Interpreting Key Trials

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

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ABSTRACTThe Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial (N Engl J Med 2012; 367:2375–2384) was designed to resolve the long-standing debate over the optimal revascularization strategy in patients with diabetes mellitus and multivessel coronary artery disease. At a median follow-up of 3.8 years, the incidence of the primary outcome (a composite of death, myocardial infarction, and stroke) was significantly lower with bypass surgery than with percutaneous intervention.


  • Patients with diabetes have a higher prevalence of multivessel coronary artery disease and often have complex, diffuse lesions.
  • Bypass surgery is the preferred method of revascularization in appropriately selected patients with diabetes and multivessel coronary artery disease.
  • In the FREEDOM trial, only about 10% of the screened patients were eligible for the study, limiting its generalizability; however, this is comparable to exclusion rates in previous large randomized trials.
  • When choosing a revascularization method, the physician team needs to discuss the options with the patient before performing diagnostic angiography. The team should include a cardiac surgeon and a cardiologist.



Many patients with diabetes mellitus develop complex, accelerated, multifocal coronary artery disease. Moreover, if they undergo revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), their risk of morbidity and death afterward is higher than in those without diabetes.1,2

Over the last 2 decades, CABG and PCI have advanced significantly, as have antithrombotic therapy and drug therapies to modify cardiovascular risk factors such as hyperlipidemia, hypertension, and diabetes.

Several earlier studies showed CABG to be more beneficial than PCI in diabetic patients with multivessel coronary artery disease.3–5 However, the topic has been controversial, and a substantial proportion of these patients continue to undergo PCI rather than CABG.

There are two main reasons for the continued use of PCI in this population. First, PCI is evolving, with new adjuvant drugs and drugeluting stents. Many cardiologists believe that earlier trials, which did not use contemporary PCI techniques, are outdated and that current, state-of-the-art PCI may be equivalent to—if not superior to—CABG.

Second, PCI is often performed on an ad hoc basis immediately after diagnostic angiography, leaving little time for discussion with the patient about alternative treatments. In this scenario, patients are inclined to undergo PCI immediately, while they are already on the table in the catheterization suite, rather than CABG at a later date.6

In addition, although the current joint guide-lines of the American College of Cardiology and the American Heart Association state that CABG is preferable to PCI for patients with diabetes and multivessel coronary artery disease, they give it only a level IIa recommendation.7

The much-anticipated Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial8 was designed to settle the CABG-vs-PCI debate, thereby leading to a stronger guideline recommendation for the preferred revascularization strategy in this patient population.


Diabetes mellitus is a major risk factor for premature and aggressive coronary artery disease. Several mechanisms have been proposed to explain this association.

Diabetic patients have higher concentrations of several inflammatory proteins than those without diabetes, including C-reactive protein, tumor necrosis factor, and platelet-derived soluble CD40 ligand. They also have higher levels of adhesion molecules such as vascular cell adhesion molecule-1 and intercellular adhesion molecule.9,10 In addition, when blood sugar levels are high, platelets express more glycoprotein IIb/IIIa receptors and are therefore more prone to aggregate.11

These prothrombotic and proinflammatory cytokines, in conjunction with endothelial dysfunction and metabolic disorders such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, and oxidative stress, lead to accelerated atherosclerosis in patients with diabetes.12 Also, because diabetes is a systemic disease, the atherosclerotic process is diffuse, and many patients with diabetes have left main coronary artery lesions and diffuse multivessel coronary artery disease.13,14

Although the short-term outcomes of revascularization by any means are comparable in patients with and without diabetes, diabetic patients have lower long-term survival rates and higher rates of myocardial infarction and need for repeat procedures.15 Diabetic patients who undergo PCI have a high rate of stent thrombosis and restenosis.16,17 Similarly, those undergoing CABG have higher rates of postoperative infection and renal and neurologic complications.18,19


The question of CABG vs PCI has plagued physicians ever since PCI came to the forefront in the 1980s. Before stents were widely used, PCI with balloon angioplasty was known to be comparable to CABG for single-vessel disease, but whether it was beneficial in patients with multivessel disease or left main disease was not entirely evident. Randomized clinical trials were launched to answer the question.

Studies of balloon angioplasty vs CABG

The BARI trial (Bypass Angioplasty Revascularization Investigation),5,20 published in 1996, compared PCI (using balloon angioplasty without a stent) and CABG in patients with multivessel coronary artery disease (Table 120–29).

Between 1988 and 1991, the trial randomly assigned 1,829 patients with multivessel disease to receive either PCI or CABG and compared their long-term outcomes. Although there was no difference in mortality rates between the two groups overall, the diabetic subgroup had a significantly better survival rate with CABG than with PCI, which was sustained over a follow-up period of 10 years.5

BARI had a significant clinical impact at the time and led to a clinical alert by the National Heart, Lung, and Blood Institute recommending CABG over PCI for patients with diabetes. However, not everyone accepted the results, because they were based on a small number of patients (n = 353) in a retrospectively determined subgroup. Further, the BARI trial was conducted before the advent of coronary stents, which were later shown to improve outcomes after PCI. Also, optimal medical therapy after revascularization was not specified in the protocol, which likely affected outcomes.

EAST (Emory Angioplasty Versus Surgery Trial)21 and CABRI (Coronary Angioplasty Versus Bypass Revascularization Investigation) 22 were similar randomized trials comparing angioplasty and CABG in patients with multivessel coronary artery disease. These showed better outcomes after CABG in patients with diabetes. However, lack of statistical significance because of small sample sizes limited their clinical impact.

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