Medical Policies - Surgery


Stem-Cell Therapy for the Treatment of Damaged Myocardium Due to Ischemia

Number:SUR703.027

Effective Date:10-01-2018

Coverage:

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Stem- or progenitor-cell therapy (autologous or allogeneic), including but not limited to skeletal myoblasts or hematopoietic stem-cells, is considered experimental, investigational and/or unproven as a treatment of damaged myocardium.

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

Description:

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

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 stem-cells (i.e., progenitor-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 stem-cells, endometrial mesenchymal stem-cells (MSCs), adult testis pluripotent stem-cells, mesothelial cells, adipose-derived stromal cells, embryonic cells, induced pluripotent stem-cells, and bone marrow MSCs, all of which can differentiate into cardiomyocytes and vascular endothelial cells.

The mechanism of benefit after treatment with stem-cells is not entirely understood. Differentiation of stem-cells into mature myocytes and engraftment of stem-cells into areas of damaged myocardium has been suggested in animal studies using tagged stem-cells. However, there is controversy concerning whether injected stem-cells engraft and differentiate into mature myocytes in humans to the degree that might result in clinical benefit. It also has been proposed that stem-cells may improve perfusion to areas of ischemic myocardium. Basic science research has also suggested that injected stem-cells secrete cytokines with antiapoptotic and pro-angiogenesis 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 (e.g., cytoprotective effects in acute ischemia and cell proliferation in chronic ischemia). Investigation of the specific factors induced by administration of stem-cells is ongoing.

There also are 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 stem-cells into the coronary circulation also is done using percutaneous, catheter-based techniques. Finally, stem-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 effects of stem-cells treatment include risks of the delivery procedure (e.g., thoracotomy, percutaneous catheter-based) and risks of the donor cells themselves. Donor stem-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 (e.g., teratomas) can arise from stem-cells, but the actual risk in humans is currently unknown.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulated 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. Stem-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. The 21st Century Cures Act (December 2016) established new expedited product development programs including one for regenerative medicine advanced therapy (RMAT). (3) The RMAT designation may be given if: 1) the drug is a regenerative medicine therapy (i.e., a cell therapy), therapeutic tissue engineering product, human cell and tissue product, or any combination product; 2) the drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and 3) preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs.

Multiple stem-cell therapies such as MyoCell® (U.S. Stem Cell, formerly BioHeart), ixmyelocel-T (Vericel, formerly Aastrom Biosciences), MultiStem® (Athersys), and CardiAMP™ (BioCardia) are being commercially developed, but none has 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. In 2017, U.S. Stem Cell reprioritized its efforts away from seeking RMAT designation for MyoCell®.

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. Vericel has received RMAT designation for Ixmyelocel-T.

MultiStem® (Athersys) is an allogeneic bone marrow-derived adherent adult stem-cell product.

CardiAMP™ Cell Therapy system consists of a proprietary assay to identify patients with a high probability to respond to autologous cell therapy, a proprietary cell processing system to isolate process and concentrate the stem-cells from a bone marrow harvest at the point of care, and a proprietary delivery system to percutaneously inject the autologous cells into the myocardium. BioCardia has received an investigational device exemption from FDA to perform a trial of CardiAMP™.

Rationale:

The policy was created in 2005 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through March 6, 2018.

Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function---including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing 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 a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use 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 medical policy focuses on phase 3 trials with at least 100 patients per arm and systematic reviews of RCTs. Relevant clinical trials and meta-analyses are reviewed for 3 different indications: 1) acute cardiac ischemia (myocardial infarction); 2) chronic cardiac ischemia; and 3) refractory or intractable angina in patients who are not candidates for revascularization. This medical policy focuses on the impact of stem-cell therapy on clinical outcomes but also includes data on physiologic outcomes, such as a change in left ventricular ejection fraction (LVEF). This policy was informed in part by a Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (2008). (4)

Stem- or Progenitor-Cells to Treat Acute Cardiac Ischemia

Systemic Reviews

Bone Marrow Cells

Four meta-analyses published from 2014 to 2015, including a Cochrane review and an individual patient data meta-analysis evaluating the use of progenitor cell therapy for treating acute ischemia (myocardial infarction), are described below. Table 1 details the reviews and summarizes the analyses.

Two meta-analysis 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 (total N=1641 patients). (5) The meta-analyses by de Jong et al. (2014) included 22 RCTs (total N=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 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 6 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 (total N=2732 patients). (7) Many were small trials and conducted outside the United States; 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 (total N=1252 patients), including the REPAIR-AMI trial (reviewed below), using a collaborative, multinational database, ACCRUE (meta-Analysis of Cell-based CaRdiac study; NCT01098591). (8) Eight trials had low risk of bias, and 4 single-blind (assessor) trials had medium-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 [MRI], single-proton emission computed tomography [SPECT], 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, 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.

