Long-Term Outcomes of Unprotected Left Main Coronary Artery Disease: Comparison of Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention

Abstract: Objective. We compared the long-term outcomes of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) disease in a real-world population. Background. CABG is the standard of care for ULMCA disease. Contemporary randomized trials have reported conflicting results with the two revascularization strategies for the treatment of ULMCA disease at intermediate-term follow-up. Methods. We evaluated 422 consecutive patients with ULMCA disease who underwent CABG (n = 273) or PCI (n = 149) from 1998-2008. The primary outcome measure was major adverse cardiac and cerebrovascular event (MACCE) rate, defined as the composite of all-cause death, myocardial infarction (MI), stroke, or target-vessel revascularization (TVR) at 10 years. Propensity-score matched (PSM) analysis was used to assess long-term MACCE. Results. The cumulative 10-year incidence of risk for MACCE was not significantly different between the PCI and CABG groups (24.8% vs 20.5%, respectively; log rank P=.22; log rank PSM P=.45). The risk for all-cause death was not significantly different between the two groups (log rank P=.09; PSM log rank P=.51). The risk for stroke was significantly lower with PCI (log rank P=.02), but was not significant after matching (PSM log rank P=.27). The risk for TVR was significantly higher with PCI vs CABG prior to and after matching (log rank P<.001; log rank PSM P=.01). There were no significant differences in MACCE between the two groups when stratified by SYNTAX scores ≤22% (log rank P=.61) and >23% (log rank P=.06). Conclusion. In patients with ULMCA disease, PCI was comparable with CABG for long-term MACCE and death rates. The TVR rate was higher in the PCI group.

Key words: coronary artery bypass surgery, left main disease, percutaneous coronary intervention

As approximately 70% of the blood supply comes from the left main artery, occlusion can lead to massive myocardial infarction (MI), cardiogenic shock, and sudden death.^1,2 Earlier guidelines identified coronary artery bypass grafting (CABG) as the gold standard for the treatment of ULMCA disease.³ However, percutaneous coronary intervention (PCI) has become a viable alternative with improvements in stent technology, refinement of techniques, increased operator experience, the growing body of evidence supporting its safety and efficacy, the inability of some patients to tolerate CABG due to comorbidities, and patient preference for non-surgical revascularization.^4-7 Although several studies have shown less favorable short-term (1-3 year) and mid-term (5-year) outcomes for PCI compared with CABG for ULMCA disease,^8-11 data on long-term outcomes are limited. We sought to compare long-term outcomes for PCI and CABG in patients with ULMCA disease.

Methods

Study design and patient population. This was a retrospective, single-center study that included 422 consecutive patients with ULMCA disease who underwent CABG (n = 273) or PCI (n = 149) at Dong-A University Hospital from October 1998 to October 2008. Patients with left main coronary artery (LMCA) lesions were assessed by angiography and diagnosed with a stenosis diameter >50% in the LMCA without a patent bypass graft to the left anterior descending (LAD) or left circumflex (LCX) artery. Patients who underwent emergent CABG were excluded. The decision to perform CABG or PCI was based upon discussion with the cardiologist, surgeon, and patient. PCI was performed exclusively with bare-metal stents from October 1998 through March 2003, whereas drug-eluting stents (DESs) were used exclusively from April 2003 through October 2008. Written informed consent was obtained from all patients. The study protocol was approved by the Institutional Ethics Committee of Dong-A University Hospital.

Study outcomes and follow-up. The primary endpoint was the major adverse cardiac and cerebrovascular event (MACCE) rate, defined as the composite of all-cause death, myocardial infarction (MI), stroke, and target-vessel revascularization (TVR) at 10 years. Myocardial infarction was defined as recurrent symptoms with new ST-segment elevation or re-elevation of cardiac markers to at least twice the upper limit of normal. Stroke was diagnosed by a neurologist on the basis of neurological deficits and imaging studies. Target-vessel revascularization was defined as any repeat revascularization in any LAD or LCX as well as in the target segment.¹² Two independent reviewers carefully analyzed the coronary angiograms, documented the characteristics of the lesions, and used the online scoring system (www.syntaxscore.com) to calculate the SYNTAX score to determine the anatomical complexity of coronary artery disease, with SYNTAX defined as low if ≤22%, intermediate if 23% to 32%, and high if ≥33%. Clinical follow-up was primarily conducted via review of inpatient and outpatient hospital charts by clinical research assistants. Additional follow-up information was collected through contact with patients, relatives, and/or referring physicians by phone interviews with questions regarding vital sign status and subsequent hospitalizations. All clinical outcomes data were confirmed by source documentation collected at Dong-A University Hospital and were centrally adjudicated by an independent group of clinicians.

