National Medical Policy

National Medical Policy Subject: Policy Number: Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction NMP316 Effective Date*: January 2007 Updated: May 2016 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State's Medicaid manual(s), publication(s), citations(s) and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 1

Current Policy Statement Health Net, Inc. considers autologous stem cell transplantation for treatment of a damaged myocardium, including but not limited to, acute myocardial infarction (ASTAMI) or treatment of heart failure, investigational. Although studies are still being done, there is insufficient peer-reviewed scientific literature to support its long-term safety and efficacy. Definitions CDCs hmscs SCIPIO MACE LVEF ABMMNCs EDV STEMI BMMCs BMC Cardiosphere-derived cells Human mesenchymal stem cells Stem cell infusion in Patients with Ischemic cardiomyopathy Major adverse cardiovascular events Left ventricular ejection fraction Autologous bone marrow mononuclear cell End-diastolic volume ST-elevation myocardial infarction Bone marrow mononuclear cells Bone marrow cells Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or non-covered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes 410-410.9 Acute myocardial infarction 411.0 411.89 Other acute and subacute forms of ischemic heart disease 414.8-414.9 Other specified forms of chronic ischemic heart disease 428-428.9 Heart failure ICD-10 Codes I21-I21.4 I22-I22.9 I23-I23.8 I24-I24.9 I25-I25.9 I50-150.9 ST elevation (STEMI) and non-st elevation (NSTEMI) myocardial infarction Subsequent ST elevation (STEMI) and non-st elevation (NSTEMI) myocardial infarction Certain current complications following ST elevation (STEMI) and non- ST elevation (NSTEMI) myocardial infarction (within the 28 day period) Other acute forms of myocardial Chronic ischemic heart disease Heart failure CPT Codes 33999 Unlisted procedure for cardiac surgery 38206 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous 38241 Hematopoietic progenitor cell (HPC); autologous transplantation Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 2

HCPCS Codes N/A Scientific Rationale Update May 2016 Fisher et al (2015) sought to determine the safety and efficacy of autologous adult bone marrow stem cells as a treatment for acute myocardial infarction (AMI), focusing on clinical outcomes. This Cochrane review is an update of a previous version (published in 2012). RCTs comparing autologous bone marrow-derived cells with no cells in patients diagnosed with AMI were eligible. Two review authors independently screened all references, assessed the risk of bias of the included trials and extracted data. The authors conducted metaanalyses using random-effects models throughout. The authors analyzed outcomes at shortterm (less than 12 months) and long-term (12 months or more) follow-up. Dichotomous outcomes are reported as risk ratio (RR) and continuous outcomes are reported as mean difference (MD) or standardised MD (SMD). They performed sensitivity analyses to evaluate the results in the context of the risk of selection, performance and attrition bias. Exploratory subgroup analysis investigated the effects of baseline cardiac function (left ventricular ejection fraction, LVEF) and cell dose, type and timing of administration, as well as the use of heparin in the final cell solution. Forty-one RCTs with a total of 2732 participants (1564 cell therapy, 1168 controls) were eligible for inclusion. Cell treatment was not associated with any changes in the risk of all-cause mortality (34/538 versus 32/458; RR 0.93, 95% CI 0.58 to 1.50; 996 participants; 14 studies; moderate quality evidence), cardiovascular mortality (23/277 versus 18/250; RR 1.04, 95% CI 0.54 to 1.99; 527 participants; nine studies; moderate quality evidence) or a composite measure of mortality, reinfarction and re-hospitalization for heart failure (24/262 versus 33/235; RR 0.63, 95% CI 0.36 to 1.10; 497 participants; six studies; moderate quality evidence) at long-term follow-up. Statistical heterogeneity was low (I(2) = 0% to 12%). Serious periprocedural adverse events were rare and were generally unlikely to be related to cell therapy. Additionally, cell therapy had no effect on morbidity, quality of life/performance or LVEF measured by magnetic resonance imaging. Meta-analyses of LVEF measured by echocardiography, single photon emission computed tomography and left ventricular angiography showed evidence of differences in mean LVEF between treatment groups although the mean differences ranged between 2% and 5%, which are accepted not to be clinically relevant. Results were robust to the risk of selection, performance and attrition bias from individual studies. The reviewers concluded the results of this review suggest that there is insufficient evidence for a beneficial effect of cell therapy for AMI patients. However, most of the evidence comes from small trials that showed no difference in clinically relevant outcomes. Further adequately powered trials are needed and until then the efficacy of this intervention remains unproven. Martino et al (2015) reported pre-clinical and few clinical studies suggest that transplantation of autologous bone marrow mononuclear cells (BMNC) improves heart function in dilated cardiomyopathies. The authors sought to determine if intracoronary injection of autologous BMNC improves the left ventricular ejection fraction (LVEF) of patients with non-ischemic dilated cardiomyopathy (NIDCM). This study was a multicenter, randomized, double-blind, placebo controlled trial with a follow-up of 12 months. Patients with NIDCM and LVEF <35% were recruited at heart failure ambulatories in specialized hospitals around Brazil. One hundred and sixty subjects were randomized to intracoronary injection of BMNC or placebo (1:1). The primary endpoint was the difference in change of LVEF between BMNC and placebo groups as determined by echocardiography. One hundred and fifteen patients completed the study. Left ventricular ejection fraction decreased from 24.0% (21.6-26.3) to 19.9% (15.4-24.4) in the BMNC group and from 24.3% (22.1-26.5) to 22.1% (17.4-26.8) in the placebo group. There were no significant differences in changes Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 3

between cell and placebo groups for left ventricular systolic and diastolic volumes and ejection fraction. Mortality rate was 20.37% in placebo and 21.31% in BMNC. The authors concluded intracoronary injection of autologous BMNC does not improve left ventricular function in patients with NIDCM. Khan et al (2016) reported the effect of stem/progenitor cells on myocardial perfusion and clinical outcomes in patients with refractory angina remains unclear because studies published to date have been small phase I-II trials. The authors performed a meta-analysis of randomized controlled trials to evaluate the effect of cell-based therapy in patients with refractory angina who were ineligible for coronary revascularization. Several data sources were searched from inception to September 2015, which yielded 6 studies. The outcomes pooled were indices of angina (anginal episodes, Canadian Cardiovascular Society angina class, exercise tolerance, and antianginal medications), myocardial perfusion, and clinical end points. The authors combined the reported clinical outcomes (myocardial infarction, cardiac-related hospitalization, and mortality) into a composite end point (major adverse cardiac events). Mean difference (MD), standardized mean differences, or odds ratio were calculated to assess relevant outcomes. The analysis showed an improvement in anginal episodes (MD, -7.81; 95% confidence interval [CI], -15.22 to -0.41), use of antianginal medications (standardized MD, -0.59; 95% CI, -1.03 to -0.14), Canadian Cardiovascular Society class (MD, -0.58; 95% CI, -1.00 to -0.16), exercise tolerance (standardized MD, 0.331; 95% CI, 0.08 to 0.55), and myocardial perfusion (standardized MD, -0.49; 95% CI, -0.76 to -0.21) and a decreased risk of major adverse cardiac events (odds ratio, 0.49; 95% CI, 0.25 to 0.98) and arrhythmias (odds ratio, 0.25; 95% CI, 0.06 to 0.98) in celltreated patients when compared with patients on maximal medical therapy. The authors concluded the present meta-analysis indicates that cell-based therapies are not only safe but also lead to an improvement in indices of angina, relevant clinical outcomes, and myocardial perfusion in patients with refractory angina. These encouraging results suggest that larger, phase III randomized controlled trials are in order to conclusively determine the effect of stem/progenitor cells in refractory angina. Scientific Rationale Update May 2015 There is a Clinical Trial on Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure (ESCORT), which is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT02057900, and it was last updated on March 31, 2015. The purpose of the study is to assess the feasibility and safety of a transplantation of cardiac-committed progenitor cells derived from human embryonic stem cells in patients with severe heart failure. The estimated study completion date is June 2017. Malliaras et al. (2014) completed a study in which autologous cardiosphere-derived cells (CDCs) (12.5 to 25 106) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-mi). Eight patients were followed as routine-care control patients. In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-mi responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDCtreated subjects were consistent with the natural relationship between scar size and ejection fraction post-mi. Intracoronary administration of autologous CDCs did not raise significant Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 4

safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year posttreatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived autologous stem CElls to reverse ventricular dysfunction [CADUCEUS]; NCT00893360. Heldman et al. (2014) completed a phase 1 and 2 randomized, blinded, placebo-controlled study to demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. It involved 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n=11) and BMCs (n=19) with placebo (n=10), with 1 year of follow-up. Injections in 10 LV sites with an infusion catheter. Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P=.03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P=.004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P=.11) or placebo (-5.2%; 95% CI, - 16.8% to 6.5%; within-group, P=.36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P=.03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P=.21) or placebo (-0.03; 95% CI, -1.9 to 1.9;P=.14). Left ventricular chamber volume and ejection fraction did not change. Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00768066. Per UpToDate, Colucci et al. (2015) Hematopoietic stem cells are bone marrow-derived cells capable of differentiating into a variety of cell types. Such cells may be obtained directly from the bone marrow or, using apheresis techniques, from peripheral blood usually after stimulation with granulocyte-colony stimulating factor (G-CSF). Some studies have used hematopoietic stem cells to repopulate the myocardium of patients with an acute myocardial infarction (MI) or ischemic cardiomyopathy. Based on the studies, it s not recommended to have bone marrow cell (BMC) therapy for patients with acute myocardial infarction (MI) except as part of an investigational study. Early unblinded studies suggested a benefit from stem cell therapy following acute myocardial infarction (MI). However, more blinded randomized trials, including BOOST (i.e., found in the Initial Scientific Rationale), (i.e. ASTAMI found in the June Scientific Rational Update), and others have not produced evidence of important clinical benefit. The American Heart Association (2013) notes: Stem cell based therapies have the potential to fundamentally transform the treatment of HF by achieving what would have been unthinkable only a few years ago myocardial regeneration. For the first time since cardiac transplantation, a therapy is being developed to eliminate the underlying cause of HF, not Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 5