Granulocyte Colony Stimulating Factor

The body of evidence on the use of granulocyte colony stimulating factor (G-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. (10) Literature was searched in November 2010, and 7 small, placebo-controlled randomized trials (total N=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 LV 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 stem-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 myocardial infarction and met strict inclusion criteria. (11-12) At 12-month follow-up, there were statistically significant decreases in the stem-cell group compared with the control group for MI (0 versus 6, p<0.03) and revascularization (22 versus 37, p<0.03), as well as for the composite outcome of death, MI, and revascularization (24 versus 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. (11, 13) Eleven deaths occurred during the 2-year follow-up, 8 in the placebo group and 3 in the stem-cell group. There was a significant reduction in MI (0% versus 7%), and a trend toward a reduction in rehospitalization for heart failure (1% versus 5%) and revascularization (25% versus 37%) in the active treatment group. Analysis of combined events (all combined events included infarction), showed significant improvement with stem-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 stem-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 (PCI). (14) Mononuclear cells were delivered 3 to 8 days after AMI. Blinded assessment of the primary outcome (the percentage of dysfunctional LV segments that had improved segmental wall thickening at 4 months) found no significant difference between the treatment groups (38.5% for bone marrow versus 36.8% for peripheral blood) and controls (42.4%). There was no significant difference between groups in LVEF; change in LV 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 for Systematic Reviews Assessing Use of Progenitor Cell Therapy to Treat 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 of 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%)

I2 = 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%)

I2=80%

0.68a

(0.36 to 1.31)

0.73a

(0.32 to 1.65)

Fisher et al. (2015) (7)

Through March 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)

Gyongyosi et al. (2015) (8)

 

12

1252

RCT of 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

Schachinger et al. (2006) (11, 12); 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) (14); 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 1 Year

By 1 Year

Mean Change from BL to 4 Months (SD)

Schachinger et al. (2006) (11, 12)

N

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=0.28

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) (14)

N

200

200

200

 

BMC therapy

0

4

0

189

PBC therapy

1

9

1

3.8 (7.4)

SOC

0

6

1

4.2 (6.2)

TEC (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; RCTA: randomized controlled trial; SOC: standard of care; TE: treatment effect.

Section Summary: Stem- or Progenitor-Cells to Treat Acute Cardiac Ischemia

The evidence on stem-cell therapy for patients with myocardial infarction includes two phase 3 RCTs that include 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 of LVEF and/or myocardial perfusion at 3 to 6 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 myocardial infarction, 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 quality of life. Overall, this evidence has suggested that stem-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.

Stem- or Progenitor-Cells to Treat Chronic 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, two phase 3 RCTs with more than 100 participants, and nonrandomized studies.

Systematic Reviews

Fisher et al. (2016) reported on a systematic review (15) that updated a 2014 Cochrane. (16) In 2016, literature was searched through December 2015, and 38 RCTs (total N=1907 patients) were included. The overall quality of the evidence was considered low because selected studies were small (only three 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. and by Xiao et al. (17, 18)

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

Variables

Short-Terma Mortality

Long-Termb Mortality

Long-Term b 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. 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). (19) 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 3 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. (20) 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) (19); 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) (20)

Russia

NR

NR

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

Bone Marrow (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) (19)

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 (0.5 to 2.7); 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) (20)

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; RR: relative risk; 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 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 PCI 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 5 years after intracoronary BMC therapy, there was a significant improvement in hemodynamics (LVEF, cardiac index), exercise capacity (NYHA classification), oxygen uptake, and LV 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 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: Stem- or Progenitor-Cells to Treat Chronic Ischemia

The evidence on stem-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 stem-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.

Stem- or 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) two phase ½ trials with more than 100 patients, (22, 27) and one phase 3 trial with more than 100 participants, which is discussed more in the section on RCTs. (28)

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. (29) The risk of bias in the included studies was rated as low. All selected randomized trials were placebo-controlled; 5 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 1 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) (29)

Up to Sep 2015

6

Refractory angina who were ineligible for coronary revascularization

353 (24-112)

RCT

6 months to 2 years

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) (29)

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

OR = 0.49 (0.25 to .98); 0.04

NR

NR

I2

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; NR: note reported.

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) (28); 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) (28)

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; 0TE: treatment effect; NR: not reported.

Section Summary: Stem- or 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 stem-cell therapy improves health outcomes in patients with refractory angina.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 11.

Table 11. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01781390a

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

105

Jun 2018

NCT01969890

Phase III Study on STem-cElls Mobilization in Acute Myocardial Infarction (STEM-AMI)

1530

Oct 2018 (suspended)

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 2018

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

Feb 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

NCT03418233a

Regeneration of lschemic 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 lschaemic Heart Failure (CIHF) (CIRCULATE)

115

Dec 2020

NCT01693042

Randomized Controlled Trial to Compare the Effects of Single Versus Repeated Intracoronary Application of Autologous Bone Marrow-derived Mononuclear Cells on Total and SHFM-predicted Mortality in Patients With Chronic Post-Infarction Heart Failure (REPEAT)

676

Jan 2025

NCT03455725a

Randomized Controlled Pivotal Trial of Autologous Bone Marrow Cells Using the CardiAMP Cell Therapy System in Patients With Refractory Angina Pectoris and Chronic Myocardial Ischemia (CardiAMP CMI Trial)

343

Dec 2026

NCT: National Cancer Trial.

a Denotes industry-sponsored or cosponsored trial.

