Daily Dose Equities - Effect of Transendocardial Delivery

ORIGINAL CONTRIBUTION

ONLINE FIRST

Effect of Transendocardial Delivery of
Autologous Bone Marrow Mononuclear Cells
on Functional Capacity, Left Ventricular Function,
and Perfusion in Chronic Heart Failure
The FOCUS-CCTRN Trial
Emerson C. Perin, MD, PhD, James T.
Context Previous studies using autologous bone marrow mononuclear cells (BMCs) in
Willerson, MD, Carl J. Pepine, MD, Timothy D. patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy.
Henry, MD, Stephen G. Ellis, MD, David X. M.
Objective To determine if administration of BMCs through transendocardial injec-
Zhao, MD, Guilherme V. Silva, MD, Dejian Lai, tions improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV),
PhD, James D. Thomas, MD, Marvin W. or enhances maximal oxygen consumption in patients with coronary artery disease or
LV dysfunction, and limiting heart failure or angina.
Kronenberg, MD, A. Daniel Martin, PhD, PT,
R. David Anderson, MD, MS, Jay H. Traverse,
Design, Setting, and Patients A phase 2 randomized double-blind, placebo-
controlled trial of symptomatic patients (New York Heart Association classification II-
MD, Marc S. Penn, MD, PhD, Saif III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejec-
Anwaruddin, MD, Antonis K. Hatzopoulos, tion fraction of 45% or less, a perfusion defect by single-photon emission tomography
PhD, Adrian P. Gee, PhD, Doris A. Taylor, (SPECT), and coronary artery disease not amenable to revascularization who were re-
ceiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute–
PhD, Christopher R. Cogle, MD, Deirdre sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April
Smith, RN, Lynette Westbrook, RN, James 29, 2009, and April 18, 2011.
Chen, RN, Eileen Handberg, PhD, Rachel E. Intervention Bone marrow aspiration (isolation of BMCs using a standardized au-
Olson, RN, MS, Carrie Geither, RN, Sherry tomated system performed locally) and transendocardial injection of 100 million BMCs
or placebo (ratio of 2 for BMC group to 1 for placebo group).
Bowman, RN, Judy Francescon, RN, Sarah
Main Outcome Measures Co-primary end points assessed at 6 months: changes
Baraniuk, PhD, Linda B. Piller, MD, MPH,
in LVESV assessed by echocardiography, maximal oxygen consumption, and revers-
Lara M. Simpson, PhD, Catalin Loghin, MD, ibility on SPECT. Phenotypic and functional analyses of the cell product were per-
David Aguilar, MD, Sara Richman, Claudia formed by the CCTRN biorepository core laboratory.
Zierold, PhD, Judy Bettencourt, MPH, Shelly Results Of 153 patients who provided consent, a total of 92 (82 men; average age:
L. Sayre, MPH, Rachel W. Vojvodic, MPH, 63 years) were randomized (n=61 in BMC group and n=31 in placebo group). Changes
in LVESV index (−0.9 mL/m2 [95% CI, −6.1 to 4.3]; P=.73), maximal oxygen con-
Sonia I. Skarlatos, PhD, David J. Gordon, MD, sumption (1.0 [95% CI, −0.42 to 2.34]; P=.17), and reversible defect (−1.2 [95% CI,
PhD, Ray F. Ebert, PhD, Minjung Kwak, PhD, −12.50 to 10.12]; P=.84) were not statistically significant. There were no differences
Lemuel A. Moye, MD, PhD,
´ found in any of the secondary outcomes, including percent myocardial defect, total
defect size, fixed defect size, regional wall motion, and clinical improvement.
Robert D. Simari, MD
Conclusion Among patients with chronic ischemic heart failure, transendocardial in-
for the Cardiovascular Cell Therapy Research
Network (CCTRN) jection of autologous BMCs compared with placebo did not improve LVESV, maximal
oxygen consumption, or reversibility on SPECT.

C
ELL THERAPY HAS EMERGED AS Trial Registration clinicaltrials.gov Identifier: NCT00824005
an innovative approach for JAMA. 2012;307(16):doi:10.1001/jama.2012.418 www.jama.com

treating patients with ad- Author Affiliations and a list of the CCTRN study group
vanced ischemic heart dis- studies have been performed primarily are listed at the end of this article.
Corresponding Author: Lemuel A. Moye, MD, PhD,
´
ease, including those with refractory an- using autologous stem/progenitor University of Texas, 1200 Pressler, W-848, Houston,
gina and/or heart failure. Early clinical cells.1-13 In patients with ischemic heart TX 77030 (lemmoye@msn.com).

©2012 American Medical Association. All rights reserved. JAMA, Published online March 24, 2012 E1

