Abstract
Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has substantially improved due to increasing operator experience and advancements in equipment, techniques, and management algorithms. However, the overall benefit of CTO PCI remains controversial, particularly since only a few randomized trials have been reported to date.
Methods:
We performed a meta-analysis to evaluate the efficacy of CTO PCI. The study outcomes were the occurrence of all-cause mortality, myocardial infarction, repeat revascularization, stroke, or freedom from angina at the longest documented follow-up period.
Results:
In five trials including 1790 patients, the mean age was 63 ± 10 years, 17% were female, with a median follow-up of 2.9 years. The procedural success rate ranged from 73% to 97% and the right coronary artery was the most involved artery (52%). There was no significant difference between CTO PCI and no intervention regarding all-cause mortality (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 0.49–2.47, P = 0.82), myocardial infarction (OR: 1.20, 95% CI: 0.81–1.77, P = 0.36), repeat revascularization (OR: 0.67, 95% CI: 0.40–1.14, P = 0.14), or stroke (OR: 0.60, 95% CI: 0.26–1.36, P = 0.22). In two trials including 686 patients, significantly more patients were free of angina at 1 year, defined as the Canadian Cardiovascular Society grading of angina pectoris Grade 0, in the CTO PCI group compared to the no intervention group (OR: 0.52, 95% CI: 0.35–0.76, P < 0.001). Meta-regression analyses based on various trial-level covariates (gender, diabetes, previous myocardial infarction, PCI or coronary artery bypass graft, SYNTAX or J-CTO scores, and CTO-related artery percentages) did not suggest any statistically significant relationships.
Conclusions:
CTO PCI appears to have a similar efficacy profile compared to no intervention at long-term follow-up, but with a significant improvement of angina favoring PCI-treated patients. Further adequately powered and long-term trials are required to identify the best management strategy for patients with coronary CTO.
Keywords: Chronic total occlusion, outcome, percutaneous coronary intervention
INTRODUCTION
Coronary chronic total occlusion (CTO) is found in approximately one-quarter to one-third of all patients undergoing diagnostic coronary angiography.[1] Despite the development of collateral circulation, abnormal coronary flow is found in more than 90% of these patients.[2,3] Indeed, CTO lesions are frequently associated with ischemic consequences, worse clinical outcomes, and mortality.[4,5] Management options involve the conservative approach with optimized medical therapy versus the revascularization approach with either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). In recent years, the success rate of CTO PCI has substantially improved due to increasing operator experience and advancements in equipment, techniques, and management algorithms.[6] Successful CTO PCI has been associated with improvement in left ventricular function and reduction in pro-arrhythmic substrate.[7,8] It has also improved the quality of life scores, including improvements in angina, physical activity, and heart failure symptoms.[9] However, the overall benefit of CTO PCI remains controversial, particularly due to the fact that only a few randomized trials have been reported to date. We conducted this meta-analysis to evaluate the efficacy of CTO PCI.
METHODS
We performed a systematic search of online databases PubMed, EMBASE, and Cochrane library until January 31, 2021, for randomized studies comparing PCI to no-PCI for the treatment of patients with coronary CTO. Eligible studies were identified using various combinations of the terms: intervention, coronary, CTO, medical therapy, PCI, and CTO in the abstract or title. Two reviewers (Y.G. and A.I.) independently performed the search and literature screen, with disputes resolved by consensus following discussion with other authors (A.A., N.S., M.F., and M.E.). We included studies that met all of the following inclusion criteria: (1) comparing PCI to no-PCI in patients with CTO and (2) reporting clinical outcomes. We excluded observational studies and duplicate studies of randomized studies.
The study outcomes were the occurrence of all-cause mortality, myocardial infarction, repeat revascularization, stroke, or freedom from angina at the longest documented follow-up period. Pooled odds ratios (OR) with 95% confidence interval (CI) were estimated for binary variables using a random-effects model by the method of DerSimonian and Laird. Heterogeneity between individual studies was explored by Chi-squared statistic and characterized with I2 statistic. All analyses were performed using (RevMan V.5.4, The Cochrane Collaboration, 2020 and StataCorp, College Station, Texas, USA).
RESULTS
Our initial search yielded a total of 365 potential studies, of which ten studies were retrieved and screened for eligibility. Of these, five randomized trials were included in the study.[10,11,12,13,14] Table 1 shows the breakdown of the reported baseline characteristics of each trial. A total of 1790 patients were included in the analysis with 964 having CTO PCI and 826 having no intervention. The mean age was 63 ± 10, and 17% were female, with a median follow-up of 2.9 years across all trials. The procedural success rate ranged from 73% to 97%, and the right coronary artery was the most commonly involved artery (52%).
