Table 1 Characteristics of the included randomised controlled trials (n = 16)
Name of study (author + year) Trial | Design | N (total) | Patients | Mean age Male (%) | Intervention | Comparator | Exercise protocol | Primary outcome | Included outcomes | Patients with HF or rEF (%) | Mean LVEF (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|
Al-Lamee 2017 ORBITA [5] | RCT (double-blind) | 200 | Patients with angina or equivalent symptoms and at least one angiographically significant lesion (≥ 70%) in a single vessel that was clinically appropriate for PCI | 66 73% | PCI | Sham | Bruce protocol | Exercise time | Exercise time, SAQ | 4 | NR |
Cobb [17] | RCT (double-blind) | 17 | Patients with seriously limited angina attributed to coronary artery disease | 59 71% | Internal mammary artery ligation | Sham | Bruce protocol | NTG use and exercise time | Exercise time | NR | NR |
Fuchs [22] | RCT (double-blind) | 10 | Patients with severe or critical stable angina pectoris (CCS class III or IV) despite maximal medical therapy and had no coronary artery revascularisation alternatives | 65 90% | Percutaneous intramyocardial delivery of AdVEGF121 | Diluent (placebo) | Treadmill using the ACIP protocol | Exercise time | Exercise time, CCS angina class, SAQ – angina frequency | NR | 53.6 |
Kastrup 2005 Euroinject One [21] | RCT (double-blind) | 80 | Patients with severe stable ischaemic heart disease and CCS class III to IV | 61 84% | Percutaneous intramyocardial plasmid gene transfer of phVEGF-A165 | Placebo plasmid | NR | Myocardial perfusion defects during stress and rest | CCS angina class | 0 | 61.5 |
Kastrup 2011 NOVA [28] | RCT (double-blind) | 17 | Patients with > 10% reversible ischaemia of LV at an adenosine stress SPECT, a coronary arteriography demonstrating at ≥ 1 main coronary vessel from which new collaterals/vessels could be supplied, CCS ≥ 2 despite optimal medicinal therapy, two baseline bicycle ETTs (> 2 and < 8 min until angina level 3 and exercise duration on the two ETTs should be within 15% of each other) | 62 76% | Intramyocardial injection of AdGVVEGF121.10NH | Placebo | Bicycle | Exercise time | Exercise time, CCS angina class, anginal episodes, and NTG use | NR | 52.3 |
Leon [20] | RCT (double-blind) | 298 | History of coronary artery disease with refractory angina (CCS class III or IV), despite optimal medical therapy | 62.9 77% | Direct Myocardial Revascularisation | Sham | Modified Bruce protocol | Exercise time | Exercise time, SAQ | NR | 49.3 |
Losordo [18] | RCT (double-blind) | 19 | Patients with CCS class III or IV angina refractory to maximum medical therapy, multivessel coronary artery disease not suitable for bypass surgery or angioplasty, and reversible ischemia on stress SPECT Tc 99 m sestamibi nuclear imaging | 61 79% | Intramyocardial injections of plasmid DNA encoding for phVEGF2 | Saline injection | Modified Bruce protocol | CCS angina class and exercise time | CCS angina class, exercise time, anginal episodes, NTG use | NR | 48.8 |
Losordo [23] | RCT (double-blind) | 24 | Patients with CCS class III or IV angina to have attempted “best” medical therapy without control of symptoms (taking ≥ 2 antianginals), noncandidates for revascularisation, have ischaemia on nuclear perfusion imaging, to complete > 1 min but < 6 min of a Bruce protocol, and to experience angina during the baseline exercise test | 62.4 79% | Intramyocardial Transplantation of Autologous CD34 + Stem Cells | Saline plus 5% autologous serum | Bruce protocol | Arrhythmia monitoring, anginal episodes, NTG use, exercise time, CCS class, QoL | Exercise time, CCS angina class, SAQ, NTG use, anginal episodes | 33 | NR |