just to achieve damage control. Since the initial report of cell therapy (i.e., skeletal myoblasts) in HF in 1998, research has proceeded at lightning speed, and numerous preclinical and clinical studies have been performed that support the ability of various stem cell populations to improve cardiac function and reduce infarct size in both ischemic and nonischemic cardiomyopathy. Nevertheless, we are still at the dawn of this therapeutic revolution. Many important issues (eg., mechanisms of action of stem cells, long-term engraftment, optimal cell types, and dose, route, and frequency of cell administration) remain to be resolved, and no cell therapy has been conclusively shown to be effective. Scientific Rationale Update May 2014 The Clinical Trial on Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) with the ClinicalTrials.gov Identifier of NCT00587990, had been completed but no study results are posted. The other Clinical Trials noted within the Scientific Rationale - Update May 2013, are still ongoing. There is a prospective, multicenter, randomized trial, that was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. This C-Cure Clinical Trial by Bartuniak et al. (2013), with the ClinicalTrials.gov Identifier of NCT00810238, has been completed but no study results are posted on the clinical trial site. However, results were noted on another site which featured the study by Bartuniak. The purpose of this clinical trial was to evaluate the feasibility, safety and efficacy of left ventricular endocardial injection of guided bone marrow-derived cardiopoietic cells (C-Cure) in the setting of chronic heart failure secondary to ischemic cardiomyopathy. the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Mesenchymal stem cell cocktail based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume ( 24.8 ± 3.0 ml vs. 8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. 15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. The C- CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. Based on the outcomes of this trial, further progression can be done to proceed with a Phase III trial (CHART-1). The therapy is currently the first-of-its-kind in a Phase III trial worldwide using organ specified cells (preprogrammed cardiac progenitor cells) for the treatment of ischemic heart failure and will recruit approximately 240 patients, with chronic advanced symptomatic heart failure. There is another Clinical Trial on Safety and Efficacy of Autologous Cardiopoietic Cells for Treatment of Ischemic Heart Failure. (CHART-1) with the ClinicalTrials.gov Identifier of NCT01768702. The study is currently recruiting participants and was last updated on January 8, 2014. The purpose of this study is to evaluate the safety and efficacy of C3BS- CQR-1 by comparing the overall response to standard of care and C3BS-CQR-1 relative to Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 6

standard of care and a sham procedure. The estimated primary completion date is March 2017. Scientific Rationale Update May 2013 The first step in the management of the patient with an acute ST elevation myocardial infarction (STEMI) is prompt recognition, since the beneficial effects of therapy with reperfusion are greatest when performed soon after presentation. For patients presenting to the emergency department with chest pain suspicious for an acute coronary syndrome (ACS), the diagnosis of STEMI can be confirmed by the ECG. Biomarkers may be normal early. Early unblinded studies suggested a benefit from stem cell therapy following acute MI. However, more recent blinded randomized trials have produced mixed results. The mechanisms of potential benefit remain uncertain. Per the Journal of the American College of Cardiology (2011): Stem cell therapy also represents an ultimate approach in advanced cardiac failure. For acute myocardial infarction and chronic ischemia, long-term mortality after 1 and 5 years, respectively, is significantly reduced. A few studies also indicate beneficial effects for chronic dilated cardiomyopathy. The clinical use of autologous bone marrow cell (BMC) therapy implies no ethical problems, when unmodified primary cells are used. With the use of primary BMCs, there are no major stem cell-related side effects, especially no cardiac arrhythmias and inflammation. Various mechanisms of the stem cell action in the human heart are discussed, for example, cell transdifferentiation, cell fusion, activation of intrinsic cardiac stem cells, and cytokine-mediated effects. New techniques allow point-of-care cell preparations, for example, within the cardiac intervention or operation theater, thereby providing short preparation time, facilitated logistics of cell transport, and reasonable cost effectiveness of the whole procedure. The 3 main indications are acute infarction, chronic ischemic heart failure, and dilated cardiomyopathy. Future studies are desirable to further elucidate the mechanisms of stem cell action and to extend the current use of intracoronary and/or intramyocardial stem cell therapy by larger and presumably multicenter and randomized trials. Important prerequisites for clinical cell therapy are the precise and careful preparation of the cells harvested from the adult bone marrow, the concentration of high cell numbers within the infarction, predominantly in the ischemic border zone, an enhanced migration of stem cells into the apoptotic and necrotic myocardial tissue, and the homing of the injected cells in the damaged myocardium, to avoid the recirculation loss of the injected cells to bone marrow, spleen, liver, and lungs. Several trials running currently are trying to answer the questions mentioned in the preceding text. Regarding the effect of intracoronary bone marrow progenitor cell infusion in the setting of acute myocardial infarction, placebo-controlled Phase II/III trials like REGEN-AMI (Bone Marrow Derived Adult Stem Cells for Acute Anterior Myocardial Infarction) are of interest. In the field of surgical cell therapy, the recently launched PERFECT (intramyocardial transplantation of bone marrow stem cells For improvement of post-infarct myocardial regeneration in addition to CABG surgery) study is the first placebo-controlled, double-blinded, multicenter Phase III trial investigating the effects of intramyocardial BMC injection combined with CABG surgery. Although representing Phase I and II levels, PROMETHEUS (Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 7

Cardiac Surgery) is highly interesting because it represents the first-in-human study analyzing the safety and efficacy of intramyocardial injection of mesenchymal stem cells during CABG in patients scheduled for coronary surgery due to ischemic heart disease, as an alternative cell population to the hematopoietic progenitor cell populations mainly used in clinical trials for cardiac regeneration so far. In this respect, the combination treatment of purified endothelial progenitor cells and mesenchymal stem cells has been addressed successfully in a Phase I trial with intramyocardial injection. There are several more interesting trials currently recruiting patients, and results from all of these are needed for a valid evaluation of the gain in cardiac function related to stem cell therapy. Future studies should aim at defining the optimum technique of cell preparation, discovering the best cell type and amount for myocardial regeneration, analyzing their homing characteristics to the cardiac endothelium and to extracardiac organs, improving cell delivery techniques, and trying to establish indications for cell therapy in various heart diseases. Joint and cooperative studies between pre-clinical and clinical research are essential. The mechanisms of stem cell-related cardiac repair need to be further investigated and alternative modes of action such as paracrine activity and immunomodulation should be considered. Attempts to create dynamic multi-lineage cardiac regeneration by combining cell therapy with tissueengineered scaffolds or cardiac resynchronization therapy should be further supported because they offer a realistic perspective to come to an integrated regenerative approach. As with each new therapy, new questions arise parallel to its clinical use: the following methodologic and therapeutic questions would be worth to be analyzed in the future: 1) to define the optimum technique of cell preparation; 2) to standardize cell separation procedures; 3) to evaluate the quality of the cell end product; 4) to discover the best cell type for myocardial regeneration; 5) to analyze cell homing characteristics to the cardiac niche; 6) to characterize the mode of action of stem cells for cardiac regeneration; 7) to improve cell delivery techniques; and 8) to label stem cells for determining stem cell fate. Interest should be focused on adult stem cell projects that have already proven significant clinical efficacy, but without having any ethical concerns. There is a Clinical Trial on Bone Marrow Derived Adult Stem Cells for Acute Anterior Myocardial Infarction (REGEN-AMI). The recruitment status of this study is unknown, with last verification in February 2011. The clincialtrials.gov identifier number of NCT00765453. The purpose of this study is to determine whether Intracoronary infusion of autologous bone marrow derived progenitor cells to patients undergoing primary angioplasty for acute anterior myocardial infarction will lead to an improvement in cardiac function greater than that seen by placebo alone. The estimated primary completion date is listed as October 2012, however, study is still not completed. There is another Clinical Trial on Intramyocardial Transplantation of Bone Marrow Stem Cells in Addition to Coronary Artery Bypass Graft (CABG) Surgery (PERFECT) that is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT00950274, and it was last verified in October 2012. The aim of the current study is to determine whether intramyocardial injection of autologous CD133+ bone marrow stem cells yields a functional benefit in addition to coronary artery bypass graft (CABG) surgery in patients with chronic ischemic coronary artery disease. The estimated primary completion date is December 2013. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 8

There is a Phase I/II Clinical Trial on Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) that has recently been completed, but no study results are posted. The clinicaltrials.gov identifier is NCT00587990, and it was last verified in April 2013. This study will evaluate the safety and effectiveness of injecting mesenchymal stem cells (MSCs) into the heart to repair and restore heart function in people who have had a heart attack and who are having heart surgery for coronary artery bypass grafting (CABG). There is a prospective, randomized, double blind, controlled Clinical Trial on Transplantation of Autologous Cardiac Stem Cells in Ischemic Heart Failure that is currently recruiting participants. The ClinicalTrials.gov Identifier is NCT01758406, and it was last verified in October 2011. The purpose of this trial is to assess the efficacy of intracoronary transplantation of autologous cardiac stem cells in 50 patients with ischemic heart failure. The estimated primary completion date is December 2015. Dawe et al. (2011) Despite timely reperfusion and subsequent optimal postinfarct pharmacotherapy and device-based treatment, the outcome in patients with severe myocardial infarction remains unfavourable. Myocardial salvage is incomplete, resulting in adverse left ventricular remodeling with concomitant morbidity and mortality. The combined risk of recurrent myocardial infarction, death or readmission for heart failure amounts to 25 % within the first year, highlighting the need for additional treatment strategies. Recent and rapidly evolving insights in cardiac biology, recognizing endogenous repair capabilities of the adult human heart, paved the path towards progenitor or stem cell based cardiac protection and repair strategies following ischemic injury. The authors critically report on the major randomized controlled clinical trials published so far concerning intracoronary transfer of autologous bone marrow cells in the setting of acute myocardial infarction. Underlying mechanisms, practical aspects, remaining questions and future challenges are highlighted. Taken together, these trials confirm the safety and feasibility of intracoronary progenitor cell transfer in the setting of myocardial infarction. Efficacy data suggests its potential to improve left ventricular function recovery beyond current state of the art therapy, but results are mixed, modest at best and do not support true cardiomyogenesis. Hence, due to its complexity, and remaining uncertainties, it is still too early to implement progenitor cell therapy in its current form in standard treatment strategies for ischemic heart disease. Future studies on strategies for cardiomyocyte regeneration in combination with myocardial protection are needed. Roncalli et al. (2011) Intracoronary administration of autologous bone marrow cells (BMCs) leads to a modest improvement in cardiac function, but the effect on myocardial viability is unknown. The aim of this randomized multicentre study was to evaluate the effect of BMC therapy on myocardial viability in patients with decreased left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) and to identify predictive factors for improvement of myocardial viability. One hundred and one patients with AMI and successful reperfusion, LVEF 45%, and decreased myocardial viability (resting Tl201-SPECT) were randomized to either a control group (n = 49) or a BMC group (n = 52). Primary endpoint was improvement of myocardial viability 3 months after AMI. Baseline mean LVEF measured by radionuclide angiography was 36.3 ± 6.9%. Bone marrow cell infusion was performed 9.3 ± 1.7 days after AMI. Myocardial viability improved in 16/47 (34%) patients in the BMC group compared with 7/43 (16%) in the control group (P = 0.06). The number of non-viable segments becoming viable was 0.8 ± 1.1 in the control group and 1.2 ± 1.5 in the BMC group (P = 0.13). Multivariate analysis including major post-ami prognostic factors showed a significant improvement of myocardial viability in BMC vs. control group (P = 0.03). Moreover, a significant adverse role for active smoking (P = 0.04) and a positive trend for microvascular obstruction (P = 0.07) were observed. Intracoronary autologous BMC Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 9