Table 1.
Baseline characteristics of included trials
| EURO-CTO[10] | EXPLORE[11,15] | IMPACTOR-CTO[12]* | REVASC[13] | DECISION-CTO[14] | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|
||||||
| CTO PCI | No PCI | CTO PCI | No PCI | CTO PCI | No PCI | CTO PCI | No PCI | CTO PCI | No PCI | |
| Population (n) | 259 | 137 | 148 | 154 | 39 | 33 | 101 | 104 | 417 | 398 |
| Follow-up | 12 months | 3.9 (2.1-5.0) years | 12 months | 12 months | 4 (2.4-5.1) years | |||||
| Age (years) | 65±10 | 65±10 | 60±10 | 60±10 | 57±8 | 65 (57-72) | 68 (61-74) | 62±10 | 63±10 | |
| Female | 44 (17) | 19 (14) | 17 (11) | 28 (18) | 12 (17) | 10 (10) | 14 (13) | 73 (17) | 79 (18) | |
| Diabetes | 85 (33) | 40 (29) | 22 (15) | 25 (16) | NR | 32 (32) | 31 (30) | 132 (32) | 134 (34) | |
| Hypertension | 189 (71) | 98 (72) | 59 (40) | 69 (45) | NR | 81 (80) | 93 (89) | 262 (63) | 238 (61) | |
| LVEF | 55±11 | 56±11 | 41±11 | 42±12 | NR | 55 (43-65) | 60 (46-64) | 57±10 | 58±9 | |
| Previous MI | 59 (23) | 25 (18) | 19 (13) | 24 (16) | NR | 39 (39) | 38 (37) | 45 (11) | 34 (9) | |
| Previous PCI | 145 (56) | 71 (52) | 9 (6) | 16 (10) | NR | 28 (28) | 33 (32) | 64 (16) | 75 (19) | |
| Previous CABG | 34 (13) | 10 (7) | 0 | 0 | NR | 12 (12) | 14 (14) | 4 (1) | 5 (1) | |
| Previous CVA | NR | NR | 5 (3) | 6 (4) | NR | 5 (5) | 9 (9) | 29 (7) | 31 (8) | |
| CTO-related artery | ||||||||||
| RCA | 165 (64) | 81 (57) | 64 (43) | 78 (51) | NR | 58 (57) | 71 (68) | 186 (45) | 186 (48) | |
| LAD | 66 (26) | 38 (27) | 36 (24) | 39 (25) | NR | 23 (23) | 17 (16) | 185 (45) | 163 (42) | |
| Cx | 28 (11) | 22 (16) | 48 (32) | 37 (24) | NR | 20 (20) | 16 (15) | 42 (10) | 42 (11) | |
| J-CTO score | 1.8±1.1 | 1.7±0.9 | 2±1 | 2±1 | NR | 2 (1-3) | 2 (1-2) | 2.1±1.2 | 2.2±1.2 | |
| SYNTAX score | NR | NR | 29±8 | 29±10 | NR | 14 (9-22) | 16 (11-21) | 21±9 | 21±10 | |
| Procedure success | 86 | NA | 73 | NA | 83 | NA | 86-97† | NA | 91 | NA |
Data are number of patients (%), mean±SD or median (IQR), *Numbers reported for the whole cohort, † First attempt CTO PCI success rate 86%, after second attempt within 30 days rose to 97%. CABG: Coronary artery bypass graft surgery, CTO: Chronic total occlusion, CVA: Cerebrovascular accident, Cx: Circumflex artery, J-CTO: Japanese CTO Registry, LAD: Left anterior descending artery, LVEF: Left ventricular ejection fraction, MI: Myocardial infarction, PCI: Percutaneous coronary intervention, RCA: Right coronary artery, IQR: Interquartile range, SD: Standard deviation, NA: Not available
There was no significant difference between CTO PCI and no intervention with regard to all-cause mortality [OR: 1.10, 95% CI: 0.49–2.47, P = 0.82, Figure 1a], myocardial infarction [OR: 1.20, 95% CI: 0.81–1.77, P = 0.36, Figure 1b], repeat revascularization [OR: 0.67, 95% CI: 0.40–1.14, P = 0.14, Figure 1c], or stroke [OR 0.60, 95% CI 0.26–1.36, P = 0.22, Figure 1d]. In two trials including 686 patients, significantly more patients were free of angina at 1 year, defined as the Canadian Cardiovascular Society grading of angina pectoris Grade 0, in the CTO PCI group compared to the no intervention group [OR: 0.52, 95% CI: 0.35–0.76, P < 0.001, Figure 2]. Meta-regression analyses based on various trial-level covariates (gender, diabetes, previous myocardial infarction, PCI or CABG, SYNTAX or J-CTO scores, and CTO-related artery percentages) did not suggest any statistically significant relationships.
