Populations	Interventions	Comparators	Outcomes
Individuals: · Who are being screened for coronary artery disease	Interventions of interest are: · Computerized 2-lead electrocardiogram analysis	Comparators of interest are: · Standard clinical workup	Relevant outcomes include: · Overall survival · Disease-specific survival · Test accuracy · Test validity · Morbid events

Background

The 12-lead resting electrocardiogram (ECG) analysis is a standard tool in the detection of acute cardiac ischemia, but has less accuracy for monitoring for chronic changes associated with coronary artery disease (CAD). Therefore, resting ECG has only a limited role in the diagnosis of chronic CAD. Stress testing, either at rest or with exercise, combined with single-photon emission computed tomography or echocardiographic imaging, is the most common initial test in the diagnostic workup of chronic CAD. Sensitivities and specificities for stress testing vary, but generally fall in the 75% to 90% range. Cardiac angiography is the criterion standard for diagnosing CAD and is used when CAD needs to be confirmed following stress testing.

The multifunction cardiogram is intended to improve on the performance of the standard ECG for diagnosing CAD. The study device records a 2-lead ECG tracing for 82 seconds, using leads II and V₅ together with proprietary hardware and software. The analogue ECG tracing is then amplified, digitized, down-sampled to a rate of 100 Hz, and encrypted for digital transmission. The digitized information is transmitted to a central server for analysis. At the central server, the tracings undergo a series of mathematical transformations and signal averaging. Six mathematical transformations are included: power spectrum, coherence, phase angle shift, impulse response, cross-correlation, and transfer function. Following these transformations, the patterns found in the tracing are compared with a large reference database collected by the manufacturer. A severity score is generated, indicating the likelihood that CAD is present. The severity score ranges from 0 to 20, with a score of 4.0 suggested as the threshold for the presence of clinically significant CAD.

Regulatory Status
There is at least 1 commercially available multifunction cardiogram. In 2003, the Premier Heart MCG™ system (Premier Heart, Port Washington, NY) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. FDA determined that this device was substantially equivalent to existing devices for use in electrocardiogram analysis.

Related Policies

• None

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was originally created 2011 and has been updated regularly with searches of the PubMed database. The most recent literature review was performed through April 30, 2018.

Assessment of a diagnostic technology typically focuses on 3 categories of evidence: (1) its technical performance (test-retest reliability or interrater reliability); (2) diagnostic accuracy (sensitivity, specificity, and positive and negative predictive value) in relevant populations of patients; and (3) clinical utility (ie, a demonstration that the diagnostic information can be used to improve patient outcomes). The following is a summary of the key literature to date.

Electrocardiogram Analysis for Diagnosis of Coronary Artery Disease

Clinical Context and Proposed Clinical Utility
The proposed clinical utility of computerized 2-lead resting electrocardiogram (ECG) analysis evaluated in this review is to improve the accuracy of coronary artery disease (CAD) screening and to identify those patients who would benefit from coronary artery intervention.

The current standard intervention is a clinical workup, which includes physical examination, family history-taking, risk score calculation, and stress testing with or without additional imaging. Standard 12-lead resting ECGs have limited diagnostic accuracy in asymptomatic patients. Thus, an objective test that can improve on the accuracy of the standard clinical workup could be clinically beneficial.

The question addressed in this policy is: In individuals being screened for CAD, does use of computerized 2-lead resting ECG analysis improve the identification of patients who would benefit from a medical or surgical coronary artery intervention and/or lead to improved health outcomes compared with a standard clinical workup?

The following PICOTS was used to select literature to inform this review.

Patients
The relevant population of interest is patients being screened for CAD.

Interventions
The intervention of interest is computerized 2-lead resting ECG analysis.

Comparators
The comparator of interest is a standard clinical workup including physical examination, family history-taking, risk score calculation, and stress testing with or without additional imaging.

Outcomes
The primary outcomes of interest are overall survival (ie, reduction in the rate of sudden cardiac death) and morbid events (eg, myocardial infarction). Other outcomes of interest are test accuracy and validity.

