New England Journal of Medicine December 20, 2012

Strategies for Multivessel Revascularization in Patients with Diabetes

Michael E. Farkouh, Michael Domanski, Lynn A. Sleeper, et al.

Bottom Line

In patients with diabetes and multivessel coronary artery disease, coronary artery bypass grafting significantly reduced the composite rate of death, myocardial infarction, and stroke compared to percutaneous coronary intervention with drug-eluting stents.

Key Findings

1. At 5 years, the primary composite outcome of death, myocardial infarction, or stroke occurred in 26.6% of patients in the PCI group and 18.7% in the CABG group, representing a statistically significant absolute difference of 7.9% and a relative risk reduction of 30% (P=0.005) [1.2].

2. All-cause mortality was significantly higher in the PCI group compared to the CABG group at 5 years (16.3% vs. 10.9%, P=0.049).

3. Rates of nonfatal myocardial infarction were significantly higher in the PCI group compared to the CABG group at 5 years (13.9% vs. 6.0%, P<0.001).

4. Conversely, the 5-year rate of stroke was significantly lower in the PCI arm than in the CABG arm (2.4% vs. 5.2%, P=0.03).

5. The need for repeat revascularization within 1 year was substantially higher in the PCI group (12.6%) compared to the CABG group (4.8%, P<0.001).

Study Design

Design

Randomized Controlled Trial

Open-Label

Sample

1,900

Patients

Duration

3.8 yr

Median

Setting

140 international centers

Population Patients 18 years or older with diabetes mellitus and angiographically confirmed multivessel coronary artery disease (>=70% stenosis in >=2 epicardial vessels/territories) without left main stenosis >=50% or prior CABG/PCI.

Intervention Percutaneous coronary intervention (PCI) with first-generation drug-eluting stents (paclitaxel- or sirolimus-eluting) and dual antiplatelet therapy for at least 12 months.

Comparator Coronary artery bypass grafting (CABG) with arterial revascularization strongly encouraged.

Outcome Composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke evaluated at 5 years.

Study Limitations

• The trial was open-label, which could have introduced bias in post-procedural care and the clinical threshold for performing repeat revascularizations [1.5].

• The vast majority of the PCI cohort (94%) received first-generation drug-eluting stents (paclitaxel or sirolimus), which have since been largely superseded by safer and more effective newer-generation stents.

• Subgroup analyses, including stratifications by SYNTAX score, were underpowered due to the overall sample size, limiting the ability to detect outcome differences based on anatomical complexity.

Clinical Significance

The FREEDOM trial provided definitive evidence that for patients with diabetes and multivessel coronary artery disease, CABG is superior to PCI with drug-eluting stents in reducing long-term rates of death and myocardial infarction, although it is associated with a slightly higher risk of peri-procedural stroke. This established CABG as the standard of care and preferred revascularization strategy for this high-risk patient population, strongly influencing subsequent international cardiovascular guidelines.

Historical Context

Prior to FREEDOM, the landmark 1996 BARI trial established that diabetic patients with multivessel disease had better survival with CABG than with balloon angioplasty. With the advent of drug-eluting stents (DES), which significantly reduced restenosis rates, many hypothesized that advanced PCI techniques might have closed the efficacy gap with CABG. The FREEDOM trial was designed to test whether PCI with DES was superior or comparable to CABG in diabetics with multivessel CAD; its results definitively demonstrated that the surgical survival advantage persisted even in the modern DES era.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

In patients with diabetes mellitus, coronary artery disease tends to be diffuse rather than focal. Based on this pathophysiology, why does CABG generally provide superior long-term outcomes compared to PCI with stenting in these patients?

Key Response

Diabetes causes widespread endothelial dysfunction and systemic inflammation, leading to diffuse, accelerated atherosclerosis. CABG is highly effective because a bypass graft (especially the LIMA to LAD) provides flow distal to the entire segment of diseased vessel, protecting against future proximal disease progression. PCI only treats specific focal lesions, leaving the patient vulnerable to the high rate of rapid plaque progression elsewhere in the native vessel.

Resident

The FREEDOM trial demonstrated an overall reduction in the composite endpoint of death, MI, and stroke with CABG compared to PCI in diabetic patients. However, which specific adverse event was actually higher in the CABG group, and how should this influence your informed consent discussions?

Key Response

Stroke rates were significantly higher in the CABG group compared to the PCI group, particularly within the first 30 days, largely due to aortic cross-clamping and surgical manipulation. Residents must balance the long-term mortality and MI benefits of CABG against this short-term upfront stroke risk during informed consent and shared decision-making.

