In recent years, drug-coated balloon catheters (DCBs) have emerged as one of the fastest growing segments of the peripheral artery disease (PAD) market, driven by an aging population, improving reimbursement rates and a growing body of clinical evidence. DCBs have been in use in Europe since 2009, with products such as Boston Scientific Corp.’s Ranger, Cardionovum’sLegflow, Eurocor GMBH’s Freeway, Bayer AG’s Cotavance and Medtronic PLC’s IN.PACT vying with CR Bard Inc.’s Lutonix for market share. Now the US is starting to enjoy the benefits DCBs can bring as they increasingly gain FDA approval. From small beginnings, the market for DCBs in the US could be worth almost $1 billion by the end of the decade, according to some estimates. (SeeAlso see "Peripheral Artery Disease: Treatments And Diagnostics Poised For Growth" - Medtech Insight, 14 August, 2014.andAlso see "Drug-Coated Balloons Fuel Multibillion-Dollar Hopes" - Medtech Insight, 30 January, 2013..)

The growing use of DCBs is a response to the relatively high restenosis rate after conventional angioplasty procedures, usually caused by growth of neointimal tissue at the site of the procedure. In coronary angioplasty, this problem has largely been overcome by the use of drug-eluting stents, which release an antiproliferative drug to inhibit neointimal formation.

However, drug-eluting stents are used much less in peripheral angioplasty procedures, principally because of a relatively high rate of stent fracture (probably associated with greater mechanical stress on peripheral stents). This may result in such undesirable complications as thrombosis, perforation or restenosis of the vessel, or migration of the stent and resultant morbidity and mortality. At the same time, the effectiveness of DCBs in preventing restenosis in coronary procedures has been shown in studies such as the PACCOCATH I and II and the PEPCAD trials, and in peripheral vessels by the FemPac trial, the results of which were published as long ago as 2008.

The first company to win FDA approval to market a DCB for the treatment of PAD was CR Bard, in October 2014. The landmark approval of the Lutonix 035 catheter authorized Bard to market the product for use in percutaneous transluminal angioplasty of de novo or restenotic lesions up to 150 mm in length in native superficial femoral or popliteal arteries. The Lutonix catheter incorporates the GeoAlign Marking System that serves as a simple-to-use, non-radiopaque ruler on the catheter shaft: although it does not replace fluoroscopy, the GeoAlign system is designed to facilitate repeatable catheter alignment at the lesion and increase procedure efficiency by minimizing fluoroscopy exposure.

Bard did not have the market to itself for very long, however. In January 2015 Medtronic announced that the FDA had approved its IN.PACT Admiral DCB for virtually identical indications as the Bard device (it was actually approved on December 30, 2014). Like Bard’s Lutonix, the IN.PACT Admiral catheter is coated with the antiproliferative drug paclitaxel. In addition, both products are the subject of FDA-mandated extended follow-up studies. (SeeAlso see "Let The U.S. Drug-Coated Balloon Battle Begin" - Medtech Insight, 5 January, 2015..)

The Lutonix approval was based on three clinical studies. The pivotal LEVANT 2 study, carried out at 54 sites across the US and Europe, involved 476 participants randomly assigned to be treated with the Lutonix DCB or conventional balloon angioplasty. "Intention to treat" analysis showed that 65.2% of Lutonix patients retained primary patency of the treated vessel one year after the procedure, compared with 52.6% of patients who received conventional angioplasty. Lutonix patients were also more likely to be free of a “major safety event” (84% vs. 79%).

Secondly, in a multicenter European trial, 101 patients were randomly allocated to receive Lutonix DCB or conventional balloon angioplasty: after six months, only 28.2% of participants treated with the Lutonix DCB required additional treatment compared with 51.4% of patients in the comparison group.

The third Lutonix trial was a single-arm safety study involving 657 patients in Europe and the US: results available at the time of the approval showed no unanticipated treatment-related adverse events.

The basis of the IN.PACT approval was the prospective, single-blinded IN.PACT SFA (superficial femoral artery) trial, in which 331 patients with intermittent claudication and/or popliteal artery disease were randomly assigned to receive treatment with IN.PACT Admiral or traditional percutaneous transluminal angioplasty (PTA). The rate of clinically driven target lesion revascularization was 2.4% in the IN.PACT arm compared with 20.6% in the PTA arm.

