CAM 20218

Progenitor Cell Therapy for the Treatment of Damaged Myocardium due to Ischemia

Category:Medicine   Last Reviewed:January 2020
Department(s):Medical Affairs   Next Review:January 2021
Original Date:April 2004    

Description
Progenitor cell therapy describes the use of multipotent cells of various cell lineages (autologous or allogeneic) for tissue repair and/or regeneration. Progenitor cell therapy is being investigated for the treatment of damaged myocardium resulting from acute or chronic cardiac ischemia and for refractory angina.

For individuals who have acute cardiac ischemia who receive progenitor cell therapy, the evidence includes 2 randomized controlled trials (RCTs) with 200 patients, numerous small RCTs, and meta-analyses of these RCTs. Relevant outcomes are disease-specific survival, morbid events, functional outcomes, quality of life, and hospitalizations. Limited evidence on clinical outcomes has suggested that there may be benefits from improving left ventricular ejection fraction, reducing recurrent myocardial infarction, decreasing need for further revascularization, and perhaps even decreasing mortality, although a recent, large, individual patient data meta-analysis reported no improvement in these outcomes. No adequately powered trial has reported benefits in clinical outcomes (eg, mortality, adverse cardiac outcomes, exercise capacity, quality of life). Overall, this evidence has suggested that progenitor cell treatment may be a promising intervention, but robust data on clinical outcomes are lacking. High-quality RCTs, powered to detect differences in clinical outcomes, are needed to answer this question. The evidence is insufficient to determine the effects of the technology on health outcomes. 

For individuals who have chronic cardiac ischemia who receive progenitor cell therapy, the evidence includes a nonrandomized comparative trial and systematic reviews of smaller RCTs. Relevant outcomes are disease-specific survival, morbid events, functional outcomes, quality of life, and hospitalizations. Studies included in meta-analyses have reported only a handful of clinical outcome events, too few for meaningful analysis. Results of the nonrandomized trial are encouraging, because this is the first controlled trial that has reported a significant mortality benefit for progenitor cell treatment. However, other clinical outcomes were not reported with sufficient methodologic rigor to permit conclusions. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have refractory angina who receive progenitor cell therapy, the evidence includes phase 2 trials and a phase 3 pivotal trial. Relevant outcomes are disease-specific survival, morbid events, functional outcomes, quality of life, and hospitalizations. The only phase 3 trial identified was terminated early and insufficiently powered to evaluate clinical outcomes. Additional larger trials are needed to determine whether progenitor cell therapy improves health outcomes in patients with refractory angina. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
Ischemia
Ischemia is the most common cause of cardiovascular disease and myocardial damage in the developed world. Despite impressive advances in treatment, ischemic heart disease is still associated with high morbidity and mortality.

Treatment
Current treatments for ischemic heart disease seek to revascularize occluded arteries, optimize pump function, and prevent future myocardial damage. However, current treatments do not reverse existing heart muscle damage.1, 2 Treatment with progenitor cells (ie, stem cells) offers potential benefits beyond those of standard medical care, including the potential for repair and/or regeneration of damaged myocardium. Potential sources of embryonic and adult donor cells include skeletal myoblasts, bone marrow cells, circulating blood-derived progenitor cells, endometrial mesenchymal stem cells, adult testis pluripotent stem cells, mesothelial cells, adipose-derived stromal cells, embryonic cells, induced pluripotent stem cells, and bone marrow mesenchymal stem cells, all of which can differentiate into cardiomyocytes and vascular endothelial cells.

The mechanism of benefit after treatment with progenitor cells is not entirely understood. Differentiation of progenitor cells into mature myocytes and engraftment of progenitor cells into areas of the damaged myocardium has been suggested in animal studies using tagged progenitor cells. However, there is controversy concerning whether injected progenitor cells engraft and differentiate into mature myocytes in humans to the degree that might result in clinical benefit. It also has been proposed that progenitor cells may improve perfusion to areas of ischemic myocardium. Basic science research has also suggested that injected stem cells secrete cytokines with antiapoptotic and proangiogenesis properties. Clinical benefit may result if these paracrine factors limit cell death from ischemia or stimulate recovery. For example, myocardial protection can occur through modulation of inflammatory and fibrogenic processes. Alternatively, paracrine factors may affect intrinsic repair mechanisms of the heart through neovascularization, cardiac metabolism, and contractility, increase in cardiomyocyte proliferation, or activation of resident stem and progenitor cells. The relative importance of these proposed paracrine actions depends on the age of the infarct (eg, cytoprotective effects in acute ischemia and cell proliferation in chronic ischemia). Investigation of the specific factors induced by administration of progenitor cells is ongoing.

There are also various potential delivery mechanisms for donor cells, encompassing a wide range of invasiveness. Donor cells can be delivered via thoracotomy and direct injection into areas of damaged myocardium. Injection of progenitor cells into the coronary circulation also is done using percutaneous, catheter-based techniques. Finally, progenitor cells may be delivered intravenously via a peripheral vein. With this approach, the cells must be able to target damaged myocardium and concentrate at the site of myocardial damage.

Adverse events of progenitor cell treatment include risks of the delivery procedure (eg, thoracotomy, percutaneous catheter-based) and risks of the donor cells themselves. Donor progenitor cells can differentiate into fibroblasts rather than myocytes. This may create a substrate for malignant ventricular arrhythmias. There also is a theoretical risk that tumors (eg, teratomas) can arise from progenitor cells, but the actual risk in humans is currently unknown.

Regulatory Status 
The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation title 21, parts 1270 and 1271. Progenitor cells are included in these regulations. FDA marketing clearance is not required when autologous cells are processed on site with existing laboratory procedures and injected with existing catheter devices. Several cell products are expanded ex vivo and require FDA approval.

