A systematic review and meta-analysis of the safety and efficacy of transmyocardial revascularization for patients with refractory angina

Abstract Background: Transmyocardial laser revascularization is a treatment option available for patients with refractory angina who are not candidates for conventional interventions such as coronary bypass grafting or percutaneous coronary interventions. TMR uses either a carbon dioxide, holmium or excimer laser to create multiple channels through the ischemic myocardial region to improve perfusion. TMR can be used as a sole therapy or as a conjunct to other surgeries. In recent years, new studies have emerged studying the synergistic effects of TMR with stem cell therapy. To date the underlying mechanism of TMR and its outcome effects remain unclear.Objective: The aim of this study is to evaluate the efficacy and safety of TMR as a sole therapy and in conjunction to other surgeries and therapies in patients with refractory angina not amenable to CABG or PCI. Methods: A systematic review and meta-analyses were undertaken to study the effects of TMR. In October 2023 and February 2025 three comprehensive literature searches were performed on databases PubMed and Ovid Medline and identified 7 RCTs on TMR versus medical treatment, 2 RCTs on TMR in conjunction with CABG vs. CABG alone and 6 non-randomized open label studies, five of which are on TMR with SC therapy and one double-arm trial on TMR with PRP vs. TMR alone. A total of 1410 patients were included in the review. Outcome measures: angina, exercise tolerance, mortality, QOL, LVEF and myocardial perfusion were included in the review and were assessed at time points 6M and 12M. Angina was assessed as both continuous variable for change in angina, defined as a reduction in angina score according to CCS or NYHA and as dichotomous variable for percent improvement in angina by at least 2 CCS classes, respectively. Given the variety of metrics used for myocardial perfusion and QOL, a systematic review was undertaken for these outcomes. Mortality was analysed as perioperative deaths to assess the safety and total deaths during study period to assess both safety and efficacy of the surgery. Results: TMR versus medical management: A standardized mean difference in angina scores for continuous variables of -16.622 (p<0.001) was observed, indicating a greater reduction in angina score in the TMR group. The analysis for angina for dichotomous variables revealed that the odds of angina improvement were significantly higher in the TMR group compared to the control with an odds ratio of 4.604 (p<0.001) and 6.66 (p<0.001) at 6M and 12M respectively. The analysis of perioperative mortality revealed that the odds of the event occurring was 0.396 times higher in the TMR group compared to the MT group(p=0.039). The odds ratio for total mortality was 0.89(p=0.659), indicating a slightly higher risk of mortality in the TMR group. The SMD for exercise tolerance at 6M was 4.509 (p<0.001), indicating a clinically meaningful increase following TMR compared to medical management. The effects were slightly reduced but remained statistically significant at 12M (1.77, p<0.001). All studies measuring QOL at 12M reported a statistically significant improvement following TMR compared to MT. The analysis on LVEF found a standardized mean difference in LVEF of -0.211 between treatment groups, indicating a worsening of LVEF following TMR. The results approached statistical significance (p=0.061). Some studies reported conflicting results on myocardial perfusion, while the proportion of ischemia decreased following TMR, the number of defects or irreversible sites increased in both groups. One trial found a statistically significant improvement in myocardial perfusion at 6M and 12M for the TMR group (p=0.02 and p=0.002, respectively).TMR with CABG versus CABG: The analysis for trials on TMR with CABG versus CABG revealed a small non statistically significant SMD of 0.228(p=0.742) in angina score between treatment groups, favoring the group who underwent CABG. The odds of perioperative death in the group who underwent TMR with CABG was 3.83 times lower compared to the group that underwent CABG (p=0.047). The analysis for total mortality revealed an OR of 1.991(p=0.131), favoring the group that received TMR with CABG. The SMD of exercise tolerance between treatment groups was 1.996(p=0.293), indicating a non-statistically significant increase in exercise time for the group who underwent TMR with CABG. An improvement in WMSI was observed at rest, at low dose and at high dose of dobutamine for the TMR with CABG group compared to CABG only, however the results were not statistically significant (p=0.53, p=0.41 and p=0.43, respectively).TMR with Stem cell and PRP therapy: The analysis on trials on TMR with SC found a statistically significant reduction in angina score at 6 and 12 months with a mean difference of 1.66 and 1.61 scores respectively. A statistically significant percent angina improvement was observed in all 49 patients who underwent TMR with SC. The double-arm trial on TMR with PRP versus TMR reported a clinically meaningful improvement in angina in both groups. One perioperative death was observed in a 60-year-old male patient with congestive heart failure symptoms receiving TMR with PRP. The pooled total mortality rate was 7.2% for patients who underwent TMR with SC. QOL was assessed in two studies and the improvement was not statistically significant. A small non statistically significant pooled mean increase in LVEF of 0.036% and 0.032% was observed at 6 and 12 months respectively. Four trials observed an improvement in myocardial perfusion, two of which observed a statistically significant improvement in ischemic score at 6M following TMR with SC (p=0.01).Conclusion: In patients with refractory angina, TMR was performed with low perioperative mortality and showed significant improvements in angina, QOL, and exercise tolerance. In the initial phases of TMR with SC therapy, the surgery appeared to be safe and may have had a synergistic effect in reducing myocardial ischemia. Future studies on TMR must mitigate methodological limitations by implementing blinding when feasible and including a larger proportion of female participants. Larger RCTs on stem cell therapy with TMR that include a comparator group, and a longer duration of follow-up are warranted to assess the safety and efficacy of TMR

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