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BONE MARROW MONONUCLEAR CELLS FOR CHRONIC HEART FAILURE

disease and heart failure, treatment with administration of 100ϫ106 total BMCs formity of cell preparation. Briefly,
autologous bone marrow mononuclear improves measures of LV performance approximately 80 to 100 mL of bone mar-
cells (BMCs) has demonstrated safety and perfusion at 6 months compared row was aspirated from the iliac crest
and has suggested efficacy.10,14-17 with baseline levels. using standard techniques. The aspirate
None of the clinical trials per- Briefly, we enrolled patients aged 18 was processed with a closed, automated
formed to date, however, have been years or older with clinically stable coro- cell processing system21 (Sepax, Biosafe
powered to evaluate specific efficacy nary artery disease, LV ejection frac- SA). Composition of CD34 and CD133
measures. In addition, autologous cell tion (LVEF) of 45% or less, limiting an- cells was determined by flow cytom-
therapy trials have usually enrolled gina (Canadian Cardiovascular Society etry. After the cells passed stipulated lot
older patients with acute or chronic left [CCS] class II-IV) and/or congestive release criteria, including viability
ventricular (LV) dysfunction without heart failure (New York Heart Associa- (Ͼ70%) and sterility, randomization was
evaluating the effect of these param- tion [NYHA] class II-III), a perfusion performed by the data coordinating cen-
eters or cell function on clinical out- defect by single-photon emission com- ter. Treatment assignment was masked
come. These factors are important puted tomography (SPECT), and no re- to all but 1 designated cell processing
because ischemic heart failure has the vascularization options while receiv- team member at each center not involved
potential to limit the beneficial influ- ing guideline-based medical therapy.20 in patient care. The target dose was
ences of cellular effects.6,18 The study was conducted at the 5 100ϫ106 total BMCs. The BMC final
The present study was undertaken by CCTRN centers; the organizational product was suspended in normal saline
the National Heart, Lung, and Blood In- structure and oversight of the CCTRN containing 5% human serum albumin
stitute–sponsored Cardiovascular Cell have been described.20 The protocol was and adjusted to a concentration of
Therapy Research Network (CCTRN).19 reviewed and approved by the local in- 100ϫ106 cells in 3 mL distributed into
It builds on work from a pilot study in stitutional review boards at each cen- three 1-mL syringes. The placebo group
Brazil,10 which in turn led to the first ter. All patients provided written in- received a cell-free suspension in the
phase 1 randomized trial of autologous formed consent. same volume.
BMC therapy for heart failure in the Randomization was computer- Within 12 hours of aspiration, BMCs
United States (FOCUS-HF) approved by generated and used variable block sizes or placebo were delivered in 15 sepa-
the US Food and Drug Administra- of 6 or 9, randomly selected and strati- rate injections (0.2 mL each) to LV en-
tion.16 These initial studies showed that fied by center. All randomized patients docardial regions identified as viable
transendocardial delivery of BMCs was underwent baseline testing, bone mar- (unipolar voltage Ն6.9 mV) by elec-
feasible and appeared safe in patients row harvesting, and automated cell pro- tromechanical mapping as described
with chronic heart failure due to multi- cessing that was performed locally.20 Pa- elsewhere.20 A 2-dimensional echocar-
vessel coronary artery disease.10,16 Al- tients were randomized in a 2:1 ratio to diogram was performed immediately af-
though these preliminary studies also receive either BMCs or a placebo (cell- ter the injection procedure and on the
evaluated LV function, perfusion, and free) preparation. The cell-containing or next day before hospital discharge. Se-
functional capacity, a definitive assess- cell-free preparation was delivered to vi- rial measurements of creatine kinase,
ment of efficacy was not possible due to able myocardial regions identified dur- creatine kinase MB, and troponin also
the small number of patients. Thus, the ing electromechanical mapping of the LV were obtained. All patients remained in
present trial was designed as a larger endocardial surface (NOGA, Biologics the hospital overnight and were then
study to investigate the effects of tran- Delivery Systems, Cordis Corpora- discharged with instructions for guide-
sendocardial-delivered BMCs in pa- tion). All caregivers and patients were line-recommended therapy. Patients
tients with chronic ischemic heart dis- masked to treatment. At 6 months, all were examined for safety and efficacy
ease and LV dysfunction with heart baseline testing was repeated in an iden- at 6 months. All events deemed to be
failure and/or angina.20 tical fashion. potential major adverse clinical events
Baseline assessments have been de- were assessed by 2 independent cardi-
METHODS scribed.20 Demographic and clinical ologists not affiliated with any clinical
A phase 2 randomized double-blind, pla- variables were determined by inter- site and masked to treatment assign-
cebo-controlled trial, FOCUS-CCTRN view and documented from each pa- ment. Follow-up for safety continues
(First Mononuclear Cells injected in the tient’s medical record. Race and eth- (up to 12 months postintervention)
United States conducted by the CCTRN) nicity were recorded as self-described with annual telephone calls at 2, 3, 4,
was designed to evaluate the safety and by the patients. and 5 years postintervention.
efficacy of BMCs in patients with chronic Cell harvesting and processing pro- The CCTRN established a cell bio-
ischemic heart disease and LV dysfunc- cedures for all CCTRN protocols have repository core laboratory to advance
tion who have no other revasculariza- been reported.21,22 Rigorous automated the understanding of the relationship
tion options. The primary objective was methods for local cell processing were between cell product characteristics
to determine whether transendocardial implemented to ensure quality and uni- (composition or phenotype and func-
E2 JAMA, Published online March 24, 2012 ©2012 American Medical Association. All rights reserved.



