The annual VEITHSymposium (veithsymposium.org) took place November 18-22, 2014, in New York City, New York.

Cath Lab Digest talks with Lawrence Garcia, MD, FACC, FAHA, FSCAI, Chief, Sections of Interventional Cardiology and Vascular Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Massachusetts.

Can you tell us about the DEFINITIVE LE study?

DEFINITIVE looked at directional atherectomy in the treatment of lower extremity disease. The study included 47 centers in the United States and Europe, and enrolled 800 patients (one patient was censored for an informed consent issue, so it really ended up as 799 patients), testing 1022 lesions. The study was published in August 2014 in JACC Interventions¹, with the lead author being my co-principal investigator, Jim McKinsey. We undertook DEFINITIVE to look specifically at outcomes with directional atherectomy in two groups: patients with claudication (n=598) and patients with critical limb ischemia (CLI) (n=201). Claudicants were tested at 12 months for primary patency, with a sonographic endpoint of 2.4 PSVR. CLI patients were reviewed at 12 months for limb salvage, i.e., amputation-free survival. Inclusion criteria included Rutherford-Baker clinical categories 2-6 and stenoses that were at least 50% or higher. What was truly unique in DEFINITIVE was that lesion lengths could be up to 20cm, so the high-end lesion length was TASC classification C, unlike any previous endovascular device trials. Also unusual is that rather than looking for a device indication, which was already present for this device (Covidien’s TurboHawk and/or SilverHawk directional atherectomy systems were used in the study), DEFINITIVE was actually looking for scientific proof that directional atherectomy works.

Lesions could have multiple locations. There may have been an 18cm lesion in the superficial femoral artery (SFA), followed by a 15cm lesion starting in the popliteal and working through the tibial plateau, and then, for a CLI patient, a surrogate lesion below the knee, perhaps a solitary outflow of a tibial lesion of 9cm. Each individual lesion counted on its own to the lesion subset; the patient, obviously, was one patient. We had patients with 40 to 50cm of treated overall lesion length. The trial stipulated how lesions were to be considered separate. Tandem lesions, for example, in the SFA, required longer than 2cm separating the two lesions, and below the knee, it was required that one centimeter be separating two lesions. 

DEFINITIVE had an all-comers trial design, so the only exclusion criteria were severe calcification (which was tested in another trial called DEFINITIVE CALCIUM), in-stent restenosis, since it is still considered off-label use for directional atherectomy, and aneurysmal dilatation of the target lesion or target vessel at the site of one of the lesions. Angiographic and sonographic core lab oversight were part of the entire trial. DEFINITIVE LE is the largest trial to date with sonographic core lab adjudication using directional atherectomy.

DEFINITIVE LE showed an overall 78% primary patency at 12 months, regardless of anatomic location. We also pre-specified the diabetic group, because there was a signal, early on, that diabetic patients would do just as well as non-diabetics, and in fact, this was proven to be true. Primary patency was at 78% for diabetics versus 77% for non-diabetics across all anatomic beds. In the claudicant group, for the SFA alone, the primary patency in the shortest lesions (<4cm) was around 80% and 83%, in the moderate (4-10cm) lesions and in the longer lesions (>10cm), it was about 65%, with lesion lengths from 6.5 up to 15cm on the longest lesions. The critical limb group had a limb salvage rate of 95% at one year. For the diabetic and non-diabetic CLI patients and gender, the primary patency was 66% female versus 69% male (P=NS), compared with around 80% for the non-diabetic female and 74% for the non-diabetic male. There is no clear difference in the impact of diabetes when it comes to primary patency in the CLI group with directional atherectomy and gender, and that is an important take-home message.  

Outcomes for the entire study cohort were remarkably robust. The treatment durability and primary patency rates of directional atherectomy ranked up there with all the stent trials that have come before DEFINITIVE. As a disclaimer, there was a bailout percutaneous transluminal angioplasty rate that occurred in over 40% of the patients with a stent rate of only 3.2%, so it is a remarkably consistent atherectomy followed by angioplasty cohort, whether a claudicant or critical limb ischemia patient.

How did patients do once results were divided by gender?

Women are generally smaller than men, and can have smaller vessels with more diffuse disease and more calcification than men. At VEITH, I presented a subgroup analysis that was not pre specified, but we wanted to look at the overall outcome by gender along with a variety of characteristics by gender. Demographics showed that the women were slightly older than the men, at about 72 versus 69 years old, and that had a statistically significant P value. The number of diabetics had a trend toward being worse for men, and current smokers numbered more men than women. Women’s reference vessel diameter was much smaller compared with men, by about half a millimeter, with a statistically significant difference. Baseline stenosis was in favor of women versus men, at 72 versus 79%. Lesion length was exactly the same between both groups. Outcome by gender showed no difference in primary patency at 12 months in both the claudicant and the critical limb ischemia groups (overall patency was 78% in the entire cohort). In the claudicant group, for women versus men, primary patency was 76 versus 78%, with a non-significant P value. In the critical limb patients, even though our primary metric was amputation-free survival, we still did an analysis of primary patency, and it was 72% for women versus 70% for men, a wash between the genders. Men and women didn’t pull away from each other in any one of these cohorts in terms of outcomes. 

