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Three Part Question

In [patients not amenable to conventional revascularisation] does [gene therapy] reduce the symptoms of [angina]?

Clinical Scenario

There are a number of patients with poor left ventricular function being referred to the cardiac surgeon with angina who have had previous multiple revascularisation procedures and are on maximal medical therapy. They are clearly unsuitable for further surgical revascularisation either due to diffuse coronary artery disease with poor targets or have no useable conduits. Although some of these patients may be eligible for orthotopic heart transplantation, current waiting times for donor hearts and limitations in organ availability render this option unlikely to occur before the patient has become severely ill and reached status I priority level. Gene based modalities for ischaemic myocardium may eventually constitute a therapeutic option for these patients.
You wish to find out what current evidence exists in this area of research.

Search Strategy

Medline 1990 to September 2005 using the OVID interface.
[exp vascular endothelial growth factor A/OR vascular endothelial growth factor.mp OR VEGF.mp OR exp Fibroblast Growth Factors/OR Fibroblast growth factor.mp OR FGF.mp] AND [Exp Thoracic surgery/OR Thoracic surgery.mp OR cardiac surgery.mp OR CABG.mp OR Coronary arter$ disease.mp OR myocardial.mp] limit to human.

Search Outcome

Four hundred and sixty-four papers were found of which only 12 papers were clinically relevant. There were 7 cohort and 5 randomised trials.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Losordo et al, 1998, USA	5 patients only Class 3 or 4 exertional angina, refractory to maximal medical therapy Multivessel coronary disease. Viable but under-perfused myocardium Mini-thoracotomy and direct injection of phVEGF165 DNA into ischaemic myocardium Dose 125ìg	Case Series (level 4)	Frequency of angina	Angina completely abolished in 2 patients 1 patient had 2 episodes of angina in 30day period compared to daily angina before gene therapy	Very small number of patients.(n=5) No control group
			Nitroglycerin usage	NTG use decreased from 7.7±1.4 to 1.4±1.0 tablet per day by day 60
			Dobutamine stress test SPECT-sestamibi imaging	Reduced ischaemia on perfusion scanning. The mean number of normally perfused segments increased from 6.0±1.1 to 8.0±0.7 (p<0.05) at day 60
Symes et al, 1999, USA	20 patients with CCS class 3 or 4 angina, reversible ischaemia on stress sestamibi scans and inoperable coronary artery disease Mini-thoracotomy and direct injection of phVEGF165 into ischaemic myocardium 125ìg(n=10) 250ìg(n=10) 2ml aliquots into 4 separate areas of myocardium	Cohort study (level 3b)	Angina frequency	Significant reduction in angina and nitroglycerin usage compared to pre-op (p<0.0001)	Small numbers Non-randomised
			Dobutamine SPECT Coronary angiography	Reduction in ischaemic defects on SPECT scanning (250ug group) P<0.025. Angiographic evidence of improved collateral filling of at least one occluded vessel was observed in all patients at day 60.
Vale et al, 2000, USA	13 patients with chronic stable angina-failed conventional therapy CCS class 3 or 4 Minithoracotomy and direct injection of phVEGF 165 DNA into ischaemic myocardium Identified by NOGA and sestamibi imaging Dosage 250ìg (n=4) 500ìg (n=8)	Cohort study (Level 3b)	Frequency of angina	All 13 patienst had significant reduction in anginal episodes (p<0.0001)	Small numbers No control group Non randomised Non blinded
			nitroglycerin usage	Reduced nitroglycerin usage (p<0.0001)
			exercise tolerance on Bruce protocol	Increase in mean exercise duration on Bruce protocol from 272 to 453 seconds (p<0.001). No significant improvement in LV ejection Fraction
Rosengart et al, 1999, USA	21 patients with clinically significant severe coronary artery disease 15 patients had AdGV VEGF 121 injected into iscahemic myocardium as adjunct to CABG(group A) 6 patients had minithoracotomy and direct injection of AdGVVEGF121 (group B)(100ìL/inj	Cohort study (level 3b)	30 day post op coronary angiograpghy and stress sestamibi scan assessment of wall motion. Assessment of angina class	2 perioperative deaths in Group A all patients reported improvement in angina class compared to preoperative state At 30days post op there was no improvement in blood flow in areas of vector administration as assessed by Tc-sestamibi images, however they report improvement in wall motion at stress (66% both groups) No P valve given Group A no improvement in treadmill exercise tolerance at 30 days post-op Group B improved treadmill exercise tolerance in 50% patients. No P values	Non-randomised Limited number of patients No meaningful statistics