tion) and clinical outcomes.23 The re- The 3 prespecified primary end Prespecified subgroup analyses for
maining processed cells (unused cells points of change (6-month follow-up hypothesis generation examined the ef-
in the BMC group and all cells from pa- minus baseline) in LVESV, maximal fects of treatment stratified by age, sex,
tients in the placebo group) were oxygen consumption, and defect size race, diabetes, serum BNP levels in pa-
shipped to the biorepository core labo- on SPECT were compared between the tients with heart failure, preexisting co-
ratory with patient consent. BMC group and the control group. morbidity, number of endothelial
Echocardiographic measurements For each co-primary end point, a colony forming cells, and baseline
were performed by an echocardiogra- sample size was computed based on es- LVEF. Two-sided significance testing
phy core laboratory according to pub- timates of the effect size and the stan- was used; P values of less than .05 were
lished guidelines24 and included LV dard deviation of the difference from the deemed statistically significant.
end-systolic volume (LVESV), LV end- prior data.20 Type I error was appor-
diastolic volume, regional wall mo- tioned at the .05 level to be conducted RESULTS
tion, and LVEF. Myocardial contrast at 80% power with 10% of patients an- Screening commenced in March 2009
was used to enhance endocardial defi- ticipated as lost to follow-up. All test- and 153 patients provided consent. Be-
nition. These measurements were com- ing was 2-sided. The study was de- tween April 29, 2009, and April 18,
puted using the biplane rule methods signed to detect a mean difference 2011, 92 patients were randomized
of Simpson as described by Maret et al.25 between the 2 groups of 27 mL for (n=61 in BMC group and n=31 in pla-
The LV volume data were normalized LVESV, 5 mL/kg/min for maximal oxy- cebo group). Of the 273 patients
for body surface area and indexed data gen consumption, and 10 absolute per- screened, most were excluded due to
are presented. centage points for reversible ische- not having evidence of reversibility
SPECT or adenosine myocardial per- mia. To ensure adequate power for each (prior to protocol amendment during
fusion tests were performed to identify of the 3 end points, the sample size was the final third period of enrollment) or
changes in ischemic (reversible) de- computed for each one, and the maxi- having an LVEF greater than 45%
fects from rest and after adenosine infu- mum sample size was selected.20 This (FIGURE 1).27
sion over 4 minutes (or if contraindi- produced a sample size of 86 patients, Briefly, this was an older, white male
cated, with a regadenoson bolus) using which was administratively increased population (TABLE 1). Most (76%) pa-
standardized protocols. To enhance vi- to 92 patients (31 in the placebo group tients had an implantable cardioverter-
ability detection on resting images, sub- and 61 in the BMC group). No type I defibrillator. No statistically significant
lingual nitroglycerin was administered error adjustment for multiple compari- differences were seen in baseline char-
15 minutes before injection of techne- sons was incorporated because this was acteristics between the BMC and pla-
tium Tc 99m sestamibi for the resting im- a phase 2 study. cebo groups, except for greater ranola-
age. Changes in fixed perfusion defects All statistical analyses were con- zine use in the BMC group (TABLE 2),
by SPECT also were measured. ducted using SAS version 9.2 (SAS In- which was consistent with more pa-
Maximal oxygen consumption was stitute Inc).26 Descriptive statistics for tients with CCS class II to IV angina in
assessed by using the Naughton tread- baseline characteristics were generated the BMC group. The mean (SD) LVEF
mill protocol. Blood flow improve- for demographic variables, medical his- on the qualifying echocardiogram was
ment was examined by magnetic reso- tory, physical examination, laboratory 32.4% (9.2%) in the BMC group and
nance imaging (MRI) in patients without data, and clinical events. ␹2 Statistics and 30.2% (7.8%) in the placebo group.
MRI contraindications. t tests were used to evaluate the differ- All randomized patients had their
Clinical improvement by CCS classi- ences between the 2 study groups. Gen- bone marrow processed with Ficoll
fication, NYHA classification, and change eral linear modeling techniques as- using the automated Sepax device.21 The
in antianginal medications was ex- sessed the effects of treatment on the mean (SD) volume of bone marrow har-
plored. Serum brain-type natriuretic pep- continuous primary and secondary out- vested was 93.7 (8.3) mL. The mean
tide (BNP) levels were collected in pa- comes of the study. Both unadjusted and (SD) time from aspiration to product
tients with congestive heart failure, and baseline covariate-adjusted treatment ef- injection was 8.9 (1.2) hours in the
changes in the levels were assessed at 6 fects were computed. Dichotomous sec- BMC group and 8.6 (2.2) hours in the
months. Major adverse clinical events ondary end points (ie, clinical improve- placebo group.
were assessed and defined as new ment at 6 months, change in CCS Of the 92 patients randomized, 5 pa-
myocardial infarction, rehospitaliza- anginal score and NYHA class, de- tients were identified as having a le-
tion for percutaneous coronary inter- crease in weekly need for antianginal sion suitable for percutaneous revas-
vention in treated coronary artery terri- medication [nitrates]) were analyzed cularization (although no patient had
tories, death, and rehospitalization for using ␹2 and Fisher exact tests. The time- such a lesion identified on the qualify-
non–myocardial infarction acute coro- to-event end points (ie, major adverse ing angiogram). Per protocol, these 5
nary syndrome or congestive heart clinical events) could not be reliably as- patients underwent revascularization
failure. sessed due to the paucity of events. rather than receive the study product.



A sixth patient experienced a limited of 100ϫ106 nucleated cells, which con- A total of 54 patients in the BMC group
retrograde catheter-related dissection of tained an average of 2.6% of CD34 cells and 28 patients in the placebo group had
the abdominal aorta that precluded and 1.2% of CD133 cells. Five of these paired LVESV data at baseline and at 6
study product delivery. patients had harvests that contained less months (FIGURE 2). The mean (SD)
Electromechanical map–guided injec- than 100 million cells (99.9, 99.6, 99, 80, LVESV index (LVESVI) at baseline was
tion of cells or placebo was conducted and 61 million cells). The other patient 57.9 (26.1) mL/m2 in the BMC group
per protocol in the remaining 86 pa- experienced recurrent ventricular tachy- and 65.0 (19.8) mL/m2 in the placebo
tients. Mean viability of the cell prod- cardia with hypotension after each in- group. At 6 months, the mean (SD)
uct (Trypan blue exclusion) was 98.6% jection and received only a small vol- LVESVI was 57.0 (25.5) mL/m2 in the
(TABLE 3). In the BMC group, all but 6 ume of cell product (approximately 13 BMC group and 65.0 (23.3) mL/m2 in
patients received the targeted total dose million cells). the placebo group. The difference in the
change in LVESVI between the BMC
group and the placebo group was not
Figure 1. Flow Diagram of Patients in FOCUS-CCTRN Trial statistically significant (−0.9 mL/m2
[95% CI, −6.1 to 4.3]; P=.73).
273 Assessed for eligibility
A total of 52 patients in the BMC
group and 27 patients in the placebo
181 Excluded
116 Did not meet eligibility criteria
group had paired maximal oxygen con-
55 No reversible ischemia sumption data at baseline and at 6
32 Other cardiac conditions
29 Left ventricular ejection fraction >45% months (Figure 2). The mean (SD) base-
27 Refused to participate line maximal oxygen consumption was
38 Other reasons
14.6 (3.8) mL/kg/min in the BMC group
and 15.3 (4.6) mL/kg/min in the pla-
92 Randomized
cebo group. At 6 months, the mean (SD)
maximal oxygen consumption was 15.0
61 Randomized to receive transendocardial injection 31 Randomized to receive placebo (4.5) mL/kg/min in the BMC group and
of 100 million bone marrow mononuclear cells 2 Did not receive intervention as randomized
4 Did not receive intervention as randomized (revascularizable lesion found at time 14.7 (5.1) mL/kg/min in the placebo
3 Revascularizable lesion found at time of intervention) group. The difference in the change in
of intervention
1 Catheter-related dissection of abdominal aorta maximal oxygen consumption be-
tween the BMC group and placebo group
Primary analysis Primary analysis was not statistically significant (1.0 [95%
54 Assessed for changes in left ventricular end- 28 Assessed for changes in LVESV by CI, −0.42 to 2.34]; P=.17).
systolic volume (LVESV) by echocardiography echocardiography
7 Excluded 3 Excluded
A total of 52 patients in the BMC
1 Other 1 Other group and 25 patients in the placebo
2 Too ill 0 Transplant
1 Lost to follow-up 1 LVAD placement
group had paired SPECT evaluations at
1 Death 1 No show baseline and at 6 months (Figure 2). The
1 LVAD placement mean (SD) percent reversible defect dur-
1 No show 27 Assessed for changes in maximal oxygen
consumption ing the baseline period was 25.1%
52 Assessed for changes in maximal oxygen 4 Excluded (27.8%) in the BMC group and 11.8%
consumption 0 Other
9 Excluded 1 Transplant (20.4%) in the placebo group. At 6
2 Other 1 LVAD placement months, the mean (SD) percent revers-
3 Too ill 1 No show
ible defect was 21.3% (26.6%) in the
1 Lost to follow-up
1 Death 26 Assessed for changes in perfusion defect BMC group and 9.2% (9.1%) in the pla-
by SPECT
1 LVAD placement
5 Excluded
cebo group. The difference in the change
1 No show
2 Other for percent reversible defect between the
50 Assessed for changes in perfusion defect 1 Transplant BMC group and placebo group was not
by single-photon emission computed 1 LVAD placement
tomography (SPECT) 1 No show statistically significant (−1.2 [95% CI,
11 Excluded −12.50 to 10.12]; P=.84).
4 Other
3 Too ill
There were no significant differ-
1 Lost to follow-up ences in the change between the 2
1 Death groups over time for percent total myo-
1 LVAD placement
1 No show cardial defect (−0.9 [95% CI, −5.0 to
3.3]), total defect size (−1.6 [95% CI,
FOCUS-CCTRN indicates First Mononuclear Cells injected in the United States conducted by the Cardiovas- −5.1 to 1.9]), or fixed defect size (−0.7
cular Cell Therapy Research Network.
[95% CI, −4.8 to 3.4]).



