July 01, 2016
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Uncertainty Below the Knee

Experts discuss available data, future use of drug-coated balloons.

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Many patients with peripheral artery disease, especially those with critical limb ischemia, require revascularization in below-the-knee arteries. Available treatments, including percutaneous transluminal angioplasty, stenting and atherectomy, do not always produce optimal results, however.

Given the success of drug-coated balloons for treatment of PAD above the knee, many experts in the field are hopeful that DCBs can one day be a solution for occluded below-the-knee arteries. But the data are lacking: Only two randomized trials have tested a DCB vs. percutaneous transluminal angioplasty (PTA) in below-the-knee arteries, and the results were neutral to negative.

“If the technology is perfected, it would really change the way we look at CLI,” Mehdi Shishehbor, DO, MPH, PhD, director of endovascular services at Cleveland Clinic, told Cardiology Today’s Intervention. “If we can have technologies that allow better patency and better luminal gain at the time of the procedure, and we can deliver a higher volume of blood to the foot, we can then focus on faster wound healing, faster ambulation, possibly less cost and better quality of life in our patients.”

Mehdi Shishehbor

Current Usage Patterns

DCBs are not currently approved by the FDA for below-the-knee applications. The two DCBs currently on the U.S. market — Lutonix 035 (Bard) and IN.PACT Admiral (Medtronic) — are indicated for above-the-knee use only.

Uncertainty Below the Knee

Cover illustration © Lisa Clark

Below-the-knee lesions must be considered differently from above-the-knee lesions because the vessels are smaller, pedal blood flow is a major consideration, and patients may be more likely to have conditions such as diabetes, chronic kidney disease and end-stage renal disease, Shishehbor said. In fact, he said, as many as 70% to 80% of patients with diabetes may have some form of below-the-knee disease.

In the United States, “the use of DCBs below the knee is nonexistent, except in the setting of a clinical trial,” Kenneth Rosenfield, MD, MHCDS, FACC, FSCAI, section head of vascular medicine and intervention at Massachusetts General Hospital and president of the Society for Cardiovascular Angiography and Interventions, said in an interview. “The sizes of the balloons that are available are for above the knee, so for off-label use, the sizes go down to 4 mm, but that’s it.”

Nor are DCBs commonly used for below-the-knee interventions elsewhere in the world.

“The use of DCBs is different from country to country,” Thomas Zeller, MD, head physician in the department of angiology, Universitäts Herzzentrum, Bad Krozingen, Germany, told Cardiology Today’s Intervention. “Many Italian physicians still believe in a DCB indication in [below-the-knee] lesions, [but], in Germany, it has become uncommon as a result of a cut in reimbursement for this indication by the insurance companies due to a lack of efficacy data [for] this treatment.”

Marianne Brodmann, MD, substitute head of the clinical division of angiology, department of internal medicine, Medizinische Universtität Graz, Austria, told Cardiology Today’s Intervention that, in Austria, DCBs tend to be used below the knee only “in special patients who have already had procedures and are now coming back because they need reintervention.”

Marianne Brodmann

The first-line interventional treatment for below-the-knee lesions remains PTA. Rosenfield, a Cardiology Today’s Intervention Editorial Board member, said many interventionalists will also perform debulking, usually with rotational atherectomy devices, “but there is the concern about sending debris downstream. ... If [the lesion] is not overly calcified, then I like [laser atherectomy] because it gives you a good microchannel that you can use to debulk and then come in with balloon angioplasty afterward, in which you can get a good cosmetic result initially without so much downstream embolization issues.”

Some clinicians will also use coronary drug-eluting stents off-label below the knee, and “I actually think they work incredibly well,” Rosenfield said. “The issue with stents is that they’re expensive, although [atherectomy devices] are also fairly expensive. ... I’ve had many cases where I’ve done stents below the knee and patients come back a year later with recurrent problems, and it’s not the stent. ... The scaffolding of the stent and the drug elution of the stent may promote longer-term patency, but they’re not perfect.”

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Room for Improvement

Questions have arisen, however, as to whether the current treatments are optimal for patients with below-the-knee lesions, especially those with CLI.

A systematic review and meta-analysis of 52 studies of 6,769 patients with 9,399 below-the-knee lesions, published in May by Jihad A. Mustapha, MD, FACC, FSCAI, director of cardiovascular catheterization laboratories at Metro Health Hospital, Wyoming, Michigan, and colleagues in Circulation: Cardiovascular Interventions concluded that “contemporary studies of the use of [PTA] as primary treatment for patients with infrapopliteal artery disease reveal suboptimal procedural and 1-year clinical outcomes.”

Mustapha and colleagues reported a technical success rate of 91.1% (95% CI, 88.8-93). One-year outcomes were as follows: primary patency, 63.1% (95% CI, 57.3-68.6), repeat revascularization, 18.2% (95% CI, 14.5-22.6), major amputation, 14.9% (95% CI, 12.3-18) and all-cause mortality, 15.1% (95% CI, 12.8-17.7).

In an accompanying editorial, Shishehbor, a Cardiology Today’s Intervention Editorial Board member, and Tarak A. Hammad, MD, from the department of cardiovascular medicine, Heart and Vascular Institute, Cleveland Clinic, noted that “there is room for improvement despite the limited number of tools that are currently available for treating infrapopliteal disease.”

Shishehbor told Cardiology Today’s Intervention that “there is still an opportunity to make an impact and improve the patency of the tibial arteries beyond what’s available. This is going to require more sophisticated trials with endpoints beyond amputation-free survival ... such as time to wound healing, time to ambulation and patency.”

