This article is more than 5 years old. Information may no longer be current.
Drug-Coated Balloons Expand Treatment Options
Recent approvals represent advance for patients with peripheral artery disease.
Click Here to Manage Email Alerts
After years of development and use in other parts of the world, the first drug-coated balloons for the treatment of lower-extremity peripheral artery disease approved in the United States have heralded great enthusiasm.
The FDA announced approval of the Lutonix 035 Drug-Coated Balloon PTA Catheter (Bard/Lutonix) in October and the IN.PACT Admiral Drug-Coated Balloon (Medtronic) in January. Use of drug-coated balloons (DCBs) also has become more widespread in Europe. In early 2015, the Stellarex Drug-Coated Balloon (Covidien) received CE mark approval, the latest among several other similar devices approved there last year.
“DCBs have provided another option for improving outcomes for our patients,” Subhash Banerjee, MD, FACC, FSCAI, chief of the division of cardiology at VA North Texas Health Care System and associate professor of internal medicine at the University of Texas Southwestern Medical Center, Dallas, said in an interview.
Although the CMS does not yet reimburse at an expanded level for DCBs, uptake has been swift, according to experts interviewed by Cardiology Today’s Intervention.
Kenneth Rosenfield
“The advantage of DCBs is the potential to reduce the incidence of restenosis without having to leave anything behind, such as metal, by using the same simple technology that we use for straightforward plain old balloons,” said Kenneth Rosenfield, MD, FACC, FSCAI, section head of vascular medicine and intervention in the division of cardiology at Massachusetts General Hospital Institute for Heart, Vascular and Stroke Care. “That’s the holy grail — effectively treating a blocked artery and having a durable result without leaving any foreign material behind.”
Cover illustration © Lisa Clark
According to Rosenfield, although stents are effective immediately for reducing recoil and improving lumen diameter, a percentage develop restenosis. “When you develop restenosis with a prosthesis, it is difficult to treat in the superficial and femoropopliteal arteries,” he said.
A main reason for the rapid adoption of DCBs is the data from pivotal trials showing lower failure rates than those traditionally associated with other treatments, Banerjee said.
“If you recall the history of success with different technologies, we have had a failure rate or restenosis rate of about 26% with conventional balloon angioplasty, about 20% with atherectomy, about 14.5% with bare-metal stents and about 10% with drug-eluting stents,” he said. “But the pooled target lesion revascularization rates have been reported at about 7.5% for the Lutonix DCB and 2.4% for the IN.PACT Admiral DCB. So we expect their use to increase over time.”
Appropriate Patient Population
Currently, DCBs are primarily used in patients with claudication and lesions in the upper leg because most patients in clinical trials have had Rutherford categories 2 or 3 ischemia, experts told Cardiology Today’s Intervention. But as more research is done, the potential patient population might expand.
“The vast majority of patients with PAD should be potential candidates for DCBs,” Peter A. Schneider, MD, chief of vascular therapy at Kaiser Foundation Hospital, Honolulu, said in an interview. “DCBs are unproven in patients with tissue loss. In terms of lesions, most of the studies with DCBs made an effort to exclude patients who would require a stent, patients with severe calcification and patients with any specific thrombotic problems. So we don’t know if the DCBs will work in those groups. But that is a small minority of patients.”
Lesions in the superficial femoral and femoropopliteal arteries are the “most natural target at this point” for DCBs because that is where clinical trial results have been most favorable, said Banerjee, a member of the Cardiology Today’s Intervention Editorial Board.
“In the below-the-knee segment, there is room for improvement,” he said. “The IN.PACT DEEP study showed us that the same drug delivered to two different locations may lead to differential success.”
In that study, rates of clinically driven TLR were similar for patients with critical limb ischemia and infrapopliteal lesions assigned the IN.PACT Amphirion drug-eluting balloon (Medtronic) or percutaneous transluminal angioplasty (9.2% vs. 13.1%; P = .291), but the DEB was associated with a higher rate of amputation (8.8% vs. 3.6%; P = .08).
Use of DCBs in locations where it is considered risky to place a stent could increase, according to Rosenfield, who also is a member of the Cardiology Today’s Intervention Editorial Board.
