Interpreting Key Trials

The FREEDOM trial: In appropriate patients with diabetes and multivessel coronary artery disease, CABG beats PCI

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WHAT DOES THIS MEAN?

FREEDOM was a landmark trial that confirmed that CABG provides significant benefit compared with contemporary PCI with drug-eluting stents in patients with diabetes mellitus and multivessel coronary artery disease. It was a large multicenter trial that was adequately powered, unlike most of the earlier trials of this topic.

Unlike previous trials in which the benefit of CABG was driven by reduction in repeat revascularizations alone, FREEDOM showed lower incidence rates of all-cause mortality and myocardial infarction with CABG than with PCI. CABG was better regardless of SYNTAX score, number of diseased vessels, ejection fraction, race, or sex of the patient, indicating that it leads to superior outcomes across a wide spectrum of patients.

An argument that cardiologists often cite when recommending PCI is that it can save money due to lower length of index hospital stay and lower procedure costs of with PCI than with CABG. However, in FREEDOM, CABG also appeared to be highly cost-effective.

FREEDOM had limitations

While FREEDOM provided robust data proving the superiority of CABG, the study had several limitations.

Although there was an overall survival benefit with CABG compared with PCI, the difference in incidence of cardiovascular deaths (which accounted for 64% of all deaths) was not statistically significant.

The trial included only patients who were eligible for both PCI and CABG. Hence, the results may not be generalizable to all diabetic patients with multivessel coronary artery disease—indeed, only 10% of those screened were considered eligible for the trial. However, it is likely that several patients screened in the FREEDOM trial may not have been eligible for PCI or CABG at the time of screening, since the revascularization decision was made by a multidisciplinary team and a more appropriate decision (either CABG or PCI) was then made.

Other factors limiting the general applicability of the results were low numbers of female patients (28.6%), black patients (6.3%), patients with an ejection fraction of 40% or less (2.5%), and patients with a low SYNTAX score (35%).

There were several unexplained observations as well. The difference in events between the treatment groups was much higher in North America than in other regions. The number of coronary lesions in the CABG group was high (mean = 5.74), but the average numbers of grafts used was only 2.9, and data were not provided regarding use of sequential grafting. Similarly, an average of only 3.5 of the six stenotic lesions per patient in the PCI group were revascularized; whether this was the result of procedural limitations with PCI was not entirely clear.

In addition, while the investigators mention that an average patient received four stents, a surprising finding was that the mean total length of the stents used was only 26 mm. This appears too small, as the usual length of one drug-eluting stent is about 20 to 30 mm.

Since only high-volume centers with good outcome data were included in the trial, the results may lack validity for patients undergoing revascularization at low-volume community centers.

It remains to be seen if the benefits of CABG will be sustained over 10 years and longer, when saphenous vein grafts tend to fail and require repeat revascularization, commonly performed with PCI. Previous data suggest that the longer the follow-up, the better the results with CABG. However, long-term results (> 10 years) in studies comparing drugeluting stents and CABG are not available.

Despite limitations, FREEDOM may change clinical practice

Despite these limitations, the FREEDOM trial has the potential to change clinical practice and strengthen current recommendations for CABG in these patients.

The trial underscored the importance of a multidisciplinary heart team approach in managing patients with complex coronary artery disease, similar to that being used in patients with severe aortic stenosis since transcatheter aortic valve replacement became available.

It should also bring an end to the practice of ad hoc PCI, especially in patients with diabetes and multivessel coronary artery disease. It is now imperative that physicians discuss current evidence for therapeutic options with the patients and their families before performing diagnostic angiography rather than immediately afterward, to give the patients ample time to make an informed decision. This is important, as most patients are likely to choose PCI in the same setting over CABG unless there is extensive discussion about the risks and benefits of both strategies done in an unbiased manner before angiography.

The fear of open heart surgery, a longer hospital stay, and a higher risk of stroke with CABG may lead some patients to choose PCI instead. In addition, factors that may preclude CABG in otherwise-eligible patients include anatomic considerations (diffuse distal vessel disease, poor conduits), individual factors (frailty, poor renal function, poor pulmonary function, patient preference), and local expertise.

Nevertheless, the patient should be presented with current evidence, and discussions regarding the optimal procedure should be held with a heart team, which should include an interventional cardiologist, a cardiothoracic surgeon, and a noninvasive cardiologist to facilitate an unbiased decision.

Regardless of the strategy chosen, the importance of compliance with optimal medical therapy (statins, antiplatelet agents, diabetes treatment) should be continuously emphasized to the patient.

WHAT DOES THE FUTURE HOLD?

Despite unequivocal evidence that CABG is superior to PCI in eligible patients with diabetes mellitus in the current era, PCI technologies continue to evolve rapidly. Newer second-generation drug-eluting stents have shown lower rates of restenosis38,39 and may shorten the duration of post-PCI dual-antiplatelet therapy, a nuisance that has negatively affected outcomes with drug-eluting stents (because of problems of cost, poor compliance, and increased bleeding risk).

At the same time, CABG has also improved, with more extensive use of complete arterial conduits and use of an off-pump bypass technique that in theory poses a lower risk of stroke, although this has not yet been shown in a randomized trial.40

Alternative approaches are being investigated. One of them is a hybrid procedure in which minimally invasive off-pump arterial grafting is combined with drug-eluting stents, which may reduce the risk of stroke and speed postoperative recovery.

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