administration to patients with decreased LVEF after AMI was associated with improvement of myocardial viability in multivariate-but not in univariate-analysis. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy and better define a group of patients that will benefit from this therapy. Clinical Trial identifier is NCT00200707. Donndorf et al. (2012) During the last decade, stem cell application in the setting of ischaemic heart failure has been evaluated in phase I and II clinical trials, proving safety and feasibility of this approach. Functional results gained so far indicate moderate benefits. However, conclusive evaluation of cell therapy will not be possible before completion of ongoing phase III multicentre trials. Moreover, questions regarding the optimal cell population for treatment in a chronic setting and the favourable time-point of cell delivery have not been ultimately answered. Cell therapy for the treatment of ischaemic heart failure needs to be evaluated separately from the setting of acute myocardial infarction. In parallel with upcoming clinical evaluation in large-scale trials, further optimization of the 'cell product' regarding the favourable cell type and periprocedural processing, as well as route and time-point of application, is mandatory. Scientific Rationale Update May 2012 Makkar et al (2012) aimed to assess safety of cardiosphere-derived cells (CDCs) in patients with left ventricular dysfunction after myocardial infarction. In the prospective, randomised CArdiosphere-Derived autologous stem CElls to reverse ventricular dysfunction (CADUCEUS) trial, investigators enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centers in the USA. An independent data coordinating centers randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1 5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumor formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). Investigators assessed preliminary efficacy endpoints on MRI by 6 months. Data analyzers were masked to group assignment. Between May 5, 2009, and Dec 16, 2010, investigators randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumors, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1 00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0 001), increases in viable heart mass (p=0 01) and regional contractility (p=0 02), and regional systolic wall thickening (p=0 015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. Investigators concluded intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. They noted the unprecedented increases in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. Bolli et al (2011) undertook a phase 1 trial (Stem Cell Infusion in Patients with Ischemic cardiomyopathy [SCIPIO]) of autologous cardiac stem cells (CSCs) for the treatment of heart failure resulting from ischemic heart disease. This study is still in progress. In stage A Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 10

of the SCIPIO trial, patients with post-infarction left ventricular (LV) dysfunction (ejection fraction [EF] 40%) before coronary artery bypass grafting were consecutively enrolled in the treatment and control groups. In stage B, patients were randomly assigned to the treatment or control group in a 2:3 ratio by use of a computer-generated block randomization scheme. 1 million autologous CSCs were administered by intracoronary infusion at a mean of 113 days (SE 4) after surgery; controls were not given any treatment. Although the study was open label, the echocardiographic analyses were masked to group assignment. The primary endpoint was short-term safety of CSCs and the secondary endpoint was efficacy. A per-protocol analysis was used. 16 patients were assigned to the treatment group and seven to the control group; no CSC-related adverse effects were reported. In 14 CSC-treated patients who were analysed, LVEF increased from 30 3% (SE 1 9) before CSC infusion to 38 5% (2 8) at 4 months after infusion (p=0 001). By contrast, in seven control patients, during the corresponding time interval, LVEF did not change (30 1% [2 4] at 4 months after CABG vs 30 2% [2 5] at 8 months after CABG). Importantly, the salubrious effects of CSCs were even more pronounced at 1 year in eight patients (eg, LVEF increased by 12 3 ejection fraction units [2 1] vs baseline, p=0 0007). In the seven treated patients in whom cardiac MRI could be done, infarct size decreased from 32 6 g (6 3) by 7 8 g (1 7; 24%) at 4 months (p=0 004) and 9 8 g (3 5; 30%) at 1 year (p=0 04). Investigators concluded the initial results are very encouraging. They suggest that intracoronary infusion of autologous CSCs is effective in improving LV systolic function and reducing infarct size in patients with heart failure after myocardial infarction, and warrant further, larger, phase 2 studies. Povsic et al (2011) sought to determine the safety and preliminary efficacy of transcatheter intramyocardial administration of myoblasts in patients with heart failure (HF). MARVEL is a randomized placebo-controlled trial of image-guided, catheter-based intramyocardial injection of placebo or myoblasts (400 or 800 million) in patients with class II to IV HF and ejection fraction <35%. Primary end points were frequency of serious adverse events (safety) and changes in 6-minute walk test and Minnesota Living With HF score (efficacy). Of 330 patients intended for enrollment, 23 were randomized (MARVEL-1) before stopping the study for financial reasons. At 6 months, similar numbers of events occurred in each group: 8 (placebo), 7 (low dose), and 8 (high dose), without deaths. Ventricular tachycardia responsive to amiodarone was more frequent in myoblast-treated patients: 1 (placebo), 3 (low dose), and 4 (high dose). A trend toward improvement in functional capacity was noted in myoblast-treated groups (Δ6-minute walk test of -3.6 vs +95.6 vs +85.5 m [placebo vs low dose vs high dose; P =.50]) without significant changes in Minnesota Living With HF scores. Investigators concluded in HF patients with chronic postinfarction cardiomyopathy, transcatheter administration of myoblasts in doses of 400 to 800 million cells is feasible and may lead to important clinical benefits. Ventricular tachycardia may be provoked by myoblast injection but appears to be a transient and treatable problem. A large-scale outcome trial of myoblast administration in HF patients with postinfarction cardiomyopathy is feasible and warranted. Perin et al (2011) evaluated the safety and efficacy of the transendocardial delivery of autologous bone marrow mononuclear cell (ABMMNCs) in no-option patients with chronic HF in a prospective study. Efficacy was assessed by maximal myocardial oxygen consumption, single photon emission computed tomography, 2-dimensional echocardiography, and quality-of-life assessment (Minnesota Living with Heart Failure and Short Form 36). Investigators also characterized patients' bone marrow cells by flow cytometry, colonyforming unit, and proliferative assays. Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly (P =.001) in cell-treated patients, but function was not affected. Quality-of-life scores improved Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 11

significantly at 6 months (P =.009 Minnesota Living with Heart Failure and P =.002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control (P =.02) but not in treated patients (P =.16). Function of patients' bone marrow mononuclear cells was severely impaired. Stratifying cell results by age showed that younger patients ( 60 years) had significantly more mesenchymal progenitor cells (colonyforming unit fibroblasts) than patients >60 years (20.16 ± 14.6 vs 10.92 ± 7.8, P =.04). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 ml/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 ml/kg per minute, P =.04). Investigators concluded ABMMNC therapy is safe and improves symptoms, quality of life, and possibly perfusion in patients with chronic HF. Leistner et al (2011) investigated the long-term safety and effects of intracoronary progenitor cell therapy in patients with acute myocardial infarction (AMI). To assess the clinical course, NT-proBNP and MRI data as objective markers of cardiac function of the TOPCARE-AMI patients at 5-year follow-up. The TOPCARE-AMI trial was the first randomized study investigating the effects of intracoronary infusion of circulating (CPC) or bone marrow-derived progenitor cells (BMC) in 59 patients with successfully reperfused AMI. Five-year follow-up data were completed in 55 patients, 3 patients were lost to followup. None of the patients showed any signs of intramyocardial calcification or tumors at 5 years. One patient died during the initial hospitalization, no patient was rehospitalized for heart failure and 16 patients underwent target vessel revascularization (TVR). Only two TVRs occurred later than 1 year after cell administration making it very unlikely that the infused cells accelerate atherosclerotic disease progression. Serum levels of NT-proBNP remained significantly reduced at the 5-year follow-up indicating the absence of heart failure. MRI subgroup analysis in 31 patients documented a persistent improvement of LV ejection fraction (from 46 ± 10% at baseline to 57 ± 10% at 5 years, p < 0.001)). Simultaneously, there was a reduction (p < 0.001) in functional infarct size measured as late enhancement volume normalized to LV mass. However, whereas LV end-systolic volume remained stable, LV end-diastolic volume increased significantly. Investigators concluded the 5-year follow-up of the TOPCARE-AMI trial provides reassurance with respect to the long-term safety of intracoronary cell therapy and suggests favorable effects on LV function. Duckers et al (2011) reported results of the SEISMIC study, an open-label, prospective, randomized study to assess the safety and feasibility of percutaneous myoblast implantation in heart failure patients with implanted cardioverter-defibrillators (ICD). Patients were randomized 2:1 to autologous skeletal myoblast therapy vs. optimal medical treatment. The primary safety end-point was defined as the incidence of procedural and device related serious adverse events, where as the efficacy endpoints were defined as the change in global LVEF by MUGA scan, change in NYHA classification of heart failure and in the distance achieved during a six-minute walk test (6MW) at 6-month follow-up. Forty subjects were randomized to the treatment arm (n=26), or to the control arm (n=14). There were 12 sustained arrhythmic events and one death after episodes of ventricular tachycardia (VT) in the treatment group and 14 events in the control group (P=ns). At 6-month follow-up, 6MW distance improved by 60.3±54.1?meters in the treated group as compared to no improvement in the control group (0.4±185.7?meters; P=ns). In the control group, 28.6% experienced worsening of heart failure status (4/14), while 14.3% experienced an improvement in NYHA classification (2/14). In the myoblast-treatment arm, one patient experienced a deterioration in NYHA classification (8.0%), whereas five patients improved Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 12

one or two classes (20.0%; P=0.06). However, therapy did not improve global LVEF measured by MUGA at 6-month follow-up. Investigators concluded the data indicate that implantation of myoblasts in patients with HF is feasible, appears to be safe and may provide symptomatic relief, though no significant effect was detected on global LVEF. Scientific Rationale Update June 2010 There is a growing interest in the clinical application for stem cell transplantation as a novel therapy for treatment of acute myocardial infarction and chronic myocardial ischemia. Potential cell sources include bone marrow-derived cells and skeletal myoblasts. Phase I/II randomised controlled clinical trials suggest that intracoronary or intramyocardial injection of bone marrow-derived cells may be safe and feasible strategies for treatment of acute myocardial infarction as well as chronic myocardial ischemia. Studies have shown a modest, but significant improvement in left ventricular ejection fraction and clinical status of patients after cell transplantation. However, most of the studies have been relatively small with only short term results (<6 months). Wöhrle et al (2010) assessed the effect of autologous bone-marrow cell (BMC) therapy in patients with acute myocardial infarction in a rigorous double-blind, randomized, placebocontrolled trial. Patients with reperfusion >6 hours after symptom onset were randomly assigned in a 2:1 ratio to receive intracoronary BMC or placebo therapy 5 to 7 days after symptom onset. The patients were stratified according to age, acute myocardial infarction localization, and left ventricular (LV) function. Rigorous double-blinding was ensured using autologous erythrocytes for the placebo preparation that was visually indistinguishable from the active treatment. Serial cardiac magnetic resonance imaging studies were performed before study therapy and after 1, 3, and 6 months. The primary end point was the difference in the LV ejection fraction from baseline to 6 months. The secondary end points included changes in the LV end-diastolic and end-systolic volume indexes and infarct size. A total of 42 patients were enrolled (29 in the BMC group and 13 in the placebo group) in the integrated pilot phase. A mean of 381 x 10(6) mononuclear BMCs were administered. The baseline clinical and cardiac magnetic resonance imaging parameters did not differ. Compared to baseline, the difference in LV ejection fraction for the placebo group versus BMC group was 1.7 +/- 6.4% versus -0.9 +/- 5.5% at 1 month, 3.1 +/- 6.0% versus 1.9 +/- 4.3% at 3 months, and 5.7 +/- 8.4% versus 1.8 +/- 5.3% at 6 months (primary end point; not significant). No difference was found in the secondary end points between the 2 groups, including changes in infarct size or LV end-diastolic and end-systolic volume indexes. The authors concluded they did not observe an evidence for a positive effect for intracoronary BMC versus placebo therapy with respect to LV ejection fraction, LV volume indexes, or infarct size. Assmus et al (2010) investigated the clinical outcome 2 years after intracoronary administration of autologous progenitor cells in patients with acute myocardial infarction (AMI). Using a double-blind, placebo-controlled, multicenter trial design, 204 patients with successfully reperfused AMI were randomized to receive intracoronary infusion of bone marrow-derived progenitor cells (BMC) or placebo medium into the infarct artery 3 to 7 days after successful infarct reperfusion therapy. At 2 years, the cumulative end point of death, myocardial infarction, or necessity for revascularization was significantly reduced in the BMC group compared with placebo (hazard ratio, 0.58; 95% CI, 0.36 to 0.94; P=0.025). Likewise, the combined end point death and recurrence of myocardial infarction and rehospitalization for heart failure, reflecting progression toward heart failure, was significantly reduced in the BMC group (hazard ratio, 0.26; 95% CI, 0.085 to 0.77; P=0.015). Intracoronary administration of BMC remained a significant predictor of a favorable clinical outcome by Cox regression analysis when adjusted for classical predictors of poor outcome after AMI. There was no evidence of increased restenosis or atherosclerotic Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 13