Statistical analysis. Categorical variables were presented as numbers and percentages and compared using the Chi-square test. Continuous variables were expressed as mean ± standard deviation, and were compared using the Student’s t-test or the Wilcoxon rank-sum test based on their distributions. Cumulative incidence was estimated by the Kaplan-Meier method, and differences were assessed with the log rank test. The effects of PCI relative to CABG for individual endpoints were expressed as hazard ratio (HR) with 95% confidence interval (CI). Time-to-event outcomes were displayed using the Kaplan-Meier methodology, and compared via the log rank test. Cox proportional hazard models were used to identify independent predictors of primary endpoints. The models were also used to estimate HR and 95% CI for clinical outcomes. Propensity-score matching (PSM) was used to reduce treatment selection bias associated with different strategies and potential confounding factors, and to adjust for significant differences in the patients’ baseline characteristics or procedural data. Propensity scores were obtained by performing multiple logistic regression analysis. The covariates included age, gender, body mass index, diagnosis, hypertension, diabetes, drinking alcohol, left ventricular ejection fraction, previous stroke, and lesion characteristics. Patients were matched with the same or closest propensity score. We then performed a matching caliper of 0.05 SDs of the logit of the estimated propensity score and 1:1 matching iteration. In subgroup analyses, interaction tests were used to identify clinical outcomes of the different treatment approaches. All statistical analyses were conducted using BMI SPSS Statistics 22.0 software (BMI Institute) and GraphPad Prism 7.00 software (GraphPad Prism Software Institute). All reported P-values were 2-tailed, and P<.05 was considered statistically significant.

Results

Patient enrollment and baseline features and procedures. The mean age was 62.4 ± 10.0 years in the PCI group and 64.0 ± 8.8 years in the CABG group (Table 1). The PCI group had a higher percentage of patients who had a previous history of MI (P<.001), while the CABG group had a higher percentage of patients who were current smokers (P<.01). The mean SYNTAX score was lower in the PCI group (24.2 ± 8.5% vs 27.2 ± 8.6%; P<.01).

Primary and hierarchical secondary endpoints. The mean follow-up period was 1989 days (interquartile range, 1103-3194 days) in both groups. The cumulative 10-year incidence of MACCE was not significantly different between the PCI and CABG groups (24.8% vs 20.5%,  respectively; log rank P=.22; HR, 1.298; 95% CI, 0.844-1.995) (Figure 1). No significant difference in MACCE was observed between the two groups with SYNTAX score ≤22% (log rank P=.61; HR, 0.800; 95% CI, 0.343-1.867) (Figure 2). The PCI group had a trend toward higher MACCE in patients with SYNTAX score ≥23% (log rank P=.06; HR, 1.568; 95% CI, 0.941-2.614).

Secondary endpoints. The risk ratio for all-cause death was not significantly different between the two groups (log rank P=.09; HR, 0.439; 95% CI, 0.200-0.968; PSM log rank P=.51; HR, 0.687; 95% CI, 0.231-2.040) (Figure 3). The risk for MI was not significantly different between the two groups (log rank P=.22; HR, 1.775; 95% CI, 0.684-4.865; PSM log rank P=.91; HR, 1.075; 95% CI, 0.311-3.716).  The risk ratio for stroke was significantly higher in the CABG group prior to matching (log rank P=.02; HR, 0.218; 95% CI, 0.086-0.551), but not after matching (PSM log rank P=.27; HR, 0.410; 95% CI; 0.093-1.807). The risk ratio for TVR was significantly higher in the PCI group compared with CABG (log rank P<.001; HR, 4.138; 95% CI, 2.171-7.887; PSM log rank P=.01; HR, 3.110; 95% CI, 1.397-6.923).