Multiple progenitor cell therapies such as MyoCell® (Bioheart, Sunrise, FL), ixmyelocel-T (Vericel, formerly Aastrom Biosciences), and MultiStem® (Athersys) are being commercially developed, but none have been approved by FDA so far.

MyoCell® comprises patient autologous skeletal myoblasts that are expanded ex vivo and supplied as a cell suspension in a buffered salt solution for injection into the area of damaged myocardium.

Ixmyelocel-T is an expanded multicellular therapeutic product produced from a patient’s bone marrow by selectively expanding bone marrow mononuclear cells for 2 weeks. The expanded cell product enriched for mesenchymal and macrophage lineages might enhance potency.

MultiStem® is an allogeneic bone marrowderived adherent adult stem cell product. 

Related Policies:
80152 Orthopedic Applications of Stem-Cell Therapy
80155 Stem-cell Therapy for Peripheral Arterial Disease

Policy:
Progenitor cell therapy, including but not limited to skeletal myoblasts or hematopoietic stem cells, is considered INVESTIGATIONAL as a treatment of damaged myocardium.

Infusion of growth factors (i.e., granulocyte colony stimulating factor [GCSF]) is considered INVESTIGATIONAL as a technique to increase the numbers of circulating hematopoietic stem cells as treatment of damaged myocardium.

Policy Guidelines
There are no specific codes for this procedure, either describing the laboratory component of processing the harvested autologous cells or for the implantation procedure. In some situations, the implantation may be an added component of a scheduled coronary artery bypass graft (CABG); in other situations, the implantation may be performed as a unique indication for a cardiac catheterization procedure.

Benefit Application
BlueCard/National Account Issues
Progenitor cell implantation/transplantation is a specialized service that may prompt request for an out of network referral.

Rationale 
This evidence review was created in April 2004 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through March 13, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients andmanaging the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The present evidence review focuses on phase 3 trials with at least 100 patients per arm and systematic reviews of RCTs. The relevant clinical trials and meta-analyses are reviewed for three different indications: (1) acute cardiac ischemia (myocardial infarction[MI]); (2) chronic cardiac ischemia; and (3) refractory or intractable angina in patients who are not candidates for revascularization. This evidence review focuses on the impact of progenitor cell therapy on clinical outcomes but also includes data on physiologic outcomes, such as a change in left ventricular ejection fraction (LVEF). This review was informed in part by a TEC Assessment (2008).4,

Progenitor Cells To Treat Acute Cardiac Ischemia
Systematic Reviews
Bone Marrow Cells
Several meta-analyses, including a Cochrane review and an individual patient data meta-analysis evaluating the use of progenitor cell therapy for treating acute ischemia (MI), are described below. Table 1 details the reviews and summarizes the analyses.

Two meta-analyses on bone marrow cell (BMC) infusion for the treatment of acute myocardial infarction (AMI) were published in 2014 and included many of the same studies. Delewi et al (2014) published a meta-analysis of 16 trials (totaln=1641 patients).5, The meta-analyses by de Jong et al (2014) included 22 RCTs (totaln=1513 patients).6, Thirteen RCTs (1300 patients) appeared in both systematic reviews. Both analyses found statistically significant increases in LVEF with BMC infusion compared with placebo. In subgroup analyses, Delewi et al showed that the treatment benefit was greater among younger patients (age <55 years) and among patients with more severely depressed LVEF at baseline (<40%), while the de Jong et al (2014) subgroup analysis, which included only trials with outcomes derived from magnetic resonance imaging (9 trials), showed that the therapy did not have an effect on cardiac function, volumes, or infarct size. With a median follow-up of six months, there was no difference between BMC infusion and placebo in all-cause mortality, cardiac mortality, restenosis rate, thrombosis, target vessel revascularization, stroke, recurrent AMI, or implantable cardioverter defibrillator usage. Based on these findings, de Jong et al concluded that, although safe, intracoronary infusion of BMCs did not improve clinical outcomes.

A Cochrane review by Fisher et al (2015) on stem cell treatment for AMI included 41 trials (totaln=2732 patients).7, Many were small trials and conducted outside the U. S.; others were reported only as conference proceedings. Studies varied by cell dose, cell type, and timing of administration. Overall, cell treatment was not associated with any changes in the risk of all-cause mortality, cardiovascular mortality, or a composite measure of mortality, reinfarction, and rehospitalization for heart failure at long-term follow-up. Reviewers concluded that there was insufficient evidence to support a beneficial effect of cell therapy for patients experiencing an AMI and that adequately powered trials are needed. 

Gyöngyösi et al (2015) conducted an individual patient data meta-analysis of 12 RCTs (totaln=1252 patients), including the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial (reviewed below), using a collaborative, multinational database,meta-Analysis of Cell-based CaRdiac study(ACCRUE; NCT01098591).8 Eight trials had low-risk of bias, and four single-blind (assessor) trials had medium-to low-risk of bias. Adjusted (for cardiovascular risk factors) random-effects meta-analyses showed no effect of cell therapy on the primary outcomes of major adverse cardiac and cerebrovascular events (a composite of all-cause death, AMI recurrence, coronary target vessel revascularization, and stroke). The meta-analysis was limited by variations in the time from AMI to cell delivery (median, 6.5 days) and in imaging modalities used to assess cardiac function (magnetic resonance imaging, single-proton emission computed tomography, angiography, echocardiography).

Fisher et al (2016) reported on the results of a trial sequential analysis using cumulative data obtained from 2 previous Cochrane reviews with updated results to March 2015.9 The intent of the analysis was to obtain estimates of sample sizes required for a meta-analysis to detect a significant treatment effect while controlling for random errors due to repeat testing. Thirty-seven AMI trials that assessed BMCs and reported on mortality as an outcome were included. Of the 37 trials, 14 reported no deaths. Of 23 trials that observed incidences of mortality in either trial arm, there were 43 (4.0%) deaths in 1073 patients who received cell therapy compared with 38 (5.0%) deaths in 754 patients who did not. Results showed that there was insufficient evidence to detect a significant treatment effect of bone marrow-derived cells on mortality and rehospitalization in AMI (relative risk [RR], 0.92; 95% confidence interval [CI], 0.62 to 1.36). Results of the sequential analysis showed that at least 4055 participants would be required to detect a relative reduction in the risk of mortality of 35% in AMI patients. Most of the meta-analyses reported so far have not reached this sample size.