Figure 1.
Long-term clinical outcomes with CTO PCI versus no intervention in patients with coronary CTO. (a) All-cause mortality. (b) Myocardial infarction. (c) Repeat revascularization, and (d) Stroke. CTO: Chronic total occlusion, PCI: Percutaneous coronary intervention, CI: Confidence interval, OR: Odds ratio
Figure 2.
Angina free at 1 year with CTO PCI versus no intervention in patients with coronary CTO. CTO: Chronic total occlusion, PCI: Percutaneous coronary intervention, CI: Confidence interval, OR: Odds ratio
DISCUSSION
This meta-analysis of five randomized trials demonstrates no significant difference between patients who had coronary CTO PCI and no intervention with respect to all-cause mortality, myocardial infarction, repeat revascularization, or stroke. However, it appears that CTO PCI reduces angina at medium-term follow-up [Figure 3]. Furthermore, our meta-regression analyses did not demonstrate any significant relationships between the long-term clinical outcome of CTO PCI and the complexity, extension, or location of CTO represented by the SYNTAX and J-CTO scores and the CTO-related artery.
Figure 3.
Summary key message. In randomized trials of patients with coronary CTO, CTO PCI appears to have a similar safety profile compared to no intervention at long-term follow-up with a significant improvement of angina favoring PCI-treated patients. CTO: Chronic total occlusion, MI: Myocardial infarction, OMT: Optimal medical therapy, PCI: Percutaneous coronary intervention. *P < 0.001
This meta-analysis has important limitations. First, two out of the five randomized trials were terminated early due to slow enrollment and did not meet their target sample size.[10,14] Second, almost half the data analyzed from the DECISION-CTO trial, which was limited by the high crossover rates between groups (almost 1 of 5 patients assigned to medical therapy crossed over to CTO PCI within 3 days of randomization). Third, enrolled patients were likely those who had fewer symptoms and less myocardial territory at jeopardy with a variable procedure success rate. Fourth, in the CTO PCI group, there are no data reported on the final procedural result. Of note, in a large cohort of patients undergoing CTO PCI, suboptimal recanalization (defined as lasting side branch occlusion, residual stenosis >30%, or final thrombolysis in myocardial infarction flow grade <3) was associated with significantly higher long-term incidence of cardiac death and myocardial infarction compared to optimal recanalization or procedural failure.[15] Therefore, definitive trials comparing CTO PCI and no-CTO PCI on a background of optimal medical therapy remain a scientific gap in current evidence.
CONCLUSION
In available randomized trials of patients with coronary CTO, PCI appears to have a similar efficacy profile compared to no intervention at long-term follow-up, but with a significant improvement of angina favoring PCI-tretaed patients. Further adequately powered and long-term trials are required to identify the best management strategy of patients with coronary CTO.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
- 1.Ybarra LF, Rinfret S, Brilakis ES, Karmpaliotis D, Azzalini L, Grantham JA, et al. Definitions and clinical trial design principles for coronary artery chronic total occlusion therapies: CTO-ARC consensus recommendations. Circulation. 2021;143:479–500. doi: 10.1161/CIRCULATIONAHA.120.046754. [DOI] [PubMed] [Google Scholar]
- 2.Werner GS, Surber R, Ferrari M, Fritzenwanger M, Figulla HR. The functional reserve of collaterals supplying long-term chronic total coronary occlusions in patients without prior myocardial infarction. Eur Heart J. 2006;27:2406–12. doi: 10.1093/eurheartj/ehl270. [DOI] [PubMed] [Google Scholar]