The incidence of the composite of all-cause death, MI, and stroke in the patients with SYNTAX score ≥23% was not significantly different between the two groups (log rank P=.56; HR, 0.825; 95% CI, 0.442-1.541) (Figure 4).

The cumulative 10-year incidence of MACCE was not significantly different between the PCI and CABG groups in patients with diabetes mellitus (log rank P=.23; HR, 1.503; 95% CI, 0.733-3.082) (Figure 5).

Discussion

The primary finding of our study was that CABG and PCI provided a similar MACCE rate at 10-year follow-up. The PCI group had a trend toward higher MACCE in patients with SYNTAX score ≥23%. Consistent with previous studies, the PCI group had a higher rate of TVR.

The ULMCA subset of the SYNTAX trial reported no significant difference in 5-year survival between CABG and PCI.¹³ Although the cumulative 5-year incidence and adjusted risk for death/MI/stroke were significantly higher in the PCI group in Japanese patients, there was no significant difference in the adjusted risk of all-cause death.¹⁴

The LE MANS trial reported no significant differences in the rates of 10-year mortality, MACCE, MI, and reintervention between CABG and PCI.¹⁰ In the MAIN-COMPARE registry, PCI showed similar rates of death and composite outcomes compared with CABG, but a higher rate of TVR at 10 years.¹⁵ Interestingly, CABG had lower mortality and serious composite outcome rates compared with PCI with DES after 5 years.

Our study contributes to the growing body of evidence that PCI is a safe, effective, and durable revascularization strategy in patients with ULMCA disease. There were no significant differences in MACCE and mortality between PCI and CABG during the 10-year follow-up period. The rate of TVR was higher with PCI than with CABG. Of particular interest is that TVR was not included in the primary composite endpoint, as it was not thought to be a clinically “hard” endpoint such as death, MI, or stroke in the EXCEL trial.¹⁶

In the SYNTAX trial, the incidence of stroke was higher in the CABG group compared with the PCI group (2.7% vs 0.3%; P<.01).¹⁷ A meta-analysis also reported lower rates of stroke in the PCI group at 1-year follow-up.¹⁸ Although our study revealed that the PCI group had a lower risk ratio for stroke, the benefits were not sustained after PSM.

The SYNTAX score is commonly calculated for patients with a complex coronary anatomy. In the SYNTAX trial, the 1-year rates of MACCE as well as mortality were higher in the PCI group in patients with high SYNTAX scores (≥33%), while there were no significant differences between the two groups for low (≤22%) and intermediate scores (23%-32%).¹⁹ These results were sustained at 5-year follow-up, while the PCI group had a higher MACCE rate for patients with high scores (46.5% vs 29.7%, respectively; P<.01).²⁰ Our results also showed that there was no significant difference in 10-year MACCE between the two groups with low SYNTAX scores. There was a trend toward a higher MACCE rate in the PCI group with SYNTAX scores ≥23%.

Study limitations. This was a small, single-center, non-randomized, retrospective study. The study entailed two different periods, as DESs were introduced halfway through the study. Whether the use of DES implantation in all PCI cases would have improved outcomes in the PCI group is unknown, as this study did not stratify based upon stent type. Only first-generation DESs were available during the study. It was during this time when PCI technique improved (especially for distal bifurcation disease) and operator experience increased. Data on the treatment strategy for distal bifurcation disease were not available. The mean SYNTAX score was lower in the PCI group, suggesting that the PCI group represented a lower-risk group. The SYNTAX score was not included among the variables for the propensity score.

Conclusion

In a real-world registry of patients with ULMCA disease, PCI and CABG provided similar rates of death, MI, stroke, and TVR. Similar to previous studies, the TVR rate was higher in the PCI group. Longer-term follow-up data from randomized trials are needed to further identify the preferred revascularization strategy for ULMCA disease.