The limb salvage rate was incredibly ubiquitous between both groups, and the changes in Rutherford-Baker classification were better for both men and women, with the women in the CLI group having the highest jump in improvement in Rutherford-Baker in compared to their male CLI counterparts. In the grand context, despite women being limited by being older and having smaller reference vessels, having less anatomic disease by a few points, but with the same lesion length as men, these two groups still came out exactly the same in primary patency. Furthermore, it was no different whether the patient had claudication or critical limb ischemia.

This trial should prove reassuring to anyone hesitant about using directional atherectomy in women because of their smaller vessels.

It is incredibly reassuring and I think the hesitation is two-fold. First, people have to become facile with the technology: they have to understand it and use it well. DEFINITIVE proved that a good, experienced operator can provide a very open artery with a large luminal gain for the best outcome in their patient population. The second point is that directional atherectomy also has to be done well in regards to the time and cost it takes to do it. It is a capital expense, a higher-priced device to effectively debulk a lesion and go down the road of leaving nothing behind. 

There is significant interest from operators treating the SFA and CLI regarding the use of debulking and/or using a drug-coated balloon as a way to leave no endoprosthesis behind. What’s old is new again. Plain old balloon angioplasty was used way back when; now we are studying atherectomy with adjunctive angioplasty or angioplasty alone with drug-coated balloons. The idea of leaving behind no endoprosthesis seems to be the best choice, because the environment of the SFA is so inhospitable. So if the leave nothing behind paradigm is true then the upfront costs of this approach must then be proven in the long-term beneficial with regards to outcomes but also costs.  

What about the use of distal protection in DEFINITIVE LE?

Distal embolic protection was used in 23% of the 800 patients, in around 200 treated lesions. In the group that did not get distal protection, there were a similar number of distal emboli compared with those that did get distal protection, so distal protection in and of itself did not lessen the occurance of distal emboli  in terms of protecting the lower extremity. The overall event rate of distal embolization requiring some form of therapy was about 1.6% in the entire cohort, or about 20 overall events.

Can you tell us about the other DEFINITIVE trials? 

DEFINITIVE CALCIUM has been completed and published.² This trial looked at a device that chips away calcium called the RockHawk (Covidien) married to a distal protection device. As a result of this trial, Covidien’s SpiderFX embolic protection device received an indication from the FDA for use in the periphery outside of carotid use, and it is presently the only FDA-approved filter for the periphery.

DEFINITIVE AR is a European pilot study that was presented at VIVA 2014 by Thomas Zeller.³ It takes DEFINITIVE LE to the next level, looking at directional atherectomy followed by a drug-coated balloon for lesion lengths up to 15cm, compared with drug-coated balloon alone. Results were evaluated by an angiographic endpoint, not a sonographic endpoint, meaning that operators took patients back to the lab at 12 months to look at their lesion(s). Directional atherectomy plus drug-coated balloon had a near 91% primary patency in the most complex lesions, 10cm and longer, compared with about 70% primary patency angiographic rate in the drug-coated balloon alone arm. This was a pilot study trying to find a signal and the 12-month primary patency rate may be a very important signal requiring further study with a larger trial. It is very timely. The idea of leaving nothing behind in the infra-popliteal segment and SFA seems ripe for the time. Leaving no endoprosthesis behind makes sense, because failure, whether it is from atherectomy or a stent, is restenosis. Restenosis means you have to retreat. If you ask a hundred operators what device they want to use in order to treat a patient, there will be about 1000 different answers, but if you ask them what kind of restenosis they would rather treat, de novo or in-stent restenosis, you would be hard pressed to find one person who loves treating in-stent restenosis, because it always comes back. So the idea of leaving nothing behind in the SFA is really attractive. 

Any final thoughts?

DEFINITIVE LE is a remarkable study. It wasn’t a trial looking for indications, but for a signal that superseded the indication for the device, which was already in place. I also want to emphasize that the data from this trial cannot be expanded into a class effect. There are many other atherectomy catheters in existence, but the study outcomes are specific to directional atherectomy alone. DEFINITIVE reveals the benefits of directional atherectomy, not atherectomy in general. 

References

1. McKinsey JF, Zeller T, Rocha-Singh KJ, Jaff MR, Garcia LA; DEFINITIVE LE Investigators. Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study. JACC Cardiovasc Interv. 2014 Aug; 7(8): 923-933. doi: 10.1016/j.jcin.2014.05.006.
2. Roberts D, Niazi K, Miller W, Krishnan P, Gammon R, Schreiber T, Shammas NW, Clair D; DEFINITIVE Ca++ Investigators. Effective endovascular treatment of calcified femoropopliteal disease with directional atherectomy and distal embolic protection: Final results of the DEFINITIVE Ca(++) trial. Catheter Cardiovasc Interv. 2014 Aug 1; 84(2): 236-244. doi: 10.1002/ccd.25384.
3. Covidien Announces 12-Month DEFINITIVE AR Results at VIVA 2014. Available online at https://www.covidien.com/news/phoenix.zhtml?c=216712&p =irol-newsArticle&ID=1985578. Accessed January 19, 2015.