The small number of patients with- Findings for stroke volume were simi- CD34 was 0.5% to 6.9% (SD, 1.2%). As-
out contraindications for MRI (n = 17) lar, with a mean (SD) increase of 2.7 suming that differences of 1.96 for SD
precluded performing an informative (12.9) mL in the BMC group and a de- or 2.4% are more likely due to biologi-
analysis on the MRI data. There were crease of −5.8 (15.2) mL in the placebo cal variability, the effect of differences
no significant differences in the change group; this difference was significant (8.4 in CD34 cell level beyond that ex-
between the 2 groups in regional wall [95% CI, 2.1 to 14.8]; P=.01). pected due to natural variability was ex-
motion (−0.1 [95% CI, −0.30 to 0.14]; In an exploratory analysis, BMC amined, using a 3% level to be conser-
P=.47) and LV end-diastolic volume in- therapy was associated with an improve- vative. Every 3% higher level of CD34
dex (2.5 [95% CI, −4.4 to 9.3]; P=.48). ment in maximal oxygen consumption cells was associated with on average a
Forty percent of patients in the BMC for patients with number of endothelial 3.0% greater absolute unit increase in
group and 47% of patients in the pla- colony-forming cells greater than the me- LVEF in a multiple variable model that
cebo group were NYHA class III at base- dian value of 80 (change: 2.5 [95% CI, included age and treatment as predictor
line. The decrease over time in the per- 0.16 to 4.88]). However the interaction variables (3.06 [95% CI, 0.14-5.98];
centage of patients in the BMC group test for this assessment was not signifi- P=.04). An analogous computation for
who were NYHA class III was statisti- cant (interaction effect size: 2.61 [95% CD133 cells (range, 0.1%-3.6%;
cally significant (40% vs 20%; for differ- CI, −0.30 to 5.51]; P=.08). SD=0.62) revealed that every 3% higher
ence: 95% CI, 3% to 37%; P=.02); there A regression analysis showed that level of CD133 cells was associated with
was no significant difference in the analo- higher CD34 cell or CD133 cell counts on average a 5.9% greater absolute unit
gous change for the placebo group. How- were associated with greater absolute increase in LVEF (5.94% [95% CI,
ever, when the between-group analysis unit increase in LVEF. The range of 0.35%-7.57%]; P=.04).
was applied, this finding was not statis-
tically significant. Similarly, there were Table 1. Patient Baseline Characteristics
no significant differences in the change BMC Group Placebo Group P
in CCS class (difference in the percent (n = 61) (n = 31) Value
change: 0.18 [95% CI, −0.07 to 0.43]; Mean (SD)
Age, y 63.95 (10.90) 62.32 (8.25) .47
P=.49), serum BNP levels (regular BNP:
Height, cm 174.50 (8.79) 177.42 (9.60) .15
−40.3 pg/mL [95% CI, −120.2 to 39.7];
Weight, kg 91.53 (22.00) 99.99 (24.23) .10
P=.32 and probrain-type natriuretic pep-
Body mass index a 30.10 (6.14) 31.80 (6.60) .23
tide: 150.2 pg/mL [95% CI, −1215.2 to
Blood pressure, mm Hg
1515.6]; P=.82), or decrease in the need Systolic 120.59 (19.69) 122.13 (15.78) .71
for antianginal medication between the Diastolic 70.95 (11.18) 74.77 (10.35) .12
2 groups at 6 months (2 in BMC group Heart rate, beats/min
and 0 in placebo group; difference in the Mean (SD) 67.90 (10.45) 72.61 (13.60) .07
percent change: 0.04 [95% CI, −0.01 to Median (range) 65.00 (51.00-100.00) 70.00 (49.00-107.00)
0.09]; P=.28). No. (%)
Female sex 8 (13.11) 2 (6.45) .49
Subgroup analyses examined the ef-
White race 58 (95.08) 30 (96.77) Ͼ.99
fects of demographics, comorbidities
Hispanic ethnicity 3 (4.92) 1 (3.23) Ͼ.99
(age, sex, diabetes mellitus, hyperten-
New York Heart Association
sion, angina, and hyperlipidemia), and classification
cell surface markers (CD34 and CD133) I 6 (9.84) 2 (6.45)
on end point measures. There were no II 32 (52.46) 14 (45.16)
.59
significant differences. Additional out- III 23 (37.70) 15 (48.39)
comes were examined for exploratory IV 0 0
purposes. Canadian Cardiovascular (n = 54) (n = 25)
Society classification
The baseline LVEF was available in 54 I 13 (24.07) 10 (40.00)
patients in the BMC group and in 28 pa- II 24 (44.44) 10 (40.00)
tients in the placebo group. The mean .45
III 16 (29.63) 5 (20.00)
(SD) baseline LVEF was 34.7% (8.8%) IV 1 (1.85) 0
in the BMC group and 32.3% (8.6%) in Qualifying LVEF by echocardiography, (n = 60) (n = 31) .25
the placebo group. At 6 months, the mean (SD), % 32.43 (9.23) 30.19 (7.76)
mean (SD) LVEF change was an in- Aspiration to injection time, h (n = 58) (n = 29)
crease of 1.4% (5.2%) in the BMC group Mean (SD) 8.95 (1.18) 8.56 (2.22) .28
and a decrease of −1.3% (5.1%) in the Median (range) 9.01 (6.52-11.40) 8.98 (0.22-11.40)
placebo group. This difference was sig- Abbreviations: BMC, bone marrow mononuclear cell; LVEF, left ventricular ejection fraction.
a Calculated as weight in kilograms divided by height in meters squared.
nificant (2.7 [95% CI, 0.3 to 5.1]; P=.03).



