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Three Part Question

In [patients with diffuse coronary artery disease undergoing CABG] is the use of [transmyocardial revascularisation in addition to CABG] of any benefit in terms of [angina relief or survival]?

Clinical Scenario

You are operating on a 67 year old diabetic who has had 4 years of gradually worsening angina. He currently has CCS grade IV angina and has told you that he has no quality of life and is desperate for something to be done. The angiogram shows a 90% proximal LAD stenosis, a 70% circumflex stenosis but with diffuse disease down the artery and down a small obtuse marginal artery. A perfusion scan demonstrated clear areas of reversible ischaemia anteriorly and laterally. The right coronary artery is occluded, with backfilling of a small PDA. At operation the LAD is graftable and the PDA is severely diseased but you find a small area where a graft can be placed. However the circumflex territory has no graftable vessels. You know that there is reversible ischaemia in this territory and a collegue has a Holmium:YAG laser next door. You elect to perform transmyocardial revascularisation to the circumflex territory, prior to placing the grafts, but you resolve to review the literature to check that you have not unnecessarily increased the risk of mortality for this patient, and that this additional procedure might improve the chances or resolving your patient's angina.

Search Strategy

Medline 1966-March 2004 using the OVID interface
[TMR.mp OR TMLR.mp OR DMR.mp OR Transmyocardial.mp OR exp laser surgery/] AND [exp coronary artery bypass/ OR coronary bypass.mp OR CABG.mp]