disease progression after BMC therapy nor any evidence of increased ventricular arrhythmias or neoplasms. In addition, regional left ventricular contractility of infarcted segments, as assessed by MRI in a subgroup of patients at 2-year follow-up, was significantly higher in the BMC group compared with the placebo group (P<0.001). The investigators concluded intracoronary administration of BMC is associated with a significant reduction of the occurrence of major adverse cardiovascular events maintained for 2 years after AMI. Moreover, functional improvements after BMC therapy may persist for at least 2 years. They noted larger studies focusing on clinical event rates are warranted to confirm the effects of BMC administration on mortality and progression of heart failure in patients with AMIs. Hare et al (2009) investigated the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hmscs) in patients with myocardial infarction (MI) in a doubleblind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hmscs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Adverse event rates were similar between the hmsc-treated (5.3 per patient) and placebotreated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes and pulmonary function testing demonstrated improved forced expiratory volume in 1 s in the hmsc-treated patients. Global symptom score in all patients and ejection fraction in the important subset of anterior MI patients were both significantly better in hmscs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hmsc treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. The authors concluded that intravenous allogeneic hmscs are safe in patients after acute MI, noting the trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. Plewka et al (2009) investigated the effect of intracoronary injection of autologous mononuclear bone marrow stem cells (BMSCs) in patients with ST-elevation myocardial infarction (STEMI) on left ventricular (LV) systolic and diastolic function using standard echocardiography and 2-dimensional systolic strain. A total of 60 patients with first anterior wall STEMI and LV ejection fraction of <40%, treated with successful primary percutaneous coronary intervention were randomly assigned to the treatment group (BMSC group) or the control group in a 2:1 ratio. Transcatheter intracoronary injection of BMSCs into the infarctrelated artery was performed 7 days after STEMI. Standard echocardiography and speckle tracking analysis was performed at baseline and 6 months after STEMI. No differences were found in the baseline echocardiographic parameters of LV systolic and diastolic dysfunction-- the LV ejection fraction was 35 +/- 6% in the BMSC group, similar to that in the control group (33 +/- 7%, p = 0.42). After 6 months, the absolute change in the LV ejection fraction was significantly greater in the BMSC group than in the control group (10 +/- 9% versus 5 +/- 8%, p = 0.04). Significant improvement was seen in 2-dimensional systolic strain in all segments (12 +/- 4 vs 14 +/- 4; p = 0.0009) and in the infarcted area (5 +/- 2 vs 6 +/- 2; p = 0.0038) only in the BMSC group. Of the diastolic function parameters, improvement in the early filling propagation velocity (30 +/- 8 cm/s vs 37 +/- 13 cm/s; p = 0.0008), early diastolic velocity - E' (4.5 +/- 1.5 vs 5.0 +/- 1.3, p = 0.02), and the E/E' ratio (17 +/- 7 vs 14 +/- 5; p = 0.03) was observed in the BMSC group. The author concluded, intracoronary injection of unselected BMSCs in patients with STEMI improved both LV systolic and diastolic function at 6 months of follow-up. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 14

Beitnes et al (2009) investigated the long-term safety and efficacy after intracoronary injection of autologous mononuclear bone marrow cells (mbmcs) in acute myocardial infarction (AMI) in a randomised, controlled trial. Patients from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) study were re-assessed 3 years after inclusion. 100 patients with anterior wall ST-elevation myocardial infarction treated with acute percutaneous coronary intervention (PCI) were randomised to receive intracoronary injection of mbmcs (n = 50) or not (n = 50). Main outcome measures were change in left ventricular (LV) ejection fraction (primary), change in exercise capacity (peak VO(2)) and quality of life (secondary), infarct size (additional aim), and safety. The rates of adverse clinical events in the groups were low and equal. There were no significant differences between groups in change of global LV systolic function by echocardiography or magnetic resonance imaging (MRI) during the follow-up. On exercise testing, the mbmctreated patients had larger improvement in exercise time from 2-3 weeks to 3 years (1.5 minutes vs 0.6 minutes, p = 0.05), but the change in peak oxygen consumption did not differ (3.0 ml/kg/min vs 3.1 ml/kg/min, p = 0.75). The authors concluded that intracoronary mbmc treatment in AMI is safe in the long term. A small improvement in exercise time in the mbmc group was found, but no other effects of treatment could be identified 3 years after cell therapy. Schächinger et al (2009) investigated the effect of intracoronary administration of bone marrow-derived mononuclear cells (BMC) within 7 days after successful reperfusion therapy for AMI, on early (within 4 months) LV remodelling processes assessed by quantitative LV angiography. Overall, 95 patients received BMC and 92 patients received placebo. Remodelling was assessed as the changes in either LVEF and end-systolic volume (ESV) or stroke volume and end-diastolic volume (EDV) at 4 months, respectively. Baseline LVEF was inversely correlated with ESV expansion at 4 months in the placebo group, but not in the BMC group. Likewise, EDV expansion was significantly correlated with baseline LVEF in the placebo (r = -0.36, P < 0.001), but not in the BMC group (r = -0.17, P = 1.0). Analysing the interaction between convalescent LV contractile function and LV volumes revealed that the increase in LVEF or stroke volume did not occur at the expense of increases in ESV or EDV, respectively, in the BMC group. The investigators concluded that intracoronary administration of BMC eliminates the correlation between depressed LVEF after reperfusion therapy and LV expansion during follow-up and, thereby, abrogates early LV remodelling after AMI. Tendera et al (2009) compared intracoronary infusion of bone marrow (BM)-derived unselected mononuclear cells (UNSEL) and selected CD34(+)CXCR4(+) cells (SEL) in patients with acute myocardial infarction (AMI) and reduced <40% left ventricular ejection fraction (LVEF) in two hundred patients. Patients were randomized to intracoronary infusion of UNSEL (n = 80) or SEL (n = 80) BM cells or to the control (CTRL) group without BM cell treatment. Primary endpoints were change of LVEF and volumes measured by magnetic resonance imaging before and 6 months after the procedure. After 6 months, LVEF increased by 3% (P = 0.01) in patients treated with UNSEL, 3% in patients receiving SEL (P = 0.04) and remained unchanged in CTRL group (P = 0.73). There were no significant differences in absolute changes of LVEF between the groups. Absolute changes of left ventricular end-systolic volume and left ventricular end-diastolic volume were not significantly different in all groups. Significant increase of LVEF was observed only in patients treated with BM cells who had baseline LVEF < median (37%). Baseline LVEF < median and time from the onset of symptoms to primary percutaneous coronary intervention > median were predictors of LVEF improvement in patients receiving BM cells. There were no differences in major cardiovascular event (death, re-infarction, stroke, target vessel revascularization) between groups. The authors concluded in patients with AMI and impaired LVEF, treatment with BM cells does not lead to a significant improvement of LVEF Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 15

or volumes. There was however a trend in favor of cell therapy in patients with most severely impaired LVEF and longer delay between the symptoms and revascularization. The clinical safety and efficacy of stem cell therapy needs to be validated in large randomized controled trials with long term results. Clinical trials are ongoing or currently recruiting participants. For example, the TRACIA STUDY (Intracoronary Autologous Stem Cell Transplantation in ST Elevation Myocardial Infarction) is currently recruiting participants and will evaluate the ejection fraction (EF) increase at 6 months follow up and major adverse cardiovascular events (MACE) after intracoronary autologous stem cell transplantation in ST elevation myocardial infarction patients versus a control group. Another study recruiting participants is the REVITALIZE study (Randomized Evaluation of Intracoronary Transplantation of Bone Marrow Stem Cells in Myocardial Infarction). This study will test whether injecting cells obtained from the patient's bone marrow into the coronary artery can regenerate and replace heart tissue to strengthen heart and prevent heart from dilating and developing heart failure. The ASTAMI study (Autologous Stem Cell Transplantation in Acute Myocardial Infarction) is ongoing, but not recruiting participants. The primary objective of this study is to test whether intracoronary transplantation of autologous mononuclear bone marrow cells (mbmc) improve left ventricular ejection fraction (LVEF) after anterior wall AMI. Another ongoing study that is no longer recruiting participants is the STEMI study (ST-elevation myocardial infarction). This study will investigate 4 years' efficacy and LV functional improvement of autologous bone marrow mononuclear cells (BMMC) transplantation in patients with ST-elevation myocardial infarction. Numerous other trials are currently available and can be found at Clinical Trials.gov. Scientific Rationale Update June 2007 Coronary heart disease is the leading cause of death for both men and women in the United States; of the approximately 1.1 million Americans who suffer an M.I. yearly, approximately 460,000 are fatal. About half of these deaths occur within 1 hour of the initial symptoms. Patients with MI s develop scar tissue in the area of infarction resulting in a decreased ability of the cardiac muscle to contract. Studies suggest that most of the myocardial cells destined to die following an acute coronary artery occlusion will do so within three to six hours. Early coronary reinstitution of blood flow with thrombolytic therapy, angioplasty, and/or stenting can salvage the ischemic myocardium and improve clinical outcome. However, late reperfusion will not salvage myocardium, and the damage is irreversible. Since cardiac cells cannot repair themselves, this could be the beginning of a downward spiral towards congestive heart failure and life-threatening arrhythmia. Other than heart transplantation with its obvious limitations, current therapeutic means aim at preventing further episodes of myocardial ischemia and at enabling the patient to survive with a heart that is working at a fraction of its original capacity. Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation. These events promote structural and functional repair. This high degree of stem cell flexibility led researchers to investigate if transplanting bone marrow cells could restore dead myocardium. This is referred to as the autologous stem cell transplantation in acute myocardial infarction (ASTAMI). The primary objective of the ASTAMI procedure is to test whether intracoronary transplantation of autologous mononuclear bone marrow cells improves left ventricular ejection fraction (LVEF) after anterior wall MI. Selective intracoronary transplantation of human autologous adult stem cells is possible under clinical conditions and it may lead to regeneration of the myocardial scar after transmural infarction. No position or policy Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 16

