Summary Of Evidence

Coverage Determinations according to IOM 100-04 Medicare Program Integrity Manual, Chapter 13 – Local Coverage Determinations and Change Request 10901, effective 01/08/2019, are listed below.

0042T
Cerebral perfusion analysis using computed tomography with contrast administration, including post-processing of parametric maps with determination of cerebral blood flow, cerebral blood volume, and mean transit time

Computed Tomographic Perfusion (CTP) (using automated post-processing software algorithmic analysis) is medically reasonable and necessary in patients with acute ischemic stroke (AIS) caused by unilateral large vessel occlusion (LVO) in the proximal anterior circulation evaluated at stroke centers, to aid in selection for endovascular mechanical thrombectomy (EVT) if all of the following conditions are fulfilled:

1. Intracranial internal carotid artery (ICA) OR middle cerebral artery (MCA) occlusion
2. The medical record documents the patient is being considered for endovascular mechanical thrombectomy (EVT) and does not have contraindications to the EVT (based on DAWN or DEFUSE3 trial criteria)
3. Treatment (femoral puncture) can be started within 6-24 hours of the last time known to be at neurologic baseline

Computed Tomographic Perfusion (CTP) accuracy: A 2020 systematic review aimed to evaluate the diagnostic accuracy of CTP in the prediction of hemorrhagic transformation and patient outcome in AIS reported CTP sensitivity as 85.9%, specificity of 73.9%, positive predictive value 60.3% and negative predictive value of 92.9%.¹¹ A 2017 systematic review identified 27 studies with a total of 2168 patients. The pooled sensitivity of CTP for acute ischemic stroke was 82% (95% CI 75–88%), and the specificity was 96% (95% CI 89–99%). They determined CTP was more sensitive than Non-contrast Computerized Tomography (NCCT) and had a similar accuracy with Computed tomography angiography (CTA), but also that the evidence was not strong, and there is a need for high-quality evidence to confirm results.¹⁸ Older systematic reviews report mixed results with a wide range in sensitivity and specificity of CTP for detection of acute ischemic stroke (AIS).¹⁸ A 2019 systematic review and meta-analysis comparing imaging modalities for evaluation of AIS concludes that while CTP was more accurate than NCCT for detection of AIS, it was less accurate than diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) (sensitivity 82%, specificity 96% vs. sensitivity 15-86%, specificity 100%, respectively).¹⁹ DWI is considered the gold standard for imaging diagnosis of acute ischemia and more accurate than NCCT, CTA, and CTP to estimate or infer the size of core and penumbra.²⁰ However, NCCT is considered the current standard for stoke evaluation as MRI use in emergency settings may be limited, as well as several contradictions for MRI.²¹ Most studies evaluated in these systematic reviews were retrospective with variability in inclusion and exclusion criteria, outcomes reported, and sampling procedures, which introduces a high risk for bias, heterogenicity, and overall reduced quality of evidence. The evidence for routine use of CTP for evaluation for AIS is low quality and there is a need for high-quality evidence to determine the role it may play in AIS evaluation.

Hemorrhagic transformation (HT) zone: 2020 systematic review reported prediction of the HT could guide decision making in regard to consideration at thrombolysis decision point and concludes CTP is a useful prognostic tool for clinicians at the point of intervention decision making for AIS.¹¹ This review, however, consisting of three prospective and nine retrospective studies, is subject to inaccuracy given the risk of bias and a high degree of heterogenicity in the selected studies. Another small retrospective study with 46 patients who received recanalization therapy also concluded usefulness in CTP as a predictor of HT.²² On the contrary, a large prospective trial with 545 patients treated with IV tPA or thrombectomy had CTP at admission, and day three follow-up looked at the ability of the technology to predict HT (by measurement of the blood brain barrier permeability (BBBP). While univariate analysis associated BBBP measured by CTP as an independent predictor of HT, the multivariant analysis did not reproduce those findings, and the addition of BBBP as a variable did not change the AUC (0.77, 95% CI 0.71–0.83) of the model. The authors concluded BBBP measured by CTP did not improve prediction of HT, and improvements are needed before being considered “a useful addition to decision making”.²³ At this point, there are mixed results, lack of high-quality data, and lack of standardized scoring to determine treatment threshold to support the use of CTP for prediction of HT zone.

