Subset Analysis of DEFINITIVE LE: An Interview With Lawrence A. Garcia, MD

At the 5th Annual Amputation Prevention Symposium, Vascular Disease Management asked Lawrence A. Garcia, MD, to share details about subset analysis and new insights from the DEFINITIVE LE trial. The DEFINITIVE LE study was conducted at 47 sites in Europe and the United States to assess use of directional atherectomy using the SilverHawk and TurboHawk Plaque Excision Systems (Covidien). The study enrolled 800 patients with PAD in the superficial femoral, infrapopliteal and popliteal arteries. Dr. Garcia and colleagues recently published a subset analysis comparing patients with and without diabetes.

VDM: Could you give us some information about what’s new and what you think the most important points are about DEFINITIVE LE that you’re sharing with the CLI therapists here?

Garcia: DEFINITIVE LE came out in 2012, and when we first presented and published the data then, it was really the first scientific pursuit of atherectomy in a real-world population of claudicants and critical limb ischemic patients. We really tried to understand the applicability of atherectomy in both the claudication group and the critical limb ischemia group. Of around 800 enrolled patients, 600 were the claudication group and 200 were in the CLI group. And of the nearly 1,100 lesions that we tested or treated in the claudication group using a peak systolic velocity ratio of 2.4, we reported primary patency of 78%. 

But this was not a study to determine an indication for a device but rather the scientific pursuit of what it does. So that 78% is actually drawn from data on all anatomic territories, so it includes outcomes above the knee, at the knee, and below the knee. If you really break out the SFA data, at an 8 cm metric with 2.4 peak systolic velocity ratio (PSVR), there was 83% primary patency and for 6 cm at the popliteal and infrapopliteal space there was 78% and a near 90% primary patency for a claudicant group. Those numbers show that atherectomy, or the leave nothing behind strategy, works. 

Atherectomy for critical limb ischemia seems appealing, but is it actually beneficial to the patients? Using a fairly consistent endpoint, which is amputation-free survival (AFS), the primary AFS for the CLI group in DEFINITIVE was 95% limb salvage. That’s a remarkable number when you look at the trials that went before it. Most trials have AFS in the 90% range. 

Additional subgrouping has been done within the CLI group by the DEFINITIVE principal investigators, led by Thomas Zeller, MD. Looking at the primary patency above the knee, at the knee, and below the knee, for the claudicant group, most of the targets were in the SFA. However, in the CLI group, 50% of targets were in the SFA with the remainder in the knee and below the knee. The below-knee primary patency for the CLI group was a primary patency at 1 year of 78%, with PSVR of 2.4 and a 6 cm metric. No other trial to date has ever shown a primary patency above 30%-40% when it comes to angioplasties and similar therapies. Even though the AFS was good, the atherectomy group at a 6 cm metric had a 78% primary patency. This is a very important take-home point, and this is one of the main reasons that atherectomy is attracting more interest again since 2012. It may be a class effect; a lot of companies are trying to gravitate toward DEFINITIVE’s numbers, but these sets of numbers are really specific to SilverHawk directional atherectomy and not the class as a whole.

VDM: How do you think this will influence future study? What subsets should be looked at more closely or in terms of those patencies and CLI patients?

Garcia: There are things that really bear some re-evaluation from DEFINITIVE. One critical point is that DEFINITIVE suggests the leave nothing behind strategy is beneficial. It can benefit both in regard to primary outcome, i.e. patency or limb salvage, as well as with failures that need reintervention. If you have to come back and treat it again, every opportunity is open to you; you can still treat with balloon angioplasty, stenting, or even more atherectomy. 

Also, there’s a big interest in moving forward with combined therapy, or atherectomy to prep the vessel followed by drug-coated balloon. There’s a big interest in the United States and many other countries now in the utility of drug-coated balloon technology, particularly above the knee. DEFINITIVE bore out a next-generation pilot study called DEFINITIVE AR. That study did a so-called “shave and pave” approach, which is atherectomy followed by a drug-coated balloon, particularly in long lesion subsets, and in an angiographic outcome – not in an ultrasound-driven outcome – there was a 91% primary patency at a 10 cm metric. That trial needs to go on to the next step in being tested, which is a dedicated randomized, controlled trial to either confirm these findings or not. 

