Direct Deposit: PAD Stents & Balloons Deliver Drugs Where They Count

Interventional cardiologists, vascular surgeons and others in the U.S. now have a cornucopia of treatments for patients with peripheral artery disease (PAD), thanks to recent FDA approvals for drug-eluting stents and drug-coated balloons. But using these devices is no slam-dunk. Questions about patients and payments make some physicians hesitant to incorporate them into practice.

Staggering stats

PAD has proliferated over the years in both wealthy and lower-income countries. Globally, the prevalence of PAD increased 25 percent between 2000 and 2010, with an estimated 202 million people living with the disease. In the U.S., more than 8.5 million adults in their fourth decade or beyond have PAD, and the disease claimed more than 62,000 lives in 2011.

The marketplace has kept pace with the growing demand for treatments, particularly for lower-extremity PAD. Device-based approaches for patients with PAD have expanded beyond atherectomy, conventional percutaneous transluminal balloon angioplasty (PTA) and bare-metal stents to self-expanding stents, vascular memetic implants, stent grafts and more. Now add to that the ability to deliver therapeutic drugs in this vascular bed, either through drug-eluting stents or drug-coated balloons.

“Obviously, the first step with anybody with PAD and intermittent claudication who doesn’t have critical limb ischemia is exercise therapy and medications and risk-factor reduction,” says Kenneth Rosenfield, MD, the section head for vascular medicine and intervention at Massachusetts General Hospital in Boston. “But if that doesn’t work, or if the patient feels disabled, or isn’t tolerating the medications well, or is not able to exercise or walk, then intervention is the next consideration. Once you start thinking about intervention, there is a wide array of tools in our armamentarium.”

In 2012, the FDA approved Cook’s Zilver PTX drug-eluting stent for use in the femoropopliteal artery in patients with PAD, making it the first drug-eluting stent to become available in the U.S. for this indication. The beauty of the device is its ability to deliver a dose of paclitaxel directly to the arterial wall to help prevent restenosis.

Then in October 2014, the agency gave the all-clear to Bard’s Lutonix drug-coated balloon for use in the superficial femoral artery (SFA) and the popliteal artery. This, too, was a first. Like the Zilver PTX, the Lutonix drug-coated balloon provided a concentrated hit of paclitaxel to arteries during the balloon inflation process but it did not leave a permanent implant. Less than three months later, the FDA approved another paclitaxel-coated balloon, Medtronic’s Admiral device, as a therapy for patients with atherosclerosis in the SFA or proximal popliteal artery.

But having these newer options doesn’t necessarily make treatment decisions easier. “Deciding amongst those is very challenging,” acknowledges Rosenfield, who served as the co-principal investigator of Bard’s pivotal LEVANT 2 (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) clinical trial. “We don’t have the comparative data to determine which therapy is better in many circumstances, so we do the best we can and people develop their preferences.”

Tested over time

Approval for the Zilver PTX was based in part on results of a randomized trial that compared the Zilver PTX with PTA, with provisional drug-eluting or bare-metal stenting in patients with acute PTA failure (Circ Cardiovasc Interv 2011;4[5]:495-504). The 12-month event-free survival rate in the drug-eluting stent group was 90.4 percent vs. 82.6 percent with PTA, with a wide spread in patency rates, at 83.1 percent vs. 32.8 percent, respectively. The drug-eluting stent also edged out the bare-metal stent at 12 months for patency and clinical benefit in the provisional group.

But for many physicians, the real test was how the intervention held up over the long term. “There were concerns that perhaps the benefit we saw at one year would not be durable, that the curves of patency between standard of care or PTA or bare-metal stents might come back and merge on the curve of drug-eluting stents, which had a higher patency,” recalls Michael Dake, MD, medical director of the catheterization and angiography laboratories at Stanford University School of Medicine and principal investigator of the Zilver PTX trial.

At five years, the drug-eluting stent not only appears to be holding its own but adding to its lead over the other two therapies, according to results presented by Dake at the 2014 Vascular Interventional Advances meeting in Las Vegas. Compared with the standard of care, the drug-eluting stent had a higher freedom from target lesion revascularization rate (83.1 percent vs. 67.6 percent); a higher patency rate (66.4 percent vs. 43.4 percent); and a higher clinical benefit, which included freedom from persistent or worsening claudication, rest pain, ulcer or tissue loss (79.8 percent vs. 59.3 percent). It jousted bare-metal stents, too, for target lesion revascularization (84.9 percent vs. 71.6 percent); patency (72.4 percent vs. 53 percent); and clinical benefit (81.8 percent vs. 63.8 percent). 

