The Lancet FEBRUARY 23, 2013

The Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) Trial

Friedrich W. Mohr, Marie-Claude Morice, A. Pieter Kappetein, et al. (The SYNTAX Investigators)

Bottom Line

The SYNTAX trial compared CABG with PCI using first-generation paclitaxel-eluting stents in patients with complex coronary artery disease, demonstrating that CABG remained the superior standard of care for patients with high-complexity anatomy, while PCI was a viable alternative for patients with less complex disease.

Key Findings

1. At 5 years, the primary endpoint of major adverse cardiac and cerebrovascular events (MACCE) was significantly higher in the PCI group (37.3%) compared with the CABG group (26.9%; p < 0.0001).

2. Repeat revascularization rates were significantly higher with PCI (25.9%) versus CABG (13.7%; p < 0.0001) over 5 years.

3. Myocardial infarction rates were significantly lower with CABG (3.8%) compared with PCI (9.7%; p < 0.0001).

4. Stroke rates were higher with CABG (3.7%) than PCI (2.4%), though this difference did not reach statistical significance in the global population at 5 years (p = 0.09).

5. Subgroup analysis revealed that for patients with low SYNTAX scores, PCI outcomes were comparable to CABG; however, for intermediate and high SYNTAX scores, PCI was associated with significantly higher MACCE rates.

Study Design

Design

RCT

Open-Label

Sample

1,800

Patients

Duration

5 yr

Median

Setting

Multicenter, US and Europe

Population Patients with de novo three-vessel disease or unprotected left main coronary artery disease.

Intervention Percutaneous coronary intervention (PCI) with first-generation paclitaxel-eluting stents.

Comparator Coronary artery bypass graft (CABG) surgery.

Outcome Composite rate of major adverse cardiac and cerebrovascular events (MACCE), defined as all-cause death, stroke, myocardial infarction, or repeat revascularization.

Study Limitations

• The use of first-generation paclitaxel-eluting stents, which are now largely obsolete and associated with higher rates of restenosis compared to modern drug-eluting stents.

• Non-inferiority was not met for the primary endpoint at the 12-month mark, necessitating cautious interpretation of subsequent secondary analyses.

• The trial was not powered to detect differences in mortality, particularly within specific subgroups.

• The inclusion of both three-vessel and left main disease in the primary analysis created potential heterogeneity that complicates direct interpretation for clinical decision-making.

Clinical Significance

The SYNTAX trial transformed revascularization decision-making by institutionalizing the 'Heart Team' approach and the use of the SYNTAX score to quantify anatomical complexity. It confirmed that CABG remains the gold standard for patients with complex multivessel coronary artery disease, while providing evidence that PCI may be a reasonable alternative in patients with simpler, low-complexity lesions.

Historical Context

Prior to SYNTAX, the debate over revascularization strategy for multivessel and left main disease was dominated by older trials from the pre-drug-eluting stent era. SYNTAX represented a critical contemporary evaluation in the modern interventional era, setting the stage for subsequent trials comparing surgery to newer-generation stents and refining contemporary revascularization guidelines.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale for why bypass grafting (CABG) might offer better long-term protection against myocardial infarction compared to percutaneous coronary intervention (PCI) in patients with diffuse atherosclerosis?

Key Response

CABG provides a 'surgical collateralization' by bypassing not only the primary culprit lesion but also the proximal segments of the coronary artery that may harbor vulnerable, non-obstructive plaques. In contrast, PCI only treats the hemodynamically significant focal stenosis, leaving other proximal segments susceptible to future plaque rupture and acute coronary syndromes.

Resident

In the context of the SYNTAX trial, how does the anatomical SYNTAX Score facilitate the 'Heart Team' approach when deciding between PCI and CABG for a patient with triple-vessel disease?

Key Response

The SYNTAX Score quantifies coronary anatomy complexity based on lesion location, bifurcation, and calcification. For patients with low scores (0-22), PCI is considered an acceptable alternative to CABG. For intermediate (23-32) and high scores (>32), CABG is the preferred standard of care because it significantly reduces the rate of major adverse cardiac and cerebrovascular events (MACCE) compared to first-generation drug-eluting stents.