Practice Guidelines and Position Statements

American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)

In 2013, ACCF/AHA issued joint guidelines on the management of ST-segment elevation myocardial infarction. (30) Stem-cell therapy was not recommended.

Summary of Evidence

For individuals who have acute cardiac ischemia who receive stem-cell therapy, the evidence includes two phase 3 randomized controlled trials (RCTs), numerous small, early-phase 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 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 (e.g., 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 two phase 3 RCTs with more than 100 participants, systematic reviews of smaller, early-phase RCTs, and a nonrandomized comparative trial. Relevant outcomes are disease-specific survival, morbid events, functional outcomes, quality of life, 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. 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.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

33999

HCPCS Codes

None

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarction: a status report. Ann Intern Med. May 4 2004; 140(9):729-37. PMID 15126257

2. Mathur A, Martin JF. Stem-cells and repair of the heart. Lancet. Jul 10 - 16 2004; 364(9429):183-92. PMID 15246732

3. U.S. Food and Drug Administration (FDA). Regenerative Medicine Advanced Therapy Designation (2018). Available at <https://www.fda.gov> (accessed - 2018 March 12).

4. Progenitor-cell therapy for treatment of myocardial damage due to ischemia. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2008 September) 23(4):1-36.

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):989-98. 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):156-67. 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. Gyongyosi 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- 60. PMID 25700037

9. 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

10. Moazzami K, Roohi A, Moazzami B. Granulocyte colony stimulating factor therapy for acute myocardial infarction. Cochrane Database Syst Rev 2013; 5:CD008844. PMID 23728682

11. Schachinger V, Erbs S, Elsasser A, et al. REPAIR-AMI Investigators. Intracoronary bone marrow-derived progenitor-cells in acute myocardial infarction. N Engl J Med. Sep 21 2006; 355(12):1210-21. PMID 16990384

12. Schachinger 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):2775-83. PMID 17098754

13. 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

14. 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):1736-47. PMID 21148540

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 ischemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2014; 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):1370-7. 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. 2014; 20:1768-77. PMID 25270584

19. 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

20. 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

21. Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary Stem-cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail. Jul 2010; 12(7):721-9. PMID 20576835

22. Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circulation Res. 2011; 109(4):428-36. PMID 21737787

23. van Ramshorst J, Bax JJ, Beeres SL, et al. Intramyocardial bone marrow cell injection for chronic myocardial ischemia. JAMA. May 20 2009; 301(19):1997-2004. PMID 19454638

24. Losordo DW, Schatz RA, White CJ, et al. lntramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/Ila double-blind, randomized controlled trial. Circulation. Jun 26 2007; 115(25):3165-3172. PMID 17562958

25. Tse HF, Thambar S, Kwong YL, et al. Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial). Eur Heart J. Dec 2007; 28(24):2998-3005. PMID 17984132

26. Jimenez-Quevedo P, Gonzalez-Ferrer JJ, Sabate M, et al. Selected CD133(+) progenitor cells to promote angiogenesis in patients with refractory angina: final results of the PROGENITOR randomized trial. Gire Res. Nov 7 2014; 115(11):950-960. PMID 25231095

27. Wang S, Cui J, Peng W, et al. lntracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology. Oct 2010; 117(2):140-147. PMID 20975266

28. 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. JAGG Gardiovasc lnte rv. Aug 8 2016; 9(15):1576-1585. PMID 27491607

29. 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. Gire Res. Mar 18 2016; 118(6):984-993. PMID 26838794

30. 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

31. Progenitor Cell Therapy for the Treatment of Damaged Myocardium Due to Ischemia. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 May) Medicine 2.02.18.

Policy History:

Date Reason
10/1/2018 Document updated with literature review. Coverage unchanged. References 3, 7, 9, 15, 19-20, 24-29 added, and some references removed.
6/1/2017 Reviewed. No changes.
10/1/2016 Document updated with literature review. Coverage unchanged.
11/1/2015 Reviewed. No changes.
12/1/2014 Document updated with literature review. Coverage unchanged. Rationale and References significantly reorganized and revised. “Due to Ischemia” was added to the policy title.
1/1/2012 Document updated with literature review. Policy titled changed from Autologous Cell Therapy for the Treatment of Damaged Myocardium to Stem-Cell Therapy for the Treatment of Damaged Myocardium. Coverage unchanged.
9/15/2009 Routine scheduled review; Revised/updated entire document; no changes to coverage statement.
9/15/2007 Revised/updated entire document
3/1/2005 New medical document

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