**_Overview_**

This is a coverage policy for contrast (also known as ultrasound enhancing
agent) administration for purposes of echocardiographic myocardial perfusion
evaluation.

Decades of work have been invested in the refinement of microbubble technology
for ultrasound enhancing agents. Much focus has also been brought to bear on
optimization of echocardiographic settings, software and hardware to
facilitate this technology. Huge advances have been made over these many
years.

Commercially available ultrasound enhancing agents (UEAs) that are approved
for use by the United States FDA are composed of encapsulated microbubbles.
The use of these microbubbles is based on their ability to undergo volumetric
oscillation in the pressure fluctuations of the ultrasound field. Microbubble
vibration can occur without compromise of its integrity (stable cavitation) or
can be accompanied by either sudden or gradual destruction from exaggerated
non-linear oscillation when ultrasound is delivered at high ultrasound
pressure amplitude. This process allows for a strong acoustic signature that
can be separated from tissue with specially designed and commercially
available imaging protocols.

There are currently 3 UEAs approved by the FDA. The only FDA-approved use in
cardiovascular disease is for left ventricular opacification (LVO) using IV
injections. LVO is used to better define endocardial borders when accurate
dimensions and volumes cannot be readily obtained because of the poor quality
of endocardial visualization. Suboptimal images limit unenhanced
echocardiographic interpretation in a substantial percentage of studies.

Many off-label uses for UEAs exist and have been investigated for years. These
uses include, but are not limited to, applications related to myocardial
perfusion and viability. This LCD addresses the issue of coverage for some of
these off-label uses.

**_Noncovered Services_**

  * Use of non-FDA approved ultrasound enhancing agents
  * The administration of ultrasound enhancing agents for myocardial perfusion evaluation strictly for screening purposes

**Myocardial Perfusion**

****

A study was done to prospectively compare patient outcomes after
echocardiography for simultaneous myocardial perfusion and wall motion
analysis (also called real-time myocardial contrast echocardiography-RTMCE)
and conventional stress echocardiography. There had been no other prospective
randomized studies prior to this one looking at this issue. The authors for
this study looked to determine whether the differences in the test led to
differences in the rate of angiography and revascularization, as well as
predicting death. The patients were recruited from consecutive patients coming
to the University of Nebraska Medical Center echo lab between 2007 and 2011
who had intermediate to high pre-test probability for coronary artery disease
(CAD). This included patients hospitalized for chest pain. Mean age for study
patients was 60 with a nearly equal male:female ratio. Follow up was captured
for 2,014 patients for a median of 2.6 years. An abnormal myocardial
perfusion/stress ECHO (RTMCE) occurred more often than an abnormal
conventional stress echo (p < 0.001) and also resulted more often in
revascularization (p=0.004). Resting wall motion abnormalities were more often
seen with RTMCE (p < 0.01) and were an independent predictor of death/nonfatal
myocardial infarction (MI) (p=0.005) for RTMCE but not for conventional stress
echo. The conclusion was that perfusion imaging with RTMCE improved the
detection of CAD during stress echocardiograms and identified those more
likely to undergo revascularization following an abnormal study.1

In a 1997 study, 28 patients were given a single IV injection of an ultrasound
enhancing agent and then harmonic transient response imaging was used to view
the heart in multiple different imaging planes. Perfusion abnormalities were
evident in the secondary and tertiary views only with 1 frame every multiple
cardiac cycles. The conclusion was that an enhancing agent could accurately
identify regional myocardial perfusion abnormalities. Sensitivity of 92% was
noted and specificity of 84%.2

In 2001, a comparative study was done to examine the feasibility and accuracy
of RTMCE in detecting abnormal myocardial perfusion during an exercise echo
compared with radionuclide tomography. One hundred patients (2:1 men:women
with median age of 57) with intermediate to high CAD probability underwent
exercise echocardiography and had segmental perfusion assessed in real time
before the test and at peak exercise using low mechanical index (0.3) and 0.3
mL bolus injections of the enhancing agent. All patients had rest thallium,
stress sestamibi studies done during the same exercise. Forty-four of these
patients had subsequent coronary angiography. Compared with angiography,
sensitivity of RTMCE and tomography was comparable (75%) with a specificity
ranging from 81-100%. The combination of RTMCE and wall motion had the best
matching between sensitivity and specificity at 86% and 88% respectively with
the highest accuracy (86%). The conclusions were described as "promising" with
regard to adding RTMCE to conventional stress echo.3