Search Outcome

A total of 233 abstracts were found from Medline of which 8 were directly relevant. In addition a systematic review recently published by the STS as a guideline for the use of TMR with or without CABG as treatment for refractory angina was included. These are presented in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bridges CR et al, 2004, USA	Findings of a systematic review, searching Medline, PubMed, contacting experts, and expert panel	Systematic review (level 2a)	Guideline for TMR + CABG (Level IIA: areas of controversy but where the balance of evidence is in favour of treatment. Level IIB: Areas of controversy but where the balance of evidence is against treatment)	Class IIA: Patients with angina CCS I-IV with CABG as standard of care with area of reversible ischaemia not amenable to revascularisation (level B) Class IIB: Patients without angina with CABG as standard of care with diffuse coronary artery disease (level C)	Keith Allen and Keith Horvath, 2 major advocates of TMR were on this committee, which may have biased the recommendations in favour of TMR.
Peterson ED et al, 2003, USA	1998-2001 Database from the Society of Thoracic Surgeons with TMR procedures from 173 US centres, were compared with those from six published randomised control studies RCTdatabase: TMR n= 722 TMR+CABG n=263 STS database: TMR n= 661 TMR+CABG n=2,475	Meta analysis (level 2a)	Mortality for TMR alone	TMR RCT group 25/722 (3.5%) TMR STS group 42/661 (6.4%)	Data limited to the STS database, which is only 2/3rds of all US centres 36% of all US sites that contribute to the database now perform a median of 12 TMR procedures (range 1-150) annually, mostly combined with CABG No post-operative data recording angina status was available from the STS database
			Mortality for TMR + CABG	TMR + CABG RCT group 4/263 (1.5%) TMR + CABG STS group 104/2475 (4.2%)
			Mortality for all CABG alone vs all CABG+TMR	CABG alone 1602/39064 (4.9%) CABG and TMR 19/390 (4.1%) p=0.37
Loubani M et al, 2003 UK	20 patients in a single centre pilot study with one or more non-graftable arteries randomised to have CABG and TMR or CABG alone at mid term follow up CABG + TMR=10, CABG=10 Median sternotomy holmium YAG laser 18 channels at 1 cm square intervals. 2.5 years follow up	Single centre PRCT (level 2b)	CCS angina score at 36 months	TMR + CABG Post-op mean CCS0.7 ± 0.4 CABG alone Post-op mean CCS 0.8± 0.5	Small study group The benefit in exercise tolerance was maintained at 18 months but not at 36 months Dobutamine stress Echo results at 36 months were also the same for both groups Angina scores were similar for both groups at 6, 18 and 36 months The degree of regional reversible ischemia not assessed prior to operation
			Exercise tolerance at 6 months	TMR + CABG Improvement of 199 ± 66 seconds CABG alone Improvement of 46.8 ±20 secs P<0.0001
			Mortality	No deaths in either group
Stamou et al, 2002, USA	169 patients undergoing CABG + TMR by one surgeon, with intractable angina and viable myocardium around an ungraftable territory. 90% had CCS grade III-IV angina Median Sternotomy, CO2 laser or YAG laser, 1cm2 intervals. Median 24 channels	Cohort study (level 3b)	Angina class at 1 year	7% of patients had CCS grade III or IV angina at 1 year	51% were repeat CABG patients Cohort study with no control group of CABG only No independent assessment of angina class Single surgeon study
			Complications	7 pts had re-exploration for bleeding (4%)
			Mortality	14 deaths (8%) 85% 1 year survival
Allen et al, 2000, USA	263 patients from 24 USA centres with CCS III-IV who had one or more viable target areas not amenable to CABG randomised to either CABG/TMR or CABG alone CABG + TMR (N=132), CABG (N=131) Holmium YAG Laser25 ± 10 channels (every square centimetre) placed on CPB after grafting 1 year follow up	Multicenter PRCT (level 1b)	Improvement in CCS angina score after 1 year of 2 or more points	CABG + TMR group 5/106 (4.7%) CABG alone 11/98 (11.2%) p=0.11	Predicted mortality for CABG + TMR group by parsonnet score was 6.3% and for CABG alone 6.6% Reversible ischaemia was not assessed prior to randomization. 4 patients in CABG/TMR group required re-exploration and 2 of these had bleeding laser channels. 1 patient in CABG alone required re-exploration.
			Survival estimates at 1 yr	CABG + TMR 95% CABG alone 89% p=0.05
			Mean angina class after 12 months	CABG + TMR Mean class CCS = 0.5 CABG alone mean class CCS = 0.6 P=0.2
			Operative mortality	CABG + TMR 2/132 (1.5%) CABG alone 10/131 (7.6%) p=0.02
Burns SM et al, 1999, UK	International transmyocardial laser revascularization registry, containing 932 procedures from 15 centres. 78% of patients were angina class III or IV 90% had ejection fraction of >30% 177 procedures were combined TMR and CABG 24 were described as emergency procedures mean no channels 28	Multicentre cohort study (level 2b)	Mortality/Morbidity	90/932 patients died (9.7%) 29% of patients had a complication, 8% bleeding, 4% MI, 8% LVF	Break down of results in CABG + TMR group not performed Only 30% of patients in the registry has pre-op and post-op angina scores and the exercise testing was performed in only 10% of the patients 12% of patients required post-operative adrenaline, 8% required an IABP. Only 59% required no post-operative support
			6 minute exercise test improvement (reported by 4 centres)	TMR groups improved their exercise test times by mean 1 min 50s at 12 months compared to pre-operatively, P<0.01
			Improvement in angina class	CCS angina score improved by 2 or more classes in 34% of patients at 12 months, and NYHA angina score 2 classes in 49 at 12 months
Trehan et al, 1997, India	56 patients in a single Indian centre underwent TMR and OFF PUMP CABG They were classed as CCSII (28/56), CCSIII (22/56) and CCSIV (6/56) preop. TMR to Cx territory only. Left thoracotomy and mid sternotomy incisions were used 1000W CO2 Laser10-12 channels 1 year follow up	Single centre cohort study (level 3b)	Improvement in CCS Angina Score after 1 year	CABG + TMR 33/38 (86.8%) were angina free	No control group identified. 33 percent had only double vessel disease on angio and 50% had grade II angina. Angina assesment not blinded. 24 pts had potentially graftable Cx but had TMR as they could not do it OFF PUMP
			Mortality	1/56 (1.78%)
Vincent et al, 1997, Switzerland	268 patients with CCS grade III – IV undergoing TMR either with or without CABG. 46% of paients had an EF<40%. 71% had previous cardiac surgery. TMR + CABG 128 pts, median sternotomy TMR alone 140 pts left anterior thoracotomy, 5th ics. 800W CO2 laser mean 22 pulses per patient	Cohort study (level 3b)	CCS grade 0 or I at 1 year follow up	TMR + CABG 85% TMR alone 42%	Retrospective cohort study Non-independent assessment of angina, no functional improvements shown by Echocardiography or perfusion scanning Unclear as to how many patients lost to follow up No demographics table
			Complications	22 pts returned for bleeding, 34 pts required IABP (13%)
			Mortality	TMR + CABG 15/127 (88%) TMR alone 12/128 (90%)
Trehan et al, 1996, India	104 patients in a single Indian centre underwent TMR and CABG preop: CCSII (23/104), CCSIII (56/104) and CCSIV (25/104) Median sternotomy incision used in all patients 1000W CO2 Laser10-12 channels to 1 year follow up	Single centre cohort study (level 3b)	Improvement in CCS Angina Score	22/24(92%) were angina free at 12 months. 50% angina free at 3mths	No control group Note that 19 pts had EF less than 35 Non independent assessment of angina Poor follow up at 12mths (only 24pts)
			Mortality	3/104 (2.88%) thirty day mortality