Fellow

Critically analyze the divergence in outcomes between Left Main disease and Triple-Vessel Disease (TVD) in the SYNTAX trial; why was PCI non-inferior in one but significantly inferior in the other?

Key Response

In the Left Main subgroup, PCI outcomes were comparable to CABG at one year because the anatomy is often less diffuse, allowing for more complete revascularization via PCI. However, in TVD, the complexity and burden of atherosclerotic disease often lead to incomplete revascularization with PCI, which drove the higher rates of repeat revascularization and myocardial infarction observed in the PCI arm.

Attending

Considering the long-term (5-10 year) follow-up of SYNTAX, how should the higher incidence of stroke in the CABG arm versus the higher incidence of myocardial infarction in the PCI arm influence the shared decision-making process for an elderly patient with high-complexity CAD?

Key Response

The trade-off involves weighing the early procedural risk of stroke associated with CABG (often due to aortic manipulation) against the long-term risk of 'spontaneous' myocardial infarction and repeat revascularization with PCI. For an elderly patient, life expectancy and the immediate impact of a neurological deficit versus the morbidity of future cardiac events must be balanced using the SYNTAX II score, which incorporates clinical factors like age and comorbidities.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Evaluate the limitations of using a composite endpoint like MACCE (Death, Stroke, MI, and Repeat Revascularization) in the SYNTAX trial, specifically regarding the weighting of 'repeat revascularization' versus 'all-cause mortality'.

Key Response

Composite endpoints assume all components have equal clinical significance. However, repeat revascularization is a lower-acuity event than death or stroke. In SYNTAX, the inferiority of PCI was driven heavily by repeat revascularization; if the endpoint were limited to hard clinical outcomes (Death/Stroke/MI), the statistical power and the resulting clinical recommendations for intermediate-risk patients might have shifted.

Journal Editor

To what extent do the results of the SYNTAX trial remain internally valid today, given that the trial utilized first-generation paclitaxel-eluting stents (TAXUS) which are now obsolete?

Key Response

The use of first-generation TAXUS stents is a major threat to contemporary external validity. Modern thin-strut everolimus-eluting stents have significantly lower rates of stent thrombosis and target lesion failure. A contemporary reviewer would argue that the 'gap' between PCI and CABG seen in SYNTAX might be narrower today, as evidenced by later trials like EXCEL and NOBLE, though the anatomical complexity principle remains a cornerstone of risk stratification.

Guideline Committee

How does the SYNTAX trial's definition of 'complex coronary anatomy' impact the current Class of Recommendation for PCI in patients with a SYNTAX score >32 according to the ACC/AHA and ESC/EACTS guidelines?

Key Response

Based largely on SYNTAX and its 5-year data, both ACC/AHA and ESC/EACTS guidelines assign a Class III (Harm) or a low-strength recommendation for PCI in patients with triple-vessel disease and a SYNTAX score >32. CABG remains a Class I (Level of Evidence A) recommendation for these patients because it offers a survival advantage and a significant reduction in the risk of myocardial infarction compared to PCI in high-complexity settings.

Clinical Landscape

Noteworthy Related Trials

2011

PRECOMBAT Trial

n = 600 · NEJM

Tested

PCI with sirolimus-eluting stents

Population

Patients with unprotected left main coronary artery disease

Comparator

CABG surgery

Endpoint

Composite of death, myocardial infarction, or stroke at 12 months

Key result: PCI was noninferior to CABG for the composite of major adverse cardiac or cerebrovascular events at 1 year.

2012

FREEDOM Trial

n = 1,900 · NEJM

Tested

CABG surgery

Population

Patients with multivessel coronary artery disease and diabetes

Comparator

PCI with drug-eluting stents

Endpoint

Composite of death, nonfatal myocardial infarction, or stroke at 5 years

Key result: CABG was superior to PCI in reducing the rate of all-cause mortality, MI, and stroke in diabetic patients with multivessel CAD.

2016

EXCEL Trial

n = 1,905 · NEJM

Tested

PCI with everolimus-eluting stents

Population

Patients with unprotected left main coronary artery disease

Comparator

CABG surgery

Endpoint

Composite of death, stroke, or myocardial infarction at 3 years

Key result: PCI was noninferior to CABG in terms of the primary composite endpoint at 3 years in patients with left main disease.

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