Revascularization of low-surgical risk patients with disease of the left main coronary artery: a fresh look at the evidence

CABG, coronary artery bypass grafting; DES, drug-eluting stent; EACTS, European Association for Cardio-Thoracic Surgery; ESC, European Society of Cardiology; EXCEL, Evaluation of XIENCE vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization trial; NOBLE, Nordic–Baltic-British left main revascularisation study; PCI, percutaneous coronary intervention; PRECOMBAT, Bypass Surgery Versus Angioplasty Using Sirolimus Eluting Stent in Patients With Left Main Coronary Artery Disease trial; SYNTAX, Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery trial.

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This editorial refers to ‘2022 joint ESC/EACTS review of the 2018 guideline recommendations on the revascularization of left main coronary artery disease in patients at low surgical risk and anatomy suitable for PCI or CABG’, by R.A. Byrne et al., https://doi.org/10.1093/eurheartj/ehad476.

The European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) have collaborated on the development of clinical practice guidelines for myocardial revascularization since 2010, and the publication of the ‘2018 ESC/EACTS Guidelines on myocardial revascularization’ [1] represented the third collaboration on this topic. In December 2019, the EACTS raised a number of concerns about the implications for practice of the 5-year results of the Evaluation of XIENCE vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial (Graphical Abstract) [2]. As a result of these concerns, the EACTS decided to unilaterally withdraw support for the guideline recommendations specifically relating to patients at low surgical risk with stable coronary artery disease that is amenable to both coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) [3].

Faced with this breakdown in the consensus, and in the absence of an agreed process for resolving such disagreements, the ESC and EACTS leadership agreed to a bespoke process in which a group of independent experts would examine the evidence and advise the ESC and EACTS whether, in their view, the particular guideline recommendation under discussion should be revised. According to the principle that any review of the evidence should include a detailed examination of all of the relevant randomized trial data, it was agreed that the work of the Task Force should coincide with the completion of a meta-analysis of individual patient data from randomized clinical trials comparing PCI using drug-eluting stents (DES) with CABG with at least 5 years of follow-up. This meta-analysis included four trials: Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) [4], Bypass Surgery Versus Angioplasty Using Sirolimus Eluting Stent in Patients With Left Main Coronary Artery Disease (PRECOMBAT) [5], Nordic-Baltic-British left main revascularisation study (NOBLE) [6], and EXCEL [2]. These discussions led to agreement on the terms of reference (reproduced in the Supplementary data of the report by Byrne et al. published in this issue of the European Heart Journal [7]) for a joint ESC/EACTS Task Force, starting work in October 2021, with the ESC and EACTS each nominating one co-chair and five ordinary members. The meta-analysis of individual patient data from four trials of DES in PCI vs. CABG was reported by Sabatine and colleagues [8] shortly thereafter.

One of the principal concerns leading to the withdrawal of EACTS's support for the 2018 guidelines was that the 5-year results of the EXCEL trial had shown that mortality at 5 years was significantly lower for patients treated with CABG (9.9%) as compared with PCI (13.0%): absolute difference 3.1% [95% confidence interval (CI) 0.2%-6.1%]. However, this result was from a single trial, and on its own was not statistically robust. A systematic assessment ought to involve examination of the results of all trials with 5-year follow-up, not just those from EXCEL. In the meta-analysis of individual patient data considered by the Task Force, the median age was 66 years, 23% were female, and the median SYNTAX score was 25 (with around three-quarters of patients having a score of ≤32). When all of the trials were considered, the Kaplan–Meier estimate of 5-year all-cause death was 11.2% (95% CI 9.9-12.6) with PCI and 10.2% (95% CI 9.0-11.6) with CABG (hazard ratio 1.10, 95% CI 0.91-1.32; P = 0.33), resulting in a non-statistically significant absolute risk difference at 5 years of 0.9% (95% CI −0.9 to 2.8). At 10 years, there was also no significant difference in mortality, either when examining all four trials (22.4% vs. 20.4%; hazard ratio 1.10, 95% CI 0.93-1.29), or when examining the two trials (SYNTAX and PRECOMBAT) for which there were complete 10-year data. These findings illustrate the importance of considering all of the relevant randomized trial evidence, since the 5-year results of the EXCEL trial were not reinforced by the other three trials, but they also left open the possibility that further follow-up might reveal true differences in survival between PCI and CABG.