Comment(s)

Allen et al in 2000 performed a Multicentre PRCT with 263 patients. Patients had one or more viable target areas not amenable to CABG. They found only 2 patients died in the TMR + CABG group compared to 10 in the CABG alone group which was a significant finding. Furthermore the 7.6% mortality in the CABG alone group was similar to that predicted by parsonnet score. This survival benefit remained out to 12 months follow up. Unfortunately no benefit in terms of angina or improved exercise treadmill performance was shown. Of note, while this was a well conducted study, areas of reversible ischaemia were not established pre-operatively. Trehan et al in 1997 published 2 cohort studies of 104 patients who had CABG and TMR and 54 patients who had off pump TMR + CABG. They had only 3 deaths and 87% of patients were angina free at one year. However due to the lack of a control group, they could not establish that their results were due to the TMR rather than the CABG, and thus only acceptable mortality can really be noted from this study. Loubani et al in 2003 performed a single centre PRCT in 20 patients comparing CABG alone with TMR + CABG. There were no deaths and they found a considerably improved exercise tolerance at 6 months and 18 months. However this benefit was lost at 36 months and in addition there were no differences seen in angina score at any stage, and no measurable echocardiographic improvements. It must be noted that this was a very small study with only 10 patients in each group. Vincent et al reported a retrospective cohort of 268 'no option' patients, who underwent TMR using carbon dioxide laser revascularization, 128 of whom also underwent CABG. They reported a 12% operative mortality in the TMR+CABG group, with 13% of patients needing an IABP and an 8% reoperation for bleeding rate. They did report that 84% of TMR+CABG patients and 40% of TMR alone patients had either CCS grade 0 or 1 angina at one year, but this was assessed by the operating surgeons and thus should be read with caution. Stamou reported their 1 year findings after combined TMR + CABG in 169 patients operated on by a single surgeon. They had an 8% mortality, but they reported that whereas 90% of patients had CCS grade III-IV angina pre-operatively, only 7% still had this level of angina at one year. However this single surgeon series had no control group and no independent assessment of angina scoring, and thus the findings that may have been achieved without TMR are unknown in this cohort. Burns et al in 1999 reported the results of an international registry which was set up in 1994 to collect data on this emerging procedure. They reported 937 procedures from 15 centres, including 177 combined CABG+TMR procedures. Although they provided no breakdown of the combined CABG + TMR cohort, they found an overall 10% mortality, 30% complication rate and only 34% of patients had an improvement of CCS class of more than 2 classes at 12 months. Peterson et al in 2003 compared current clinical practise of TMR+CABG and TMR alone as reported in the STS databse from the USA with those results from clinical trials. They found that as of 2001, 36% of US centres now perform TMR procedures, mostly combined with CABG, and that there has been a large expansion in this procedure nationally even though CABG + TMR is not FDA approved. They furthermore found no difference in mortality between CABG alone (4.9%) and CABG + TMR (4.1%). They had no data on post-operative angina scoring, and they could not reliably compare CABG + TMR with incomplete revascularisation by CABG which would have been a fairer comparison. However the two most important findings here are that CABG + TMR is now widespread in the USA and it is not associated with an increased mortality as compared to CABG alone. Bridges et al have recently published the first of a series of guidelines from the Society of Thoracic Surgeons. This guideline was on the use of TMR, and TMR+CABG. They reviewed the same papers that are summarized here and concluded that although there was divergence of opinion, the balance of evidence favoured TMR + CABG in patients undergoing CABG where there was an area of reversible ischaemia, with the area not amenable to bypass either because of diffuse disease, lack of suitable targets, or lack of suitable conduit. Guidelines such as these usually have a great impact on practise, but it is interesting to note that no mention of the lack of FDA approval was made and both Keith Allen, and Keith Horvath, major advocates of TMR were on the guideline committee. However it was a well balanced document and weaknesses in the literature were addressed. While TMR + CABG is now recommended by the Society of Thoracic Surgeons in America, the available studies do not conclusively find that angina is significantly reduced by adding TMR to CABG. There does however consensus that it does not seem to increase mortality in these patients.

