Populations	Interventions	Comparators	Outcomes
Individuals: With acute cardiac ischemia	Interventions of interest are: Progenitor cell therapy	Comparators of interest are: Standard therapy	Relevant outcomes include: Disease-specific survival Morbid events Functional outcomes Quality of life Hospitalizations
Individuals: With chronic cardiac ischemia	Interventions of interest are: Progenitor cell therapy	Comparators of interest are: Standard therapy	Relevant outcomes include: Disease-specific survival Morbid events Functional outcomes Quality of life Hospitalizations
Individuals: With refractory angina	Interventions of interest are: Progenitor cell therapy	Comparators of interest are: Standard therapy	Relevant outcomes include: Disease-specific survival Morbid events Functional outcomes Quality of life Hospitalizations

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,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 for regenerative medicine advanced therapy (RMAT).^2,The RMAT designation may be given if: (1) the drug is a regenerative medicine therapy (ie, 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.

Regulatory Status

Multiple progenitor cell therapies such as MyoCell^® (U.S. Stem Cell, formerly Bioheart), ixmyelocel-T (Vericel, formerly Aastrom Biosciences), MultiStem^® (Athersys), and CardiAMPTM (BioCardia) are being commercially developed, but none has been approved by the U.S. Food and Drug Administration (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. weeks. The expanded cell product enriched for mesenchymal and macrophage lineages might enhance potency. Vericel has received RMAT designation for Ixmyelocel-T.

MultiStem® 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 the FDA to perform a trial of CardiAMP.

Related Policies

• Orthopedic Applications of Stem Cell Therapy (Including Allografts and Bone Substitutes Used with Autologous Bone Marrow) (Policy #129 in the Treatment Section)
• Stem-Cell Therapy for Peripheral Arterial Disease (Policy #133 in the Treatment Section)

Evidence reviews assess the clinical evidence to determine whether the use of 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 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 technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 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 policy 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 3 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 policy 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 policy was informed in part by a TEC Assessment (2008).^3,

Progenitor Cells to Treat Acute Cardiac Ischemia
Clinical Context and Therapy Purpose

The purpose of progenitor cell therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as medication, angioplasty and stenting, bypass surgery, and enhanced external counterpulsation, in patients with acute cardiac ischemia.

The question addressed in this policy is: Does the use of progenitor cell therapy improve the net health outcome in individuals with acute cardiac ischemia?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with acute cardiac ischemia.

Interventions

The therapy being considered is progenitor cell therapy. Progenitor cell therapy is the use of multipotent cells of various cell lineages (autologous or allogeneic) to repair and/or regenerate tissue, including damaged myocardium caused by cardiac ischemia.

Patients with acute cardiac ischemia who are receiving progenitor stem cell therapy are actively managed by cardiologists, generally in a tertiary care setting.

Comparators

Comparators of interest are standard of care measures, such as medication, angioplasty and stenting, bypass surgery, and enhanced external counterpulsation.

Patients with acute cardiac ischemia are actively managed by cardiologists, generally in a tertiary care setting if accompanied by chest pain.

Outcomes

The general outcomes of interest are disease-specific survival, morbid events, functional outcomes, quality of life, and hospitalizations. For studies, follow-up of at least 6 months to 2 years is preferable; however, cardiac ischemia can be a chronic condition, and patients are managed by cardiologists for all their lives.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

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 (myocardial infarction [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 ( N = 1641 patients).^4,De Jong et al (2014) included 22 RCTs ( N = 1513 patients) in their meta-analysis.^5, 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 (2014) showed that the treatment benefit was greater among younger patients (age < 55 years) and among patients with more severely depressed LVEF at baseline (< 40%), whereas 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 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.