Lalu et al (2018) reported results of a systematic review and meta-analyses including both randomized and non-randomized studies.8, The review did not include any RCTs in acute cardiac ischemia published after the preceding Fisher et al (2015) review and will not be discussed further.

Granulocyte Colony Stimulating Factor
The body of evidence on the use ofG-CSF as a treatment for coronary heart disease is smaller than that for the use of stem cells. A few RCTs on the treatment of acute ischemia have reported physiologic outcomes. Additionally, meta-analyses of the available trials have been published. Moazzami et al (2013) published a Cochrane review evaluating G-CSF for AMI.9, Literature was searched in November 2010, and 7 small, placebo-controlled randomized trials (totaln=354 patients) were included. The overall risk of bias was considered low. All-cause mortality did not differ between groups (RR=0.6; 95% CI, 0.2 to 2.8; p=0.55; I2=0%). Similarly, change in LVEF left ventricular end-systolic volume and left ventricular end-diastolic volume did not differ between groups. Evidence was insufficient to draw conclusions about the safety of the procedure. Similarly, reviewers concluded there was a lack of evidence for the benefit of G-CSF therapy in patients with AMI.

Randomized Controlled Trials
Key studies, including phase 3 RCTs with more than 100 patients per arm, are described next. Summaries of trial characteristics and results are in Tables 2 and 3.

REPAIR-AMI Trial
REPAIR-AMI was a double-blinded trial that infused bone marrow-derived progenitor cells or a placebo control infusion of the patient’s serum; it enrolled 204 patients from 17 centers in Germany and Switzerland who had acute ST-segment elevation MI and met strict inclusion criteria.11,12 At 12-month follow-up, there were statistically significant decreases in the progenitor cell group compared with the control group for MI (0 vs 6, p<0.03) and revascularization (22 vs 37, p<0.03), as well as for the composite outcome of death, myocardial infarction, and revascularization (24 vs 42, p<0.009), all respectively. Two-year clinical outcomes from the REPAIR-AMI trial, performed according to a study protocol amendment filed in 2006, were reported in 2010.10,11, Eleven deaths occurred during the two-year follow-up, eight in the placebo group and three in the progenitor cell group. There was a significant reduction in MI (0% vs 7%), and a trend toward a reduction in rehospitalizations for heart failure (1% vs 5%) and revascularization (25% vs 37%) in the active treatment group. Analysis of combined events (all combined events included infarction) showed significant improvement with progenitor cell therapy after AMI. There was no increase in ventricular arrhythmia, syncope, stroke, or cancer. It was noted that investigators and patients were unblinded at 12-month follow-up. Also, the REPAIR-AMI trial was not powered to determine definitively whether administration of progenitor cells reduces mortality and morbidity after AMI.

HEBE Trial
Hirsch et al (2011) reported on a multicenter, phase 3, RCT that compared bone marrow or peripheral blood mononuclear cell infusion with standard therapy in 200 patients with AMI treated with primary percutaneous coronary intervention.12, Mononuclear cells were delivered three to eight days after AMI. Blinded assessment of the primary outcome (the percentage of dysfunctional left ventricular segments that had improved segmental wall thickening at 4 months) found no significant difference between the treatment groups (38.5% for bone marrow vs 36.8% for peripheral blood) and controls (42.4%). There were no significant differences between groups in LVEF; change in left ventricular volumes, mass, or infarct size; or rates of clinical events. At 4 months, a similar percentage of patients had New York Heart Association (NYHA) class II or higher heart failure (19% for bone marrow, 20% for peripheral blood, 18% for controls).

Table 1. Summary of Systematic Reviews Assessing Use of Progenitor Cell Therapy to Treat of Acute Ischemia

             

  Outcomes (95% CI) 

   
Study Dates  Trials   Patients Design Mean Time Between Acute Event and Cell Infusion Median Trial Duration (Range), mo

Mean Change or % Change in LVEF

 Risk All-Cause Mortality Risk of CV    Mortality    

Delewi et al(2014)5

1980-Feb 2013

16 1641 RCT  ≤1 mo

6 (3-6)

 

2.55%
(1.83% to 3.26%)
       /²=84%     

NR  NR 
De Jong et al (2014)6 Jan 2002-Sep 2013 22 1513 RCT   ≤1 mo

6 (3-60)

2.10%
(0.68% to 3.52%)
/²=80%  
0.68a
(0.36 to 1.31) 
0.73a
(0.32 to 1.65) 
Fisher et al (2015)7

Through Mar 2015

41 2732 RCT ≤14 d

<12

1.05b
(-0.56 to 2.67)

0.80c
(0.43 to 1.49)

   0.72c
(0.28 to 1.82) 
  

 

 

       

 

≥12 

1.27b
(-1.14 to 3.68) 

0.93c
(0.58 to 1.50) 

1.04c       (0.54 to 1.99 

Gyöngyösi et al (2015)13   12 1252 RCT or cohort ≤14 d 6 (3-12) 0.96
(-0.2 to 2.1)
0.70
(p=0.499)
NR 

CI: confidence interval; CV: cardiovascular; LVEF: left ventricular ejection fraction; NR: not reported; RCT: randomized controlled trial.
a Mantel-Haenszel odds ratio (95%CI).
b As measured by magnetic resonance imaging.
c Relative risk (95% CI).