One of the more recent large studies (2013), a large European multicenter
study by Senior et al. was performed to compare microbubble enhanced
myocardial contrast echocardiography with single-photon emission computed
tomography (SPECT) relative to coronary angiography for assessment of coronary
artery disease (CAD). Thirty-four centers were involved in this study and 628
total patients were included. The patients studied included 71% males and the
mean age for the patients was 64 years. Ninety-nine percent of the patients
had more than 1 cardiovascular risk factor. The methodology intent for this
study was for the patients to undergo myocardial contrast echocardiogram (MCE)
with an ultrasound enhancing microbubble agent, standard SPECT and
quantitative coronary angiography within a 1-month time frame. The myocardial
ischemia assessments were made by 3 independent, blind readers for MCE and 3
readers for SPECT with the majority agreement for each prevailing, and
therefore, collapsed to 1 diagnosis per patient per technique and compared to
coronary angiography which was read by 1 independent blinded reader. Of the
628 total patients, 516 underwent all 3 examinations. One hundred sixty-one
(31%) had _>_ 70% stenosis. One hundred thirty-one had single vessel disease
and 30 had multi-vessel disease. Three hundred ten of these 516 patients (60%)
had _>_ 50% stenosis identified. Higher sensitivity was obtained with MCE than
with SPECT, 75% vs. 49%; p < 0.0001. Specificity though was lower for MCE, 52%
vs. 81%, p < 0.0001 for coronary artery stenosis _>_ 70%. These findings were
similar for patients with _>_ 50%.4

The authors of this study did postulate that a contribution to the lower
specificity of myocardial contrast echocardiography (MCE) may have been
related to its sensitivity for microvascular disease. Microvascular disease
was felt to likely be quite high in this study population. The authors
admitted that single-center studies had often shown much better sensitivity
and specificity for both MCE and SPECT testing. They suggested the possible
role played by readers of the imaging who were completely unaware of
individual patient characteristics which may have driven the lower sensitivity
and specificity values. The authors also noted reader reproducibility issues
were commonly seen in other studies as well. Lastly, the authors felt that
fractional flow reserve with angiography would have provided better
information, but it was unavailable at the time.

The Journal of the American Society of Echocardiography published a
prospective randomized comparison in 2012 which compared the myocardial
perfusion and wall motion analysis of real time MCE with conventional stress
echocardiography. One thousand seven hundred seventy-six patients with
suspicion of CAD were randomized to either non-RTMCE, for which contrast was
used only as approved for the indication of enhancing left ventricular
opacification, or RTMCE, for which UEA infusion was used in all cases to
examine both wall motion and myocardial perfusion. Results showed that the
patients randomized to RTMCE had significantly higher test positivity (22% for
RTMCE vs 15% with non-RTMCE, P = 0.0002). The increased test positivity
occurred without a difference in positive predictive value in predicting >50%
diameter stenoses by coronary angiography (67% for non-RTMCE, 73% for RTMCE).
Overall, the conclusion was that ultrasound enhancement for myocardial
perfusion during a stress echo with dobutamine or exercise did improve the
detection of CAD and that was mostly due to the detection of subendocardial
wall thickening abnormalities that would have otherwise gone undetected.5