“We might assume, at best case, these curves might continue parallel out, but in point of fact, the curve for patency actually diverged,” Dake says. From one to five years, they found a 35 percent increase in benefit between standard of care and drug-eluting stents. “That is something that not necessarily would have been expected or anticipated. It recalibrates everyone’s thinking of what we can achieve and maybe expect to achieve in the future.”

Entering the no-stent zone

Drug-coated balloons offer an option to stenting in patients with lesions in areas of the SFA or popliteal artery that undergo a high degree of inflection, which may cause stents to fracture. PTA may give relief in these patients but high restenosis rates often make it more of a patch than a fix. 

“In areas where you really don’t want a stent, the drug-coated balloon seems a good compromise,” says Sahil Parikh, MD, a cardiologist at the University Hospitals Case Medical Center in Cleveland, director of the Experimental Interventional Cardiology Laboratory at the center’s Harrington-McLaughlin Heart & Vascular Institute and a LEVANT 2 investigator. “You will get the drug delivery and hopefully keep the artery open for a longer period of time without having to place a stent.”

The FDA approved the Lutonix drug-coated balloon after a review of safety and efficacy results from LEVANT 2, a prospective trial that randomized patients with occlusive disease in the femoropopliteal arteries to either treatment with a drug-coated balloon or standard PTA. The drug-coated balloon proved superior for efficacy, according to the premarket approval documents, and noninferior for safety. Primary patency, which included target lesion restenosis and target lesion revascularization, was 65.2 percent for the drug-coated balloon group and 52.6 percent for the control group at 12 months. The primary safety endpoint, a combination of freedom from perioperative death, index limb amputation, reintervention and index limb-related death, gave the balloon a slight edge, at 83.9 percent vs. 79 percent.

In January of this year the FDA allowed a second drug-coated balloon, Medtronic’s IN.PACT Admiral device, to enter the U.S. market based on 12-month findings from its pivotal trial. The study compared the paclitaxel-coated balloon with PTA as a treatment in the SFA and popliteal arteries for patients with PAD. The drug-coated balloon scored a victory on patency (82.2 percent vs. 52.4 percent), with a target lesion revascularization rate of 2.4 percent vs. 20.6 percent and it fared favorably on safety, too (Circulation, online Dec. 3, 2014). 

John Laird, MD, medical director of the University of California, Davis Vascular Center and a principal investigator in the IN.PACT SFA trial, says that based on research on other devices, their team expects longer-term patency rates to be maintained. “Once you get past that first year where there is that higher risk of restenosis, usually things settle down,” he offers.

The fact that drug-coated balloons don’t leave an implant behind makes them a welcome addition to physicians’ toolbox. “When stents fail, it can be a little more complicated to deal with that failed stent, whereas if the vessel restenoses after a drug-coated balloon, it is a relatively straightforward reintervention,” Laird says. “You don’t burn any bridges. You don’t leave any metal behind that could cause later problems. That is the attraction with this approach for a lot of people.”

New but necessary?

Physicians and their patients had been succeeding in the battle against PAD, even before the introduction of drug-eluting technologies in the U.S., at least among elderly patients. An analysis of Medicare claims between 1996 and 2011 determined that the rate of lower limb amputations fell 45 percent in the 15-year period, from 196 to 119 procedures per 100,000 patients (JAMA Surg 2015;150[1]:84-86). Toe amputations decreased slightly and above-the-knee and below-the knee amputations declined by 48 percent and 39 percent, respectively.

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According to their analysis, therapeutic endovascular interventions, which included angioplasty, stenting and atherectomy, picked up steam as well during that period—a lot of steam. They increased from 138 to 584 interventions per 100,000 patients. But the use of preventive measures also soared. Routine foot exams jumped from 40 to 68 per 100 diabetic patients and routine blood glucose testing rose from 41 to 72 per 100 patients.

“It is not just vascular care that is changing. There are a lot of other preventive measures that have changed at the same time,” Goodney says, citing statin therapy, more attentive wound care and improvements in diabetic care as examples. “Rather than any one element out of all those ingredients, it instead is more likely the whole soup. All of these things go together.”

Pouring more money into PAD treatments may not make a difference for patients, though. An analysis by Goodney’s team of SFA stenting practices between 2010 and 2012 found that adding items such as stent grafts, atherectomy or embolic protection devices facilitated technical success at an increased cost of about $4,500 but with little effect on patency (J Vasc Surg 2014;60[3]:825).

