationale 
Acute coronary syndromes (ACS) represent continuous events starting with angina, reversible injury, progressing to unstable angina, are frequently associated with minor myocardial damage, and myocardial infarction (MI) that results in extensive tissue necrosis (Thygesen et al., 2007). Patients with ACS usually present with chest pain and associated signs and symptoms. These patients are subdivided into two major categories based on the 12-lead electrocardiogram (ECG). If an ST-segment elevation is observed on the ECG, it is indicative of acute ST-elevation myocardial infarction (STEMI) type of ACS. If the ECG shows ST-segment depression, T-wave changes, or no ECG abnormalities, it is indicative of non-ST elevation myocardial infarction (NSTEMI) and unstable angina. ACS are complex. However, the most common cause is atherosclerotic coronary artery disease with rupture of atherosclerotic plaque (Amsterdam et al., 2014). The first documented definition of acute MI was established in 1979 by the World Health Organization (WHO). It included in the criteria for MI diagnosis the recommendation to use the rise or fall patterns of cardiac biomarkers, such as creatine kinase (CK), creatine kinase’s MB isoenzyme (CK-MB), lactate dehydrogenase (LDH) or aspartate aminotransferase (AST) activities (WHO, 1979). Since then, other societies have proposed their own criteria for diagnosis. The third universal definition of MI includes typical clinical symptoms, suggestive ECG changes, or imaging evidence of new loss of viable myocardium or new regional wall abnormality with a rise and/or fall of cardiac biomarkers (Thygesen et al., 2012). Nonetheless, the universal criteria are being refined by cardiovascular societies and will likely change with scientific progress and better understanding of MI pathophysiology.

Myocardial infarction results in cardiac injury and extensive tissue necrosis. The cellular membranes

Table 1 Characteristics of AMI biomarkers

AST, aspartate aminotransferase; LDH, lactate dehydrogenase; CK, creatine kinase; CK-MB, creatine kinase MB isoenzyme; Ctnl, cardiac troponin l; cTnT, cardiac troponin T. 

Myocardial infarction results in cardiac injury and extensive tissue necrosis. The cellular membranes become compromised and release structural proteins and other macromolecules into cardiac interstitial, called cardiac biomarkers. The levels of these cardiac biomarkers in blood will rise and fall with time after MI (Thygesen et al., 2007). The first cardiac biomarker, aspartate aminotransferase (AST), was used for MI diagnosis in 1954. AST is present in human tissues as two isoenzymes: cytoplasmic and mitochondrial. AST is a non-specific biomarker and its activity could also be elevated in other conditions, such as hepatic congestion secondary to congestive heart failure. Since then, other cardiac biomarkers were used as an aid in diagnosis of MI, but due to their non-specificity and other reasons, many of them are no longer used in clinical  practice or their use remains very limited (Danese & Montagnana, 2016). The most common cardiac biomarkers and their characteristics are summarized in the table from (Danese & Montagnana, 2016):

Proprietary tests for various biomarkers are available in several clinical settings. Platforms including Roche’s “CARDIAC Trop T Sensitive test” and Responsebio’s battery of cardiac tests emphasize their speed (on the scale of minutes) and versatility (ResponseBio, 2020; Roche, 2020).

Lactate Dehydrogenase (LDH, also known as LD)
Lactate dehydrogenase is a cytoplasmic enzyme present in many different tissues, such as skeletal muscle, liver, heart, kidney, and red blood cells. Five isoenzymes have been identified by gel electrophoresis and other techniques (Marshall, Williams, & Williams, 1991). The heart isoenzymes, LD1 and LD2, have activity increases in blood five to ten hours after MI symptoms onset and remains elevated for up to ten days (Danese & Montagnana, 2016). LD has poor specificity for cardiac tissue and is generally not recommended as a biomarker for the diagnosis of MI (Amsterdam et al., 2014; Jaffe & Morrow, 2019).

Myoglobin
Myoglobin is an oxygen-binding, cytoplasmic, heme protein. It is one of the first cardiac biomarkers measurable in the serum that appears between one and three hours after MI symptoms onset. Myoglobin is present in skeletal and cardiac muscles and is cleared by the kidneys (Vaidya, 1994). Its clinical utility is limited by its poor specificity. The main reason of using myoglobin in a clinical setting was its sensitivity for MI (Danese & Montagnana, 2016); but with appearance of sensitive troponin assays, myoglobin use offers little advantage for the diagnosis of MI (Eggers, Oldgren, Nordenskjold, & Lindahl, 2004; Kavsak et al., 2007). Currently, there are no recommendations for myoglobin to be used in the diagnosis of MI (Amsterdam et al., 2014), and its use as cardiac biomarker is discouraged (Jaffe & Morrow, 2017).