Evaluation for Endovascular mechanical thrombectomy (EVT): There are two level I randomized controlled trials (RCTs), which both conclude CTP is useful in determining eligibility for EVT in the late time period (6-24 hr.) of an acute (<24 hr.) ischemic stroke (AIS). The DAWN trial (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) studied whether patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late EVT.⁸ Their protocol included stringent inclusion and exclusion criteria. All patients had evidence of occlusion in internal carotid artery (ICA) with computed tomography (CT) or MRI imaging with CTP or DWI to determine infarct volume. Patients were randomly assigned to EVT plus standard medical management (MM) (N=107, mean age 69.4 yr.) or to MM alone (N=99, mean age 70.7 yr.). Median National Institutes of Health Stroke Scale (NIHSS) score was 17 (moderate to severe stroke) for both groups. The trial was stopped for efficacy at the first interim analysis. At 90 days, the rate of functional independence, as defined by a score of 0-2 on the modified Rankin scale (mRS) of 0-6, was greater for EVT than MM (49% versus 13%; adjusted difference, 33%; 95% CI, 21–44; posterior probability of superiority >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the EVT group and 3% in the MM group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00).

The DEFUSE 3 trial (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) was a multicenter, randomized, open-label trial randomizing patient with occlusion in the ICA or middle cerebral artery (MCA) based on computed tomography angiography (CTA) or magnetic resonance angiogram (MRA). Perfusion study with CTP or MRI diffusion was used to determine perfusion-core mismatch and maximum core size as imaging criteria to select patients for late EVT.³ Patients were randomly assigned to EVT plus standard MM or standard MM alone. The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (EVT N=92, median age 70; MM N=90, median age 71). The median NIHSS score was 16 (moderate to severe stroke) for both groups. The EVT group showed a benefit in functional outcome at 90 days (mRS score 0–2, 44.6% versus 16.7%; RR, 2.67; 95% CI, 1.60–4.48; P<0.0001). The 90-day mortality rate trended in favor of EVT (14% vs. 26% (P=0.05)), and there was no significant difference between groups in the rate of symptomatic intracranial hemorrhage (7% and 4%) or serious adverse events (43% and 53%). In a subgroup analysis, both the favorable outcome rate and treatment effect did not decline in transfer patients compared to direct-admission patients.²⁴

Both trials were designed to assess the effectiveness of EVT within 6-24 hours, but also provided evidence on the utility of CTP for aiding in management decisions. A subsequent prospective review²⁵ and retrospective registry²⁶ analysis also support the value of CTP in late period EVT eligibility assessment.

While DWI is considered the gold standard, CTP has the advantage of more availability, faster acquisition, and a similar estimate of mismatch, therefore becoming the dominant advanced imaging tool for identifying the core and penumbra.²⁰ CTP was used as an acceptable modality for triage for EVT in both the DAWN and DEFUSE3 studies and appear to be useful in aiding patient selection for thrombectomy (risk ratio for functional independence at day 90 was CPT 2.50, 95%CI: 1.32 to 4.75 and MRI 3.17, 95%CI: 1.35 to 7.43).^21,27 Results, however, must still be interpreted with caution. A 2020 retrospective study that evaluated patients undergoing CTP for EVT triage included 176 consecutive patients undergoing CTP and CTA. Automated calculations were performed with proprietary software, and failures were reprocessed manually. The primary outcome was postprocessing failure, defined as the presence of perfusion abnormalities caused by artifact and verified on follow-up images, and was reported in 11% of cases (20/176). Causes included severe motion, streak artifact, and poor arrival of contrast. Half of the failures (n=6) led to erroneous ischemic core volumes that may have resulted in different treatment decisions if the CTP results had not been corrected. The authors conclude that results from automated CPT should be interpreted with caution, and failures should be recognized and corrected to ensure appropriate management decisions are made.²⁸ In most cases, the key to improved diagnostic certainty is to interpret the CTP, not in isolation, but in conjunction with the NCCT, CTA, NIHSS, and clinical history.²⁰

0525T-0532T
0525T Insertion or replacement of intracardiac ischemia monitoring system, including testing of the lead and monitor, initial system programming, and imaging supervision and interpretation; complete system (electrode and implantable monitor)
0526T Insertion or replacement of intracardiac ischemia monitoring system, including testing of the lead and monitor, initial system programming, and imaging supervision and interpretation; electrode only
0527T Insertion or replacement of intracardiac ischemia monitoring system, including testing of the lead and monitor, initial system programming, and imaging supervision and interpretation; implantable monitor only
0528T Programming device evaluation (in person) of intracardiac ischemia monitoring system with iterative adjustment of programmed values, with analysis, review, and report
0529T Interrogation device evaluation (in person) of intracardiac ischemia monitoring system with analysis, review, and report
0530T Removal of intracardiac ischemia monitoring system, including all imaging supervision and interpretation; complete system (electrode and implantable monitor)
0531T Removal of intracardiac ischemia monitoring system, including all imaging supervision and interpretation; electrode only
0532T Removal of intracardiac ischemia monitoring system, including all imaging supervision and interpretation; implantable monitor only.
Holmes et al.: The randomization technique is not described. The sample size is not justified. The investigation is for six months with an additional six month follow-up. The authors state that more work is needed to understand the false positive and false negative rates and the actual clinical benefit; these are important issues in determining coverage.