IN.PACT DEEP was a big negative trial for below-the-knee drug-coated balloons. Despite this, I believe a combined therapy of atherectomy plus drug-coated technology may actually improve the primary patency to give you the durability you need with similar AFS but ultimately longer duration patency. Ultimately where the rubber meets the road, at least in this country, will be the economics -- if you pay a lot upfront for these combined technologies but the downstream cost is less, that’s a huge victory, not only for the healthcare dollar, but also for your patients with critical limb ischemia. If the opposite is true then this approach may not be either feasible or economically attractive. 

VDM: How is the data from DEFINITIVE LE applicable, or what’s the key message for someone who’s not an interventional cardiologist, someone who’s a podiatrist or vascular surgeon: what’s the key message for them from DEFINITIVE LE?

Garcia: It’s a challenge because if you look at the clinicians who use atherectomy, I think most are in a non-surgical group. I think the surgeons have always believed that angioplasty trumps most everything else. A simple angioplasty gives you an AFS. The problem is that the failure modes on angioplasty may require more work, and ultimately from a surgical standpoint, most surgeons would suggest that if you work downstream, and you mucked up an artery, it’s no longer bypassable, so they have gone to a very simplistic approach. 

Podiatrists see benefit in the opportunity for revascularization with the least amount of downside, and that is an endovascular approach. As long as you re-establish blood flow, the podiatrist can then do TMA, ray amputations, or reconstructions and get the blood flow and energy that’s necessary to heal the foot or wound. So I think the future of atherectomy when it comes to those outside of a cardiovascular space is how good it is at fixing an artery, salvaging limbs, and remaining durable. 

There are those who think that an alternative therapy other than endovascular is the right answer. But we will continue to collect data on atherectomy, directional or otherwise, combined with drug-coated balloon or whatever future technologies we may not understand right now in the future that may come along. If data are shown to be beneficial in terms of durable outcomes, then that’s certainly going to become the default if not the only mainstay therapy. You still have the same options in your back pocket, you can play that trump card, as I say, of surgical revascularization at any time in the future should endovascular therapy fail.

VDM: Is there anything that I missed about DEFINITIVE LE that you wanted to point out?

Garcia: The DEFINITIVE LE trial was driven to understand the science of atherectomy, particularly directional atherectomy in those two groups -- claudicants and CLI. We prespecified in the claudicant group to evaluate diabetics because we’re hard-wired to learn the difference in a claudicant group on the diabetic/nondiabetic population. There was the signal from previous atherectomy trials that the diabetics did just as well with atherectomy as they did if they were nondiabetic and with this trial, we proved it. If you looked at that overall primary patency, which was 78% and when you separate out the curves for the claudicates, 79% for the nondiabetic and 77% for the claudicant group, it’s a wash. Both Kaplan-Meier curves are exactly parallel to each other. We just published this data in August in the Journal of Endovascular Therapy. 

Also, my colleague Thomas Zeller and his colleagues in his lab are publishing the popliteal and infrapopliteal CLI group, specific to the CLI group. There is a wealth of information in DEFINITIVE. There is the primary manuscript and the manuscript on diabetes. We will have the CLI manuscript, and we have a gender manuscript in the works. We also have the acute complication manuscript in the works. 

We’ll see how DEFINITIVE plays out scientifically with all the data sets that comes out, but critically, overall it does well, in the diabetics it’s a wash, and between men and women, despite women being smaller and having presented later with more disease, did just as well as their male counterparts. There’s still so much information to be gleaned from DEFINITIVE that we are still in the beginning stages of understanding all there is to this trial and its outcomes. 

Lawrence A. Garcia, MD, is an interventional cardiologist with St. Elizabeth’s Medical Center in Boston, where he serves as Chief of Interventional Cardiology and Vascular Interventions and Director of Vascular Medicine. Dr. Garcia reports grants from Abbott Vascular and Covidien/Medtronic, unpaid consultation to Covidien/Medtronic, Boston Scientific, and Abbott Vascular, and stock ownership with Arsenal, Primacea, TissueGen, CV Ingenuity, Spirox, Scion Cardiovascular, Syntervention, and Essential Medical. Address for correspondence: Lawrence A. Garcia, MD, Section of Interventional Cardiology, St. Elizabeth’s Medical Center, 736 Cambridge Street, Boston, MA 02135 United States. Email: Lawrence.garcia@steward.org