A second key issue that was raised at the time of withdrawal of support for the 2018 guidelines was that, in the EXCEL trial [2], despite pre-specifying analyses of procedural myocardial infarction (MI) using the universal definition of MI [9] in the Statistical Analysis Plan, the authors had not published those results. The results of the meta-analysis showed that, when using the protocol-specified definition of procedural MI for each trial, a significantly lower proportion of PCI-treated patients than CABG-treated patients had a procedural MI (3.2% vs. 4.7%; P = 0.013). In analyses using the universal definition of MI criteria in the SYNTAX [4] and EXCEL [2] trials, however (the only two trials with such data available), the proportion of patients with a procedural myocardial infarction was non-significantly higher in the PCI group (3.2% vs. 2.3%; P = 0.15). Considering these findings, the Task Force concluded that the outcome of procedural MI depended on the definition used. The results of the meta-analysis were, however, unambiguous for spontaneous MI, where PCI resulted in a higher rate than CABG (6.2% vs. 2.6%; P < 0 .0001), and for repeat revascularization, where PCI also resulted in a higher rate (18.3% vs. 10.7%; P < 0.0001).

In its report, the Task Force concluded that, for low-surgical risk patients, both treatment options are clinically reasonable based on patient preference, available expertise, and local operator volumes. However, based on their review of the evidence, they advised that the Class of Recommendation and Level of Evidence for CABG should be Class I and Level of Evidence A, whilst for PCI it should be Class IIa and Level of Evidence A. The Task Force's conclusions resulted from at least 75% consensus within the Task Force on all suggested changes to the guidelines. The document underwent two rounds of peer review (by members of the Boards of both the ESC and EACTS) and revision, followed by formal approval by both Boards. However, it is important to note that the document does not have the status of a guideline, since the process followed by the Task Force, albeit rigorous, was not the formal one agreed between the ESC and EACTS for guideline development. Therefore, the Task Force's advice is now being considered, together with any other relevant evidence that has emerged since 2018, by the Task Force developing the guidelines on Chronic Coronary Syndromes, scheduled for publication in August 2024. It remains to be seen whether the latter Task Force will endorse the key proposed change, namely a shift in the Class of Recommendation for PCI for patients with intermediate SYNTAX score (23-32) from I (treatment is recommended/indicated) to IIa (treatment should be considered).

For now, the ESC and EACTS Boards have accepted the Task Force's conclusions that, for low-surgical risk patients, both treatment options are clinically reasonable based on patient preference, available expertise, and local operator volumes. The ESC and EACTS have also agreed that the Heart Team remains central to decisions about the choice of treatment offered to patients. Guidelines can only ever offer guidance, and they are meant to be applied intelligently in the light of a practitioner's specialist expertise, which could be informed by new data that have become available since guidelines were published. Therefore, the ESC and EACTS agree that Heart Teams should continue to be guided in their decisions about revascularization in patients with stable coronary artery disease by the 2018 ESC/EACTS Guidelines on myocardial revascularization, albeit with the proviso that practitioners should be cognisant of the 2022 Task Force's conclusions in cases where this might influence decision-making.

DECLARATIONS

Disclosure of Interest

Colin Baigent declares a support grant from Boehringer Ingelheim to the University of Oxford (EMPA-KIDNEY trial); grants or contracts from the Medical Research Unit as Director (2019-2024), for Capital award (2020), for the Therapy Acceleration Laboratory Award (2021); grants or contractsfrom the NIHR HTA as co-applicant for the study 17/140/02: ‘Cost-effectiveness of statin therapies evaluated using individual participant data from large randomised clinical trials’ (2019-2022); grants or contracts from the Health Data Research UK as co-applicant to the Substantive Site award (2018-2023). Colin Baigent declares unpaid work for his participation on a Data Safety Monitoring Board or Advisory Board from Merck (Chair of ‘Phase II trial of factor X1-inhibitor for dialysis patients’), from NIHR HTA (Chair of ‘Prepare for kidney care trial’), from the British Heart Foundation (LACI-1/2 [Small vessel disease and cognitive decline]. Colin Baigent declares unpaid work for his contribution as Chair to the European Society of Cardiology Clinical Practice Guidelines Committee, as Chair to both ‘ATTACK: Aspirin To Target Arterial Events in Chronic Kidney Disease’ and ‘DASH: Desmopressin for acute stroke due to haemorrhage’ of the NIHR HTA. Rafael Sádaba declares no conflict of interest for this contribution.

The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Cardio-Thoracic Surgery nor of the European Association for Cardio-Thoracic Surgery.

REFERENCES

Author notes