Gibson et al.: The randomization technique is not described. The authors state, “Although the trial did not meet its pre-specified primary efficacy endpoint, results suggest…” Obviously, this is too preliminary to support coverage.

Fischell et al.: This is a non-randomized feasibility study.

Correspondence: Acceptance by individual health care providers, or even a limited group of health care providers, normally does not indicate general acceptance by the medical community. Testimonials indicating such limited acceptance are not sufficient evidence of general acceptance by the medical community.

Summary of Safety and Effectiveness Data: Is not able to be utilized to support coverage.

User’s Guide, Manual, and Programming Guide: Is not able to be utilized to support coverage.

ACC/AHA Guidelines: These are not germane to the issue of coverage of a specific device, and is not current information, dated 2004.

Mirzaei et al.: This reviewer did not see the relevance of this article related to your request.

DeVon et al.: This article describes a weak selection methodology and seems directed to providing guidance for nursing education of patients. This reviewer did not see the relevance to coverage of a specific device.

Sheifer et al.: This article does not seem to address the issue at hand and is not current information, dated 2001.

Flynn et al.: This case series does not seem to address the issue at hand related to your request.

Gersch et al.: This article does not address the issue at hand related to your request.

Kwong et al. with correction: Case series apparently not germane to question at hand related to your request.

Moser et al.: Consensus statement that does not address the issue at hand related to your request.

Sanchez et al.: This case-control can be used to generate hypotheses for further study, but it cannot address the issue at hand.

Wasson et al.: This is an investigation of the quality of life burden of post-traumatic stress disorder due to acute coronary syndrome. This reviewer does not see its relevance to the issue at hand.

0398T

MRgFUS unilateral thalamotomy is considered medically reasonable and necessary in patient with one of the following:

1. Essential Tremor (ET)- defined as refractory to at least two trials of medical therapy, including at least one first-line agent
2. Tremor-Dominant Parkinson’s disease (TDPD) (and both a & b)
   1. refractory (or intolerant) to levodopa or levodopa equivalent daily dosage (LEDD) ≥ 900 mg
   2. On-medication Unified Parkinson’s Disease Rating Scale (UPDRS) ratio of the mean score for tremor items (items 16, 20, and 21) to the mean postural instability/gait disorder score (items 13-15, 29, and 30) of ≥ 1.5

And all of the following:

• Moderate to severe postural or intention tremor of the dominant hand (defined by a score of ≥2 on the Clinical Rating Scale for Tremor (CRST)
• Disabling tremor (defined by a score of ≥2 on any of the eight items in the disability subsection of the CRST
• Not a surgical candidate for deep-brain stimulation (DBS) (e.g., advanced age, anticoagulant therapy, or surgical comorbidities

Exclusion from Coverage:

1. Treatment of head or voice tremor
2. Bilateral thalamotomy
3. Following conditions:
   1. A neurodegenerative condition other than Parkinson’s disease
   2. Unstable cardiac disease
   3. Untreated coagulopathy
   4. Risk factors for deep-vein thrombosis
   5. Severe depression, i.e., a score greater than or equal to 20 on the Patient Health Questionnaire 9 (PHQ-9)
   6. Cognitive impairment defined by a score of less than 24 on the Mini-Mental Status Examination
   7. Previous brain procedure (transcranial magnetic stimulation, deep brain stimulation, stereotactic lesioning, or electroconvulsive therapy)
   8. A skull density ratio (the ratio of cortical to cancellous bone) of <0.45 ± 0.05 as calculated from the screening CT.
   9. MRI contraindication
   10. Drug-induced Parkinsonism
   11. History of seizures, brain tumor, intracranial aneurysm or arteriovenous malformation requiring treatment
   12. pregnancy

Essential tremor (ET)
Elias, JW, Lipsman N, Ondo WG,et al conducted a randomized clinical trial with masked assessment and recognized outcome parameter with a one year follow up.² There is a relatively high adverse event rate, but it is a relatively non-invasive intervention compared to the currently available interventions. It does provide some criteria to determine the proper population for coverage.

Chang, JW, Park CK, Lipsman N, et al provided a two-year follow up on the cohort of the above investigation.¹ The therapeutic effect does seem to be maintained and there were no apparent late adverse events. There was a 12% drop out rate, and the authors acknowledged the rate and accounted for the dropouts.