Losordo [27] ACT34-CMI | RCT (double-blind) | 167 | Patients with CCS class III-IV chronic refractory angina despite optimum medical management and with no suitable revascularisation options | 61 87% | Intramyocardial injection of autologous CD34 + cells | Placebo injection | Modified Bruce protocol | Angina frequency | Anginal episodes, Exercise time, CCS angina class, NTG use, SAQ | 31 | 59.8 |
Povsic 2016 The RENEW [31] | RCT (double-blind) | 112 | Patients with CCS class III or IV angina, ejection fraction of ≥ 25%; reproducible exercise-limiting angina (between 3 and 10 min on 2 consecutive EETs), minimum of 7 angina episodes per week during a 4-week screening period, were on maximally tolerated medical therapy and had demonstrable ischaemia on stress testing | 64 84% | Intramyocardial Autologous CD34 + Cell administration | Placebo injection or no intervention | Modified Bruce protocol | Total exercise time | Exercise time, anginal episodes | 26 | 52.8 |
Salem 2004 BELIEF [19] | RCT (double-blind) | 82 | Patients with stable CCS class III or IV angina refractory to maximally tolerated doses of > 2 antianginal medications; evidence of reversible myocardial ischaemia on exercise testing or technetium sestamibi stress myocardial perfusion scanning; and ejection fraction > 25% and wall thickness > 8 mm in the target region for PMLR | 66 91% | Percutaneous Myocardial Laser Revascularisation | Sham | Bicycle and treadmill | CCS angina class | Exercise time, SAQ | 2 | 63.5 |
Tse 2007 PROTECT-CAD [24] | RCT (double-blind) | 28 | Patients with a history of stable CCS class III or IV angina refractory to medical therapy, with no revascularisation option, able to complete > 3 min but < 10 min of treadmill exercise and 1 or 2 coronary territories of viable ischaemic myocardium | 66 75% | Direct endomyocardial implantation of bone marrow cells | Autologous plasma injection | Modified Bruce protocol | Exercise time | Exercise time, CCS angina class | NR | 50 |
Van Ramshorst [25] | RCT (double-blind) | 50 | Patients with severe angina (CCS class III-V) despite optimal medical therapy, and myocardial ischaemia in at least 1 myocardial segment on Tc-99 m tetrofosmin SPECT | 64 86% | Intramyocardial Bone Marrow Cell Injection | Placebo solution | Bicycle | Summed stress score | CCS angina class | NR | 55.1 |
Perin [29] | RCT (double-blind) | 20 | CCS class II to IV angina or NYHA class II or III heart failure (able to walk on a treadmill) on maximum tolerable medical therapy, ejection fraction ≤ 45%, the presence of a reversible perfusion defect on SPECT, coronary artery disease ineligible for percutaneous or surgical revascularisation | 58 85% | Transendocardial injection of autologous aldehyde Dehydrogenase bright stem cells | Placebo solution | Not evaluated | Occurrence of adverse events | CCS angina class | 100 | 34.1 |
Wang [26] | RCT (double-blind) | 112 | Patients with diffuse triple vessel disease and CCS class III or IV angina, receiving conventional medical therapy, considered non-candidates for conventional revascularisation, required to have ischaemia on nuclear perfusion imaging, to complete > 1 min and < 6 min of a standard Bruce protocol and to experience angina during the baseline exercise test | 57.8 51% | Intracoronary Autologous CD34 + Stem Cell Therapy | Placebo solution | Bruce protocol | Safety, angina frequency, NTG use, exercise time, CCS class, SPECT perfusion imaging | Anginal episodes, NTG use, exercise time, CCS class | 6 | NR |
Verheye 2015 COSIRA [30] | RCT (double-blind) | 104 | CCS class III or IV angina despite efforts to control symptoms with medical therapy for at least 30 days before screening | 67.8 81% | Coronary sinus reducer | Sham | Bicycle ergometry stress test (adapted ACIP protocol) | Improvement of 2 or more CCS angina classes | Exercise time, Improvement in CCS class, SAQ | NR | 54.2 |