The patients were divided based on significant effect of therapy was seen for cent reversibility on SPECT) for age. No
median age of the population (Յ62 the primary end points (LVESV, maxi- significant differences were seen on the
years and Ͼ62 years). No statistically mal oxygen consumption, and per- secondary end points or cell product
variables in the subgroup analysis, ex-
cept for those described below.
Table 2. Baseline Patient Medical History, Medication Use at Time of Randomization, and
Laboratory Evaluations When LVEF was assessed, patients
No. (%) of Patients a
aged 62 years or younger showed a sta-
tistically significant effect of therapy. Pa-
BMC Group Placebo Group P tients in the BMC group demon-
(n = 61) (n = 31) Value
Medical history
strated a mean (SD) increase in LVEF
Diabetes 21 (34.43) 16 (51.61) .12 of 3.1% (5.2%) from baseline to 6
Hypertension 49 (80.33) 24 (77.42) .79 months, whereas patients in the pla-
Hyperlipidemia 57 (93.44) 29 (93.55) Ͼ.99 cebo group showed a decrease of −1.6%
Angina 21 (34.43) 12 (38.71) .82 (6.6%). The difference in the change be-
Former or current smoking 46 (75.41) 20 (64.52) .33 tween groups was significant (4.7%
Prior myocardial infarction (n = 57) (n = 31) Ͼ.99 [95% CI, 1.0% to 8.4%]; P =.02).
53 (92.98) 29 (93.55)
There were no in-hospital events
Prior revascularization 51 (83.61) 26 (83.87) Ͼ.99
Prior coronary artery bypass graft surgery 47 (77.05) 25 (80.65) .79
(other than the dissection noted ear-
No. of operations
lier). One patient died 29 days after
1 33 (70.21) 21 (84.00) BMC delivery due to pump failure,
2 13 (27.66) 4 (16.00) .39 which was deemed unlikely to be as-
3 1 (2.13) 0 sociated with cell therapy. Another pa-
Congestive heart failure tient had a myocardial infarction 61
Yes 36 (59.02) 20 (64.52) .66
days after BMC delivery; the infarc-
Prior hospitalization 14 (22.95) 9 (29.03) .61
tion did not occur in the targeted in-
Asymptomatic carotid disease 11 (18.03) 3 (9.68) .37
History of stroke or transient ischemic attack 8 (13.11) 1 (3.23) .26
jection area, and the patient was dis-
Valvular heart disease 18 (29.51) 8 (25.81) .81
charged from the hospital 4 days later.
Peripheral vascular disease 13 (21.31) 3 (9.68) .25 There were no rehospitalizations in
History of arrhythmia (n = 56) (n = 28) Ͼ.99 either group for percutaneous coro-
29 (51.79) 14 (50.00) nary intervention prior to the 6-month
Cardiac pacemaker 42 (68.85) 23 (74.19) .64 visit. Eight patients (3 in the BMC group
Implantable cardioverter-defibrillator 3 (4.92) 2 (6.45) Ͼ.99 and 5 in the placebo group) were re-
Dual chamber pacing 17 (18.5) 10 (10.9) .81 hospitalized for congestive heart fail-
Medication use at time of randomization ure, with 1 additional patient in the
ACE inhibitor or ARB 37 (60.66) 22 (70.97) .37
Aldosterone inhibitor 9 (14.75) 8 (25.81) .26
BMC group rehospitalized for acute
Aspirin/P2 Y12 53 (86.89) 29 (93.55) .49 coronary syndrome during this same
␤-Blockers 57 (93.44) 30 (96.77) .66 time frame. One patient in the pla-
Warfarin 10 (16.39) 4 (12.90) .77 cebo group underwent heart transplan-
Digitalis 4 (6.56) 4 (12.90) .44 tation, and 2 other patients (1 in each
Diuretics 41 (67.21) 23 (74.19) .63 group) had LV assist device place-
Nitrates 39 (63.93) 18 (58.06) .65 ments before the 6-month visit.
Statins 44 (72.13) 21 (67.74) .81
Ranolazine 21 (34.43) 3 (9.68) .01 COMMENT
Laboratory evaluations, median (range) The CCTRN was developed by the Na-
Hemoglobin, g/dL 14.0 (10.0-16.9) 14.3 (12.4-16.6) .21
tional Heart, Lung, and Blood Insti-
High-sensitivity C-reactive protein, mg/L (n = 54) (n = 29) .60
1.4 (0.1-37.0) 1.1 (0-86.4) tute to advance cell therapy for pa-
Glomerular filtration rate, mL/min/1.73 m2 (n = 58) (n = 29) .96 tients with cardiovascular diseases by
71.2 (29.6-155.4) 70.1 (30.5-107.3) using a collaborative network ap-
Brain-type natriuretic peptide, pg/mL (n = 46) (n = 23) .68 proach to facilitate larger studies with
132.0 (16.0-545.0) 105.0 (26.0-140.0)
Probrain natriuretic peptide, pg/mL (n = 15) (n = 8) .95
wide applicability. The FOCUS-CCTRN
833.0 (50.0-9793.0) 828.0 (103.0-5778.0) trial is the first, to our knowledge, ad-
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMC, bone marrow mono- equately powered study of cell therapy
nuclear cell.
SI conversion factors: To convert C-reactive protein to nmol/L, multiply by 9.524; hemoglobin to g/L, multiply by 10.0; in patients with chronic ischemic heart
natriuretic peptide to ng/L, multiply by 1.0.
a Unless otherwise indicated.
disease and LV dysfunction (LVEF
Յ45%) to be completed in the United