statements, from the various Cardiac Societies, addressing the use of autologous stem cell transplantation for acute MI, were identified in the available literature. There is currently a clinical trial, called the (MYSTAR) study, recruiting 360 patients for myocardial stem cell administration after acute MI. This is the first randomized, multicenter, prospective, single-blinded trial, to investigate the effects of the combined (intramyocardial and intracoronary) administration of nonselected autologous bone marrow stem cells to patients. This study started in January 2005 with the expected completion to be December 2008. In addition to this clinical trial there are approximately twenty more currently underway regarding stem cell therapy for various cardiac scenarios. In a larger study that involved a shorter follow-up period, Lunde et al (2006) enrolled 100 patients who underwent successful stent implantation 2 to 12 hours after an ST-elevation MI. All patients had 3 hypokinetic segments and they were randomly assigned to equally sized transplant and control groups. Patients in the transplant group underwent infusion of stem cells from bone marrow 4 to 8 days after stenting; however, this procedure could not be completed in 2 (4%) patients due to stent thrombosis and 1 (2%) patient due to inadequate viability of the cells to be infused. At 6 months follow-up, there were no statistically significant differences between the transplant and control groups in infarct size, LVEF, or end-diastolic volume. Hematopoietic stem cells are bone marrow derived cells capable of differentiating into a variety of cell types. Such cells may be obtained directly from the bone marrow or, using apheresis techniques, from peripheral blood usually after stimulation with granulocyte - colony stimulating factor (G-CSF). An increasing number of studies have used hematopoietic stem cells to repopulate the myocardium of patients with an acute myocardial infarction or ischemic cardiomyopathy, and to improve the left ventricular ejection fraction. Although stem cell therapy following acute MI seems promising, the majority of the studies have been small and the long-term safety and efficacy of this procedure has not yet been demonstrated. Further controlled, prospective, randomized clinical trials, and variations of cell preparations are needed to determine the role of autologous intracoronary mononuclear bone marrow cell transplantation for the treatment of these patients. Larger trials are needed to address the effect of bone-marrow cell transfer on clinical endpoints such as the incidence of heart failure and survival. Although clinical trials are currently ongoing, there are no definitive outcomes at this time, regarding the appropriateness of this procedure. The ultimate goal of autologous stem cell transplantation in this specific scenario, is to improve cardiac function and myocardial perfusion in patients after acute MI. This procedure remains investigational and therefore not medically necessary at this time, since there is a lack of published peer-reviewed evidence from prospective clinical studies, as well as a lack of long-term follow up data, to support its safety and efficacy. Scientific Rationale - Initial Heart failure, also called congestive heart failure (CHF), is a life-threatening condition in which the heart can no longer pump enough blood to the rest of the body. Heart failure is almost always a chronic, long-term condition, although it can sometimes develop suddenly. This condition may affect the right side, the left side, or both sides of the heart. As the heart's pumping action is lost, blood may back up into other areas of the body, including the liver, the gastrointestinal tract and extremities (right-sided heart failure) and the lungs (left-sided heart failure). The most common causes of heart failure are hypertension and obstructive coronary artery disease. Other structural or functional causes of heart failure include valvular heart disease, congenital heart disease, dilated cardiomyopathy, and Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 17

primary pulmonary hypertension. Heart failure becomes more common with advancing age. Risk factors include obesity, diabetes, smoking cigarettes, abuse alcohol, or use of cocaine. An enlargement of the heart or decreased heart functioning may be seen on several tests. The mainstays of treatment consist of: (1) ACE inhibitors (e.g., captopril and enalapril) which dilate peripheral blood vessels and decrease the work load of the heart; (2) Diuretics that rid body of fluid and sodium; (3) digitalis glycosides that increase the ability of the heart muscle to contract properly and prevent heart rhythm disturbances; (4) angiotensin receptor blockers (ARBs) which reduce the workload of the heart; and (5) beta-blockers for those with a history of coronary artery disease. Sometimes, hospitalization is required for acute CHF. Hospitalized patients may receive oxygen and intravenous medications such as vasodilators and diuretics. Medicines such as nesiritide (Natrecor) help dilate blood vessels and may also be helpful. Medicines called inotropic agents help improve the heart's ability to pump blood. Such drugs include dobutamine and milrinone and are given intravenously. Severe cases of CHF require more drastic measures. For example, excess fluid can be removed through dialysis, biventricular pacing (cardiac resynchronization therapy) can be established and circulatory assistance can be provided by implanted devices such as the intra-aortic balloon pump (IABP) and the left ventricular assist device (LVAD). These devices can be life-saving, but they are not permanent solutions and do not treat the cause. Patients who are refractory to medical treatment and become dependent on circulatory support need a heart transplant as a definitive treatment. There is no question that contemporary medical therapy has dramatically improved the prognosis of heart failure, and new drugs still at an investigational stage may further favorably affect patient outcomes. Nevertheless, the mortality still remains high, reaching 60% within 1 year for individuals in New York Heart Association functional Class IV. Thus, a substantial number of patients remain candidates for more aggressive approaches such as cardiac transplantation, left ventricular remodeling operations, and circulatory assist devices (as bridges to transplantation or destination therapy). In spite of their distinct advantages, all these mechanically-oriented interventions have limitations, are invasive, and require long-term anticoagulation and hospitalization. This accounts for the active research on conceptually different, biologically-oriented therapeutic options that basically encompass gene and cell therapy. Cell therapy attempts to limit any consequences from the loss of contractile function of a damaged left ventricle and is based on two major assumptions: (1) the development of heart failure is mechanically linked to the irreversible loss of cardiomyocytes below a critical threshold, and (2) function can thus be improved by replacing these dead cells by new contractile ones, provided that they can colonize the tissue they are implanted in and form stable, functionally integrated intramyocardial grafts with a high degree of differentiation into new myocytes, coronary arterioles, and capillaries. It is already established that hematopoietic stem cells are capable of differentiating into a variety of cell types and their transplantation has paved the way for an exogenous delivery of primative immature cells as the most clinically relevant approach to repopulate viable myocytes. Such cells may be obtained directly in an autologous manner from the bone marrow or, using apheresis techniques, from peripheral blood usually after stimulation with granulocyte-colony stimulating factor (G-CSF). A number of research groups have already demonstrated that direct injection of various cell suspensions into experimental myocardial infarcts improved remodeling and function of the heart. These cells include cardiomyocytes (fetal or neonatal), bone marrow derived stem cells, embryonic stem cells, and skeletal myoblasts and their use challenges the conventional dogma that the heart is unable to repair itself; however, further work needs to be done to establish the degree to which self repair can occur and also if the implicated cells are capable of such repair. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 18

Wollert et al (2004) in the BOOST trial randomly assigned 60 patients with an acute MI who had undergone percutaneous coronary intervention (PCI) to receive bone marrow cell harvest and intracoronary infusion into the infarct-related artery and compared their results with those of a control group. The left ventricular ejection fraction (LVEF) was similar in the bone marrow and control groups at baseline post-mi (51.3 and 50.0 percent, respectively). After six months, the increase in mean global LVEF was significantly greater in the bone marrow group (6.7 versus 0.7 percentage points in controls). However, this difference was no longer significant at late follow-up at 18 months (5.9 versus 3.1 percentage points), suggesting that the benefit was limited to acceleration of LVEF recovery. Bone marrow cell infusion did not increase the risk of adverse clinical events, in-stent restenosis, or proarrhythmia. Similar findings were noted by Strauer et al (2005) in a nonblinded observational study of 18 consecutive patients who had had a myocardial infarction five months to nine years previously; these patients were compared to a representative control group that did not receive cellular therapy. At three months after intracoronary transplantation of autologous bone marrow mononuclear cells, infarct size was reduced by 30 percent, the LVEF increased by 15 percent, and infarction wall movement velocity increased by 57 percent. There were no significant changes in the control group. The benefits on left ventricular function were less prominent in another trial of similar design in which Janssens et al (2006) randomly assigned 67 patients who underwent successful primary PCI for an ST elevation MI to bone marrow cell harvest and intracoronary infusion of isolated bone marrow stem cells into the infarct-related artery or a control group. At four months, there was no difference between the two groups in LVEF. However, the patients who underwent stem cell transfer had a significant 28% reduction in infarct size and better recovery of regional systolic function, changes that may reflect improved infarct remodeling. The largest experience comes from the REPAIR-AMI trial, the results of which were presented by Goyal at the American Heart Association meeting in November 2005. In this multicenter trial, 204 patients who underwent primary PCI after an ST elevation MI were randomly assigned to receive an intracoronary infusion into the infarct-related artery of autologous mononuclear progenitor cells or a placebo medium three to six days after the MI. The primary end point, the absolute increase in LVEF at four months, was significantly higher with active therapy (5.5 versus 3.0 percent with placebo). Subgroup analyses found that the benefit was limited to patients with a baseline LVEF < 49% and to those treated more than five days after the MI. In contrast to the benefit noted in the above trials in the short term, the ASTAMI of 100 patients with anterior MI undergoing primary PCI who were randomly assigned to bone marrow mononuclear cell infusion or control, found no differences in LVEF or infarct size in the two groups. The potential value of granulocyte-colony stimulating factor (G-CSF) in comparison to or in combination with stem cell infusion was assessed in the MAGIC trial by Kang et al (2004). Twenty-seven patients with an acute MI undergoing PCI were randomly assigned to stem cell mobilization with G-CSF followed by stem cell apheresis and intra-coronary reinfusion, to G-CSF alone, or to a control group. Six-month follow-up data in 10 of the study patients demonstrated an improvement in LVEF with stem cell infusion (from 48.7 to 55.1 percent) but not with G-CSF alone. Stem cell infusion also increased treadmill exercise time and reduced the size of the myocardial perfusion defect. However, administration of G-CSF was associated with an unexpectedly high rate of in-stent restenosis of the culprit lesion. A similar lack of benefit has been shown in other trials of G-CSF alone in patients with an acute MI. The largest experience comes from the REVIVAL-2 trial (Colter et al 2001) in Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 19