Creatine Kinase (CK) Isoenzymes and Isoform MB (CKMB)
The cytosolic enzyme creatine kinase (CK), formerly known as creatine phosphokinase (Danese & Montagnana, 2016), is present as three cytosolic isoenzymes and one mitochondrial isoenzyme. These isoenzymes are dimers of M (muscle) and B (brain) chains that exist in three combinations: MM, MB and BB  (Bessman & Carpenter, 1985). The CKMM is predominant in both heart and skeletal muscle, but CKMB is more specific for the myocardium. The total CK activity could be detected in blood 3-9 hours after MI, but it reaches the maximum levels in blood in 10-20 hours and returns to normal in about 72 hours (Penttila, Penttila, & Rantanen, 2000). The measurement of total CK activity is not specific to MI because it also increases in liver, biliary tract, kidneys, and skeletal muscle disease, and its measurement is problematic in older individuals with lower muscle mass (Dillon et al., 1982; Heller, Blaustein, & Wei, 1983; Yusuf et al., 1987). CKMB mass (CKMB protein concentration measurements) was once the cardiac biomarker of the choice that replaced CK, CKMB activity, AST, and LDH (Danese & Montagnana, 2016). However, with arrival of cardiac troponin assays, the use of CKMB became less popular. Some clinicians advocate for the use of CKMB for diagnosis and prognosis of MI, but cardiac troponins have shown either equally reliable or superior results compared to CKMB; consequently, troponin is the recommended test for MI diagnosis now (Amsterdam et al., 2014; Jaffe & Morrow, 2017).

Engel and Rockson (2020) studied the use of CK-MB in early diagnosis of myocardial infarction within the first nine hours of the hospital stay. 528 patient charts with complaints of chest pain within the past year were studied. An enzymatic diagnosis was assigned if CK-MB exceeded the normal values. The diagnosis of each patient before 9 hours (early diagnosis) was compared to the ultimate diagnosis at 14-24 hours (final diagnosis). Of the 528 patients, 195 (36.9%) had an early MI diagnosis within 9 hours and 190 patients (97.4%) of these did have an ultimate diagnosis of MI. Therefore, the authors conclude that "standard CK-MB measurements within 9 hours of arrival provided an accurate clinical assessment in > 99% of the cases (Engel & Rockson, 2020)."

Troponins
The regulatory protein troponin in the troponin complex is composed of three isoforms. Troponin C (TnC) is responsible for calcium binding and has no role to play as a cardiac biomarker. Troponin I (TnI) and Troponin T (TnT) are responsible for inhibition of ATPase activity and tropomyosin binding, respectively (Greaser & Gergely, 1971). Contrary to all previously used cardiac biomarkers, cardiac troponins have high specificity for cardiac tissue. The cardiac troponins have a specific pattern of expression because they have different amino sequences encoded by different genes for skeletal and cardiac muscles. Cardiac TnI has an additional 31-amino acid residue compared to skeletal muscle.  This protein is not expressed in normal, regenerating, or diseased skeletal muscle from human or animal origin (Bodor, Porterfield, Voss, Smith, & Apple, 1995). Cardiac TnT has an additional 11-amino acid residue, but this protein was also found in regenerating rat skeletal muscle, during human fetal development, and in diseased human skeletal muscle (Anderson, Malouf, Oakeley, Pagani, & Allen, 1991; Bodor et al., 1997; Saggin, Gorza, Ausoni, & Schiaffino, 1990). In addition, cardiac TnT was also found in skeletal muscle specimens from patients with muscular dystrophy, polymyositis, and chronic renal disease (Bodor et al., 1997; McLaurin, Apple, Voss, Herzog, & Sharkey, 1997).

Neumann et al. evaluated high-sensitivity troponin (troponin I and T)’s ability to predict myocardial infarction and subsequent 30-day outcomes. The authors developed a risk assessment tool based on patients presenting to the emergency department with “symptoms suggestive of myocardial infarction”. Concentrations of troponin I or T were measured at presentation and after early or late serial sampling. Cutoffs were then determined to create cutoffs for risk assessment. Among the 22,651 patients (9,604 in derivation cohort, 13,047 in validation cohort), the total prevalence of myocardial infarction was 15.3%. The authors found that “lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events” (Neumann et al., 2019).