Timing
Because patients are asymptomatic, longer term outcome measurement would be appropriate (eg, assessing morbid events and overall survival after 6 months, 1 year, or longer).

Setting
Patients would be tested in the nonacute primary care or specialty care (eg, cardiology) setting.

Technical Performance
No specific studies of technical performance were identified.

Diagnostic Accuracy

Systematic Reviews
A systematic review and meta-analysis was published by Strobeck et al (2009).¹ This combined analysis included 44 diagnostic accuracy studies (total N=1076 patients). Hemodynamically significant CAD was diagnosed in 43.4% (467/1076) of patients. The calculated sensitivity and specificity of the multifunction cardiograms were 91.2% and 84.6%, respectively. The positive predictive value (PPV) was 78% and the negative predictive value (NPV) was 94%. The area under the curve (AUC) by receiver operating characteristic (ROC) analysis was 88.1% (95% confidence interval [CI], 86% to 90.3%). Using a severity score of 4.0 as the cutoff for a positive test, the positive likelihood ratio was 5.9, and the negative likelihood ratio was 0.10. There were only minor differences across participating centers in the sensitivity and specificity; the statistical significance of these differences was not tested.

Diagnostic Accuracy Studies
Grube et al (2007) published the largest study on the accuracy of the multifunction cardiogram for diagnosing CAD.² The study population consisted of 562 patients with no history of coronary revascularization who were scheduled to receive coronary angiography over a 1-year period at 1 institution in Germany. All patients underwent multifunction cardiogram and coronary angiography, with results of each modality interpreted independently and blinding of the results of the other test(s). A total of 139 (24.7% of total) patients were excluded from analysis; 17 because of poor-quality ECG tracing and 122 because full risk-factor data were not available, leaving 423 patients in the final analysis. Obstructive coronary disease, defined as at least 1 stenosis greater than 70%, was diagnosed in 47.5% (201/423) of patients. Multifunction cardiograms in this group had a reported sensitivity of 89.1% and a specificity of 81.1%; the PPV was 79% and the NPV was 90%. The calculated AUC by ROC analysis was 84.3% (95% CI, 80.2% to 88.4%).

Grube et al (2008) also published a companion article on 213 patients scheduled for angiography who had previously undergone revascularization.³ The protocol and analysis for this study was identical to the earlier article, except for the presence or absence of prior revascularization. A total of 41 patients were excluded from analysis, leaving a final sample of 172 patients. In this sample, obstructive coronary disease, defined as at least 1 stenosis greater than 70%, was diagnosed in 32% (55/172) of patients. The estimated sensitivity and specificity were 90.9% and 88.0%, respectively. The PPV was 62.7% and the NPV was 97.8%.

Weiss et al (2002) assessed 200 ambulatory patients scheduled for coronary angiography at 1 institution in New York.⁴ All patients underwent multifunction cardiogram; however, 64 (32% of total) patients had ECG tracings of insufficient quality and were excluded from analysis, leaving 136 patients in the final sample. The authors did not state whether the test results were interpreted in an independent and blinded manner. Obstructive coronary disease, defined as at least 1 stenosis greater than 70%, was diagnosed in 57.4% (78/136) of patients. The reported sensitivity and specificity of multifunction cardiogram were 93.3% and 83%, respectively. The PPV was 91.2%, and the NPV was 86.7%. The calculated AUC by ROC analysis was not reported.

Hosokawa et al (2008) enrolled 222 patients who were scheduled to receive coronary angiography over a 6-month period at 5 medical centers in Asia.⁵ All patients underwent multifunction cardiogram and coronary angiography, with results of each modality interpreted independently and blinded to the results of the other test(s). A total of 33 (14.9% of total) patients were excluded from analysis, 3 because of poor-quality ECG tracing and 30 because coronary angiograms were not available for interpretation, leaving 189 patients in the final analysis. Obstructive coronary disease, defined as at least 1 stenosis greater than 60%, was diagnosed in 40.7% (77/189) of patients. The reported sensitivity and specificity of multifunction cardiogram were 94.8% and 86.6%, respectively. The PPV was 78.4% and the NPV was 97.1%. The calculated AUC by ROC analysis was 91.4% (95% CI, 86.8% to 96.1%).