States. We found no significant differ-
Table 3. Bone Marrow Mononuclear Cell Product Characteristics
ences in a priori selected primary end
Mean (SD)
points between patients treated with
BMCs and placebo in this first-in-man BMC Group Placebo Group P
(n = 61) (n = 31) Value
study that administered 100 million
Total nucleated cells/product, ϫ 106 99.03 (5.58) 100.03 (0.18) .32
cells via transendocardial injection. The
% Viability/product by Trypan blue exclusion 98.56 (1.11) 98.70 (0.89) .52
protocol randomized 92 patients from
% of CD34 cells/product a (n = 57) (n = 30) .67
a cohort of 153 patients who provided 2.71 (1.19) 2.60 (0.93)
consent, demonstrating the efficiency % of CD133 cells/product a (n = 57) (n = 30) .59
and expertise of network recruiting as 1.21 (0.62) 1.14 (0.48)
well as the perceived need by the com- Colony-forming units-Hill/product a (n = 55) (n = 30) .40
109.41 (206.29) 151.33 (244.20)
munity with heart failure for therapy
Endothelial colony-forming cells/product a (n = 49) (n = 28) .60
to address this disease. 131.84 (164.62) 156.44 (240.12)
Primary end points used in previous Abbreviation: BMC, bone marrow mononuclear cell.
a Four patients either declined to participate or had insufficient product for the biorepository.
celltherapytrialsofheartfailurehavebeen
arbitrarily chosen due to lack of sufficient
historical data in stem/progenitor cell
trials. In these previous studies of patients In the present phase 2 study, explor- tion, a meaningful comparison of the
with ischemic heart disease, both LVEF atory analyses revealed that LVEF im- results of the 2 studies is difficult. How-
(by echocardiography) and myocardial proved in the BMC group compared ever, both CD133 and CD34 cell popu-
ischemia (by SPECT) were used to mea- with the placebo group by 2.7%. This lations have been shown to give rise to
sure outcomes of interest and suggested difference is in keeping with results endothelial and vascular progenitor
improvement.5,28 However,thesetrialsen- from a previous meta-analysis of BMC cells and to secrete chemokines and cy-
rolled patients with mostly preserved therapy in patients with chronic ische- tokines capable of recruiting cells and
LVEF (ranging from 48% to 56%). The mic heart disease and in smaller, indi- promoting cell survival.34-37 These find-
recentlypublishedFOCUS-HFtrialisone vidual trials that evaluated BMC therapy ings support a model in which CD34
of the first reported studies of autologous in similar patients.1,30-32 The modest im- and CD133 cells might improve myo-
BMC therapy in patients with ischemic provement in LVEF in our study is con- cardial oxygenation and LV function in
heart failure and low LVEF.14 That phase sistent and may be more meaningful in areas of ischemia and/or hibernating
1 trial also demonstrated a lack of im- light of the larger number of patients myocardium; however, further study is
provement in the measures that were se- enrolled. needed.
lected for the current study (LVESV, To examine this finding further, we In the FOCUS-HF trial,16 maximal
maximal oxygen consumption, and per- assessed LVEF with respect to the bone oxygen consumption improved in the
cent reversibility on SPECT); however, marrow characteristics of the patient. younger patients and was correlated
at the time the CCTRN-FOCUS was de- Improvement in LVEF correlated with with cell function in an exploratory
signed,theresultsofFOCUS-HFwereun- the percentage of CD34 and CD133 analysis. In the present study, maxi-
known. cells in BMC samples. This correla- mal oxygen consumption improve-
Power calculations for the primary tion was based on a central bio- ment was correlated with endothelial
end points selected for the current repository assessment of cell surface cell function, which warrants further in-
study assumed ambitious improve- markers present in the cell product. vestigation. Additional analyses of cell
ments after BMC injections in maxi- Evaluating inherent variability in the function will be forthcoming from the
mal oxygen consumption of 5 mL/kg/ cell product may provide mechanistic CCTRN biorepository and may pro-
min, in LVESV of 22 mL, and in insight into the relationship between vide further meaningful correlations
reversibility on SPECT of 10% based cell characteristics and both patient with outcome measures.
on results from a pilot study from Bra- baseline characteristics and clinical Establishment of the biorepository
zil.10 Since then, exercise training in outcomes. core laboratory by the CCTRN marks
patients with heart failure and low Losordo et al33 recently found a re- an important step forward in under-
LVEF (HF-ACTION [A Controlled duction in angina and increased exer- standing the role of cell function in car-
Trial Investigating Outcomes of Exer- cise duration with the delivery of au- diac cell therapy. By providing mecha-
cise Training]) resulted in only a 0.6 tologous CD34 cells in patients with nistic insight, cell phenotypic and
mL/kg/min improvement in maximal refractory angina who had normal functional studies will help to define
oxygen consumption using the same LVEF (Ն55%) overall. Because base- meaningful end points for future stud-
protocol used in FOCUS-CCTRN.29 line LVEF in patients in the BMC group ies and will aid in selecting patients
Defining end points in this field con- (32.4%) in our study represented pa- most likely to receive maximal ben-
tinues to be a major challenge. tients with significant LV dysfunc- efits from autologous therapy.