Table 2. RCT Characteristics of Progenitor Cell Therapy for Acute Ischemia

 

 

 

 

 

                     Interventions 

Study; Trial

Countries

Sites

Dates

Participants

Cell Therapies

Comparator

Schächinger et al        (2006)10,14.;               REPAIR-AMI (NCT00279175)

Germany, Switzerland

17

2004-2005

Acute ST- elevation MI; successfully re-perfused; LVEF 45%

Intracoronary              infusion of BMCs      (n=101)

Sham infusion (n=103)

Hirsch et al (2011)12;   HEBE (ISRCTN95796863)

Netherlands

8

2005-2008

ST-segment elevation MI; treated with primary PCI and stent implantation

  • Intracoronary             infusion of           autologous      mononuclear BMCs (n=69)
  • Intracoronary infusion of       mononuclear        peripheral blood cells (n=66)

Standard of care without sham infusion (n=65)

BMC: bone marrow cell; LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention.

Table 3. RCT Results of Progenitor Cell Therapy for Acute Ischemia

Study Mortality, n Major Adverse Events, n

Rehospitalization  for Heart  Failure, n  

LVEF
  By 1 Year

Death, MI, Revascularization   by Year 1   

By 1 Year

Mean Change From BL to 4  Months (SD)

Schächinger et al (2006)10,14,         
204 204 204 187
Cell therapy 6 23 0 5.5 (7.3)
Sham 2 40 3 3.0 (6.5)
TE (95% CI); p NR; p=28 NR; p=0.01  NR; p=0.25  NR; p=0.01
  By 4 Months

 Death, MI, Revascularization by 4 Months    

By 4 Months Mean Change From BL to 4 Months (SD)
Hirsch et al (2011)12             
200 200 200  
BMC therapy  0 4 0 189
PBC therapy 9 3.8 (7.4) 
SOC  4.2 (6.2)
TE (95% CI); p  NR NR NR 4.0 (5.8)

BL: baseline; BMC: bone marrow cell; CI: confidence interval; LVEF: left ventricular ejection fraction; NR: not reported; PBC: peripheral blood cell; RCT: randomized controlled trial; SOC: standard of care; TE: treatment effect; MI: myocardial infarction.

Section Summary: Progenitor Cells to Treat Acute Cardiac Ischemia
The evidence on progenitor cell therapy for patients with MI includes 2 phase 3 RCTs including more than 100 patients, numerous small, early-phase RCTs, and meta-analyses of these RCTs. Studies varied by types of cell used and methods and timing of delivery. Most studies reported outcomes for LVEF and/or myocardial perfusion at three to six months. These studies generally reported small-to-modest improvements in these intermediate outcomes. Limited evidence on clinical outcomes has suggested that there may be benefits in improving LVEF, reducing recurrent MI, decreasing the need for further revascularization, and perhaps decreasing mortality, although a recent, large, individual patient data meta-analysis reported no improvement in these outcomes. No single adequately powered trial has reported benefits in clinical outcomes, such as mortality, adverse cardiac outcomes, exercise capacity, or QOL. Overall, this evidence has suggested that progenitor cell treatment may be a promising intervention, but robust data on clinical outcomes are lacking. High-quality RCTs, powered to detect differences in clinical outcomes, are needed.

Progenitor Cells To Treat Chronic Cardiac Ischemia
Stem cell therapy is also being investigated in patients with chronic ischemic heart disease. The evidence includes systematic reviews, many small, early-phase RCTs, 2 phase 3 RCTs with more than 100 participants, and nonrandomized studies.

Systematic Reviews
Fisher et al (2016) reported on a systematic review15, that updated a 2014 Cochrane.16, In 2016, literature was searched through December 2015, and 38 RCTs (totaln=1907 patients) were included. The overall quality of the evidence was considered low because selected studies were small (only 3 included >100 participants) and the number of events was low, leading to a risk of small-study bias and spuriously inflated effect sizes. Results of the 2016 Cochrane review are shown in Table 4. While reviewers were unable to detect evidence of publication bias using funnel plots, they noted that of 28 identified ongoing trials, 11 trials with 787 participants, were recorded as having been completed or were due to have been completed in advance of the search date but had no publications. Therefore, publication bias cannot be ruled out. Similar results were reported in 2014 meta-analyses conducted by Xu et al(2014) and by Xiao et al (2014).17,18,

Lalu et al (2018) reported results of a systematic review and meta-analyses including both randomized and non-randomized studies.8, The review did not include any RCTs in chronic cardiac ischemia published after the preceeding Fisher et al (2016) review or otherwise discussed in the section below and will not be discussed further.

Table 4. Cochrane Review Results of Stem Cell Therapy for Chronic Ischemic Heart Disease

Variables Short-Terma Mortality Long- Termb Mortality Long-Termb Rehospitalization Long-Termb MACE    

Short-Terma NYHA Classification

Short- Terma  LVEF (%)c
N 1637 1010 495 201 658 352

PE (95% CI); p value

0.48 (0.26 to 0.87);0.02

0.38 (0.25 to 0.58); <0.001

       0.62 (0.36 to 1.04);      0.07

0.68 (0.41 to 1.12);  0.13

-0.42 (-0.84 to -0.00);  0.05

3.01 (-0.05 to 6.07);  0.054

I2 (p) 0% (0.76) 0% (0.97) 0% (0.70) 0% (0.80) 97% (<0.001)     59% (0.01)       

Adapted from Fisher et al (2016).15 
CI: confidence interval; LVEF: left ventricular ejection fraction; MACE: major adverse cardiac event; NYHA: New York Heart Association; PE: pooled effect. 
a Short-term: <12 months.
b Long-term:  12 months.
c Measured by magnetic resonance imaging.