“A good, lasting durable result without a metallic prosthesis is a potential advantage anywhere, but it is particularly an advantage in sites where stents might cause problems in the long term,” he said. “For example, sites of flexion where stents might be prone to fracture or where the forces of flexion might lead to more restenosis. Another site where DCBs might be favorable is the common femoral artery, which is thought to be a no-stent zone not only because there is flexion there, but because this is a site where we can access the arterial tree.”
DCBs “might be a stronger consideration in patients with smaller vessels in whom you might not want to place a stent, or in whom the odds of in-stent restenosis might be a little higher because of the size of the vessel,” Rosenfield said.
Early usage of DCBs in the United States has typically occurred after predilation with an uncoated balloon because that was the protocol in the LEVANT 2 study of the Lutonix DCB and the IN.PACT SFA trials of the IN.PACT Admiral DCB, Gary M. Ansel, MD, FACC, system medical chief for vascular at OhioHealth in Columbus, Ohio, told Cardiology Today’s Intervention. “We think that is an important part of the strategy because, so far, the data have been derived with predilation. The IN.PACT Global study will give us a better look at that because predilation was optional, but we are still waiting for those data. We are going to have to prove that it is effective without predilation because there is going to be some wiping off of the drug as you get to the blockage. We want to optimize that.”
Until there is more evidence and the details of the recently approved pass-through codes are made more clear in the United States, DCBs may not be the best option for complex lesions that may require a stent regardless of what balloon is used, said Ansel, a member of the Cardiology Today’s Intervention Editorial Board.
Gary M. Ansel
“Using more costly DCBs and then adding bare-metal stents may be more costly than using drug-eluting stents up front in the more complex lesions where multiple devices will be required,” he said. “Even in the IN.PACT Global data, where there are more complex lesions than in the pivotal trials, we are seeing stents put in about one in four treatments. We are trying to be as economical as we can be, especially until there is some expanded-level reimbursement from CMS, because right now using more than one DCB can hurt the hospital since expanded reimbursement isn’t there.”
Importance of Due Diligence
DCBs have been approved for use in Europe and other parts of the world for about 5 years, but it took longer for U.S. approval because of the level of clinical evidence and manufacturing quality required by the FDA, experts told Cardiology Today’s Intervention.
Banerjee cited three major reasons for the delayed appearance in the United States: “First, the results from all trials have not been consistent. Second, the selection of which drug and at what dose is beneficial and/or most effective has had to traverse a significant number of years and many trials to come to the formulation. Third, the exact concentration of the drug, the excipient which is most ideal, the best delivery tools and the lesions which are most effectively treated are all still slightly undefined. These three aspects have led to an intense scrutiny in the United States, and rightly so.”
Another factor, Schneider said, is that DCBs are a combination of a drug and a device, so more than one center at the FDA must be involved in analyzing applications.
Also, he said, the dosages of paclitaxel likely attracted extra scrutiny because they are higher than seen in products used to treat the coronary arteries.
“The drug dosage we are talking about is much higher than the drug dosage with the standard DCB or DES for the coronaries,” Schneider said. “That is because of the length of the artery being treated and the amount of drug that has to be placed on the balloon surface in order to have it reach a significant level in the tissues. Even though it is a well-known drug, it puts the FDA in a position where it has to do a little more due diligence.”
Options May Expand
Currently, U.S. interventional cardiologists have the approved Lutonix 035 DCB and IN.PACT Admiral DCB to choose from, but that is likely to change in the near future. Numerous other DCBs are on the market in other countries or in development.
According to a review article published in JACC: Cardiovascular Interventions by Banerjee and colleagues, other DCBs include Cotavance (Medrad), SeQuent Please (B. Braun Melsungen AG), Freeway (Eurocor), Pantera Lux (Biotronik), Protégé (Blue Medical), Elutax (Aachen Resonance), Wombat (Avidal Vascular) and Magic Touch (Concept Medical). In addition, Cook Medical, which markets Zilver PTX, the first FDA-approved DES indicated for treatment of PAD, markets the Advance 18 PTX DCB in Europe. Also, the Ranger and Agent DCBs (Boston Scientific) received CE marks last year. Aside from Magic Touch, which treats lesions with sirolimus, all others use paclitaxel.
Subhash Banerjee
“Different companies are trying out various formulations and strategies with different excipients and balloon structures,” Banerjee said. “That is why this area is still heterogeneous. We have to closely follow the results of currently ongoing studies of non-U.S. and upcoming devices that are soon to be introduced in the U.S. market.”