Anand et al. evaluated the adoption rate of the universal definition of myocardial infarction and the corresponding recommendations. 1,902 medical centers over 23 countries were surveyed, and the authors obtained answers regarding the primary biomarker, diagnostic thresholds, and clinical pathways used to identify myocardial infarction. The authors found that cardiac troponin was the primary biomarker used at 96% of surveyed sites, with 41% of these sites using high-sensitivity troponins. The sites using high-sensitivity assays were also more likely to use serial sampling (91% vs 78% using “contemporary” sensitivity troponin) and the 99% percentile diagnostic threshold (74% vs 66%). Use of creatine kinase-MB (CKMB) was “very limited” outside of Latin America (Anand, Shah, Beshiri, Jaffe, & Mills, 2019).

In addition, other cardiac biomarkers, such as heart-type fatty acid binding protein (H-FABP) and copeptin, have been reported in the scientific literature. However, they are not commonly used in clinical settings (Jaffe & Morrow, 2017).

Boeddinghaus et al. (2020) compared the diagnostic accuracy of high-sensitivity cardiac troponin (hs-cTn) TriageTrue assay in patients with suspected myocardial infarction (MI) with other laboratory assays including f hs-cTnTElecsys assay and hs-cTnI-Architect assay. 1,261 patients with symptoms suggestive of MI were enrolled in the study. The TriageTrue assay ruled out patients with troponin I concentration < 3 ng/l and classified these patients as low risk of MI and ruled in patients with a troponin I concentration > 60 ng/l. 178 out of the 1,261 patients enrolled in the study were diagnosed with MI based on troponin I levels of > 60 ng/l using the TriageTrue assay. TriageTrue troponin I concentrations were higher in patients with MI than in patients with other final diagnoses. Other diagnosis included unstable angina in 13 of 1,261 (9%), tachyarrhythmia, Takotsubo syndrome, heart failure, or myocarditis in 208 patients (17%), and noncardiac symptoms in 714 patients (57%). The AUC of the TriageTrue assay was 0.95, the hs-cTnT-Elecsys assay AUC was 0.93, and hs-cTnI-Architect assay AUC was 0.92. The TriageTrue algorithm allowed providers to make a triage decision after 1 hour in 401 of 545 patients. The efficacy for rule-out or rule-in was 43% for the TriageTrue, 25% in f hs-cTnTElecsys, and 22% in hs-cTnI-Architect. Ruled-out patients had cumulative event rates of 0% at 30 days and 1.6% at 2 years. Overall, the authors conclude that “POC-hs-cTnI-TriageTrue assay provides high diagnostic accuracy in patients with suspected MI with a clinical performance that is at least comparable to that of best-validated central laboratory assays (Boeddinghaus et al., 2020).”

Heart-type fatty acid binding protein (H-FABP)
H-FABP, a small cytoplasmic protein present in cardiomyocytes, is believed to have a function in myocardial lipid homeostasis (Glatz & van der Vusse, 1990). Because of its small size, this protein appears in the blood after MI almost as early as myoglobin, but it has better specificity than myoglobin for cardiac tissue (Van Nieuwenhoven et al., 1995). Seino et al compared the use of H-FABP with rapid troponin in 371 patients with acute chest pain (Seino et al., 2003). Their study demonstrated that H-FABP had significantly higher sensitivity (89%) than troponin T (22%) and myoglobin (38%), but it has lower specificity (52%) than troponin (94%). Other studies were performed to compare H-FABP to troponins; however, they were unable to demonstrate superior results compared to troponins. H-FABP is not encouraged for assessment of MI as troponins are generally superior (Jaffe & Morrow, 2017).

In a prospective, cross-sectional study, Nguyen et al. (2020) studied the diagnostic utility of H-FABP in the early diagnosis of acute MI in comparison with troponin I and CK-MB. 216 patients enrolled in the study with 179 of those diagnosed with acute MI. H-FABP, CK-MB, and troponin I levels were compared. H-FABP reached its highest concentration in 6 – 12 hours after symptoms of chest pain, with a mean value of 169 ng/mL in acute MI patients. The cut-off value was 5.7 ng/ml with 90.5% sensitivity and 100% specificity. The combination of H-FABP, CK-MB and troponin I together had the highest sensitivity of 97.2%. The AUC of H-FABP was observed to be 0.99, which was higher than CK-MB (0.92) and troponin I (0.86). The authors conclude that "H-FABP can be used as a reliable diagnostic cardiac biomarker in the early detection of AMI for patients who came to the emergency room within 12h of onset of chest pain (Nguyen et al., 2020)."