A large meta-analysis examined the prognostic value of myocardial perfusion
imaging during contrast stress echocardiography in patients with known or
suspected CAD. Conducted through May 2019, it encompassed 12 studies-7
dipyridamole and 5 exercise/dobutamine which had enrolled 5953 total patients,
47% female, for whom 8-80 months of follow-up occurred. Hazard ratios (HRs)
revealed that a perfusion abnormality [pooled HR 4.75; 95% confidence interval
(CI) 2.47-9.14] was a higher independent predictor of total events than
abnormal wall motion (WM, pooled HR 2.39; 95% CI 1.58-3.61) and resting left
ventricular ejection fraction (LVEF, pooled HR 1.92; 95% CI 1.44-2.55) with
significant subgroup differences (P=0.002 compared with abnormal WM and 0.01
compared with abnormal LVEF). Abnormal myocardial perfusion was associated
with higher risks for death [Risk ratio (RR) 5.24; 95% CI 2.91-9.43], non-
fatal MI (RR 3.09; 95% CI 1.84-5.21) and need for coronary revascularization
(RR 16.44; 95% CI 6.14-43.99). The authors concluded that myocardial perfusion
analysis during stress echocardiography was an effective tool for prognosis in
patients known or suspected to have coronary artery disease. They also felt
the perfusion analysis added value to just LVEF or wall motion assessment in
predicting clinical outcomes.6

Utilization of imaging in an emergency department context regarding risk-
stratification for patients presenting with chest pain has also been an area
of interest. Specifically, the ability to be able to assess both myocardial
perfusion and regional function has often been theorized to provide
incremental value over routine clinical and EKG evaluation within the ED. A
study in 2004 looked at this issue. One thousand seventeen patients were
studied, mean age 60, 53% male. Contrast echocardiography was performed in the
ED with evaluation of regional function and myocardial perfusion. On follow
up, 16.3% of the patients had early events (within 48 hours) such as death,
acute MI, unstable angina, heart failure or revascularization. The addition of
regional function analysis increased the prognostic information significantly
(Bonferroni corrected P < 0.0001) for predicting these events. With myocardial
perfusion added, significant prognostic information was also obtained
(Bonferroni corrected P=0.0002). All these patients were followed for a median
of 7.7 months and 28.7% had events. Adding regional function increased the
ability to determine that risk significantly (Bonferroni corrected P <
0.0001), which was further increased by adding myocardial perfusion
(Bonferroni corrected P < 0.0001). Overall, adding both regional function and
myocardial perfusion evaluation provided significant value and indicated
enhanced echocardiography could be a valuable tool for early triage and
management in an ED setting with chest pain patients.7

Looking at post MI residual myocardial viability, a study was done to
determine how well MCE predicted hard cardiac events. Ninety-nine stable
patients underwent low-power MCE at 7 +/- 2 days after acute myocardial
infarction (AMI). Contrast defect index (CDI) was obtained by adding contrast
scores (1 = homogenous; 2 = reduced; 3 = minimal/absent opacification) in all
16 left ventricular (LV) segments divided by 16. At discharge, 68% of these
patients had either undergone or were scheduled for revascularization. The
patients were then followed for cardiac death and nonfatal AMI. Of the 99
patients, 95 were followed up. During the follow-up time of 46 +/- 16 months,
there were 15 (16%) events (8 cardiac deaths and 7 nonfatal AMIs). Amongst
several markers of prognosis, the extent of residual myocardial viability was
an independent predictor of cardiac death (p = 0.01) and cardiac death or AMI
(p = 0.002). A CDI of < or = 1.86 and < or = 1.67 predicted survival and
survival or absence of recurrent AMI in 99% and 95% of the patients,
respectively. The conclusion was made that the extent of residual myocardial
viability predicted by MCE was a powerful independent predictor of hard
cardiac events after AMI.8

In an earlier 2001 study, the issue of LV dysfunction after MI secondary to
stunning and necrosis was considered. Thirty-four patients with recent MI and
known residual wall motion abnormalities related to the infarct-related artery
were examined to see if normal perfusion by myocardial contrast
echocardiography (MCE) would accurately predict recovery of segmental left
ventricular (LV) function. Each patient after a recent MI underwent baseline
wall motion assessment and then had MCE 2 days after admission with follow-up
echocardiography a mean of 55 days later. Results showed that perfusion by MCE
predicted recovery of segmental function with a sensitivity of 77%,
specificity of 83%, positive predictive value of 90% and overall accuracy of
79%. The mean wall motion score at follow-up was significantly better in
perfused, compared with nonperfused, segments (1.4 vs. 2.2, p < 0.0001).
Additionally, 90% of perfused segments improved, while the majority of
nonperfused segments remained unchanged. The authors felt that MCE, by
identifying stunned myocardium, could accurately predict recovery of segmental
LV function in patients with recent MI.9



The analysis of evidence for this LCD is a challenge. A large quantity of
evidence-based literature, usually such a benefit, has instead presented a
quandary when viewed over many years and with many intervening and evolving
aspects to the technology and associated equipment and performance skill sets.