Fisher et al (2016) also reported on the results of a sequential trial analysis using cumulative data obtained from 2 previous Cochrane reviews with updated results to March 2015.19, The intent of their analysis was to obtain estimates of sample sizes required for a meta-analysis to detect a significant treatment effect while controlling for random errors due to repeat testing. Twenty-two trials that included all-cause mortality were selected. Six trials reported no deaths, while the remaining 16 trials reported 25 (5.6%) deaths in 444 patients who received progenitor cells compared with 50 (15.9%) deaths in 315 patients who did not. Meta-analysis of the pooled data revealed a significant reduction in mortality associated with cell therapy in patients with heart failure (RR=0.42; 95% CI; 0.27 to 0.64; p<0.001).

Randomized Controlled Trials
Two phase 3 RCTs with more than 100 participants were identified. Trial characteristics and results are shown in Tables 5 and 6. Bartunek et al (2017) reported on the results of a well-conducted double-blind trial in which 271 patients with NYHA class II or greater symptomatic heart failure (LVEF ≤35%) were randomized to bone marrow-derived mesenchymal cardiopoietic cells (n=120) or sham (n=151).20, The primary outcome was Finkelstein-Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-minute walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. Sixteen patients who died and three who withdrew consent after randomization were not included in the analysis. Also, 19 patients whose cell product did not meet release criteria were excluded from analysis in the cardiopoietic cell group. The probability that the treatment group had a better outcome on the composite primary outcome was 0.54 (a value >0.5 favors active treatment; 95% CI, 0.47 to 0.61; p=0.27). Exploratory subgroup analysis reported treatment benefit in patients, with baseline left ventricular end-diastolic volumes of 200 to 370 mL (60% of patients) (0.61; 95% CI, 0.52 to 0.70; p=0.015). There was no statistical difference in serious adverse events between treatment arms. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death.

Pokushalov et al (2010) reported on the results of an RCT of intramyocardial injections of autologous bone marrow mononuclear cells (n=55) compared with optimal medical management (n=54) in patients who had chronic, ischemic heart failure.21, The trial appears to have been conducted in Russia; dates of study conduct were not reported. Power calculations were not reported and it is not clear if the trial was registered. Comparative treatment effects were not calculated for many outcomes. Characteristics and results are shown in Tables 5 and 6. The RCT reported statistically significant improvements in mortality rates at 12 months for cell therapy (11%)vs medical therapy (39%) favoring medical therapy (p<0.001).

Table 5. RCT Characteristics of Progenitor Cell Therapy for Chronic Ischemic Heart Disease

          Interventions 
Study; Trial Countries     Sites               Dates         Participants Cell Therapy Comparator
Bartunek et al (2017)20; CHART-1 (NCT01768702) Multinationala 39

2012- 2015 

LVEF  35%, NYHA class  ≥II on guidelines-directed therapy               

Cardiopoietic cells (n=157) Sham (n=158)
Pokushalov et al (2010)21 Russia NR NR

LVEF <35%, end-stage, chronic heart failure, on optimal medical therapy, not eligible for revascularization

Bone marrow cells (n=55) Medical management, no sham (n=54)

LVEF: left ventricular ejection fraction; NR: not reported; NYHA: New York Heart Association.
a  Belgium, Bulgaria, Hungary, Ireland, Israel, Italy, Poland, Serbia, Spain, Sweden, Switzerland, and United Kingdom.

Table 6. RCT Results of Progenitor Cell Therapy for Chronic Ischemic Heart Disease

Study Mortality, n (%)  Change in Heart Failure, n (%) MLHFQ Score, n (%) 6-Minute Walk LVEF
  At 39 Weeks

Worsening; 1 Event Through 39 Weeks

10-point Improvement From BL to 39 Weeks

40 m Improvement From BL to 39 Weeks, n (%)

   ≥4%     Improvement    From BL to 39 Weeks, n (%)

Bartunek et al (2017)20          
N 271 271 244 239 226
Cell therapy 11 (9%) 20 (17%) 64 (59%) 50 (46%) 69 (68%)
Sham 12 (8%) 23 (15%) 66 (49%) 40 (31%) 82 (66%)
TE (95% CI); p

HR=1.2 (0.5 to 2.7); 0.70 

Oddsa=1.03 (0.9 to 1.2); 0.72

Oddsa=0.8 (0.7 to 1.0); 0.12

Oddsa=0.8 (0.7 to 1.0); 0.07

Oddsa=1.0 (0.8 to 1.2); 0.73

  At 12 Months Improvement in NYHA Class by 1 Class at 3 Months   Mean Distance Walked at 12 Months (SD), m Mean at 3 Months (SD)
Pokushalov et al (2010)21          
N 109 107   NR 107
Cell therapy 6 (11%) 25 (46%)   359 (69) 28 (6)
Sham 21 (39%) 4 (8%)   196 (42) 27 (6)
TE (95% CI); p <0.001 NR   0.03 NR

BL: baseline; HR: hazard ratio; LVEF, left ventricular ejection fraction; MLHFQ: Minnesota Living with Heart Failure Questionnaire; NR: not reported; SD: standard deviation; TE: treatment effect.
a Mann-Whitney odds for worse outcome in cell therapy vs sham for ordered categories; note, not all categories are shown in this table. Values <1.0 favor cell therapy treatment

Nonrandomized Controlled Trials
STAR-Heart Trial
The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heART failure (STAR-Heart) trial evaluated stem cell therapy for chronic heart failure due to ischemic cardiomyopathy. This nonrandomized open-label study, reported by Strauer et al (2010), evaluated 391 patients with chronic heart failure.21 In this trial, 191 patients received intracoronary BMC therapy, and 200 patients who did not accept the treatment agreed to undergo follow-up testing served as controls.Mean time between percutaneous coronary intervention for infarction and admission to the tertiary clinic was 8.5 years. For BMC therapy, mononuclear cells were isolated and identified (included CD34-positive cells, AC133-positive cells, CD45-/CD14-negative cells). Cells were infused directly into the infarct-related artery. At up to five years after intracoronary BMC therapy, there was a significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (NYHA classification), oxygen uptake, and left ventricular contractility compared with controls. There also was a significant decrease in long-term mortality in the BMC-treated patients (0.75% per year) compared with the control group (3.68% per year, p<0.01). However, the trial was limited by the potential for selection bias (patient self-selection into treatment groups). For example, there was a 7% difference in baseline ejection fraction rates between groups, suggesting that the groups were not comparable on important clinical characteristics at baseline. Additionally, lack of blinding raises the possibility of bias in patient-reported outcomes such as NYHA class.