The 4 studies described above were included in the systematic review by Strobeck et al. Three other relevant studies have been published since that time. In 2011, Strobeck et al compared the accuracy of the multifunction cardiogram to single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) using angiography as the criterion standard.⁶ This study enrolled 165 consecutive patients with known or suspected CAD and/or valvular heart disease who agreed to participate. Of the 165 patients, 49 did not undergo angiography due to a normal SPECT exam and no other indications for angiography; of these, 8% (4/49 patients) had an abnormal computerized 2-lead ECG test. These patients were excluded from further analysis, leaving 116 patients who received all 3 tests (computerized 2-lead resting ECG, SPECT MPI, angiography). The sensitivity and specificity of the computerized 2-lead resting ECG were 91% (95% CI, 79% to 97%) and 87% (95% CI, 76% to 94%), respectively, compared with a sensitivity of 85% (95% CI, 72% to 93%) and a specificity of 14% (95% CI, 7% to 25%) for SPECT MPI. Subgroup analyses revealed similar accuracy by sex, severity of coronary obstruction, and age. The specificity for SPECT MPI in this study was markedly lower than that reported previously. In a recent meta-analysis of 13 studies (total N=1323 subjects), the pooled estimate for the specificity of SPECT was 77% (95% CI, 64% to 86%) and the pooled sensitivity was 83% (95% CI, 81% to 91%).⁷ The reduced specificity reported in the Strobeck study might have been related to the performance of angiography in patients with valvular disease, because these patients might have had higher rates of false-positive SPECT exams than patients with suspected ischemia.

Two smaller studies of diagnostic accuracy were published in 2014 and 2015.^8,9 They enrolled 100 and 112 patients, respectively, who were scheduled to undergo coronary angiography. In both, individuals interpreting the computerized 2-lead resting ECG were independent and blinded to the results of angiography. In 1 study, the reported specificity of computerized 2-lead resting ECG was high (90.4%; 95% CI, 87.0% to 93.9%), and the sensitivity was lower (48.1%; 95% CI, 38.5% to 57.8%), with an NPV of 82.5% (95% CI, 78.3% to 86.7%). In the other study, the reported specificity (67%) and sensitivity (32%) for functional ischemia were lower, with an NPV of 57%.

Section Summary: Diagnostic Accuracy
There are a number of diagnostic accuracy studies and a 2009 systematic review. The systematic review found a calculated sensitivity of 91.2% and specificity of 84.6%. However, most published studies have methodologic limitations that reduce their internal validity. In all but one, the population was a convenience sample of patients who underwent angiography. These patient populations are thus subject to a referral or “workup” bias in that the population of patients that might be considered for the computerized 2-lead resting ECG in clinical practice are not the same population being referred for angiography. Also, the number of patients enrolled but not included in the analysis was relatively high, ranging from 14.9% to 32% of the total number of enrollees. These high rates of exclusion raise the potential for biased estimates of test sensitivity and specificity. Finally, in 1 cohort, angiogram and multifunction cardiogram results were not interpreted in an independent and blinded manner. These methodologic limitations create a substantial degree of uncertainty regarding the reported results for diagnostic accuracy.

Clinical Utility
There were no published articles that directly addressed the clinical utility of a computerized 2-lead resting ECG. The impact of this technology on patient management decisions is uncertain. While it is possible that the results of this test may influence patient management (eg, decisions to perform angiography), the evidence on this question is incomplete. As a result, clinical utility has not been demonstrated and the impact on health outcomes is unknown.

Section Summary: Clinical Utility
No published studies were identified that demonstrated how computerized 2-lead resting ECG analysis can be used to change clinical management in ways that improve health outcomes. Moreover, given the uncertainties in the diagnostic accuracy of this technology and how it might be incorporated into clinical practice, a chain of evidence demonstrating potential clinical utility is unavailable.