which 114 patients with an acute ST elevation involving at least 5 percent of the left ventricle underwent successful reperfusion by primary PCI and five days later were randomly assigned to G-CSF (10 µg/kg) or placebo daily for five days. Despite a marked increase in circulating stem cells, there was no difference between the groups in the primary end point, a reduction in infarct size at four to six months, as assessed by myocardial perfusion imaging (6.2 versus 4.9 percent with placebo), or in the secondary end points of improvement in LVEF (+0.5 versus +2.0 percent) and angiographic restenosis (35 versus 31 percent). A similar lack of benefit was noted in the STEMMI trial (Ripa et al 2006) in which 78 patients with an STEMI who underwent successful primary PCI were randomly assigned to G-CSF (10 µg/kg) or placebo daily for six days. At six months, there was no difference between the two groups in the primary end point of change in systolic wall thickening on cardiac magnetic resonance imaging (17 percent improvement), LVEF, or target vessel revascularization. Recent studies have indicated that stem cell implantation increases cardiac function by repairing damaged myocardium. We investigated whether intracoronary transplantation of autologous bone marrow-derived mononuclear cells (BMMCs) confers beneficial effects in patients with refractory chronic heart failure. Twenty-eight patients received standard heart failure medication and BMMC transplantation (BMMC treatment) or standard medication only (controls). BMMCs were harvested from each patient. Clinical manifestations, biochemical assays, rhythm studies, echocardiograms, and positron emission tomograms were recorded. Fourteen patients with cell grafting had symptomatic relief of heart failure within 3 days. Left ventricular ejection fraction increased by 9.2% and 10.5% at 1 week and 3 months after the procedure, respectively, versus baseline (p <0.01 for the 2 comparisons). Left ventricular end-systolic volume decreased by 30.7% after 3 months (p <0.01). Brain natriuretic peptide levels at days 3 and 7 after cell infusion significantly decreased by 69.2% and 70.4%, respectively, whereas atrial natriuretic peptide levels increased by 30.1% at day 7. Positron emission tomographic analysis showed a significant increase in cell viability of 10.3% in the infarcted zone. No patient died in the BMMC-treated group at 6-month follow-up. In contrast, heart failure did not improve in any control patient. Left ventricular ejection fraction decreased by 7.2% after 3 months. Two control patients died from heart failure within 6 months. In conclusion, this is the first demonstration in humans that intracoronary BMMC transplantation is a feasible and safe therapeutic strategy to decrease symptoms, increase cardiac function, and possibly prolong life in patients with end-stage heart failure refractory to standard medical therapy. Although there is much controversy regarding stem cell biology and cardiac regeneration, most investigators have confirmed that cell transplantation increases heart function. However, the actual mechanisms of cell transplantation-induced functional improvement in heart failure remain elusive. In 2006, Gao et al demonstrated for the first time that intracoronary transplantation of autologous bone marrow mononuclear cells (BMMCs) led to prompt therapeutic effects in patients with end-stage heart failure refractory to standard therapy. These beneficial effects, such as relief of dyspnea and pulmonary edema, occurred within several days after cell transplantation and were accompanied by increased LVEF. After 3 months, the increase in LVEF persisted and an increase in myocardial viability in the infarcted area was evident. There is also controversy as to whether infused bone marrow-derived stem cells can differentiate into cardiac myocytes, most current studies have concluded that cellular transplantation might contribute to the increase in heart function. However, autologous stem cell transplantation therapy for regeneration of myocardial cell activity remains an investigational technique that may have the potential to reduce myocardial infarct size and improve cardiac function in patients with ischemic heart disease and heart failure. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 20

Experience with this approach is still limited to a few small trials, some which were not blinded or had other design problems. The mechanism of benefit, long-term safety, and clinical efficacy of this new technology requires further study. Review History January 2007 Medical Advisory Council initial approval March 2007 Code Updates June 2007 Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) has been added to this policy as investigational and therefore not medically necessary because the safety and efficacy for this indication has not been established. June 2008 Update - No revisions. Codes reviewed. June 2010 Update no revisions. July 2010 Update - Added Medicare Table. No revisions. June 2011 Update no revisions May 2012 Update no revisions May 2013 Update no revisions. Codes updated. May 2014 Update no revisions. Codes updated. May 2015 Update no revisions. Codes updated. May 2016 Update no revisions This policy is based on the following evidence-based guideline: 1. Phillips MI, Tang YL, Pinkernell K. Stem cell therapy for heart failure: the science and current progress. Future Cardiology. May 2008, Vol. 4, No. 3, Pages 285-298. 2. Hayes. Health Technology Brief. Autologous Stem Cell Transplantation for Acute Myocardial Infarction. March 6, 2007. Updated March 6, 2009. Archived April 2010 3. Journal of the American College of Cardiology. (JACC). 10 Years of Intracoronary and Intramyocardial Bone Marrow Stem Cell Therapy of the Heart: From the Methodological Origin to Clinical Practice. Volume 58, Issue 11, Sept 06, 2011. Available at: http://content.onlinejacc.org/article.aspx?articleid=1146756 4. Sanganalmath SK, Bolli R. Heart Failure Compendium. Cell Therapy for Heart Failure. A Comprehensive Overview of Experimental and Clinical Studies, Current Challenges, and Future Directions. Circulation Research. 2013; 113: 810-834.. References Update May 2016 1. Fisher SA, Doree C, Taggart DP, et al. Cell therapy for heart disease: Trial sequential analyses of two cochrane reviews. Clin Pharmacol Ther. 2016 Jan 28. 2. Fisher SA, Zhang H, Doree C, et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2015 Sep 30;9:CD006536. 3. 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. 2016 Mar 18;118(6):984-93 4. Martino H, Brofman P, Greco O, et al. Multicentre, randomized, double-blind trial of intracoronary autologous mononuclear bone marrow cell injection in non-ischaemic dilated cardiomyopathy (the dilated cardiomyopathy arm of the MiHeart study). Eur Heart J. 2015 Nov 7;36(42):2898-904. 5. Menasché P. Stem cells for the treatment of heart failure. Philos Trans R Soc Lond B Biol Sci. 2015 Oct 19;370(1680):20140373. 6. Wehman B, Siddiqui OT, Mishra R, et al. Stem cell therapy for CHD: towards translation. Cardiol Young. 2015 Aug;25 Suppl 2:58-66. References Update May 2015 Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 21

1. Clinicaltrials.gov. Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure (ESCORT). ClinicalTrials.gov Identifier: NCT02057900. March 31, 2015. Available at: https://clinicaltrials.gov/ct2/show/nct02057900?term=stem+cell+for+heart+failure&r ank=4 2. Heldman AW, DiFede DL, Fishman JE, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 2014; 311:62. 3. Kim Sung-Whan, Mackenzie H, Milton B, et al. Cultured Human Bone Marrow Derived CD31 + Cells Are Effective for Cardiac and Vascular Repair Through Enhanced Angiogenic, Adhesion, and Anti-Inflammatory Effects. J Am Coll Cardiol. 2014; 64(16):1681-1694.. 4. Malliaras K, Makkar RR, Smith RR, et al. Intracoronary Cardiosphere-Derived Cells After Myocardial Infarction: Evidence of Therapeutic Regeneration in the Final 1-Year Results of the CADUCEUS Trial (CArdiosphere-Derived autologous stem CElls to reverse ventricular dysfunction). J Am Coll Cardiol. 2014;63(2):110-122. 5. Michler RE. Stem Cell Therapy for Heart Failure. Methodist Debakey Cardiovasc J. 2013 Oct-Dec; 9(4): 187 194. 6. Rosen M, Myerburg RJ, Francis DP, et al. Translating Stem Cell Research to Cardiac Disease Therapies: Pitfalls and Prospects for Improvement. J Am Coll Cardiol. 2014;64(9):922-937. 7. Yanqing G, Yujing Z, Ying L, et al. Plasminogen Regulates Cardiac Repair After Myocardial Infarction Through its Noncanonical Function in Stem Cell Homing to the Infarcted Heart. J Am Coll Cardiol. 2014;63(25_PA):2862-2872. References Update May 2014 1. Bartnik J, Behfar A, Dolatabadi D, et al. Cardiopoietic stem cell therapy in heart failure: The C-CURE (Cardiopoietic stem Cell therapy in heart failure) multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol. 2013;61(23):2329-2338. C-Cure Clinical Trial; NCT00810238. 2. Clinicaltrials.gov. Safety and Efficacy of Autologous Cardiopoietic Cells for Treatment of Ischemic Heart Failure. (CHART-1). ClinicalTrials.gov Identifier #NCT01768702. January 8, 2014. Available at: http://www.clinicaltrials.gov/ct2/show/nct01768702?term=chart+-+1&rank=1 3. Murry CE, Palpant NJ, Maclellan WR. Cardiopoietry in motion: Primed mesenchymal stem cells for ischemic cardiomyopathy. J Am Coll Cardiol. 2013;61(23):2339-2340 4. Surder D, Manka R, Lo Cicero V, et al. Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: Effects on global left ventricular function. Circulation. 2013;127(19):1968-1979. References Update May 2013 1. Clinicaltrials. gov. Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS). ClinicalTrials.gov Identifier:NCT00587990. April 2013. Available at: http://www.clinicaltrials.gov/ct2/show/nct00587990?term=stem+cell+transplant+for+ heart+failure&rank=17 2. Clinicaltrials.gov. Intramyocardial Transplantation of Bone Marrow Stem Cells in Addition to Coronary Artery Bypass Graft (CABG) Surgery (PERFECT). ClinicalTrials.gov Identifier: NCT00950274. October 2012. Available at: http://clinicaltrials.gov/ct2/show/nct00950274 3. Clinicaltrials. gov. Transplantation of Autologous Cardiac Stem Cells in Ischemic Heart Failure. ClinicalTrials.gov Identifier: NCT01758406. October 2011. Available at: Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 22

http://www.clinicaltrials.gov/ct2/show/nct01758406?term=stem+cell+transplant+for+ heart+failure&rank=4 4. Clinicaltrials.gov. Bone Marrow Derived Adult Stem Cells for Acute Anterior Myocardial Infarction (REGEN-AMI). Clinicaltrials.gov identifier: NCT00765453. February 2011. Available at: http://clinicaltrials.gov/ct2/show/nct00765453 5. Clinicaltrials.gov. BONAMI (Bone Marrow in Acute Myocardial Infarction). Clinicaltrials.gov identifier: NCT00200707. June 2009. Available at: http://www.clinicaltrials.gov/ct2/show/nct00200707?term=nct00200707&rank=1 6. Colucci WS, Simons M. Genetic and cellular therapy in heart failure and myocardial infarction. UpToDate. April 9, 2013. Updated March 2015. 7. Dauwe DF, Janssens SP. Stem cell therapy for the treatment of myocardial infarction. Curr Pharm Des. 2011 Oct;17(30):3328-40. 8. Donndorf P, Strauer BE, Steinhoff G. Update on cardiac stem cell therapy in heart failure. Curr Opin Cardiol. 2012 Mar;27(2):154-60. 9. Rosenson RS. Overview of the acute management of ST elevation myocardial infarction. UpToDate. March 7, 2013. 10. Reeder GS, Kennedy HL, Rosenson RS. Overview of the non-acute management of ST elevation myocardial infarction. UpToDate. February 14, 2013. 11. Roncalli J, Mouquet F, Piot C, et al. Intracoronary autologous mononucleated bone marrow cell infusion for acute myocardial infarction: results of the randomised multicenter BONAMI trial, Eur Heart J 32 2011 1748-1757 12. Yousef M, Schannwell CM, Köstering M, et al. The BALANCE study. Clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction, J Am Coll Cardiol 53 2009 2262-2269. References Update May 2012 1. Bolli R, Chugh AR, D'Amario D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011 Nov 26;378(9806):1847-57. 2. Duckers HJ, Houtgraaf J, Hehrlein C, et al. Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial. EuroIntervention. 2011 Feb;6(7):805-12. 3. Leistner DM, Fischer-Rasokat U, Honold J, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy. Clin Res Cardiol. 2011 Oct;100(10):925-34. 4. Leistner DM, Schmitt J, Palm S, et al. Intracoronary administration of bone marrowderived mononuclear cells and arrhythmic events in patients with chronic heart failure. Eur Heart J. 2011 Feb;32(4):485-91 5. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012 Mar 10;379(9819):895-904. 6. Oguz E, Ayik F, Ozturk P, et al. Long-term results of autologous stem cell transplantation in the treatment of patients with congestive heart failure. Transplant Proc. 2011 Apr;43(3):931-4. 7. Perin EC, Silva GV, Zheng Y, et al. Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure. Am Heart J. 2012 Mar;163(3):415-421.e1. 8. Perin EC, Silva GV, Henry TD, et al. A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF). Am Heart J. 2011 Jun;161(6):1078-87.e3. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 23