Table. Two Randomized Controlled Trials of DCB in Patients With CLI

Table. Two Randomized Controlled Trials of DCB in Patients With CLI

Available Data

The available data so far, however, do not support DCBs for improved outcomes below the knee. Both randomized controlled trials that have been published did not find DCBs superior to PTA for most endpoints.

In the IN.PACT DEEP trial, published in the Journal of the American College of Cardiology in 2014, Zeller and colleagues randomly assigned 358 patients with CLI to PTA or a drug-eluting balloon (DEB; IN.PACT Amphirion, Medtronic). The researchers reported no differences between the groups in the primary efficacy endpoints of clinically driven target lesion revascularization and late lumen loss at 12 months; the primary safety endpoint at 6 months was higher in the DEB group but met the noninferiority hypothesis; and there was a trend toward more major amputations in the DEB group (see Table).

In the BIOLUX P-II trial, published in JACC: Cardiovascular Interventions in 2015, Zeller and colleagues randomly assigned 72 patients with claudication or CLI and infrapopliteal artery lesions to PTA or a novel paclitaxel DEB (Passeo-18 LUX, Biotronik). While the primary safety endpoint, the primary performance endpoint and major amputations of the target extremity were all lower in the DEB group, none of the differences reached statistical significance (see Table).

“DCBs need to show better patency results as compared to [PTA],” Zeller told Cardiology Today’s Intervention. “As long as such an independently controlled study does not exist, there will be no increase in use of DCB below the knee.”

Kenneth Rosenfield

Rosenfield cautioned against extrapolating too much from the data.

“The numbers are small, and then all of the sudden, everybody’s jumping up and down over the results,” he said. “I think it’s a long-term view we need to hold here. We need to continue to iterate to come up with better devices. ... We will get to the goal line where [DCBs] will have a very important role below the knee.”

Technological Advancements Needed

While reactions to IN.PACT DEEP and BIOLUX P-II have varied, there is consensus that if DCBs are to become a viable option for below-the-knee intervention, advancements in the technology are required.

“There is a lot of improvement going on in a scientific way, but not in a commercialized way,” Brodmann said. “There are ... new drug technologies, such as using limus instead of paclitaxel and giving a dexamethasone injection into the vessel wall after treatment. Also, there is research into the combination of DCBs and different kinds of atherectomy, as well as different kinds of vessel preparation.”

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While little progress has been made in recent years, researchers now understand why the efforts have not borne fruit, and are working to address those issues, Shishehbor said.

“We believe there are a number of reasons why [past trials] have failed, including the fact that all of these balloons have used paclitaxel,” he said. “There are some data now that maybe sirolimus is a better agent than paclitaxel for the tibial vessel. There is also concern that there is extensive calcification in the tibial vessels, and that in order to be able to get the drug transmitted to the adventitia and the media, we need to deal with the calcium first. There is also an issue related to the excipient and some concerns about how the drug is transferred to the delivery balloon.”

In addition, Shishehbor said, better study designs are needed, because very few devices have been able to significantly impact endpoints such as amputation-free survival and major adverse limb events.

“But we may be able to impact other endpoints that are very relevant and very important to the patient such as time to wound healing, time to ambulation, cost, quality of life and pain control,” he said. “If we have devices that allow better patency and better luminal gain, we may be able to achieve those incremental endpoints that are also very important.”

Possible Future Role

In the meantime, vascular interventionalists are awaiting the results of a third randomized controlled trial, this one of the Lutonix 014 DCB (Bard) vs. PTA in up to 480 patients with stenosis or occlusion of below-the-knee arteries. Primary outcomes are freedom from all-cause death, above-ankle amputation or major reintervention at 30 days, freedom from above-ankle amputation at 12 months and primary patency at 12 months. Data on the primary outcomes could be available in 2017, according to the trial’s page on clinicaltrials.gov.

Thomas Zeller

“Currently, only Bard is running a study which actively enrolls patients with [a below-the-knee] DCB indication,” Zeller said. “Other companies are still hesitant because they still do not completely understand the challenge of DCB efficacy in [below-the-knee] vessels.”

It is important to press on with new development, because there are several patient populations who could benefit if DCB technology is ever perfected for use below the knee, experts said.

“For patients with [CLI], we do not have the best treatment options, particularly if ischemia is still an issue,” Brodmann said. “I also would say that patients who are claudicants ... with long lesions in below-the-knee arteries might profit from DCB treatment, as might patients at risk for limb amputation, because [they] are usually older and obese, and [if multiple reinterventions are required], renal function may be worse and you may not be able to do reintervention, and groin access may be difficult. ... If [treatment with DCB] works, we will know that we do not have to do a reintervention.”

Rosenfield agreed. “We’re still in process, and still have a lot to learn,” he said. “I firmly believe that DCBs will have a role below the knee and it will be an important role as they are above the knee and elsewhere. I remain very optimistic about this.” — by Erik Swain

Disclosures: Brodmann reports serving on advisory boards for Bard, Intact Vascular, Medtronic and Spectranetics. Rosenfield reports consulting for SurModics; serving on advisory boards for Abbott Vascular and Cardinal Health; and serving as a compensated board member for VIVA Physicians, a 501(c)3 organization. Shishehbor reports no relevant financial disclosures. Zeller reports consulting for or receiving honoraria from Alvimedica, Bard, Bayer HealthCare, Boston Scientific, Medtronic and Spectranetics.