Section Summary: Progenitor Cells to Treat Chronic Cardiac Ischemia
The evidence on progenitor cell therapy for chronic ischemia includes RCTs, systematic reviews of RCTs, and a nonrandomized comparative trial. The studies included in the meta-analyses were generally early-phase, small (<100 participants) trials; they only reported on a small number of clinical outcome events. The findings from early-phase 2 trials need to be corroborated in a larger phase 3 trial. One well-conducted, phase 3 trial failed to demonstrate superiority for cell therapy for the primary outcome that included death, worsening heart failure, and other multiple events. The nonrandomized STAR-Heart trial showed a mortality benefit as well as a favorable hemodynamic effect but the lack of randomization limits interpretation due to concerns about selection bias and differences in known and unknown prognostic variables at baseline between arms. Overall, this evidence has suggested that progenitor cell treatment may be a promising intervention, but robust data on clinical outcomes are lacking. High-quality RCTs, powered to detect differences in clinical outcomes, are needed.

Progenitor Cell Therapy to Treat Refractory Angina
Stem cell therapy also is being investigated in patients with intractable angina who are not candidates for revascularization. The evidence includes a systematic review, 4 trials from 2007 through 2014 with fewer than 100 patients,22-26 2 phase 1/2 trials with more than 100 patients,22,27 and 1 phase 3 trial with more than 100 participants, which is discussed more in the section on RCTs.22,

Systematic Reviews
Khan et al (2016) reported on the results of a systematic review of RCTs evaluating cell therapy in patients with refractory angina who were ineligible for coronary revascularization.23, The risk of bias in the included studies was rated as low. All selected randomized trials were placebo-controlled; five RCTs were blinded and in one blinding was not reported. The systematic review characteristics and results are shown in Tables 7 and 8. The trials varied in durations of follow-up but appear to have been pooled regardless of the timing of the outcome in the analysis. Although there was a beneficial effect of cell therapy on frequency of angina in the pooled analysis, there was significant heterogeneity for the angina outcome, which was attributed to one RCT. With removal of this RCT, there was an attenuation of the effect (mean difference, -3.38; 95% CI, -6.56 to 0.19). 

Table 7. Systematic Review Characteristics of Progenitor Cell Therapy for Refractory Angina  

Study Dates Trials Participants      N (Range)      Design   Length of FU 
Khan et al (2016)23 Up to Sep 2015 6 Refractory angina who were ineligible for coronary revascularization

353 (24-112)

RCT 6 mo to 2 y

FU: follow-up; RCT: randomized controlled trial.

Table 8. Systematic Review Results of Progenitor Cell Therapy for Refractory Angina

Study       Frequency of Angina CCS Angina Class       MACE        Mortality QOL
Khan et al (2016)23          
Total N 271 210 NR NR NR

PE (95% CI); p value

MD = -7.8 (-15.2 to -0.41); 0.04

MD = -0.58 (-1.00 to - 0.16); 0.007

 NR NR   NR
I2 (p) 90% (<0.001) 0% (0.67) 0% (NR) NR NR

CCS: Canadian Cardiovascular Society; CI :confidence interval; MACE: major adverse cardiac events; MD: mean difference; OR: odds ratio; PE: pooled effect; QOL: quality of life.

Randomized Controlled Trials
One phase 3 trial of cell therapy in patients with refractory angina who were ineligible for coronary revascularization including more than 100 participants has been reported. Characteristics and results are shown in Tables 9 and 10.

RENEW Trial  
Povsic et al (2016) reported on the industry-sponsored Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells (RENEW) trial.28 This 3-arm multicenter trial compared outcomes from the intramyocardial administration of autologous CD34-positive cells using exercise capacity at 3, 6, or 12 months. Patients underwent cell mobilization with G-CSF for 4 days followed by apheresis. The peripheral cell product was shipped to a central processing facility (Progenitor Cell Therapy) for selection of CD34-positive cells. The trial was terminated after enrollment of 112 of a planned 444 patients before data analysis due to strategic considerations. The progenitor cell group had greater exercise capacity than the standard therapy group but was no better than the double-blinded placebo group, consistent with a placebo effect. Additionally, with only 122 participants, the trial was not adequately powered to detect a between-group difference.

Table 9. RCT Characteristics of Progenitor Cell Therapy for Refractory Angina

          Interventions
Study; Trial Countries Sites Dates Participants Cell Therapy Comparator
Povsic et al (2016)22 ; RENEW (NCT01508910) U.S. 41

2012-2013

CCS class III/IV angina, LVEF ≥25%, on maximally tolerated drug therapy, not eligible for revascularization

Autologous CD34-positive (G- CSF stem cell mobilization, apheresis, and IM CD34- positive injection) (n=54)

  • Standard of care: no additional intervention, not blinded (n=28)
  • Active control: G- CSF stem cell mobilization, apheresis, and IM placebo injection (n=27)

CCS: Canadian Cardiovascular Society; G-CSF: granulocyte colony stimulating factor; IM: intramyocardial; LVEF: left ventricular ejection fraction.