Tremor-Dominant Parkinson’s disease (TDPD)
Tremor is a common motor feature of Parkinson disease (PD), and TDPD is a clinical subtype distinct from the akinesia/rigidity (AR) and postural instability/gait disorder subtypes. This subtype may be more resistant to dopamine-replacement therapy than other motor symptoms. DBS and traditional thalamic lesioning are accepted treatments of motor symptoms of PD. Several small observational studies also demonstrated efficacy of MRgFUS thalamotomy in TDPD out to one year.^{5-7, 9}

A small prospective, sham-controlled RCT looked at the safety and efficacy of unilateral MRgFUS thalamotomy at 3 and 12 months in patients with TDPD³. Twenty-seven patients (median age 67.8 years; interquartile range [IQR], 62.1-73.8) were randomized (2:1) to MRgFUS (20) vs. sham (7). Predefined primary outcomes were safety and difference in improvement between groups at 3 months in the on-medication treated hand tremor CRST subscore. Secondary outcomes included descriptive results of UPDRS scores and quality of life measures. Three-month on-medication median tremor scores improved 62% (17 to 4.5; IQR, 22%-79%) in the treatment group, and 22% (23 to 17; IQR, −11% to 29%) in the sham group (P = .04). Secondary outcomes showed non-statistical improvement trends in the treatment group. At 3 months, 6 sham patients crossed-over to MRgFUS treatment. Three months after crossover the median baseline CRST score improved from 21 to 5.5, like the 3 months outcomes in the group originally allocated to treatment. One-year follow-up of 14 treatment and 5 sham crossover patients demonstrated CRST score maintenance. Early in the study, heating of the internal capsule resulted in 2 cases (8%) of mild hemiparesis, which improved and prompted monitoring of an additional axis during magnetic resonance thermometry. Other persistent adverse events were orofacial paresthesia (20%), finger paresthesia (5%), and ataxia (5%). A sub-analysis reported no change in cognitive, mood, or behavioral perspective at 3 and 12 months.

On 12/16/2018, the Exablate MRgFUS device FDA indication was expanded to include unilateral thalamotomy (ventralis intermedius) treatment of TDPD with medication-refractory tremor in patients at least age 30.^4.

Analysis of Evidence

Level of Evidence for 0042T
The 2019 update to the 2018 American Heart Association (AHA)/American Stroke Association (ASA) guidelines ²⁹ for the early management of patients with AIS state “In selected patients with AIS within 6 to 24 hours of last known normal who have large vessel occlusion (LVO) in the anterior circulation, obtaining CTP, DW-MRI, or MRI perfusion is recommended to aid in patient selection for mechanical thrombectomy, but only when imaging and other eligibility criteria from RCTs showing benefit are being strictly applied in selecting patients for mechanical thrombectomy”. (Class of recommendation I-strong; level (quality) of evidence A) ³⁰. Since only the DAWN and DEFUSE 3 RCTs show a benefit of late-period EVT, they further warn: “DAWN or DEFUSE 3 eligibility should be strictly adhered to in clinical practice.” These guidelines do not recommend CTP to determine eligibility for either thrombolytic therapy or EVT in the early (<6 hours) period (Class of recommendation I-strong; level (quality) of evidence B-Nonrandomized), or for any other indication (e.g., prediction of hemorrhagic transformation in acute ischemic injury). Other guidelines have similar recommendations ^31-33.
The guidelines also caution that advanced, multimodal pretreatment imaging should not delay administration of IV tPA referencing “failed to demonstrate clinical efficacy in patients with various pretreatment imaging biomarkers compared with those without those markers” (Class of recommendation-III: Strong for Harm; level of evidence; quality of evidence B-NR).

National Institute for Health and Care Excellence recommends: “If thrombectomy might be indicated, perform imaging with CT contrast angiography following initial non-enhanced CT. Add CT perfusion imaging (or MR equivalent) if thrombectomy might be indicated beyond 6 hours of symptom onset.” They also recommend thrombectomy with intravenous thrombolysis for occlusion of the proximal posterior circulation on CTA or MRA if CTP of DWI shows limited infarct core volume with the potential to salvage brain tissue ³⁴. However, there is minimal evidence regarding the appropriate threshold and utility of CTP in the posterior circulation, and accurate calculations are limited in posterior fossa by skull base and orbit artifact ¹⁴. There is evidence DWI has an advantage over CTP for posterior fossa stokes, lacunar infarcts, and small watershed infarcts ¹⁴.