Hendel et al, 2000, USA	14 patients with severe coronary artery disease not suitable for bypass or angioplasty pre-op ETT, Dobutamine or dipyridamole myocardial perfusion SPECT (phase I trial) Intracoronary administration of rhVEGF Low-dose group (0.005 and 0.017ìg/kg) High-dose (0.05 and 0.167ìg/kg)	Cohort Study (level 3b)	Exercise tolerance, dobutamine or dipyridamole SPECT imaging performed at baseline, 30 and 60 days after rhVEGF	Failed to demonstrate any improvement in angina or exercise tolerance. Improved perfusion after rhVEGH at 30days (p<0.05)
Grines et al, 2002, AGENT Trial, USA	79 patients with chronic stable angina CCS 2 or 3) angiographic coronary evidence of coronary atherosclerosis double-blind randomisation (1:3) Placebo n=19 Ad5-FGF4 (n=60) Ad5-FGF4(n=60) 6 ascending doses of vector from 3.3x108 to 1011 infused over 90seconds via intracoronary catheter	Double-blind RCT (level 1b)	Exercise tolerance	20 to 30% improvement in ETT compared to baseline at 4 and 12 weeks (p<0.01 and p<0.047)
			Angina frequency	no significant improvement in angina
			Stress echocardiograms	no improvement in stress-induced wall motion scores at 4 or 12 weeks
Henry et al, 2003, The VIVA Trial	178 patients with exertional angina unsuitable for standard revascularization evidence of underperfused myocardium on perfusion imaging Randomised to receive a 20-minute intracoronary infusion of placebo (n=63) , low-dose brhVEGF (17ng.kg-1.min-1) or high-dose (n=59) rhVEGF (50ng.kg-1.min-1) followed by 4-hour intravenous infusion on days 3,6, and 9.	Double blind, PRCT (level 1b)	Exercise Treadmill test	The primary end point of trial, change in ETT time from baseline to day 60, was negative.
			Angina Frequency	Significant improvement in angina class and frequency, ETT and QOL at 120 days in high-dose rhVEFG group (p=0.05)
			Ejection Fraction SPECT	Myocardial perfusion scans at rest and stress at 60 days- No significant improvement. Ejection Fraction measurements- No significant improvement
Fortuin et al, 2003, USA	30 patients with 'no-option'angina given VEGF-2 via mini-thoracotomy and 4 intramyocardial injections 1 year follow up	Cohort study (Level 3b)	Episodes of Angina per week	Drop from 32±26 to 10±19 per week at 1 year	1 death post-procedure
			Treadmill test	Increase from 367±213 to 483±162 seconds at 12 months
			Angiography	No evidence of angiogenesis
Kastrup et al, 2005, The Euroinject One Trial, Denmark	80 patients with 'no option' angina randomized to receiving 10 intramyocardial injections of 0.5 mg of phVEGF-A165, or placebo via a percutaneous route	Double-blind PRCT (level 1b)	Myocardial Perfusion analysis	No differences between groups	1 cardiac tamponade caused
			Clinical outcomes	No significant differences in angina scores , exercise capacity , GTN usage.
			Ejection fraction	No difference between Ejection fractions, but significantly improved regional wall motion in VEGF group
Reilly et al, 2005, USA	2 year follow up of 30 patients post VEGF-2 intramyocardial injection via mini thoracotomy	Cohort study (level 3b)	CCS Angina score	3.6±1.5 pre-op but only 1.5±1.2 at 2 years
			Complications	48% had a complication by 2 years including 3 deaths, 4MIs 4 PCI , 1 stroke.
Simons et al, 2002, USA	337 patients with coronary disease and ETT from 3 to 13 mins . 20 minute intracoronary infusion of 0.3, 3 or 30mcg/kg of rFGF-2 or placebo.	Multi-centre PRCT (Level 1b)	Treadmill testing	No significant improvements between groups ( p=0.44)
			CCS angina class improvement more than 2 classes	25% improvement compared to 15% in placebo groups (P=0.03) at 90 days. No difference at 180 days
			Nuclear perfusion imaging	No significant changes between groups
Hedman et al, 2003, KAT Trial, Finland	103 patients with coronary disease CCSII to III undergoing PCI, randomized to VEGF adenovirus 37pts VEGF plasmid liposome 28pts and 38 control patients received Ringer's lactate. 6 month follow up	Double Blind PRCT (level 1b)	Angiography	6% restenosis in both groups
			Clinical outcomes	No differences in CCS classification, working ability, or in the need of oral nitrates

Comment(s)