Table 10. RCT Results of Progenitor Cell Therapy for Refractory Angina

Study Angina Frequency Exercise Time, s  MACE, n, (%)   Death, n, (%)     QOL
  Mean Episodes/Week at 12 Months (SD) Mean Change From BL to 12 Months (SD)  At 24     Months   At 24 Months  
Povsic et al (2016)22          
N  84  84 106  106  NR
CT  3.8 (6.2)  109 (194)  23 (46%)  2 (4%)   
SOC  NR  NR  19 (68%)  2 (7%)   
AC   2.7 (4.6)  90 (185)  12 (43%)  3 (11%)   
TE for CT vs AC (95% CI); p  RR=1.02 (NR); 0.95 

20.4 (-68.9 to 109.6); 0.65

NR  NR   

TE for CT vs SOC (95% CI); p 

NR  NR  NR  NR   

AC: active control; BL: baseline; CT: cell therapy; MACE: major adverse cardiac events; QOL: quality of life; SOC: standard of care; RR: relative risk; SOC: standard of care; TE: treatment effect; RCT: randomized controlled trial; SD: standard deviation.

Section Summary: Progenitor Cell Therapy to Treat Refractory Angina
Evidence on stem cell therapy for refractory angina includes early-phase trials, as well as a phase 3 pivotal trial terminated early and insufficiently powered to evaluate clinical outcomes. Additional larger trials are needed to determine whether progenitor cell therapy improves health outcomes in patients with refractory angina.

Summary of Evidence
For individuals who have acute cardiac ischemia who receive progenitor cell therapy, the evidence includes two phase 3 RCTs, numerous small, early-phase RCTs, and meta-analyses of these RCTs. The relevant outcomes are disease-specific survival, morbid events, functional outcomes, QOL, and hospitalizations. Limited evidence on clinical outcomes has suggested that there may be benefits from improving LVEF, reducing recurrent MI, decreasing the need for further revascularization, and perhaps decreasing mortality, although a recent, large, individual patient data meta-analysis reported no improvement in these outcomes. No adequately powered trial has reported benefits in clinical outcomes (eg, mortality, adverse cardiac outcomes, exercise capacity, QOL). Overall, this evidence has suggested that progenitor cell treatment may be a promising intervention, but robust data on clinical outcomes are lacking. High-quality RCTs, powered to detect differences in clinical outcomes, are needed to answer this question. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic cardiac ischemia who receive progenitor cell therapy, the evidence includes 2 phase 3 RCTs with more than 100 participants, systematic reviews of smaller, early-phase RCTs, and a nonrandomized comparative trial. The relevant outcomes are disease-specific survival, morbid events, functional outcomes, QOL, and hospitalizations. The studies included in the meta-analyses have reported only on a small number of clinical outcome events. These findings from early phase 2 trials need to be corroborated in larger phase 3 trials. A well-conducted, phase 3 RCT trial failed to demonstrate superiority of cell therapy for its primary composite outcome that included death, worsening heart failure events, and other multiple events. The nonrandomized STAR-Heart trial showed a mortality benefit as well as favorable hemodynamic effect, but a lack of randomization limits interpretation due to the concern about selection bias and differences in known and unknown prognostic variables at baseline between both arms. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have refractory angina who receive progenitor cell therapy, the evidence includes a systematic review of RCTs, phase 2 trials, and a phase 3 pivotal trial. The relevant outcomes are disease-specific survival, morbid events, functional outcomes, QOL, and hospitalizations. The only phase 3 trial identified was terminated early and insufficiently powered to evaluate clinical outcomes. Additional larger trials are needed to determine whether progenitor cell therapy improves health outcomes in patients with refractory angina. The evidence is insufficient to determine the effects of the technology on health outcomes.

PRACTICE GUIDELINES AND POSITION STATEMENTS
The American College of Cardiology Foundation and American Heart Association (2013) issued joint guidelines on the management of ST-segment elevation myocardial infarction. 

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable.

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing

NCT01781390a

A Prospective, Double Blind, Randomized, Placebo-controlled Clinical Trial of Intracoronary Infusion of Immunoselected, Bone Marrow-derived Stro3 Mesenchymal Precursor Cells (MPC) in the Treatment of Patients With ST-elevation Myocardial Infarction (AMICI)

105 Apr  2021

NCT02323620

The Impact of Repeated Intracoronary Injection of Autologous Bone-marrow Derived Mononuclear Cells for Left Ventricle Contractility and Remodeling in Patients With STEMI Prospective Randomized Study (RACE-STEMI)

200 Dec 2022

NCT00526253a

A Multicenter Study to Assess the Safety and Cardiovascular Effects of Myocell™ Implantation by a Catheter Delivery System in Congestive Heart Failure Patients Post Myocardial Infarction(s) 170 Feb 2019

NCT02032004a

A Double-blind, Randomized, Sham-procedure-controlled, Parallel-group Efficacy and Safety Study of Allogeneic Mesenchymal Precursor Cells (CEP-41750) in Patients With Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction of Either Ischemic or Nonischemic Etiology (STEM-AMI)

600 Dec 2019

NCT01569178

The Effect of Intracoronary Reinfusion of Bone Marrow-derived Mononuclear Cells (BM- MNC) on All Cause Mortality in Acute Myocardial Infarction (BAMI) 350 Oct 2019

NCT02501811 

A Phase II, Randomized, Placebo-Controlled Study of the Safety, Feasibility, and Efficacy of AutologousMesenchymal Stem Cells and C-kit+ Cardiac Stem Cells, Alone or in Combination, Administered Transendocardially in Subjects With Ischemic Heart Failure  144  May 2020 

NCT03418233a 

Regeneration of Ischemic Damages in Cardiovascular System Using Wharton's Jelly as an Unlimited Source of Mesenchymal Stem Cells for Regenerative Medicine. Project of the National Centre for Research and Development (Poland) 'STRATEGMED II'. Randomized Clinical Trial to Evaluate the Regenerative Capacity of CardioCell in Patients With Chronic Ischaemic Heart Failure (CIRCULATE) 115  Dec 2020 

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial. 