Copeptin
Copeptin is the 39 amino acid C-terminal fragment cleaved from pro-arginine vasopressin (AVP). After MI, copeptin levels increase rapidly and decline over the next two to five days (Khan et al., 2007). In the Copeptin Helps in the Early Detection of Patients With Acute Myocardial Infarction (CHOPIN) 16-site study involving 1,967 patients presenting within 6 hours of pain onset, copeptin was shown to have a potential value in ruling out MI with a negative predictive value greater than 99% when combined with TnI measurements (Maisel et al., 2013). The Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) multicenter study, involving 1,439 patients presenting with MI symptoms, demonstrated no benefit in using copeptin as a an early rule-out cardiac biomarker for MI (Hillinger et al., 2015). Copeptin is not encouraged for assessment of MI as troponins are generally superior (Jaffe & Morrow, 2017).

Jeong et al. (2020) studied the diagnostic value of copeptin for early diagnosis of acute MI in comparison with troponin I and CK-MB. 271 patients complaining of chest pain within 6 hours of onset were studied within the emergency department. The diagnostic performance of copeptin, troponin I, and CK-MB was compared by assessing the AUC and ROC curve analysis. After comparing AUC, copeptin had a significantly better diagnosis value than troponin I in patients with chest pain within two hours of onset. In addition, troponin I and copeptin together had better diagnostic performance than CK-MB and troponin I combination. Overall, the authors conclude that "the combination of troponin I and copeptin improves AMI diagnostic performance in patients with early-onset chest pain in an ED setting (Jeong et al., 2020)."

2018 ESC/ACC/AHA/WHF Fourth Universal Definition of Myocardial Infarction (Jaffe et al., 2018)
Both cTnI and cTnT are recommended for evaluation of myocardial injury, and high-sensitivity cTn assays are recommended for routine clinical use. An acute MI is designated when a rising/falling pattern is seen with cTn levels and if there is at least one measurement greater than the 99^th percentile of the upper reference limit (URL) (Jaffe et al., 2018).

CKMB is considered less sensitive and specific than either troponin. However, in the absence of a cTn assay, CK-MB is considered the best alternative. A measurement of CK-MB above the 99th percentile of the URL should be “designated as the decision level for the diagnosis of MI”. Sex-specific CK-MB values should be used (Jaffe et al., 2018). 

In the 2019 AHA guideline discussing the “Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease [MINOCA]”, the AHA notes that the diagnostic criteria of MINOCA follows the “Fourth Universal Definition of Myocardial Infarction” above, specifically the rise or fall of cardiac troponin levels with at least one value above the 99th percentile of the reference limit. The guideline considers this definition “fundamental” to identifying and defining MINOCA (Tamis-Holland Jacqueline et al., 2019).

2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes (NSTE-ACS) (Amsterdam et al., 2014) 
The American College of Cardiology (ACC) and the American Heart Association (AHA) have developed clinical practice guidelines to provide recommendations applicable to patients with or at risk of developing cardiovascular disease and to provide guidance to clinicians on optimal management of patients with NSTE-ACS. In their comprehensive document, the AHA/ACC panel has provided recommendations for initial evaluation and management of patients presenting with ACS symptoms, for the early hospital care, myocardial revascularization, late hospital care, hospital discharge and posthospital discharge care, special patient groups and quality of care and outcomes for ACS. The Task Force recommended to stratify patients with suspected ACS based on the likelihood of ACS and those with high-risk features should be referred immediately to the emergency department (ED). They have provided specific recommendations for the use of cardiac biomarkers in the diagnosis and prognosis of MI. They specifically recommended using troponin (troponin I or T when contemporary assay is used) for the diagnosis of MI. According to AHA/ACC guidelines, the cardiac troponin is recommended and should be measured at presentation and 3 to 6 hours after symptom onset in all patients who present with ACS symptoms. The panelists recommended identifying rising and/or falling pattern of troponin.  In addition, they recommended measuring troponin levels beyond 6 hours after symptom onset in patients with normal troponins on serial examination when ECG changes and/or clinical presentation suggests ACS. If the onset of symptoms is not clearly identified, they recommended using the time of presentation as the time of onset for measuring troponin. The AHA/ACC guideline clearly highlighted that CKMB or myoglobin should not be used for the diagnosis of ACS. All recommendations for the use of cardiac biomarkers in the diagnosis of MI were level A evidence.  