Angiogenesis is a theoretically highly attractive strategy for patients for whom conventional revascularisation may not be an option. There are several agents that have been studied but Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGF) have been most studied in clinical trials. In addition, several methods of application have been studied, including intracoronary injection, percutaneous intramyocardial injection, intramyocardial injection via mini-thoracotomy and intramyocardial injection during coronary surgery. We identified seven cohort studies that initially reported highly positive results. Using a minithoracotomy Losordo, Symes, Vale, and Fortuin all presented cohorts of patients followed up to 2 years post-injection. They found highly significant improvements in angina scoring, some improvements in exercise testing and even some angiographic or perfusion scanning benefits. Rosengart reported initial findings on injection during coronary surgery and found some improvements in regional wall motion after injection. While these studies were very positive, they suffered from a lack of control groups to compare their results with. We identified five randomised trials. Unfortunately their findings were less positive. The AGENT trial recruited 79 patients and utilised Ad5-FGF4 delivered via intracoronary catheter. They failed to show improvement in angina or myocardial contractility at 4 and 12 weeks. However, they did show 20–30% improvement in exercise tolerance test at 4 and 12 weeks compared to baseline. The VIVA trial recruited 178 patients and the primary outcome demonstrated significant improvement in angina class, frequency, QOL and ETT at 120 days post gene therapy using a dose of 50 ng.kg–1.min–1 of rhVEGF. There was no correlation between subjective improvement and objective measurement of myocardial perfusion and ventricular ejection fraction. The FIRST Trial recruited 337 patients to receive rFGF2 via an intracoronary 20 min infusion or placebo, in a double blinded study. Despite the large size of the study, they failed to show any benefits in treadmill testing, angina scores or on nuclear perfusion scanning. The Euroinject One Trial randomised 80 patients with 'no option' angina to VEGF injection or placebo. Both groups received 10 intramyocardial injections via a percutaneous route. No differences were found in symptoms, exercise testing, ejection fraction or myocardial perfusion scanning. A significant improvement was detected in local wall abnormalities, but this was the only positive finding. The KAT Trialists randomised 103 patients already undergoing stenting to receiving placebo or VEGF via intracoronary infusion. They found a significant improvement in myocardial perfusion scanning, although they found no difference in angiographic findings, or clinical outcomes.

Clinical Bottom Line

Gene therapy for ischaemic heart disease is in its infancy with evaluation trials of novel vectors, delivery methods and targeted patient population. The initial results from the randomised clinical trials using gene therapy for severe CHD are interesting but clear benefits are yet to be demonstrated. Longer term outcomes from the AGENT trial and VIVA trials are awaited.

References

1. Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, Ashare AB, Lathi K, Isner JM. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998;98:2800–2804.
2. Symes JF, Losordo DW, Vale PR, Lathi KG, Esakof DD, Mayskiy M, Isner JM. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg 1999;68:830–836.
3. Vale PR, Losordo DW, Milliken CE, Maysky M, Esakof DD, Symes JF, Isner JM. Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 2000;102:965–974.
4. Rosengart TK, Lee LY, Patel SR et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe CAD. Circulation 1999;100:468–474.
5. Hendel RC, Henry TD, Rocha-Singh K, Isner JM, Kereiakes DJ, Giordano FJ, Simons M, Bonow RO. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. Circulation 2000;101:118–121.
6. Grines CL, Watkins MW, Helmer G, Penny W, Brinker J, Marmur JD, West A, Rade JJ, Marrott P, Hammond HK, Engler RL. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002;105:1291–1297.
7. Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, Shah PK, Willerson JT, Benza RL, Berman DS, Gibson CM, Bajamonde A, Rundle AC, Fine J, McCluskey ER. Investigators VIVA. The VIVA trial: vascular endothelial growth factor in ischaemia for vascular angiogenesis. Circulation 2003;107:1359–1365.
8. Fortuin FD, Vale P, Losordo DW et al. One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients. Am J Cardiol 2003;92:436–439.
9. Kastrup J, Jorgensen E, Ruck A, Tagil K, Glogar D, Ruzyllo W, Botker HE, Dudek D, Drvota V, Hesse B, Thuesen T, Blomberg P, Gyongyosi M, Sylven C. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable angina pectoris:a randomised double-blind placebo-controlled study:The Euroinject One Trial. J Am Coll Cardiol 2005;45:982–988.
10. Reilly JP, Grise MA, Fortuin FD, Vale P, Schaer GL, Lopez JJ, Van Camp J, Henry T, Richenbacher W, Losordo DW, Schatz RA, Isner JM. Long-term (2-year) clinical events following transthoracic intramyocardial gene transfer of VEGF-2 in no option patients. J Intervent Cardiol 2005;18:27–31.
11. Simons M, Annex BH, Laham RJ, Kleiman N, Henry T, Dauerman H, Udelson JE, Gervino EV, Pike M, Whitehouse MJ, Moon T, Chronos NA. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomised, controlled clinical trial. Circulation 2002;105:788–793.
12. Hedman M, Hartikainen J, Syvanne M et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty..phase II results of the Kuopio Angiogenesis Trial. Circulation 2003;107:2677–2683.