Schneider said an encouraging sign for future potential approvals is that “once the studies were done, the approval process came at a good rate.” He noted that the Lutonix DCB was approved less than a year after results of the LEVANT 2 study were presented at Transcatheter Cardiovascular Therapeutics in October 2013, and the IN.PACT Admiral was approved less than a year after results of the IN.PACT SFA were presented at the Charing Cross international symposium in April 2014.
Platform Choice
Choosing which DCB to use in a particular patient is not a simple task because the two FDA-approved DCBs are different in design and drug dose and there were major differences in their pivotal trials, so it is not simply a matter of comparing the trial data, experts said.
“In the absence of a head-to-head comparison, it is impossible to define whether one DCB is superior,” Rosenfield said. “My own suspicion is that based on hard evidence such as the presence of drug in the tissues, levels of drug in the tissues, ultrasound findings, etc, that the Lutonix and IN.PACT Admiral DCBs are probably equivalent. They both show that restenosis and late lumen loss are reduced, but neither is perfect. They are just another one of the tools in our armamentarium that we can use in the appropriate setting.”
Direct comparison based on existing evidence is not feasible because “the trial designs were different in fundamental ways that preclude direct head-to-head comparison,” Rosenfield said. “The results from the two trials were different, and if one looks on the surface of things one might say there may be a difference between these two DCB products. I don’t think the evidence is clear one way or the other in that regard because of the differences in technique, patient selection and blinding techniques in the trials.”
Ansel agreed. “It is hard to compare the two, so you have to consider what kind of lesions they looked at vs. what kind of lesions you’re looking at, and decide on your own,” he said. “We have to evaluate the things we can compare, such as restenosis data and patency data.”
Besides evaluating which balloon might be most appropriate for a certain patient, interventional cardiologists must also consider the best method of vessel preparation for each patient, Schneider said.
Although the instructions for use of both approved DCBs state that “the patient should have a predilation of the lesion using a plain balloon of a slightly smaller caliber, that, in my opinion, is a poor man’s way of doing vessel preparation,” he said.
Peter A. Schneider
“These lesions are so incredibly heterogeneous that it just doesn’t make sense that giving a balloon with a drug on it is going to work in the same way in all these different types of lesions. We need to have some type of method of making the lesions a little less heterogeneous, so the drug can work its best. My sense is that pretreatment of the lesion is going to be necessary. I can envision that in some patients with heavy calcification, debulking of heavily calcified lesions may be in order. For patients with occlusions that are heavily thrombus-laden, it makes a lot of sense to aggressively dilate an occlusion before getting to the point where you put medication in. For a lot of different types of garden-variety lesions, it is going to make sense to use some type of modified balloon approach to try to decrease the heterogeneity of all these different types of lesions and provide opportunities for the drug to be taken up into the wall readily, regardless of plaque type, thickness, calcification and other factors,” Schneider said.
Future Use
Given the enthusiasm for DCBs as a treatment for PAD, the technology will be tried in many patients, likely even those with more severe symptoms than those studied in the pivotal trials.
“Even before more clinical trials are done to illustrate DCB use in every single area, clinicians are going to put it to the test across a large variety of lesions and patient symptoms. So I definitely foresee its use in patients with more advanced symptoms, including critical limb ischemia,” Banerjee said. “I do believe we will see growing use in post-atherectomy treatments, where operators are looking for sustained patency after atherectomy. Post-atherectomy treatments for claudication and [critical limb ischemia] and patients with more advanced, Rutherford category 4 and 5 symptoms are two areas where there is a great need for improved patency of non–stent-based treatments, and where this technology could tested in the near future.”
What is known is that clinicians will have a plethora of new DCB data to consider in the next few years. Longer-term data from trials of existing technologies will emerge, as will data for different DCB technologies. Registry data from Europe and the United States will offer insight into the use and success in real-world settings. Cost-effectiveness data comparing DCBs with uncoated balloons are anticipated, as a favorable cost-effectiveness profile could significantly increase the use of DCBs.
“DCBs entering into the practice environment is a huge opportunity for all of us because most of the progress we have made in the past 15 years has been small incremental steps toward improved results,” Schneider said. “And this could be a big step, a chance to improve the absolute value of patency at 1 year in these patients.” – by Erik Swain