9. Plewka M, Krzemińska-Pakuła M, Peruga JZ, et al. The effects of intracoronary delivery of mononuclear bone marrow cells in patients with myocardial infarction: a two year follow-up results. Kardiol Pol. 2011;69(12):1234-40. 10. Povsic TJ, O'Connor CM, Henry T, et al. A double-blind, randomized, controlled, multicenter study to assess the safety and cardiovascular effects of skeletal myoblast implantation by catheter delivery in patients with chronic heart failure after myocardial infarction. Am Heart J. 2011 Oct;162(4):654-662.e1. 11. Santoso T, Irawan C, Alwi I, et al. Safety and feasibility of combined granulocyte colony stimulating factor and erythropoetin based-stem cell therapy using intracoronary infusion of peripheral blood stem cells in patients with recent anterior myocardial infarction: one-year follow-up of a phase 1 study. Acta Med Indones. 2011 Apr;43(2):112-21. References Update June 2011 1. Anversa P, Kajstura J, Leri A. Cardiac Stem Cells and Myocardial Diseases. Chapter 11, Cardiovascular Regeneration and Tissue Engineering. Bonow: Braunwald's Heart Disease. A Textbook of Cardiovascular Medicine, 9th ed. 2011. 2. Scadden DT, Raajjmakers M HGP. Overview of Stem Cells. February 16, 2011. References Update June 2010 1. 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. 2010 Jan;3(1):89-96. 2. Beitnes JO, Hopp E, Lunde K, et al. Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study. Heart. 2009 Dec;95(24):1983-9. 3. Benetti F, Peñherrera E, Maldonado T, et al. Direct myocardial implantation of human fetal stem cells in heart failure patients: long-term results. Heart Surg Forum. 2010 Feb 1;13(1):E31-5. 4. Chachques JC. Cellular cardiac regenerative therapy in which patients? Expert Rev Cardiovasc Ther. 2009 Aug;7(8):911-9 5. Chang SA, Kang HJ, Lee HY, et al. Peripheral blood stem cell mobilization by granulocyte-colony stimulating factor in patients with acute and old myocardial infarction for intracoronary cell infusion. Heart. 2009 Aug;95(16):1326-30 6. Dill T, Schächinger V, Rolf A, et al. Intracoronary administration of bone marrowderived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J. 2009 Mar;157(3):541-7 7. Dinsmore JH, Dib N. Stem cell therapy for the treatment of acute myocardial infarction. Cardiol Clin. 2010 Feb;28(1):127-38. 8. Fischer-Rasokat U, Assmus B, Seeger FH, et al. A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circ Heart Fail. 2009 Sep;2(5):417-23. 9. Gonzales C, Pedrazzini T. Progenitor cell therapy for heart disease. Exp Cell Res. 2009 Nov 1;315(18):3077-85 10. Gyöngyösi M, Lang I, Dettke M, et al. Combined delivery approach of bone marrow mononuclear stem cells early and late after myocardial infarction: the MYSTAR prospective, randomized study. Nat Clin Pract Cardiovasc Med. 2009 Jan;6(1):70-81 Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 24

11. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol. 2009 Dec 8;54(24):2277-86. 12. Herrmann JL, Abarbanell AM, Weil BR, et al. Cell-based therapy for ischemic heart disease: a clinical update. Ann Thorac Surg. 2009 Nov;88(5):1714-22 13. Joggerst SJ, Hatzopoulos AK. Stem cell therapy for cardiac repair: benefits and barriers. Expert Rev Mol Med. 2009 Jul 8;11:e20 14. Krause K, Jaquet K, Schneider C, et al. Percutaneous intramyocardial stem cell injection in patients with acute myocardial infarction: first-in-man study. Heart. 2009 Jul;95(14):1145-52 15. Lee J, Terracciano CM. Cell therapy for cardiac repair. Br Med Bull. 2010 Mar 2 16. Mansour S, Roy DC, Lemieux B, et al. Stem cell therapy for the broken heart: miniorgan transplantation. Transplant Proc. 2009 Oct;41(8):3353-7. 17. Martin-Rendon E, Brunskill S, Dorée C, et al. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006536 18. Mathiasen AB, Haack-Sørensen M, Kastrup J. Mesenchymal stromal cells for cardiovascular repair: current status and future challenges. Future Cardiol. 2009 Nov;5(6):605-17 19. Martin-Rendon E, Brunskill SJ, Hyde CJ, et al. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J. 2008 Aug;29(15):1807-18. 20. Menasché P. Stem cell therapy for heart failure: are arrhythmias a real safety concern? Circulation. 2009 May 26;119(20):2735-40 21. Pasquet S, Sovalat H, Hénon P, et al. 5.Long-term benefit of intracardiac delivery of autologous granulocyte-colony-stimulating factor-mobilized blood CD34+ cells containing cardiac progenitors on regional heart structure and function after myocardial infarct. Cytotherapy. 2009;11(8):1002-15. 22. Peruga J, Plewka M, Kasprzak J, et al. Intracoronary administration of stem cells in patients with acute myocardial infarction - angiographic follow-up. Kardiol Pol. 2009 May;67(5):477-84. 23. Plewka M, Krzemińska-Pakuła M, Lipiec P, et al. Effect of intracoronary injection of mononuclear bone marrow stem cells on left ventricular function in patients with acute myocardial infarction. Am J Cardiol. 2009 Nov 15;104(10):1336-42 24. Qazilbash MH, Amjad AI, Qureshi S, et al. Outcome of allogeneic hematopoietic stem cell transplantation in patients with low left ventricular ejection fraction. Biol Blood Marrow Transplant. 2009 Oct;15(10):1265-70. 25. Schächinger V, Assmus B, Erbs S, et al. Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction: insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial. 26. Singh S, Arora R, Handa K, et al. Stem cells improve left ventricular function in acute myocardial infarction. Clin Cardiol. 2009 Apr;32(4):176-80 27. Siu CW, Liao SY, Liu Y, et al. Stem cells for myocardial repair. Thromb Haemost. 2010 Mar 29;104(1). 28. Taljaard M, Ward MR, Kutryk MJ, et al. 2.Rationale and design of Enhanced Angiogenic Cell Therapy in Acute Myocardial Infarction (ENACT-AMI): the first randomized placebocontrolled trial of enhanced progenitor cell therapy for acute myocardial infarction. Am Heart J. 2010 Mar;159(3):354-60. 29. Tendera M, Wojakowski W, Ruzyłło W, et al. Intracoronary infusion of bone marrowderived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 25

Stem Cells in Acute Myocardial Infarction (REGENT) Trial. Eur Heart J. 2009 Jun;30(11):1313-21 30. Trzos E, Krzemińska-Pakuła M, Rechciński T, et al. The effects of intracoronary autologous mononuclear bone marrow cell transplantation on cardiac arrhythmia and heart rate variability. Kardiol Pol. 2009 Jul;67(7):713-21. 31. Wöhrle J, Merkle N, Mailänder V, et al. Results of intracoronary stem cell therapy after acute myocardial infarction. Am J Cardiol. 2010 Mar 15;105(6):804-12. 32. Yang Z, Zhang F, Ma W, et al. A Novel Approach to Transplanting Bone Marrow Stem Cells to Repair Human Myocardial Infarction: Delivery via a Noninfarct-relative Artery. Cardiovasc Ther. 2010 Mar 10 33. Yeo C, Mathur A. Autologous bone marrow-derived stem cells for ischemic heart failure: REGENERATE-IHD trial. Regen Med. 2009 Jan;4(1):119-27. 34. Yerebakan C, Uğurlucan M, Kaminski A, et al. Autologous stem cell therapy with surgical myocardial revascularization - The Rostock University experience. Anadolu Kardiyol Derg. 2009 Dec;9(6):457-64 35. Zhang SN, Sun AJ, Ge JB, et al. Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: a meta-analysis of randomised controlled trials. Int J Cardiol. 2009 Aug 14;136(2):178-85. 36. Zhang S, Sun A, Xu D, et al. Impact of timing on efficacy and safety of intracoronary autologous bone marrow stem cells transplantation in acute myocardial infarction: a pooled subgroup analysis of randomized controlled trials. Clin Cardiol. 2009 Aug;32(8):458-66 References Update June 2008 1. Sieff C. Negrin RS, Landaw SW. Overview of hematopoiesis and stem cell function. Feb. 5, 2008. 2. Tatsumi T, Ashihara E, Yasui T, et al. Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction. Circ J. 2007 Aug;71(8):1199-207. 3. Dimmler S, Mann DL, Zeiher AM. Emerging Therapies and Strategies in the Treatment of Heart Failure. Libby: Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed.2007. 4. Zohlnhöfer D, Kastrati A, Schömig A. Stem cell mobilization by granulocyte-colonystimulating factor in acute myocardial infarction: lessons from the REVIVAL-2 trial. Nat Clin Pract Cardiovasc Med. 2007 Feb;4 Suppl 1:S106-9. 5. Zenovich AG, Davis BH, Taylor DA. Comparison of intracardiac cell transplantation: autologous skeletal myoblasts versus bone marrow cells. Handb Exp Pharmacol. 2007;(180):117-65. 6. Tao ZW, Li LG. Cell therapy in congestive heart failure. J Zhejiang Univ Sci B. 2007 Sep;8(9):647-60. 7. Tatsumi T, Ashihara E, Yasui T, et al. Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction. Circ J. 2007 Aug;71(8):1199-207. References Update June 2007 1. Nyolczas N, Gyongyosi M, Beran G, et al. Design and rationale for the Myocardial Stem Cell Administration After Acute Myocardial Infarction (MYSTAR) Study: a multicenter, prospective, randomized, single-blind trial comparing early and late intracoronary or combined (percutaneous intramyocardial and intracoronary) administration of nonselected autologous bone marrow cells to patients after acute myocardial infarction. American Heart Journal. Volume 153, Issue 2 (February 2007). 2. Mills J, Rao S. Future Cardiology. March 2007, Vol. 3, No. 2, Pages 137-140 Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 26

