The FREEDOM trial: Is it sui generis?

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I have never understood how the cardiology community is able to organize so many excellent trials while vascular surgeons struggle to complete a small handful. Appearing long after the well done NASCET and ECST, the recent CREST trial raised as many questions as it answered. In the future it will be exponentially more difficult to organize valid trials because many need to have three-armed studies: one for each intervention, presumably open and endovascular, and a noninterventional arm for medical/nonrevascularization approaches. As far as investigations on legs are concerned our only reliable example is the BASIL trial, now approaching its 10th anniversary.

Dr. George Andros

Whatever the reasons in the past, I am convinced that we need to do a better job stratifying our patients and their disease on clinical grounds before we embark on selecting diagnostic studies and therapies. While there is no shortage of literature on the theory and practice of vascular intervention, I believe we lack a credible evidence base for much of what we do to patients. Such is not the case for cardiologists, however, for the management of triple vessel coronary disease in diabetics.

Academic cardiologists are standing in line to commend the recently completed FREEDOM trial. FREEDOM was many years in the planning and execution to answer the question “Should diabetic patients with multivessel coronary artery occlusive disease be treated with open or percutaneous intervention?” What were the limitations of prior trials that made it necessary to conduct this massive 8-year effort involving 136 centers in 20 countries? When surgical therapy appeared to best PCI catheter therapy the comparison was inapproriate; angioplasty needed to include stents. When newer trials yielded similar results indictating surgical superiority over stents the same line of reasoning was invoked; you’re comparing surgery to out-dated technology. It wasn’t a proper trial if it didn’t include drug-eluting stents. The surgeons couldn’t keep up because just around the corner there would always be the “new new thing” that would demonstrate PCI dominance. The same limitation also applied to surgical bypass; during the era of PCI hegemony the surgeons were actively improving their long-term outcomes by using better conduits for revascularization such as internal mammary and radial arteries and other operative improvements. Unfortunately, the matter remained unsettled because the studies were inadequately powered or failed to enroll enough diabetic patients. As a result, this large and important population eluded the generalizability of the trials. The FREEDOM trial addressed these limitations and concluded that diabetic patients with triple vessel disease were advised not to receive ad hoc PCI at the time of the “diagnostic coronary angiogram.” No more “we’re already here, we may as well fix it;” “those other two arteries really aren’t so bad, let’s just do the LAD, etc., etc.” Instead, the patient should either receive CABG and if uncertainty lingers, then come to a consensus under the auspices of a “multidisciplinary team”. That all makes sense to me. Just because the catheter is positioned to do an angioplasty, that’s no reason to do the wrong procedure.

After hearing about the FREEDOM trial and then reading the paper and its supporting references, three questions nag at me. The first one is the simplest. In the dominion of cardiology, what is a multidisciplinary team? The cardiology conferences that I have attended center the discussion on which stent, how many stents, etc. When have we gone a stent too far rarely seems to come up. Although there is expressed interest in expanding the team approach, the main cardiac multidisciplinary teams seem to be those associated with implanting transcatheter aortic valves (TAVI), in which case they team up with thoracic surgeons.

The concept of a multidisciplinary team has been around for decades when dealing with the neuro-ischemic diabetic foot. The team approach has proven its effectiveness in preventing ulceration and healing feet in jeopardy of amputation. I’ll be on the look out for this new cardiac team in the hospitals where I practice.

Secondly, I wonder if arterial disease in the coronary circulation might have some lessons to teach us in the diabetic foot. The heart has three vessels with regionalized perfusion corresponding with myo-ischemic lesions in the three arterial territories. To me this suggests a similarity to the diabetic foot with its three runoff vessels that develop patterns of arterial occlusion that are cognate to the sites of foot ulceration. All three cardiac and leg vessels are in the 2- to 3-mm diameter range. I wonder if there might be a lesson in these parallels? And that’s not just because the overwhelming majority of the patients in the FREEDOM study had triple-vessel disease. And I’m not referring to the so-called angiosome theory. The majority of neuro-ischemic ulcerated diabetic feet have triple-vessel arterial disease, most with arterial calcification thrown in for good measure just to make things harder.

Of course not all diabetic foot ulcers are ischemic and many can achieve healing with skillful foot care by a diabetic podiatrist. My point is this. Three out of three vessel disease is as sign of aggressive arteriosclerosis and durable revascularization occurred in the cardiac setting only with bypass surgery. On average, each patient who underwent angioplasty needed three or four more additional interventions. This need for repeat intervention occurs all too commonly in the neuro-ischemic diabetic foot as well. I lack the data to support the policy of bypass first but by a similar token there is no evidence to recommend “angioplasty first.”

Isn’t is about time that we, too, devise flexible and appropriate treatment paradigms to revascularize diabetic feet at risk and heal them in the shortest possible time? It is probably too much to hope for a trial as conclusive as the FREEDOM trial but we need to organize trials or a registry for ourselves before the tsunami of diabetic patients engulfs us.

Thirdly, I was unable to understand how so many patients were eligible for inclusion and so few were trial-eligible: 32,966 patients were considered possibly eligible by virtue of receiving a coronary arteriogram for angina pectoris/signs of myocardial ischemia; only 3,309 met the criteria for randomization. I wish that the trialist had provided more information on why the other 29,657 were excluded. What happened to those patients during the 7 years required to complete this study? Likewise, of the 3,309 patients eligible for randomization, 1,409 refused randomization; what happened to them? It was quite an undertaking to screen nearly 33,000 patients and end up with 1,900 – less than 6% trial-eligible patients that were randomized. That percentage is less than the BASIL trial. Having said all of that, congratulations to the investigators on their study and for getting someone to pay for it. The money was well spent.

Dr. Andros is the Medical Editor of Vascular Specialist.

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