Summary of Evidence
For individuals who are being screened for coronary artery disease (CAD) with computerized 2-lead electrocardiogram analysis, the evidence includes several diagnostic accuracy studies and a systematic review. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, and morbid events. The systematic review found a calculated sensitivity and specificity of 91.2% and 84.6%, respectively. However, studies included in the systematic review had several methodologic limitations that reduced their internal validity. For example, they used convenience samples and had high rates of participants exclusion from analyses. These methodologic limitations create a substantial degree of uncertainty concerning the reported results for diagnostic accuracy. The clinical utility of the technology is also uncertain. Even if this test has good accuracy for diagnosing CAD, its application in clinical practice would still need to be determined. Use of the computerized 2-lead electrocardiogram analysis to screen for CAD would depart from usual practice, because screening for CAD has not been shown to improve outcomes. In the nonacute setting, the most common method for diagnosing CAD is stress testing, and there is no evidence comparing the diagnostic accuracy of computerized 2-lead electrocardiogram analysis with stress testing. The evidence is insufficient to determine the effects of the technology on health outcomes.

Supplemental Information

Practice Guidelines and Position Statements
No guidelines or statements were identified.

U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for computerized 2-lead resting electrocardiogram analysis in patients being screened for coronary artery disease have been identified.

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in April 2019 did not identify any ongoing or unpublished trials that would likely influence this review.]

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Computerized 2-Lead Resting Electrocardiogram Analysis for the Diagnosis of Coronary Artery Disease
Multifunction Cardiogram
3DMP Device
Premier Heart 3DMP Device

References:
1. Strobeck JE, Shen JT, Singh B, et al. Comparison of a two-lead, computerized, resting ECG signal analysis device, the MultiFunction-CardioGram or MCG (a.k.a. 3DMP), to quantitative coronary angiography for the detection of relevant coronary artery stenosis (>70%) - a meta-analysis of all published trials performed and analyzed in the US. Int J Med Sci. 2009;6(4):143-155. PMID 19381351

2. Grube E, Bootsveld A, Yuecel S, et al. Computerized two-lead resting ECG analysis for the detection of coronary artery stenosis. Int J Med Sci. 2007;4(5):249-263. PMID 18026565

3. Grube E, Bootsveld A, Buellesfeld L, et al. Computerized two-lead resting ECG analysis for the detection of coronary artery stenosis after coronary revascularization. Int J Med Sci. 2008;5(2):50-61. PMID 18345283

4. Weiss MB, Narasimhadevara SM, Feng GQ, et al. Computer-enhanced frequency-domain and 12-lead electrocardiography accurately detect abnormalities consistent with obstructive and nonobstructive coronary artery disease. Heart Dis. Jan-Feb 2002;4(1):2-12. PMID 11975826

5. Hosokawa J, Shen JT, Imhoff M. Computerized 2-lead resting ECG analysis for the detection of relevant coronary artery stenosis in comparison with angiographic findings. Congest Heart Fail. Sep-Oct 2008;14(5):251-260. PMID 18983288

6. Strobeck JE, Mangieri A, Rainford N. A paired-comparision of the Multifunction Cardiogram (MCG) and sestamibi SPECT myocardial perfusion imaging (MPI) to quantitative coronary angiography for the detection of relevant coronary artery obstruction (>/=70%) - a single-center study of 116 consecutive patients referred for coronary angiography. Int J Med Sci. 2011;8(8):717-724. PMID 22135619

7. de Jong MC, Genders TS, van Geuns RJ, et al. Diagnostic performance of stress myocardial perfusion imaging for coronary artery disease: a systematic review and meta-analysis. Eur Radiol. Sep 2012;22(9):1881-1895. PMID 22527375

8. Amano T, Shinoda N, Kunimura A, et al. Non-invasive assessment of functionally significant coronary stenoses through mathematical analysis of spectral ECG components. Open Heart. 2014;1(1):e000144. PMID 25469309

9. Kawaji T, Shiomi H, Morimoto T, et al. Noninvasive detection of functional myocardial ischemia: Multifunction Cardiogram Evaluation in Diagnosis of Functional Coronary Ischemia Study (MED-FIT). Ann Noninvasive Electrocardiol. Sep 2015;20(5):446-453. PMID 25594689

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*