Fisher et al (2015) published a Cochrane review on stem cell treatment for AMI that included 41 trials ( N = 2732 patients).^6, 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 ( N =1252 patients)with data from a collaborative, multinational database, Meta-analysis of Cell-Based Cardiac Study (ACCRUE; NCT01098591).^7,The meta-analysis included the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial (reviewed below).Eight trials had low risk of bias, and 4 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 [MRI], single-photon 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.^8, 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 deaths in 1073 patients (4.0%) who received cell therapy compared with 38 deaths in 754 patients (5.0%) 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%CI, 0.62-1.36). 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 nonrandomized studies.^9, 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 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 ( 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, 0.2-2.8; P =.55; I² = 0%). Similarly, change in left ventricular ejection fraction (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 (Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction) 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<.03) and revascularization (22 vs. 37, P <.03), as well as for the composite outcome of death, myocardial infarction, and revascularization (24 vs. 42, P<.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.^12,13, Eleven deaths occurred during the 2-year follow-up, 8 in the placebo group and 3 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.^14,In the Clinical Study to Examine the Effects of Erythropoietin on Left Ventricular Function After Acute Myocardial Infarction (HEBE) trial, mononuclear cells were delivered 3 to 8 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 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)4,	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)5,	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)6,	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)7,		12	1252	RCT or cohort	≤ 14 d	6 (3-12)	0.96 (-0.2 to 2.1)	0.70 (P =.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).
^bAs measured by magnetic resonance imaging.
^c Relative risk (95% CI).

					Interventions
Study; Trial	Countries	Sites	Dates	Participants	Cell Therapies	Comparator
Schächinger 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)

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)
Schächinger 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-value	NR; P =.28	NR; P =.01	NR; P =.25	NR; P =.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)
TE; p	NR	NR	NR	4.0 (5.8)

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 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 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 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.

Progenitor Cells to Treat Chronic Cardiac Ischemia
Clinical Context and Therapy Purpose

The purpose of progenitor cell therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as medication, angioplasty and stenting, bypass surgery, and enhanced external counterpulsation, in patients with chronic cardiac ischemia.

The question addressed in this policy is: Does the use of progenitor cell therapy improve the net health outcome in individuals with chronic cardiac ischemia?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with chronic cardiac ischemia.

Interventions

The therapy being considered is progenitor cell therapy. Progenitor cell therapy is the use of multipotent cells of various cell lineages (autologous or allogeneic) to repair and/or regenerate tissue, including damaged myocardium caused by cardiac ischemia.

Patients with chronic cardiac ischemia who are receiving progenitor stem cell therapy are actively managed by cardiologists in an outpatient clinical setting; progenitor cell therapy is generally performed in a tertiary care setting.

Comparators

Comparators of interest are standard of care measures, such as medication, angioplasty and stenting, bypass surgery, and enhanced external counterpulsation.

Patients with chronic cardiac ischemia are actively managed by cardiologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are disease-specific survival, morbid events, functional outcomes, quality of life, and hospitalizations. Available literature reports follow-up of up to 5 years; however, cardiac ischemia is a chronic condition, and patients are managed by cardiologists for all their lives.

Study Selection Criteria

Methodologically credible studies were selected using the principles described in the first indication.

in patients with chronic ischemic heart disease. The evidence for stem cell therapy for chronic ischemic heart disease includes systematic reviews, many small, early-phase RCTs, 2 phase 3 RCTs with more than 100 participants, and nonrandomized studies.

Review of Evidence
Systematic Reviews

Fisher et al (2016) published a systematic review^15, that updated a 2014 Cochrane review.^16, In 2016, literature was searched through December 2015, and 38 RCTs ( N = 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. Although 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. Xu et al (2014) and Xiao et al (2014) reported similar results in 2014 in their meta-analyses(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 nonrandomized studies.^9, The review did not include any RCTs on chronic cardiac ischemia published after the preceding Fisher et al (2016) review or otherwise discussed in the section below and will not be discussed further.