(doi:10.2217/14796678.3.2.137). 3. Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N. Engl. J. Med. 355, 1210 1221 (2006). 4. Meyer, GP, Wollert, KC, Lotz, J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (Bone marrow transfer to enhance ST-elevation infarct regeneration) trial. Circulation 2006; 113:1287. 5. Colucci W, Simons M. Genetic and cellular therapy in heart failure and myocardial infarction. September 12, 2006. 6. Goyal A, Tricoci P, Melloni C, et al. AHJ at the meetings: highlights from the American Heart Association Scientific Sessions, November 2005. Am Heart J 2005; 151:295. 7. Lunde K, Solheim S, Aakhus S, et al. Autologous stem cell transplantation in acute myocardial infarction: The ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J 2005; 39:150. 8. Cleland, JG, Freemantle, N, Coletta, AP, Clark, AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006; 8:105. 9. Tse HF, Kwong YL, Chan JK, et al. Angiogenesis in ischemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet. 2003;361(9351):47-49. 10. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: The BOOST randomized controlled clinical trial. Lancet. 2004;364(9429):141-148. 11. Obradovic S, Rusovic S, Balint B, et al. Autologous bone marrow-derived progenitor cell transplantation for myocardial regeneration after acute infarction. Vojnosanit Pregl. 2004;61(5):519-529. 12. Penn MS, Francis GS, Ellis SG, et al. Autologous cell transplantation for the treatment of damaged myocardium. Prog Cardiovasc Dis. 2002;45(1):21-32. 13. Hughes S. Cardiac stem cells. J Pathol. 2002;197(4):468-478. 14. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106:1913-1918. 15. Abbate A, Bussani R, Biondi-Zoccai GG, et al. Persistent infarct-related artery occlusion is associated with an increased myocardial apoptosis at postmortem examination in humans late after an acute myocardial infarction. 2002; 106: 1051 1054. References - Initial 1. Gao, LR, Wang ZG, Fei YX, et al. Effect of Intracoronary Transplantation of Autologous Bone Marrow-Derived Mononuclear Cells on Outcomes of Patients With Refractory Chronic Heart Failure Secondary to Ischemic Cardiomyopathy. The American Journal of Cardiology Sept 2006;98(5) 2. Janssens, S, Dubois, C, Bogaert, J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006; 367:113. 3. Meyer, GP, Wollert, KC, Lotz, J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrow transfer to enhance ST-elevation infarct regeneration) trial. Circulation 2006; 113:1287. 4. Cleland, JG, Freemantle, N, Coletta, AP, Clark, AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail 2006; 8:105. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 27

5. Zohlnhofer, D, Ott, I, Mehilli, J, et al. Stem cell mobilization by granulocyte colonystimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 2006; 295:1003. 6. Ripa, RS, Jorgensen, E, Wang, Y, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute STelevation myocardial infarction: result of the double-blind, randomized, placebocontrolled stem cells in myocardial infarction (STEMMI) trial. Circulation 2006; 113:1983. 7. Gavira, JJ, Herreros, J, Perez, A, et al. Autologous skeletal myoblast transplantation in patients with nonacute myocardial infarction: 1-year follow-up. J Thorac Cardiovasc Surg 2006; 131:799. 8. Kloner, RA. Attempts to recruit stem cells for repair of acute myocardial infarction: a dose of reality. JAMA 2006; 295:1058. 9. Minami, E, Laflamme, MA, Saffitz, JE, Murry, CE. Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart. Circulation 2005; 112:2951. 10. Strauer, BE, Brehm, M, Zeus, T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol 2005; 46:1651. 11. Goyal, A, Tricoci, P, Melloni, C, et al. AHJ at the meetings: highlights from the American Heart Association Scientific Sessions, November 13 to 16, 2005, Dallas, TX. Am Heart J 2005; 151:295. 12. Thum, T, Bauersachs, J, Poole-Wilson, PA, et al. The dying stem cell hypothesis: immune modulation as a novel mechanism for progenitor cell therapy in cardiac muscle. J Am Coll Cardiol 2005; 46:1799. 13. Lunde, K, Solheim, S, Aakhus, S, et al. Autologous stem cell transplantation in acute myocardial infarction: The ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J 2005; 39:150. 14. Hill, JM, Syed, MA, Arai, AE, et al. Outcomes and risks of granulocyte colony-stimulating factor in patients with coronary artery disease. J Am Coll Cardiol 2005; 46:1643. 15. Zbinden, S, Zbinden, R, Meier, P, et al. Safety and efficacy of subcutaneous-only granulocyte-macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J Am Coll Cardiol 2005; 46:1636. 16. Dib, N, Michler, RE, Pagani, FD, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up. Circulation 2005; 112:1748. 17. Murry, CE, Soonpaa, MH, Reinecke, H, et al. Hematopoietic stem cells do no transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428:664. 18. Melo, LG, Pachori, AS, Kong, D, et al. Molecular and cell-based therapies for protection, rescue, and repair of ischemic myocardium: reasons for cautious optimism. Circulation 2004; 109:2386. 19. Losordo, DW, Dimmeler, S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation 2004; 109:2692. 20. Mathur, A, Martin, PJ. Stem cells and repair of the heart. Lancet 2004; 364:183. 21. Wollert, KC, Meyer, GP, Lotz, J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004; 364:141. 22. Kang, HJ, Kim, HS, Zhang, SY, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004; 363:751. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 28

23. Chen, SL, Fang, WW, Ye, F, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004; 94:92. 24. Perin, EC, Dohmann, HF, Borojevic, R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation 2004; 110:II213. 25. Vulliet, PR, Greeley, M, Halloran, SM, et al. Intra-coronary arterial injection of mesenchymal stromal cells and microinfarction in dogs. Lancet 2004; 363:783. 26. Deb, A, Wang, S, Skelding, KA, et al. Bone marrow-derived cardiomyocytes are present in adult human heart: A study of gender-mismatched bone marrow transplantation patients. Circulation 2003; 107:1247. 27. Britten, MB, Abolmaali, ND, Assmus, B, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003; 108:2212. 28. Tse, HF, Kwong, YL, Chan, JK, Lo, G. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 361:47. 29. Fuchs, S, Satler, LF, Kornowski, R, et al. Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol 2003; 41:1721. 30. Perin, EC, Dohmann, HF, Borojevic, R, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003; 107:2294. 31. Hagege, AA, Carrion, C, Menasche, P, et al. Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 2003; 361:491. 32. Menasche, P, Hagege, AA, Vilquin, JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003; 41:1078. 33. Pagani, FD, DerSimonian, H, Zawadzka, A, et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 2003; 41:879. 34. Smits, PC, van Geuns, RJ, Poldermans, D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 2003; 42:2063. 35. Makkar, RR, Lill, M, Chen, PS. Stem cell therapy for myocardial repair: is it arrhythmogenic?. J Am Coll Cardiol 2003; 42:2070. 36. Ghostine, S, Carrion, C, Souza, LC, et al. Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction. Circulation 2002; 106:I131. 37. Reinecke, H, Poppa, V, Murry, CE. Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting. J Mol Cell Cardiol 2002; 34:241. 38. Xu, C, Police, S, Rao, N, Carpenter, MK. Characterization and enrichment of cardiomyocytes derived from human stem cells. Circ Res 2002; 91:501. 39. Strauer, BE, Brehm, M, Zeus, T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106:1913. 40. Assmus, B, Schachinger, V, Teupe, C, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 2002; 106:3009. 41. Jackson, KA, Majka, SM, Wang, H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001; 107:1395. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 29

42. Jain, M, DerSimonian, H, Brenner, DA, et al. Cell therapy attenuates deleterious ventricular remodeling and improves cardiac performance after myocardial infarction. Circulation 2001; 103:1920. 43. Kehat, I, Kenyagin-Karsenti, D, Snir, M, et al. Human embryonic stem cells can differentiate into myocytes with structural and functional properties of cardiomyocytes. J Clin Invest 2001; 108:407. 44. Menasche, P, Hagege, AA, Scorsin, M, et al. Myoblast transplantation for heart failure. Lancet 2001; 357:279. 45. Wang, JS, Shum-Tim, D, Galipeau, J, et al. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg 2000; 120:999. 46. Scorsin, M, Marotte, F, Sabri, A, et al. Can grafted cardiomyocytes colonize peri-infarct myocardial areas?. Circulation 1996; 94:II337. 47. Li, RK, Jia, ZQ, Weisel, RD, et al. Cardiomyocyte transplantation improves heart function. Ann Thorac Surg 1996; 62:654. Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peerreviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior notice or posting on the website is required before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. In some states, prior notice or website posting is required before an amendment is deemed effective. No Medical Advice. The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. No Authorization or Guarantee of Coverage. The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service or supply. Members and providers should refer to the Member contract to determine if exclusions, limitations, and dollar caps apply to a particular procedure, drug, service or supply. Policy Limitation: Member s Contract Controls Coverage Determinations. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 30

Statutory Notice to Members: The materials provided to you are guidelines used by this plan to authorize, modify, or deny care for persons with similar illnesses or conditions. Specific care and treatment may vary depending on individual need and the benefits covered under your contract. The determination of coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is subject to the facts of the individual clinical case, terms and conditions of the member s contract, and requirements of applicable laws and regulations. The contract language contains specific terms and conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and other relevant terms and conditions of coverage. In the event the Member s contract (also known as the benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member s contract shall govern. The Policies do not replace or amend the Member s contract. Policy Limitation: Legal and Regulatory Mandates and Requirements The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. Reconstructive Surgery CA Health and Safety Code 1367.63 requires health care service plans to cover reconstructive surgery. Reconstructive surgery means surgery performed to correct or repair abnormal structures of the body caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do either of the following: (1) To improve function or (2) To create a normal appearance, to the extent possible. Reconstructive surgery does not mean cosmetic surgery," which is surgery performed to alter or reshape normal structures of the body in order to improve appearance. Requests for reconstructive surgery may be denied, if the proposed procedure offers only a minimal improvement in the appearance of the enrollee, in accordance with the standard of care as practiced by physicians specializing in reconstructive surgery. Reconstructive Surgery after Mastectomy California Health and Safety Code 1367.6 requires treatment for breast cancer to cover prosthetic devices or reconstructive surgery to restore and achieve symmetry for the patient incident to a mastectomy. Coverage for prosthetic devices and reconstructive surgery shall be subject to the co-payment, or deductible and coinsurance conditions, that are applicable to the mastectomy and all other terms and conditions applicable to other benefits. "Mastectomy" means the removal of all or part of the breast for medically necessary reasons, as determined by a licensed physician and surgeon. Policy Limitations: Medicare and Medicaid Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid members shall not be construed to apply to any other Health Net plans and members. The Policies shall not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation. Stem Cell Therapy for Treatment of Heart Failure and Acute Myocardial Infarction May 16 31