Although this study enrolled more SPECT sestamibi often underesti- nificant amount of myocardial viabil-
patients than previous heart failure mates myocardial viability and revers- ity was noted on electromechanical
trials in patients with ischemic heart ibility in patients with multivessel coro- mapping. For this reason and to facili-
disease and low LVEF, the sample nary artery disease compared with tate enrollment because many pa-
size was still relatively small. The SPECT thallium or positron emission tients were being excluded due to the
sample size chosen required large tomography.38-41 After approximately 20 SPECT reversibility criterion, in No-
improvements in selected end points months of enrollment in the present vember 2010 the protocol was amended
to show a significant treatment effect. study, investigators noted a discrep- during the final third period of enroll-
This choice occurred principally due ancy between the amount of reversibil- ment to include patients with any per-
to the paucity of data available for ity present on baseline SPECT and the fusion defects (ie, fixed or reversible).
these evaluations. A large percentage subsequent finding of viable myocar- This may have skewed the population
of the patients in our study had con- dium by electromechanical mapping as to patients with a lesser degree of myo-
traindications for MRI, thus preclud- well as the presence of angina. cardial viability, limiting the areas suit-
ing a meaningful evaluation of the Even with minimal reversibility (eg, able for cell injection. In addition, the
MRI data. 1%) on baseline SPECT sestamibi, a sig- study size precludes any determina-

Figure 2. Changes in Major Outcomes Over Time by Therapy

Change in left ventricular end systolic
volume (LVESV) by echocardiography Change in maximal oxygen consumption

160 35

140 Maximal Oxygen Consumption, mL/kg/min 30

120
25
100
LVESV, mL

20
80
15
60
10
40

20 5

0 0
Baseline 6 mo Baseline 6 mo Baseline 6 mo Baseline 6 mo

Bone marrow Placebo BMC Placebo
mononuclear cells (n = 28) (n = 52) (n = 27)
(BMC)
(n = 54)

Change in reversible defect by single-photon emission
computed tomography Change in global left ventricular ejection fraction (LVEF)

100 60

90
50
80

70
40
Reversibility, %

60
LVEF, %

50 30

40
20
30

20
10
10

0 0
Baseline 6 mo Baseline 6 mo Baseline 6 mo Baseline 6 mo

BMC Placebo BMC Placebo
(n = 52) (n = 25) (n = 54) (n = 28)

Solid circles indicate mean values at baseline and 6 months. Error bars indicate 95% confidence intervals.