Randomized Controlled Trials

Bartunek et al (2017) reported on a multinational, sham-controlled RCT on cardiopoietic cell therapy for advanced ischemic heart failure.^19,Researchers for the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial initially screened 484 patients with symptomatic ischemic heart failure who were on standard therapy; of those, 348 underwent bone marrow harvest and mesenchymal stem cell expansion. The 315 who achieved > 24 million mesenchymal cells were randomized to either cardiopoietic stem cell therapy (n = 157) or sham treatment (n = 158). Before treatments began, 37 patients in the stem cell group and 7 patients in the control group withdrew from the study; therefore, the 39-week follow-up analysis included 120 patients who had received the stem cells and 151 who had undergone sham treatment. 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, 0.47-0.61; P =.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, 0.52-0.70; P =.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 4 and 5. The RCT reported statistically significant improvements in mortality rates at 12 months for cell therapy (11%) versus medical therapy (39%) favoring medical therapy (P <.001).

Table 4. 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 cells (n = 55)	Medical management, no sham (n = 54)

CHART-1: Congestive Heart Failure Cardiopoietic Regenerative Therapy; 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.

Study	Mortality, n (%)	Change in Heart Failure, n (%)	MLHFQ Score, n (%)	6-Minute Walk Test	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-value	HR = 1.2 (0.5 to 2.7);.70	Oddsa = 1.03 (0.9 to 1.2);.72	Oddsa = 0.8 (0.7 to 1.0);.12	Oddsa = 0.8 (0.7 to 1.0);.07	Oddsa = 1.0 (0.8 to 1.2);.73
	At 12 Months	Improvement in NYHA Class by 1 Class at 3 Months		Mean Distance Walked at 12 Months (SD), m	zzzzSD)
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)
TEP-value	<.001	NR		.03	NR

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. Strauer et al (2010) reported on this nonrandomized open-label study, which 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 5 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 <.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 outcomes, including death, worsening heart failure, and other 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 suggests 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
Clinical Context and Therapy Purpose

The purpose of progenitor cell therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as medication, angioplasty and stenting, bypass surgery, and enhanced external counterpulsation, in patients with refractory angina.

The question addressed in this policy is: Does the use of progenitor cell therapy improve the net health outcome in individuals with refractory angina?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with refractory angina.

Interventions

The therapy being considered is progenitor cell therapy. Progenitor cell therapy is the use of multipotent cells of various cell lineages (autologous or allogeneic) to repair and/or regenerate tissue, including damaged myocardium.

Patients with refractory angina who are receiving progenitor stem cell therapy are actively managed by cardiologists in an outpatient clinical setting; progenitor cell therapy is generally performed in a tertiary care setting.

Comparators

Comparators of interest are standard of care measures, such as medication, angioplasty and stenting, and bypass surgery.

Patients with refractory are actively managed by cardiologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are disease-specific survival, morbid events, functional outcomes, quality of life, and hospitalizations. Available literature reports follow-up of up to 2 years.

Study Selection Criteria

Methodologically credible studies were selected using the principles described in the first indication.

The evidence for stem cell therapy for patients with intractable angina who are not candidates for revascularization includes a systematic review,^22, 4 trials from 2007 through 2014 with fewer than 100 patients,^23,24,25,26, 2 phase 1/2 trials with more than 100 patients,^27,28, and 1 phase 3 trial with more than 100 participants,^29, which is discussed more in the section on RCTs.

Review of Evidence
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.^22, 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 1 blinding was not reported. The systematic review characteristics and results are shown in Tables 6 and 7. 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 6. Systematic Review Characteristics of Progenitor Cell Therapy for Refractory Angina

Study	Dates	Trials	Participants	N (Range)	Design	Length of FU
Khan et al (2016)22,	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 7. Systematic Review Results of Progenitor Cell Therapy for Refractory Angina

Study	Frequency of Angina	CCS Angina Class	MACE	Mortality	QOL
Khan et al (2016)22,
Total N	271	210	NR	NR	NR
PE (95% CI); P-value	MD = -7.8 (-15.2 to -0.41);.04	MD = -0.58 (-1.00 to -0.16);.007	OR = 0.49 (0.25 to 0.98);.04	NR	NR
I2 (P-value)	90% (<.001)	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 8 and 9.

