Cell Therapy for Refractory Angina: A Reappraisal

Table 1

Published cell therapy trials in RA.

Trial	Design	Treated/controls	Baseline LVEF%	Cell type	Delivery	FU (months)	Efficacy outcomes	Safety
ACT34-CMI [17, 18]	RCT, Phase II, dose finding	111/56	Normal	PB-CD34^+	IM^endo	6/12/24	↓ CCS and NTG use; ↓ angina frequency in the low-dose group only; ↑ perfusion; ↑ exercise capacity in the low-dose group only	No differences, cell therapy versus control groups
Adler et al. [19]	Phase I, dose finding	9/0	Normal	BM-CD133^+	IC	24	↔ angina frequency; ↑ perfusion	No MACE reported
ATHENA; ATHENA II [14]	RCT, phase II, dose finding	17/14	31.1 ± 8.2%	AT-MSC	IM^endo	12	↓ CCS and NYHA; ↔ perfusion; ↑ MVO2; ↔ LVEF, LVEDV, and LVESV	No differences, cell therapy versus controls groups
Babin-Ebell et al. [20]	Phase I	6/0	66.67% of patients < 50%	BM-CD133^+	IM^epi	3/6/12	↓ CCS; ↑ LVEF	1 possible cell related death
Beeres et al. [21]	Phase I	25/0	47% ± 13%	BM-MNC	IM^endo	3/6/12	↓ CCS, angina frequency, and NTG use; ↑ perfusion; ↑ LVEF, LVESV, and RWM; ↔ LVEDV	1 not cell therapy-related death and 1 MACE, 1 SAE
Briguori et al. [22]	Phase I	10/0	30% of patients < 50%	BM-MNC	IM^endo	12	↓ CCS, angina frequency; ↑ perfusion	1 not cell therapy-related MACE
Fuchs et al. [23]	Phase I	27/0	48 ± 9%	BM-MNC	IM^endo	3/12	↓ CCS, angina frequency; ↑ perfusion; ↑ treadmill exercise; ↔ LVEF	1 cell therapy-related periprocedural SAE (aortic dissection); 3 not cell therapy-related MACE at follow-up
FOCUS-HF [24]	RCT, phase II	20/10	37 ± 10.6% cell therapy group, 39 ± 9.1% control group	BM-MNC	IM^endo	3/6	↓ CCS and ↔ NYHA; ↑ perfusion; ↔ MVO2; ↔ LVEF and LVWMI	SAEs evenly distributed between control and cell therapy groups
FOCUS-CCTRN [16]	RCT, phase II	61/31	34.7 ± 8.8% cell therapy group, 32.3 ± 8.6% control group	BM-MNC	IM^endo	6	↔ CCS, NYHA and NTG use; ↔ perfusion; ↔ MVO2; ↑ LVEF; ↔ LVESV, LVEDV, and LVWMI	No significant differences between control versus cell therapy groups
Haack-Sørensen et al. [25–27]	Phase I	31/0	Normal	BM-MSC	IM^endo	12/36	↓ CCS, angina frequency, and NTG use; ↔ perfusion; ↑ MET; ↑ LVEF	Not cell therapy-related SAEs and MACE
Klein et al. [28]	Phase I	10/0	15.8 ± 5	BM-CD133^+	IM^epi	9	↓ CCS; ↑ LVEF, LVEDV	1 possible cell therapy-related death
Lee et al. [29]	Phase I, dose finding	38/0	Normal	PB-CD34^+	IC	6/9/12	↓ CCS and NYHA; ↔ perfusion; ↑ LVEF, LVEDV, and LVESV	2 not cell therapy-related deaths; 2 not cell therapy-related MACE
Losordo et al. [30]	RCT, phase II, dose finding	18/6	NA	PB-CD34^+	IM^endo	3/6/9/12	↓ CCS, angina frequency, NTG use; ↔ perfusion; ↑ exercise capacity	SAEs evenly distributed between control and cell therapy groups
Mann et al. [31]	Phase I	23/0	Normal	BM-MNC	IM^endo	3/6/12	↓ CCS, angina frequency; ↑ perfusion; ↔ exercise capacity; ↔ LVEF, LVEDV, and LVESV	No safety issues