Apart from Bard and Medtronic, a number of other companies are developing DCBs for the PAD market in the US, including Boston Scientific, Spectranetics Corp.and SurModics Inc.Boston’s Ranger balloon catheter is already marketed in the EU, but still appears to be some distance from US approval. In February 2015, Boston signed up with Bard as US distributor of the Lutonix catheter in a move widely seen as giving it a foothold in the US market before its own product is approved by the FDA, thus avoiding having to be third or fourth to market. For Bard the deal provides additional marketing "clout" in its battle with Medtronic for market supremacy. (See[A#01150216004].)

Spectranetics acquired its DCB product, Stellarex, from Covidien PLC as part of an antitrust settlement when Covidien merged with Medtronic at the beginning of 2015.[See Deal] Like Boston’s product, Stellarex has been approved in the EU: the company’s 2014 annual report says it anticipates US approval and commercialization during 2017. There are four active above-the-knee clinical trials of Stellarex currently underway (ILLUMENATE trials), in addition to a completed first-in-human trial. Meanwhile, Eden Prairie, MN-based SurModics recently obtained FDA approval for clinical trials of its SurVeil DCB, which are expected to commence shortly. SurModics is traditionally a supplier of surface modification technologies for medical devices, but last November it acquired the Irish company Creagh Medical Ltd., a manufacturer of angioplasty balloon catheters, to help accelerate its transition into a whole-product solutions provider. (See Exhibit 1.)

Exhibit 1

Selected Current And Emerging Drug-Coated Balloon Catheters

Company publications

Device	Company	Coating	FDA Approved?
Lutonix 035	CR Bard	Paclitaxel	Yes
IN.PACT Admiral	Medtronic	Paclitaxel	Yes
Ranger	Boston Scientific	Paclitaxel	No
Stellarex	Spectranetics	Paclitaxel	No
SurVeil	SurModics	Paclitaxel	No

The year 2015 saw the publication of three major studies of peripheral DCBs: the LEVANT 2 and IN.PACT SFA trials already mentioned, and the THUNDER (Local Taxan with Short Time Contact for Reduction of Restenosis in Distal Arteries) trial. The THUNDER trial was actually the first study to investigate the treatment of femoropopliteal arteries with a paclitaxel-coated balloon, and involved 154 patients who were followed up for five years. Over that period, the cumulative number of patients needing target lesion revascularization remained significantly lower in the paclitaxel group than in the control group (21% vs. 56%). At the same time, no signs of drug-related local vessel abnormalities were detected.

What does all this mean in market terms? According to a recent note by analysts at Citi Research, the total number of US PAD interventional procedures involving the SFA, which stood at around 489,000 last year, will rise to about 504,000 this year and could reach 550,000 by 2019. Over the same period, the use of DCBs will increase from 26% of all SFA procedures this year to nearly 53% in 2019. This translates into a market worth $346.5 million in 2016 to $884.7 million in 2019, equivalent to a CAGR of 37%, as shown in Exhibit 2.

Exhibit 2

DCB Market Growth In SFA Procedures

Note: SFA = superficial femoral artery. Some figures have been rounded.

Citi Research estimates

At the JP Morgan Healthcare Conference in January 2016, CR Bard Chairman and CEO Timothy M. Ring told analysts that the short-term market opportunity for Lutonix had exceeded the company's initial expectations. However, Ring sees an even larger long-term opportunity for the technology. "We're pursuing the international expansion of Lutonix including studies in Japan and China. We're also pursuing expanded indications for use including in-stent restenosis, AV access and below-the-knee applications. We believe we're well positioned with a very safe and effective disruptive technology with a very large global market opportunity."

Medtronic is pursuing similar indications for the IN.PACT Admiral DCB and is moving quickly toward label expansion. In January 2016, the company announced that the IN.PACT had received CE marking for arteriovenous (AV) access to help maintain hemodialysis access in patients with end-stage renal disease.