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.^29, 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 8. RCT Characteristics of Progenitor Cell Therapy for Refractory Angina

					Interventions
Study; Trial	Countries	Sites	Dates	Participants	Cell Therapy	Comparator
Povsic et al (2016)29,; 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; RENEW: Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells.

Table 9. 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)29,
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-value	RR = 1.02 (NR);.95	20.4 (-68.9 to 109.6);.65	NR	NR
TE for CT vs. SOC (95% CI); P-value	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 2 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 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 (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 2 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 Stem Cell Transplantation in 191 Patients With Chronic Heart Failure (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.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements

In 2015, the American College of Cardiology Foundation, American Heart Association, and the Society for Cardiovascular Angiography and Interventions issued a Focused Update on Primary Percutaneous Coronary Interventions for Patients With ST-Elevation Myocardial Infarction.^30,This guideline was an update of the 2011 guideline for percutaneous coronary intervention^31, and the 2013 guideline on managing ST-elevation myocardial infarction.^32, Progenitor cell therapy was not mentioned in this update or in the 2013 guidelines.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 10.

Table 10. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
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) (Status unknown, last updated July 2017)	170	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) (Status unknown, last updated June 2017)	350	Oct 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
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
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
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	Prospective, multi-center, 2:1 randomized (Treatment vs. Sham Control), blinded trial comparing 2 parallel groups of patients with CMI treated with CardiAMP cell therapy system vs. sham treatment (CardiAMP CMI)	343	Dec 2026

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

Horizon BCBSNJ Medical Policy Development Process:

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

___________________________________________________________________________________________________________________________

Index:
Progenitor Cell Therapy for the Treatment of Damaged Myocardium Due to Ischemia
Autologous Cell Therapy for the Treatment of Damaged Myocardium
Cellular Cardiomyoplasty
Cardiomyoplasty, Cellular
MyoCell
Prochyma
Provacel
MultiStem
Autologous Cell Transplant, Heart Disease
BioHeart
Ixmyelocel-T
CardiAMP

References:
1. Lee MS, Makkar RR. Stem-cell transplantation in myocardial infarction: a status report. Ann Intern Med. May 04 2004; 140(9): 729-37. PMID 15126257

2. U.S. Food and Drug Administration. Regenerative Medicine Advanced Therapy Designation. 2018; https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm537670.htm. Accessed March 31, 2020.

3. 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.

4. 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

5. 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 2014; 7(2): 156-67. PMID 24668227

6. 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

7. 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

8. 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

9. Lalu MM, Mazzarello S, Zlepnig J, et al. 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. Dec 2018; 7(12): 857-866. PMID 30255989

10. Moazzami K, Roohi A, Moazzami B. Granulocyte colony stimulating factor therapy for acute myocardial infarction. Cochrane Database Syst Rev. May 31 2013; (5): CD008844. PMID 23728682

11. 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

12. Schachinger 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): 1210-21. PMID 16990384

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 ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. Apr 29 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. Oct 01 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): 160-8. 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. 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): 984-93. PMID 26838794

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

24. Losordo DW, Schatz RA, White CJ, et al. Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. Jun 26 2007; 115(25): 3165-72. 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. Circ Res. Nov 07 2014; 115(11): 950-60. PMID 25231095

27. Wang S, Cui J, Peng W, et al. Intracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology. 2010; 117(2): 140-7. PMID 20975266

28. Losordo DW, Henry TD, Davidson C, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. Aug 05 2011; 109(4): 428-36. PMID 21737787

29. 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 08 2016; 9(15): 1576-85. PMID 27491607

30. Levine GN, Bates ER, Blankenship JC, et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial Infarction: An update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. May 2016; 87(6): 1001-19. PMID 26489034

31. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. Dec 06 2011; 124(23): e574-651. PMID 22064601

32. 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-e140. PMID 23256914