Clinical Bottom Line

While the Society of Thoracic Surgeons now recommend TMR + CABG, and the available studies indicate that mortality is not increased by this additional procedure, it is currently not clear whether TMR reduces symptoms of angina in addition to CABG alone.

References

1. Bridges CR, Horvath KA, Nugent WC et al. The Society of Thoracic Surgeons Practise Guidelines Series: Transmyocardial Laser Revascularization. Ann Thorac Surg 2004;77:1494-1502.
2. Peterson ED, Kaul P, Kaczmarek RG et al. From Controlled Trials to Clinical Practise: Monitoring Transmyocardial Revascularization Use and Outcomes. J Am Coll Cardiol 2003;42:1611-1616.
3. Loubani M, Chin D, Leverment JN, et al. Mid-Term Results of Combined Transmyocardial Laser Revascularization and Coronary Artery Bypass Ann Thorac Surg 2003;76:1166.
4. Stamou SC, Boyce SW, Cooke RH, et al. One-year outcome after combined coronary artery bypass grafting and transmyocardial laser revascularization for refactory angina pectoris. Am J Cardiol 1997;11:888-894.
5. Allen KB, Dowling KB, DelRossi AJ, et al. Transmyocardial Laser revascularization combined with coronary artery bypass grafting: A multicentre, blinded, prospective,randomized controlled trial. J Thorac Cardiovasc Surg 2000;119:540-549.
6. Burns SM, Sharples LD, Tait S, et al. The transmyocardial laser revascularization international registry report. Eur Heart J 1999;20:31-37.
7. Trehan N, Mishra M, Bapna R, A Transmyocardial Laser Revascularisation combined with coronary artery bypass grafting without cardiopulmonary bypass. Eur J Cardio-Thorac Surg 1997;12:276-284.
8. Vincent JG, Bardos P, Kruse J, et al. End stage coronary disease treated with the transmyocardial CO2 Laser revascuilarisation: a chance for the inoperable patient. Eur J Cardio-Thorac Surg 1997;11:888-894.
9. Trehan N, Mishra M, Kohli A, et al. Transmyocardial Laser Revascularisation as an Adjunct to CABG. Indian Heart J 1996;48:381-388.