From the ¹Department of Cardiology, Dong-A University Hospital, Busan, Republic of Korea; and the ²Division of Cardiology, UCLA Medical Center, Los Angeles, California.

Funding: This work was supported by the Dong-A University research fund.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted July 24, 2019, provisional acceptance given August 1, 2019, final version accepted August 27, 2019.

Address for correspondence: Moo Hyun Kim, MD, FACC, Department of Cardiology, Dong-A University Hospital, 32 Daesingongwon-ro, Seo-gu, Busan, Republic of Korea, 602-714. Email: kimmh@dau.ac.kr

1. Ragosta M, Dee S, Sarembock IJ, Lipson LC, Gimple LW, Powers ER. Prevalence of unfavorable angiographic characteristics for percutaneous intervention in patients with unprotected left main coronary artery disease. Catheter Cardiovasc Interv. 2006;68:357-362.
2. Chikwe J, Kim M, Goldstone AB, Fallahi A, Athanasiou T. Current diagnosis and management of left main coronary disease. Eur J Cardiothorac Surg. 2010;38:420-430.
3. Anderson HV, Shaw RE, Brindis RG, et al. Risk-adjusted mortality analysis of percutaneous coronary interventions by American College of Cardiology/American Heart Association guidelines recommendations. Am J Cardiol. 2007;99:189-196.
4. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2205-2241.
5. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: executive summary. Circulation. 2011;124:2574-2609.
6. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35:2541-2619.
7. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Thorac Cardiovasc Surg. 2015;149:e5-e23.
8. Capodanno D, Stone GW, Morice MC, Bass TA, Tamburino C. Percutaneous coronary intervention versus coronary artery bypass graft surgery in left main coronary artery disease: a meta-analysis of randomized clinical data. J Am Coll Cardiol. 2011;58:1426-1432.
9. Morice MC, Serruys PW, Kappetein AP, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial. Circulation. 2014;129:2388-2394.
10. Buszman PE, Buszman PP, Banasiewicz-Szkróbka I, et al. Left main stenting in comparison with surgical revascularization: 10-year outcomes of the (Left Main Coronary Artery Stenting) LE MANS trial. JACC Cardiovasc Interv. 2016;9:318-327.
11. Mäkikallio T, Holm NR, Lindsay M, et al; NOBLE study investigators. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet. 2016;388:2743-2752.
12. Baber U, Mehran R, Giustino G, et al. Coronary thrombosis and major bleeding after PCI with drug-eluting stents: risk scores from PARIS. J Am Coll Cardiol. 2016;67:2224-2234.
13. Morice MC, Serruys PW, Kappetein AP, et al. Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation. 2010;121:2645-2653.
14. Shiomi H, Morimoto T, Furukawa Y, et al; CREDO-Kyoto PCI/CABG Registry Cohort-2 Investigators. Comparison of percutaneous coronary intervention with coronary artery bypass grafting in unprotected left main coronary artery disease — 5-year outcome from CREDO-Kyoto PCI/CABG registry cohort-2. Circ J. 2015;79:1282-1289.
15. Park DW, Ahn JM, Yun SC, et al. 10-year outcomes of stents versus coronary artery bypass grafting for left main coronary artery disease. J Am Coll Cardiol. 2018;72:2813-2822.
16. Stone GW, Sabik JF, Serruys PW, et al; EXCEL Trial Investigators. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med. 2016;375:2223-2235.
17. Morice MC, Serruys PW, Kappetein AP, et al. Outcomes in patients with de novo left main disease treated with either percutaneous coronary intervention using paclitaxel-eluting stents or coronary artery bypass graft treatment in the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial. Circulation. 2010;121:2645-2653.
18. Cao C, Manganas C, Bannon P, Vallely M, Yan TD. Drug-eluting stents versus coronary artery bypass graft surgery in left main coronary artery disease: a meta-analysis of early outcomes from randomized and non-randomized studies. J Thorac Cardiovasc Surg. 2013;145:738-747.
19. Serruys PW, Morice MC, Kappetein AP, et al; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360:961-972.
20. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet. 2013;381:629-638.