References:

  1. Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarction: a status report. Ann Intern Med. May 4 2004;140(9):729-737. PMID 15126257.
  2. Mathur A, Martin JF. Stem cells and repair of the heart. Lancet. Jul 10-16 2004;364(9429):183-192. PMID 15246732.
  3. U.S. Food and Drug Administration. Regenerative Medicine Advanced Therapy Designation. 2018; https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm537670.htm. Accessed March 12, 2018.
  4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Progenitor cell therapy for treatment of myocardial damage due to ischemia. TEC Assessments. 2008;Volume 23:Tab 4.
  5. Delewi R, Hirsch A, Tijssen JG, et al. Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur Heart J. Apr 2014;35(15):989-998. PMID 24026778.
  6. de Jong R, Houtgraaf JH, Samiei S, et al. Intracoronary stem cell infusion after acute myocardial infarction: a meta-analysis and update on clinical trials. Circ Cardiovasc Interv. Apr 1 2014;7(2):156-167. PMID 24668227.
  7. Fisher SA, Zhang H, Doree C, et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. Sep 30 2015(9):CD006536. PMID 26419913.
  8. Lalu, MM, Mazzarello, SS, Zlepnig, JJ, Dong, YY, Montroy, JJ, McIntyre, LL, Devereaux, PP, Stewart, DD, David Mazer, CC, Barron, CC, McIsaac, DD, Fergusson, DD. Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Transl Med, 2018 Sep 27;7(12). PMID 30255989.
  9. Moazzami K, Roohi A, Moazzami B. Granulocyte colony stimulating factor therapy for acute myocardial infarction. Cochrane Database Syst Rev. May 31 2013;5(5):CD008844. PMID 23728682.
  10. Schchinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. Sep 21 2006;355(12):1210-1221. PMID 16990384.
  11. Assmus B, Rolf A, Erbs S, et al. Clinical outcome 2 years after intracoronary administration of bone marrow- derived progenitor cells in acute myocardial infarction. Circ Heart Fail. Jan 2010;3(1):89-96. PMID 19996415.
  12. Hirsch A, Nijveldt R, van der Vleuten PA, et al. Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial. Eur Heart J. Jul 2011;32(14):1736-1747. PMID 21148540.
  13. Gyngysi M, Wojakowski W, Lemarchand P, et al. Meta-analysis of cell-based CaRdiac stUdiEs (ACCRUE) in patients with acute myocardial infarction based on individual patient data. Circ Res. Apr 10 2015;116(8):1346- 1360. PMID 25700037.
  14. Schchinger V, Erbs S, Elsasser A, et al. Improved clinical outcome after intracoronary administration of bone- marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J. Dec 2006;27(23):2775-2783. PMID 17098754.
  15. Fisher SA, Doree C, Mathur A, et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. Dec 24 2016;12:Cd007888. PMID 28012165.
  16. Fisher SA, Brunskill SJ, Doree C, et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. Apr 29 2014;4(4):CD007888. PMID 24777540.
  17. Xu R, Ding S, Zhao Y, et al. Autologous transplantation of bone marrow/blood-derived cells for chronic ischemic heart disease: a systematic review and meta-analysis. Can J Cardiol. Nov 2014;30(11):1370-1377. PMID 24726092.
  18. Xiao C, Zhou S, Liu Y, et al. Efficacy and safety of bone marrow cell transplantation for chronic ischemic heart disease: a meta-analysis. Med Sci Monit. Oct 01 2014;20:1768-1777. PMID 25270584.
  19. Fisher SA, Doree C, Taggart DP, et al. Cell therapy for heart disease: Trial sequential analyses of two Cochrane reviews. Clin Pharmacol Ther. Jul 2016;100(1):88-101. PMID 26818743.
  20. Bartunek J, Terzic A, Davison BA, et al. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur Heart J. Mar 01 2017;38(9):648-660. PMID 28025189.
  21. Pokushalov E, Romanov A, Chernyavsky A, et al. Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: a randomized study. J Cardiovasc Transl Res. Apr 2010;3(2):160-168. PMID 20560030.
  22. Povsic TJ, Henry TD, Traverse JH, et al. The RENEW Trial: Efficacy and safety of intramyocardial autologous CD34(+) cell administration in patients with refractory angina. JACC Cardiovasc Interv. Aug 8 2016;9(15):1576- 1585. PMID 27491607.
  23. Khan AR, Farid TA, Pathan A, et al. Impact of cell therapy on myocardial perfusion and cardiovascular outcomes in patients with angina refractory to medical therapy: a systematic review and meta-analysis. Circ Res. Mar 18 2016;118(6):984-993. PMID 26838794.
  24. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Jan 29 2013;61(4):e78-140. PMID 23256914.

Coding Section

Codes Number Description
CPT   No specific CPT codes
ICD-9 Diagnosis   Investigational for all diagnoses
ICD-10-CM (effective 10/01/15)   Investigational for all diagnoses
ICD-10-PCS (effective 10/01/15)   No specific code found for intracoronary infusion of stem cells 
  30243AZ Transfusion, central vein, percutaneous, embryonic stem cells
  30243X0, 30243X1, 30243Y0, 30243Y1 Transfusion, central vein, percutaneous, cord blood and hematopoietic stem cells, code list
Type of Service Surgery  
Place of Service inpatient  

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 and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

01/10/2020 

Annual review, no change to policy intent. Updating rationale and references. 

01/16/2019 

Annual review, no change to policy intent. Updating rationale and references.

02/07/2018 

Annual review, no change to policy intent. Updating regulatory status, rationale and references. 

01/17/2017 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

01/19/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. Deleting Index. 

01/22/2015 

Annual review, no change to policy intent. Updated rationale and references, added coding.

01/15/2014

Annual review. Updated rationale, references and regulatory status. Added benefit application and related policies. No change to policy intent.


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