Pokushalov et al. [32]	RCT, Phase II	55/54	27.8 ± 3.4% cell therapy group, 26.8 ± 3.8% control group	BM-MNC	IM^endo	3/6/12	↓ CCS, NYHA, angina frequency and NTG use; ↑ perfusion; ↑ exercise capacity; ↑ LVEF	Significant difference in mortality rate between cell therapy versus control groups (6 versus 21 deaths, resp.)
Pompilio et al. [33]	Phase I	5/0	40% of patients < 50%	BM-CD133^+; PB-CD133^+	IM^epi		↓ CCS, angina frequency; ↑ perfusion; ↔ LVEF	No safety issues
PRECISE [34]	RCT, phase II	21/6	36.7 ± 7.5% cell therapy group, 34.2 ± 9.5% control group	AT-MSC	IM^endo	6/12/18	↔ CCS and NYHA; ↑ perfusion; ↑ MVO2 and MET; ↔ LVEF, LVEDV, and LVESV; ↑ LV mass and LVWMI	SAEs evenly distributed between control and cell therapy groups
PROGENITOR [15]	RCT, phase II	19/9	Normal	PB-CD133^+	IM^endo	6/12/24	↔ CCS, angina frequency, and NTG use; ↔ perfusion; ↔ treadmill exercise; ↔ LVEF, LVEDV, and LVESV	SAEs and MACE evenly distributed between control versus cell therapy groups
PROTECT-CAD [35]	RCT, phase II, dose finding	19/9	51.9 ± 8.5% cell therapy group, 45.7 ± 8.3% control group	BM-MNC	IM^endo	3/6	↔ CCS; ↓ NYHA; ↔ perfusion; ↑ treadmill exercise; ↑ LVEF; ↔ LVEDV and LVESV	1 death and 1 MACE in control group; 1 SAE in cell therapy group at follow-up
ReACT [36, 37]	Phase I	14/0	Normal	BM-MNC	IM^epi	3/6/12	↓ CCS; ↑ perfusion; ↔ LVEF	2 deaths (1 for cardiogenic shock due to MI, 1 MI)
RegentVsel [13]	RCT, phase II	16/15	Normal	BM-CD133^+	IM^endo	4/12	↔ CCS and NTG use; ↔ perfusion; ↔ LVEF; ↑ LV volumes	MACE evenly distributed between control versus cell therapy groups; 1 SAE in cell therapy group (pseudoaneurysm of the femoral artery)
RENEW [12, 38]	RCT, phase II	57/55	Normal	PB-CD34^+	IM^endo	3/6/12	↓ angina frequency; ↑ exercise capacity	No safety issues
Tse et al. [8]	Phase I	8/0	Normal	BM-MNC	IM^endo	3	↓ angina frequency and NTG; ↑ perfusion; ↔ LVEF; ↑ target wall thickening and motion	No MACE reported
Tuma et al. [39]	Phase I	14/0	31.2%	BM-MNC	IV	24	↓ CCS, angina frequency; ↑ perfusion; ↑ exercise capacity; ↑ LVEF	No safety issues
van Ramshorst et al. [40]	RCT, phase II	25/25	Normal	BM-MNC	IM^endo	3/6	↓ CCS; ↑ perfusion; ↑ LVEF; ↑ exercise capacity; ↔ LVEDV and LVESV	MACE and SAEs evenly distributed between control versus cell therapy groups
Wang et al. [41]	RCT, phase II	56/56	NA	BM-CD34^+	IC	3/6	↓ CCS, angina frequency, NTG use; ↑ perfusion; ↑ exercise capacity	No significant differences between control versus cell therapy groups

AT: adipose tissue; BM: bone marrow; CABG: coronary artery bypass grafting; FU: follow-up; LVEDV: left ventricular end-diastolic volume; LVEF: left ventricular ejection fraction (normal EF defined as ≥50%); LVESV: left ventricular end-systolic volume; LVWMI: left ventricular wall motion index; MACE: major adverse cardiac events; MET: maximal metabolic equivalent; MI: myocardial infarction; MNC: mononuclear cells; MSC: mesenchymal cells; NA: not available; NTG: nitroglycerin; PB: peripheral blood; PCI: percutaneous coronary intervention; RCT: randomized controlled trial; RWM: regional wall motion; SAEs: serious adverse events.