- 3.Sachdeva R, Agrawal M, Flynn SE, Werner GS, Uretsky BF. The myocardium supplied by a chronic total occlusion is a persistently ischemic zone. Catheter Cardiovasc Interv. 2014;83:9–16. doi: 10.1002/ccd.25001. [DOI] [PubMed] [Google Scholar]
- 4.Tomasello SD, Boukhris M, Giubilato S, Marzà F, Garbo R, Contegiacomo G, et al. Management strategies in patients affected by chronic total occlusions: Results from the Italian registry of chronic total occlusions. Eur Heart J. 2015;36:3189–98. doi: 10.1093/eurheartj/ehv450. [DOI] [PubMed] [Google Scholar]
- 5.Jang WJ, Yang JH, Choi SH, Song YB, Hahn JY, Choi JH, et al. Long-term survival benefit of revascularization compared with medical therapy in patients with coronary chronic total occlusion and well-developed collateral circulation. JACC Cardiovasc Interv. 2015;8:271–9. doi: 10.1016/j.jcin.2014.10.010. [DOI] [PubMed] [Google Scholar]
- 6.Brilakis ES, Mashayekhi K, Tsuchikane E, Abi Rafeh N, Alaswad K, Araya M, et al. Guiding principles for chronic total occlusion percutaneous coronary intervention. Circulation. 2019;140:420–33. doi: 10.1161/CIRCULATIONAHA.119.039797. [DOI] [PubMed] [Google Scholar]
- 7.van Dongen IM, Kolk MZ, Elias J, Meijborg VM, Coronel R, de Bakker JM, et al. The effect of revascularization of a chronic total coronary occlusion on electrocardiographic variables. A sub-study of the EXPLORE trial. J Electrocardiol. 2018;51:906–12. doi: 10.1016/j.jelectrocard.2018.07.012. [DOI] [PubMed] [Google Scholar]
- 8.Megaly M, Brilakis ES, Abdelsalam M, Pershad A, Saad M, Garcia S, et al. Impact of chronic total occlusion revascularization on left ventricular function assessed by cardiac magnetic resonance. JACC Cardiovasc Imaging. 2021;14:1076–8. doi: 10.1016/j.jcmg.2020.10.012. [DOI] [PubMed] [Google Scholar]
- 9.Grantham JA, Jones PG, Cannon L, Spertus JA. Quantifying the early health status benefits of successful chronic total occlusion recanalization: Results from the FlowCardia’s approach to chronic total occlusion recanalization (FACTOR) trial. Circ Cardiovasc Qual Outcomes. 2010;3:284–90. doi: 10.1161/CIRCOUTCOMES.108.825760. [DOI] [PubMed] [Google Scholar]
- 10.Werner GS, Martin-Yuste V, Hildick-Smith D, Boudou N, Sianos G, Gelev V, et al. A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. Eur Heart J. 2018;39:2484–93. doi: 10.1093/eurheartj/ehy220. [DOI] [PubMed] [Google Scholar]
- 11.Henriques JP, Hoebers LP, Råmunddal T, Laanmets P, Eriksen E, Bax M, et al. Percutaneous intervention for concurrent chronic total occlusions in patients with STEMI: The EXPLORE trial. J Am Coll Cardiol. 2016;68:1622–32. doi: 10.1016/j.jacc.2016.07.744. [DOI] [PubMed] [Google Scholar]
- 12.Obedinskiy AA, Kretov EI, Boukhris M, Kurbatov VP, Osiev AG, Ibn Elhadj Z, et al. The IMPACTOR-CTO trial. JACC Cardiovasc Interv. 2018;11:1309–11. doi: 10.1016/j.jcin.2018.04.017. [DOI] [PubMed] [Google Scholar]
- 13.Mashayekhi K, Nührenberg TG, Toma A, Gick M, Ferenc M, Hochholzer W, et al. A Randomized trial to assess regional left ventricular function after stent implantation in chronic total occlusion: The REVASC trial. JACC Cardiovasc Interv. 2018;11:1982–91. doi: 10.1016/j.jcin.2018.05.041. [DOI] [PubMed] [Google Scholar]
- 14.Lee SW, Lee PH, Ahn JM, Park DW, Yun SC, Han S, et al. Randomized trial evaluating percutaneous coronary intervention for the treatment of chronic total occlusion. Circulation. 2019;139:1674–83. doi: 10.1161/CIRCULATIONAHA.118.031313. [DOI] [PubMed] [Google Scholar]
- 15.Guan C, Yang W, Song L, et al. Association of Acute Procedural Results With Long-Term Outcomes After CTO PCI. JACC Cardiovasc Interv. 2021;14:278–288. doi: 10.1016/j.jcin.2020.10.003. HYPERLINK 舠https//doiorg/10.1016/j.jcin.2020.10.003”10.1016/j.jcin.2020.10.003. [DOI] [PubMed] [Google Scholar]