The paradigm of ischemic heart disease has seen an ongoing shift away from a
sole relationship between myocardial ischemia and obstructive epicardial
coronary artery disease toward more attention dedicated to the possible role
of anatomic and functional abnormalities of the coronary microcirculation.
This fact must be considered in coverage determinations related to the
emerging technology related to coronary microvasculature functional
assessments.10

There has been long-standing, great hope that echocardiography utilizing
ultrasound enhancing agents would be a valuable tool in the diagnostic arena
for myocardial perfusion purposes. This is especially true given the fact that
it can be employed relatively quickly-even at bedside, is radiation free, is
economically advantageous, and offers its information in real time.11

However, part of the challenge of this data analysis lies in the fact that
this technology has existed for decades. A multitude of single center studies
and observational reports have shown impressive sensitivity/specificity
results for myocardial perfusion via enhanced echocardiography. However,
smaller numbers of larger scale, multicenter studies have not consistently
replicated some of the impressive results, particularly regarding specificity.

The analysis per this A/B MAC seems to suggest that any claim to defined,
replicable superiority is difficult to achieve for any type of cardiac imaging
in terms of myocardial perfusion accuracy. However, it is also fair to say
that no substantial number of studies has noted significant inferiority for
myocardial perfusion evaluation via enhanced echocardiography. Despite years
of trying to prove delineated superiority for echocardiographic myocardial
perfusion, the weight of collective results so far seems to largely suggest no
concerning inferiority such that no collective health benefit would be
achieved. To utilize echocardiography for accurate wall motion assessment
often requires ultrasound enhancing agents to delineate the endocardial
border. Expansion of this approach to employ appropriate harmonic imaging with
mechanical indices to allow use of the enhancing agent to assess myocardial
blood flow does not appear to cause harm or to significantly increase cost and
could offer very valuable prognostic and diagnostic information for
appropriate patients with known or suspected coronary artery disease with or
without the additional concerns of myocardial viability. In short, there does
not appear to be a particularly compelling reason to deny coverage for
myocardial perfusion measurement in patients at risk for or known to have CAD.

At this juncture in time, the current landscape of available non-invasive
cardiac imaging modalities remains complicated. Exercise electrocardiography
is used except for patients who are unable to exercise adequately and/or have
uninterpretable electrocardiograms. SPECT myocardial perfusion imaging has
become the reference standard, but requires radiation, has poor spatial and
temporal resolution, and remains expensive, non-portable, and not always
available in timely fashion. Coronary computed tomography angiography only
provides anatomical delineation, and the functional significance of stenosis
has required additional costly fractional flow reserve measurements or
additional functional and anatomic studies. Stress cardiovascular magnetic
resonance (CMR) shows good sensitivity and specificity even though it is not
yet widely available, is time consuming, and may be contraindicated in
patients with previous metallic implants or decreased renal function.
Myocardial perfusion assessment, in this landscape, has a role for potentially
improving not only the detection of CAD but also predicting outcome, all while
potentially containing costs.

Therefore, this A/B MAC has made the decision not to allow the lack of FDA
approval for myocardial perfusion indications as a sole or absolute reason not
to provide coverage for clinically valid off label uses in a patient
population that could benefit greatly.

This A/B MAC does believe there will be ongoing refinements and research
related to microbubble technology and the relationship to mechanical index
destruction with replenishment flow for purposes of myocardial perfusion
evaluation. Monitoring of this evidence will continue, and revisions will be
made to the local coverage determination if needed.