tion of the effect of therapy on the oc- Geither, Bowman, Francescon, Piller, Zierold, Vojvodic, The CCTRN also acknowledges its industry partners:
Moye. ´ Biosafe, Biologics Delivery Systems Group, and Cordis
currence of community-wide ac- Analysis and interpretation of data: Perin, Willerson, Corporation for their contributions of equipment and
cepted clinical outcomes (eg, total Pepine, Henry, Ellis, Zhao, Silva, Lai, Thomas, technical support during the conduct of the trial.
Kronenberg, Martin, Penn, Hatzopoulos, Gee, Taylor, Role of the Sponsor: The NHLBI had a role in the de-
mortality), which must be addressed in Cogle, Baraniuk, Piller, Simpson, Loghin, Aguilar, sign and conduct of the study; and had a minimal role
larger forthcoming studies. Although Richman, Zierold, Vojvodic, Gordon, Ebert, Kwak, in the collection, management, analysis, or interpre-
there was a difference in LVEF in an ex- Moye, Simari.
´ tation of the data; and preparation, review, or ap-
Drafting of the manuscript: Perin, Willerson, Pepine, proval of the manuscript.
ploratory analysis, its clinical signifi- Ellis, Silva, Westbrook, Geither, Moye, Simari.
´ NHLBI Project Office Team: Sonia Skarlatos, PhD, Da-
cance is conditional. Critical revision of the manuscript for important in- vid Gordon, MD, PhD, Ray Ebert, PhD, Wendy Taddei-
tellectual content: Perin, Willerson, Pepine, Henry, Peters, PhD, Minjung Kwak, PhD, and Beckie Cham-
Zhao, Silva, Lai, Thomas, Kronenberg, Martin, berlin.
CONCLUSIONS Anderson, Traverse, Penn, Anwaruddin, Hatzopoulos, CCTRN Steering Committee Chair: Robert Simari, MD.
Gee, Taylor, Cogle, Smith, Westbrook, Chen, FOCUS Trial Investigators and Clinical Teams: Min-
In the largest study to date of autolo- neapolis Heart Institute Foundation: Timothy Henry,
Handberg, Olson, Bowman, Francescon, Baraniuk,
gous BMC therapy in patients with Piller, Simpson, Loghin, Aguilar, Richman, Zierold, MD, Jay Traverse, MD, David McKenna, MD, Beth
Jorgenson, RN, and Rachel Olson, RN, MS. Cleve-
chronic ischemic heart disease and LV Bettencourt, Sayre, Vojvodic, Skarlatos, Gordon, Ebert,
land Clinic Foundation: Stephen Ellis, MD, Marc Penn,
Kwak, Moye, Simari.
´
dysfunction, we found no effect of BMC Statistical analysis: Lai, Thomas, Baraniuk, Vojvodic,
MD, PhD, Saif Anwaruddin, MD, James Harvey, MD,
Carrie Geither, RN, Mark Jarosz, RN, Cindy Oblak, and
therapy on prespecified end points. Fur- Moye. ´
Jane Reese Koc, MT. Texas Heart Institute: James
ther exploratory analysis showed a sig- Obtained funding: Willerson, Pepine, Penn, Willerson, MD, Emerson Perin, MD, PhD, Guilherme
Hatzopoulos, Taylor, Handberg, Piller, Simpson. Silva, MD, James Chen, RN, Casey Kappenman,
nificant improvement in LVEF associ- Administrative, technical, or material support: Perin, Deirdre Smith, RN, and Lynette Westbrook, RN, MS.
ated with treatment. Our findings Willerson, Pepine, Zhao, Thomas, Kronenberg, Martin, University of Florida Department of Medicine: Carl
Anderson, Traverse, Smith, Westbrook, Chen,
provide evidence for further studies to Handberg, Olson, Bowman, Francescon, Piller,
Pepine, MD, Barry Byrne, MD, Christopher Cogle, MD,
David Anderson, MD, John Wingard, MD, Eileen
determine the relationship between the Simpson, Aguilar, Bettencourt, Sayre, Vojvodic, Handberg, PhD, Tempa Curry, RN, and Diann Fisk,
composition and function of bone mar- Gordon, Ebert. MT. Vanderbilt University School of Medicine: David
Study supervision: Willerson, Zhao, Thomas, Zhao, MD, Antonis Hatzopoulos, PhD, Allen Naftilan,
row product and clinical end points. Hatzopoulos, Simpson, Loghin, Skarlatos, Kwak, MD, Sherry Bowman, RN, Judy Francescon, RN, and
Understanding these relationships will Simari. Karen Prater.
Conflict of Interest Disclosures: The authors have com- Data Coordinating Center and Laboratory Teams: Uni-
improve the design and interpretation pleted and submitted the ICMJE Form for Disclosure versity of Texas School of Public Health: Lemuel Moye,
of future studies of cardiac cell therapy. of Potential Conflicts of Interest. All of the authors re- MD, PhD, Lara Simpson, PhD, Linda Piller, MD, MPH,
ported receiving research grant funding and support Sarah Baraniuk, PhD, Dejian Lai, PhD, Shreela Sharma,
Published Online: March 24, 2012. doi:10.1001 for travel expenses to meetings for the Cardiovascu- PhD, Judy Bettencourt, MPH, Shelly Sayre, MPH, Ra-
/jama.2012.418 lar Cell Therapy Research Network (CCTRN) from the chel Vojvodic, MPH, Larry Cormier, Robert Brown,
Author Affiliations: Texas Heart Institute, St Luke’s National Heart, Lung, and Blood Institute (NHLBI). Dr PhD, Diane Eady, Crystal Maitland, MBA, Courtney
Episcopal Hospital, Houston (Drs Perin, Willerson, Perin reported serving as a consultant to Amorcyte, Ransom, Maybelle Sison, RN, and Michelle Cohen.
and Silva, Mss Smith and Westbrook, and Mr Teva, Cytori, and Aldagen. Dr Pepine reported receiv- Baylor College of Medicine: Adrian Gee, PhD, Sara
Chen); School of Medicine (Drs Pepine, Anderson, ing research grants from Baxter, BDI, Amrin, Angio- Richman, and David Aguilar, MD. University of Texas
Cogle, and Handberg) and College of Public Health blast, Neostem, Harvest Technologies, Daiichi San- Medical School: Catalin Loghin, MD. Cleveland Clinic
and Health Professions (Dr Martin), University of kyo, Pfizer, Gilead Sciences, and GlaxoSmithKline. Dr C5 Research Imaging Core: James Thomas, MD, Al-
Florida, Gainesville; Minneapolis Heart Institute at Henry reported serving on steering committees for and len Borowski, Annitta Flinn, and Cathy McDowell (echo
Abbott Northwestern Hospital, Minneapolis, Min- receiving research grants from Aastrom and Meso- core laboratory). Vanderbilt University School of Medi-
nesota (Drs Henry and Traverse and Ms Olson); blast. Dr Martin reported receiving research grants from cine: Marvin Kronenberg, MD, Doreen Judd, and Amy
School of Medicine, University of Minnesota, Min- the University of Texas to provide an exercise testing Wright (SPECT core laboratory). University of Florida
neapolis (Drs Henry, Traverse, Taylor, and Zierold); core laboratory and received financial support for travel Department of Physical Therapy: Daniel Martin, PhD,
Cleveland Clinic Foundation, Cleveland, Ohio (Drs expenses. Dr Penn reported receiving research grants PT, Eileen Handberg, PhD (maximal oxygen consump-
Ellis and Thomas and Ms Geither); School of Medi- from Athersys Inc; serving as a board member for Ju- tion core laboratory). Center for Cardiovascular Re-
cine, Vanderbilt University, Nashville, Tennessee ventas Therapeutics; serving as a consultant to Juven- pair: Doris Taylor, PhD, Claudia Zierold, PhD, and Mar-
(Drs Zhao, Kronenberg, and Hatzopoulos and Mss tas Therapeutics and Aastrom Biosciences; and hold- jorie Carlson (biorepository core in Minnesota).
Bowman and Francescon); Schools of Public Health ing patents, receiving royalties, and owning stock in University of Florida Department of Medicine: Chris-
(Drs Lai, Baraniuk, Piller, Simpson, and Moye and ´ Juventas Therapeutics. Dr Hatzopoulos reported re- topher R. Cogle, MD, and Elizabeth Wise (bioreposi-
Mss Bettencourt, Sayre, and Vojvodic) and Medi- ceiving payment for lectures from Washington Uni- tory core in Florida).
cine (Dr Loghin), University of Texas, Houston; versity, University of Minnesota, and Tennessee State Additional Contributions: We thank the NHLBI
Northeast Ohio Medical University, Akron (Dr University. Dr Taylor reported receiving payment gene and cell therapies data and safety monitoring
Penn); Penn Heart and Vascular Hospital, University for a lecture at an annual meeting of the Cell Society. board and the protocol review committee for their
of Pennsylvania, Philadelphia (Dr Anwaruddin); Dr Handberg reported receiving grants from Baxter, review and guidance of the FOCUS trial and
College of Medicine, Baylor University, Houston, BDI, Amrin, Angioblast, Neostem, Harvest Technolo- Rebecca A. Bartow, PhD, of the Texas Heart Insti-
Texas (Drs Gee and Aguilar and Ms Richman); gies, Daiichi Sankyo, Pfizer, Gilead Sciences, and tute at St Luke’s Episcopal Hospital for editorial
National Heart, Lung, and Blood Institute, GlaxoSmithKline. Ms Olson reported receiving re- assistance. Dr Bartow was not financially compen-
Bethesda, Maryland (Drs Skarlatos, Gordon, Ebert, search grants from Mesoblast and Aastrom. Ms Gei- sated for her contribution.
and Kwak); and Mayo Clinic, Rochester, Minnesota ther reported receiving support for travel expenses to
(Dr Simari). meetings from the Cleveland Clinic. Dr Aguilar re-
Author Contributions: Dr Moye had full access to all
´ ported being a consultant to Amylin Pharmaceutical REFERENCES
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