Fellow

The FREEDOM trial utilized primarily first-generation paclitaxel- and sirolimus-eluting stents. How might the contemporary use of ultra-thin strut, second-generation drug-eluting stents, combined with intravascular imaging (IVUS/OCT) and physiology-guided (FFR/iFR) PCI, challenge the magnitude of the CABG benefit seen in this trial?

Key Response

First-generation DES had higher rates of late stent thrombosis and restenosis. Modern PCI utilizing second-generation DES, physiological assessment to ensure only ischemia-producing lesions are treated, and intravascular imaging for optimal stent expansion significantly reduce target lesion failure. Fellows must consider whether state-of-the-art PCI narrows the outcome gap with CABG, a nuance explored in subsequent trials like FAME 3, though CABG generally maintains an edge in complex diabetic multivessel CAD.

Attending

Translating the FREEDOM trial into practice requires the Heart Team approach. When assessing a diabetic patient with multivessel CAD who strongly prefers PCI to avoid surgery, what specific clinical and angiographic features would you identify to either support their preference or firmly recommend CABG?

Key Response

While CABG is superior overall in this demographic, a patient with a low SYNTAX score (focal disease), severe COPD, frailty, or poor surgical conduit targets might still be a better candidate for PCI. Attendings must synthesize trial data with individual patient complexity, weighing angiographic severity against operative risk factors to guide nuanced shared decision-making.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The FREEDOM trial used a composite primary outcome of all-cause mortality, nonfatal MI, and nonfatal stroke. Given that the components of this composite endpoint move in opposite directions (e.g., mortality decreases but stroke increases with CABG), how does this complicate traditional time-to-first-event survival analyses, and what alternative statistical frameworks could better capture the net clinical benefit?

Key Response

Traditional time-to-first-event (Cox proportional hazards) analyses treat all events in a composite equally and ignore subsequent events. Since CABG has an early hazard for stroke but late benefit for MI and death, a competing risks model, win ratio analysis, or recurrent event analysis (like the Andersen-Gill model) would provide a more statistically rigorous representation of the total burden of disease and hierarchical clinical benefit over time.

Journal Editor

As a critical peer reviewer, how would you evaluate the threat to external validity posed by the rapid evolution of optimal medical therapy (OMT) for diabetes (e.g., SGLT2 inhibitors, GLP-1 receptor agonists) that occurred after the FREEDOM trial's completion?

Key Response

A major editorial flag is the shifting landscape of baseline medical therapy. The FREEDOM trial was conducted before the widespread use of SGLT2 inhibitors and GLP-1 RAs, which have profound independent cardiovascular mortality benefits. A reviewer must question whether the absolute risk reduction provided by CABG over PCI would be significantly attenuated in a modern cohort fully optimized on contemporary disease-modifying cardiometabolic agents.

Guideline Committee

Based on the FREEDOM trial, current ACC/AHA guidelines give CABG a Class 1 recommendation for revascularization in diabetic patients with multivessel CAD. However, how should guidelines address the subgroup of patients with low anatomical complexity (SYNTAX score < 22) when comparing CABG to PCI?

Key Response

The 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization gives CABG a Class 1 (Level of Evidence A) recommendation over PCI for diabetic patients with multivessel disease to improve survival. However, for patients with low anatomical complexity (SYNTAX score <= 22), the guidelines indicate PCI is a reasonable alternative (Class 2b) if CABG is high risk or patient preference is strong, because subgroup analyses suggest the survival benefit of CABG is most pronounced in those with intermediate to high anatomical complexity.

Clinical Landscape

Noteworthy Related Trials

2009

BARI 2D Trial

n = 2,368 · NEJM

Tested

Prompt revascularization (CABG or PCI)

Population

Patients with type 2 diabetes and stable ischemic heart disease

Comparator

Intensive medical therapy alone

Endpoint

All-cause mortality at 5 years

Key result: There was no significant difference in all-cause mortality between prompt revascularization and medical therapy, though the CABG subgroup had fewer major cardiovascular events.

2009

SYNTAX Trial

n = 1,800 · NEJM

Tested

PCI with paclitaxel-eluting stents

Population

Patients with left main or three-vessel coronary artery disease

Comparator

Coronary artery bypass grafting (CABG)

Endpoint

Major adverse cardiac or cerebrovascular events (MACCE) at 12 months

Key result: CABG significantly reduced the rate of MACCE compared to PCI, primarily driven by a lower need for repeat revascularization.

2016

EXCEL Trial

n = 1,905 · NEJM

Tested

PCI with everolimus-eluting stents

Population

Patients with left main coronary artery disease and low or intermediate SYNTAX scores

Comparator

Coronary artery bypass grafting (CABG)

Endpoint

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

Key result: PCI was noninferior to CABG with respect to the primary composite endpoint at 3 years in this specific patient subset.

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