ECRI Clinical Evidence Assessment on Perfusion CTP reviewed the literature on CTP as an alternative imaging evaluation in addition to NCCT and determined the evidence was “inconclusive” due to mixed results. They report “CTP’s clinical utility compared with that of NCCT and magnetic resonance imaging (MRI) for assessing AIS has not been established because of too few data. No studies compared CTP clinical utility with other imaging methods. The RCT focused on treatment and did not randomly assign imaging methods, which created a risk of selection bias when comparing CTP to perfusion MRI. Most studies assessed in the SRs, as well as the diagnostic accuracy studies published after the SRs, were at high risk of bias due to retrospective design and single-center focus ²¹.

We consider the concordant level I evidence of a large clinical benefit after CTP imaging (using automated post-processing software algorithmic analysis) in AIS secondary to LVO, to assist in late EVT eligibility determination per AHA/ASA guidelines, medically reasonable and necessary. While there is a promise to CTP technology applied to other neuroimaging areas, there is still insufficient evidence. Other stroke or non-stroke indications, including routine assessment of AIS, determination of HT, and other indications, are not considered medically reasonable and necessary at this time.

Level of Evidence for 0525T-0532T
Evaluation of the evidence: The issue is whether to provide coverage of the service represented by CPT® 0525T-0532T. The 681 pages of material submitted is largely irrelevant to the issue. The articles that touch on the issue are marred by a weak methodology or at least a weak description of the methodology. (Pease see “Summary of the Evidence.”) Coverage will be denied as not reasonable and medically necessary.

Level of Evidence for 0398T
Quality -Moderate
Strength - Moderate
Weight – Moderate

While more trials would be helpful, the evidence submitted in the reconsideration request does indicate that this may have a role in avoiding more invasive interventions. The evidence submitted also allows the establishment of indications for coverage and exclusions from coverage.

However, given the support for traditional thalamotomy, generally, as an alternative “if DBS is not available or practical”, and the support for MRgFUS thalamotomy, specifically, as an alternative in patients “who are not a candidate for DBS” by the American Association of Neurological Surgeons (AANS), Congress of Neurological Surgeons (CNS) and the American Association of Stereotactic and Functional Neurosurgery (ASSFN)⁸, WPS GHA considers MRgFUS reasonable and necessary in that context.

The American Medical Association (AMA) develops temporary Current Procedural Terminology (CPT) Category III codes to track the utilization of emerging technologies, services, and procedures. The CATEGORY III CPT Code description does not establish a service or procedure as safe, effective or applicable to the clinical practice of medicine.

Indications and Limitations:
Section 1862(a)(1)(A) of the Social Security Act (SSA) is the statutory basis for denying payment for types of care, items, services, and procedures, not excluded by any other statutory clause while meeting all technical requirements for coverage, that are determined to be any of the following:

1. Not generally accepted by the medical community as safe and effective in the setting and for the condition for which it is used;
2. Not proven safe and effective based on peer review or scientific literature;
3. Experimental;
4. Not medically necessary for a particular patient;
5. Furnished at a level, duration, or frequency that is not medically appropriate;
6. Not furnished in accordance with accepted standards of medical practice; or
7. Not furnished in a setting appropriate to the patient’s medical needs and condition.

Items and services must be established as safe and effective to be considered medically necessary. That is, the items and services must be:

1. Consistent with the symptoms of diagnosis of the illness or injury under treatment; and
2. Necessary for, and consistent with, generally accepted professional medical standards of care (e.g., not experimental) and;
3. Not furnished primarily for the convenience of the patient, the provider or supplier; and
4. Furnished at the most appropriate level of care that can be provided safely and effectively to the patient.

Medical devices that are not approved for marketing by the Food and Drug Administration (FDA) are considered investigational and are not considered reasonable and necessary under SSA 1862(a)(1)(A). Medicare payment, therefore, may not be made for procedures performed using devices that have not been approved for marketing by the FDA unless performed within the context of a clinical trial qualifying under the National Coverage Determination (NCD) for Routine Costs in Clinical Trials (310.1) or in approved FDA Investigational Device Exemption (IDE) trial.

A/B MACs (B) continue to determine if a service is reasonable and necessary to treat illness or injury. If a service is not reasonable and necessary to treat illness or injury for any reason (including lack of safety and efficacy because it is an experimental procedure, etc.), A/B MACs (B) consider the service noncovered notwithstanding the presence of a payment amount for the service in the Medicare fee schedule.

FDA designation/ determination of a device as 510(k) mean(s) that the device has been approved for marketing by the FDA because it is similar to something already on the market that was "grandfathered in" by the FDA and therefore these devices are eligible for coverage.

In addition, items, services, or devices may also be not covered under SSA 1862 (a) (1) (D), (E), or (O).