The AHA/ACC guideline considered all recommendations in the use of cardiac biomarkers for ACS prognosis as level of evidence B. They considered the presence and magnitude of troponin elevations useful for short- and long-term prognosis. The re-measurement of troponin once on day 3 or day 4 in patients with MI was considered reasonable to estimate the infarct size and dynamics of necrosis. Finally, they considered the use of B-type natriuretic peptide to be reasonable for additional prognostic information.  

Table 2:  Summary of Recommendations for Cardiac Biomarkers and the Universal Definition of MI 

ACS indicates acute coronary syndromes; BNP, B-type natriuretic peptide; CK-MB, creatine kinase myocardial, isoenzyme; COR, Class of Recommendation; LOE, Level of Evidence; and MI, myocardial infarction.

The recommendations for the use of cardiac biomarkers in the diagnosis and prognosis of MI was well summarized in Table from 2014 AHA/ACC guidelines p.2655 (Amsterdam et al., 2014)

2013 (published 2014) Society for Cardiovascular Angiography and Interventions (SCAI) (Moussa et al., 2013) 
In their expert consensus document titled "Consideration of a New Definitions of Clinically Relevant Myocardial Infarction After Coronary Revascularization," the SCAI expert panel introduced a new definition of clinically relevant MI after coronary revascularization percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). In their definition of clinically relevant MI after both PCI and CABG procedures, authors gave recommendations according to 3 different types of clinical presentation. In the first case, when patient has a normal CKMB baseline: “The peak CK-MB measured within 48 hours of the procedure rises to > 10x the local laboratory ULN, or to > 5x ULN with new pathologic Q-waves in > 2 contiguous leads or new persistent LBBB, OR in the absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level measured within 48 hours of the PCI rises to > 70x the local laboratory ULN, or > 35x ULN with new pathologic Q-waves in > 2 contiguous leads or new persistent LBBB.” In the case when patients have elevated baseline CKMB (or cTn) with stable of falling biomarkers levels, they issued the following recommendation: “The CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above from the most recent pre-procedure level.” And, in patients with elevated CKMB (or cTn), but without stable or falling biomarkers level, the recommendation was: “The CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above plus new ST-segment elevation or depression plus signs consistent with a clinically relevant MI, such as new onset or worsening heart failure or sustained hypotension.” The authors have expressed preference to use CKMB instead of cTn, but they have included cTn in their definition if CKMB was not available.

2015 AHA Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care 
In their review of previously issued guidelines, the expert panel introduced new recommendations for diagnostic interventions in ACS regarding cardiac biomarkers. They still recommended to use Troponin in following situations: “We recommend against using hs-cTnT and cTnI alone measured at 0 and 2 hours (without performing clinical risk stratification) to identify patients at low risk for ACS (Class III: Harm, LOE B-NR). We recommend that hs-cTnI measurements that are less than the 99th percentile, measured at 0 and 2 hours, may be used together with low-risk stratification (TIMI score of 0 or 1 or low risk per Vancouver rule) to predict a less than 1% chance of 30-day MACE (Class IIa, LOE B-NR). We recommend that negative cTnI or cTnT measurements at 0 and between 3 and 6 hours may be used together with very low-risk stratification (TIMI score of 0, low-risk score per Vancouver rule, North American Chest Pain score of 0 and age less than 50 years, or low-risk HEART score) to predict a less than 1% chance of 30-day MACE (Class IIa, LOE B-NR).” They did not express a preference in cardiac biomarkers to use, nor did they gave any recommendations regarding CKMB (O’Connor Robert et al., 2015).

European Society of Cardiology (ESC) (Collet et al., 2021; Gencer et al., 2016; Knuuti et al., 2019) 
The ESC notes measurement of cardiac troponins as “mandatory” in all patients with suspected non-ST-elevation acute coronary syndromes. The guidelines assert that cardiac troponins are more sensitive and specific biomarkers of cardiomyocyte injury than CK, CKMB, and myoglobin. However, if troponin measurement is not possible, measurement of copeptin is recommended. 