“I don’t think there are data just yet to reach the conclusion that the fancy new device or the really expensive new treatment option is a must-have,” Goodney says. “Rather, let’s make sure we engaged patients in a total system of care, where they get vascular care, podiatric care and diabetic care, to get the best results.”

Money matters

Costs and lack of comparative data may pose the biggest obstacles to the uptake of drug-eluting stents and drug-coated balloons. “It is not clear what is the best therapeutic strategy for patients with PAD,” says Parikh. As a member of the American College of Cardiology’s Peripheral Vascular Disease Section Leadership Council, he is aware of the challenges physicians face right now. “In Europe, where these devices have been approved for some time, there has been variable uptake because there isn’t a clear gold standard for therapy. Consequently what is driving practice more is reimbursement as opposed to clinical data because there is very little in the way of comparative effectiveness.” 

The Zilver PTX got a boost in 2013 when the Centers for Medicare & Medicaid Services (CMS) granted it a new technology add-on payment to help hospitals recover some of the additional cost of the device. The designation gave hospitals up to $1,705 in additional reimbursement from Medicare, at least for a few years.

In February of 2015, CMS approved supplemental reimbursement for the two drug-coated balloons in the outpatient but not inpatient setting. Medtronic announced that it expected CMS to make a decision on a similar add-on for inpatient use this summer. In the meantime, hospitals may have to shoulder steeply higher costs for drug-coated balloons over standard balloons in inpatient interventions, which may create headwinds.

“Some practitioners, particularly in private practice or in systems where the hospital controls purchasing, will have to really justify the use of a drug-coated balloon every time they ask for one,” he observes. “That could be an impediment to the introduction of these devices into the marketplace and to the patient.”

With few head-to-head comparisons, physicians trying to choose between new technologies, and particularly the drug-bearing options, have little to guide them. “In these first trials, it was important to prove the concept that these drug-coated balloons actually worked better than a regular balloon,” Laird says. “That now has been proven well in this trial [IN.PACT SFA] and other trials. The next logical question is, how does it stack up against the other commonly used therapies, meaning atherectomy maybe, or bare-metal stents, or drug-eluting stents? You just look at the trials, and it is comparing apples to oranges.”

One small, single-center study in Germany that compared drug-eluting stents and drug-coated balloons called it a tie (J Endovasc Ther 2014;21[3]:359-368) but it offered a glimmer rather than a beacon of light. And as yet the drug-coated balloons have not duked it out in a clinical trial.

“Which drug-coated balloon do you choose?” Rosenfield asked. “We don’t have any data to go on except for the results of the individual trials.”

BEST of all worlds

But that could change. Rosenfield and two other physicians in Boston are spearheading a clinical trial that compares endovascular therapy and open-surgery treatment in patients with critical limb ischemia (CLI). The BEST-CLI randomized clinical trial (Best Endovascular versus best Surgical Therapy in patients with CLI) will compare efficacy, functional outcomes and cost-effectiveness in patients with CLI in North America who are eligible for either type of treatment (Tech Vasc Interventional Rad 17:221-224). As a prospective, pragmatic and open-label study, it will allow all commercially available devices except for cryoplasty and all surgical bypass approaches.

“One of the features about the BEST-CLI trial is that it will incorporate new technologies,” Rosenfield says. “It is not going to be one where you start with generation X device and you don’t incorporate anything new as it develops.” The researchers deliberately designed the study to allow them to address drug-coated balloons, which were then poised for market entry in the U.S. “The hope is CMS will recognize the potential benefit of these devices and enhance reimbursement to enable us to offer these to our patients.”

Goodney anticipates that BEST-CLI will help physicians and PAD patients make informed decisions that reflect the needs and wishes of the patient and also conserve limited healthcare resources. “If we treat everybody with the most expensive treatment, we probably overspent; whereas if we don’t provide treatments that are necessary, then some people may end up losing limbs that might have been saved,” he says. “There is a lot in the balance. I look forward to this important research to provide clarity.”

Dake, who serves on the BEST-CLI executive committee, predicts there will be no one overarching approach for treating this complex disease. “We have an enhanced appreciation of the nuances of different types of disease that may respond relatively better or worse with different types of therapies,” he says, noting that the knowledge base has grown exponentially in the past decade and will continue to be refined. “Now it is making sure that we are taking advantage of all the different opportunities.”