The ESC also acknowledges the natriuretic peptides (B-type natriuretic peptide, N-terminal pro-B-type natriuretic peptide and midregional pro-A-type natriuretic peptide) as providing useful prognostic information along with the troponins. The ESC mentions other biomarkers such as midregional pro-adrenomedullin, growth differentiation factor 15 and copeptin, but they cannot recommend them at this time as their added value in risk assessment seems “marginal” (Gencer et al., 2016). 

The 2019 ESC guidelines focusing on chronic coronary syndromes states that for “clinical suspicion of coronary artery disease instability … management should follow the Guidelines for ACS without persistent ST-segment elevation”, which is discussed above (Knuuti et al., 2019). 

The 2021 ESC guidelines focus on diagnosis of acute coronary syndrome. In regard to MI, they recommend that “the routine use of copeptin as an additional biomarker for the early rule-out of MI should be considered where hs-cTn assays are not available.” In addition, “CK-MB shows a more rapid decline after MI and may provide added value for detection of early reinfarction (Collet et al., 2021).” 

ACC/AATS/AHA/ASE/ASNC/SCAI/ SCCT/STS 2016 Appropriate Use Criteria for Coronary Revascularization in Patients With Acute Coronary Syndromes Guidelines (Patel et al., 2016) 
In 2016, the American College of Cardiology (ACC), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Thoracic Surgeons (STS), and American Association for Thoracic Surgery (AATS), along with key specialty and subspecialty societies created an Appropriate Use Task Force with the mission to revise the appropriate use criteria (AUC) for coronary revascularization. They have used clinical scenarios to mimic patient presentations seen in everyday clinical practice and included information on symptom status, presence of clinical instability or ongoing ischemic symptoms and other characteristics. They follow 2014 AHA/ACC recommendations for the use of cardiac biomarkers (Amsterdam et al., 2014).

2017 International Liaison Committee on Resuscitation (ILCOR) Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary (Olasveengen et al., 2017).  
No recommendations were given regarding the use of cardiac markers.

American Society for Clinical Pathology (ASCP, 2015) 
The ASCP recommends against testing CK-MB or myoglobin to diagnose an acute myocardial infarction. Instead, they recommend testing either troponin I or T. They also assert that both troponins are specific to cardiac injury and that there is much support for relying solely on troponin (ASCP, 2015).

National Institute for Health and Care Excellence (NICE, 2016, 2020) 
NICE recommends diagnosis of MI using the “detection of rise and/or fall of cardiac biomarkers values [preferably cardiac troponin (cTn)] with at least one value above the 99th percentile of the upper reference limit and at least one of the following: 

• symptoms of ischaemia 
• new or presumed new significant ST‑segment‑T wave (ST‑T) changes or new left bundle branch block (LBBB) 
• development of pathological Q waves in the ECG 
• imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
• identification of an intracoronary thrombus by angiography” (NICE, 2016). 

In 2020, NICE released recommendations on the use of high sensitivity troponin tests to help rule out NSTEMI earlier in those presenting to an emergency department with chest pain and suspected acute coronary syndrome. NICE recommends the use of the following assays: Access High-Sensitivity Troponin I Assay, ADVIA Centaur High-Sensitivity Cardiac Troponin‑I Assay, Alinity High Sensitive Troponin‑I assay, ARCHITECT STAT High Sensitive Troponin‑I assay, Atellica IM High-Sensitivity Cardiac Troponin I Assay, Dimension Vista High-Sensitivity Cardiac Troponin I Assay, Dimension EXL High-Sensitivity Cardiac Troponin I Assay, Elecsys Troponin T-high sensitive assay, Elecsys Troponin T-high sensitive STAT assay, VIDAS High sensitive Troponin I assay, and VITROS High Sensitivity Troponin I Assay. NICE mentions that although the “TriageTrue test has the potential to be cost effective, its diagnostic accuracy when used on whole blood is uncertain (NICE, 2020).” Regarding use of these assays, NICE recommends using a threshold at or near the limit of detection, which varies depending on the assay used. If this sample is positive, it should not be used to rule in NSTEMI. If taking multiple samples, take a sample at initial assessment followed by a second sample taken 30 minutes to 3 hours after. Use 99th percentile thresholds or thresholds at or near the limit of detection of the assay (NICE, 2020).    

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Coding Section  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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