In 2016, an improved reimbursement climate should help drive further adoption and market growth of DCBs in the US. In August 2015, the US Centers for Medicare and Medicaid Services (CMS) granted a New Technology Add-on Payment (NTAP) for these devices, which follows prior positive policy rulings in the outpatient setting. Under a policy finalized in the Medicare hospital inpatient prospective payment system, procedures in fiscal year 2016 that employ either the Lutonix or IN.PACT Admiral DCB will be reimbursed by up to an additional $1,035.72 from the standard payment for a peripheral artery percutaneous intervention. (SeeAlso see "Drug-Coated Balloons Net Medicare Inpatient Bonus Payments" - Medtech Insight, 4 August, 2015..)

New Stents For PAD

While DCBs have been grabbing the headlines, there has also been a stream of new products in other areas, too. The year 2015 saw the FDA accept premarket approval applications for two new self-expanding stents for treating PAD, plus a PMA supplement widening the indications of a stent that was hitherto approved for use only in patients with carotid artery stenosis.

In May 2015, the FDA approved Terumo Medical Corp.’s PMA for the Misago peripheral self-expanding stent system, which is indicated for improving luminal diameter in symptomatic patients with de novo or restenotic native lesions or occlusions of the SFA and/or proximal popliteal artery.

In addition to annual reporting on the safety and effectiveness of the device, the approval mandated an extension of the pivotal OSPREY clinical trial that formed the basis of the approval. The OSPREY Extended Follow-Up Study is a multicenter, single arm, prospective study designed to evaluate the long-term safety and effectiveness of the Misago stent. All surviving patients from the original OSPREY study are being followed up annually for three years: the primary endpoints of the study are freedom from clinically driven target lesion revascularization at 24 and 36 months post-procedure.

The Misago was not the first peripheral stent on the market, nor, indeed, the first self-expanding peripheral stent. (There are a number of differences between self-expanding and balloon-expanded stents, the main one being that self-expanding stents more closely follow the anatomy of the native vessel, which may have implications for long-term outcomes.) Other companies that market self-expanding peripheral stents include: Abbott Laboratories Inc.'s Abbott Vascular (Absolute Pro vascular self-expanding stent system), Boston Scientific (EPIC system), Cardinal Health Inc.'s Cordis Endovascular(PRECISE and S.M.A.R.T CONTROL systems), InSitu Technologies Inc. (XOLO system) and Medtronic (Complete SE stent system).

During the first half of this decade the market for lower-extremity stenting systems was growing with a CAGR of roughly 4.6%, according to Medtech Insight estimates, and was worth in the region of $595 million last year. Assuming growth continues at a similar rate, the market will be worth around $623 million in 2016 and could reach $780 million by 2020. (See Exhibit 3.)

Exhibit 3

Lower-Extremity Stent Market Growth, 2016–2020 ($ millions)

Note: Sales of lower-extremity stenting systems. Assumes CAGR of 4.6%.

Medtech Insight estimates

Meanwhile, in July 2015 the FDA approved Boston Scientific’s PMA for its Innova Vascular Self-Expanding Stent System. This device is indicated to improve luminal diameter in the treatment of symptomatic de novo or restenotic lesions in the native SFA and/or proximal popliteal artery with lesion lengths up to 190 mm. The basis of the approval was the SuperNOVA clinical study of stenting of the SFA and/or proximal popliteal artery performed in almost 300 patients in the US, Europe, Canada and Japan. The study met its primary and secondary safety endpoints but, although the observed patency for the co-primary effectiveness endpoints exceeded the established performance goal in absolute numbers, the lower confidence bounds did not, so the primary effectiveness objective was not met. Nevertheless, treatment with the Innova stent system did provide improvement in symptoms and quality of life, and the therapy showed a good safety profile and a positive benefit/risk ratio.

The Innova system has been marketed in the EU and certain other countries since 2011: there was a recall in 2012 because of partial deployment, following which the delivery system was modified, with no further incidents being reported.

A third recent development in the peripheral stent area was the granting of a PMA supplement for Covidien subsidiary ev3 Inc.’sProtégé GPS Carotid Stent System, which was originally approved in January 2007 for the treatment of patients who require percutaneous carotid revascularization and who are at high risk for adverse events from carotid endarterectomy. The supplement, approved in January 2015, extended the indication to include use in common and/or external iliac arteries.

Mechanical Atherectomy Devices

Another area that has seen the approval of new products for PAD over the past year or so is mechanical atherectomy. Mechanical atherectomy is a transcatheter technique that is used to remove or reduce atherosclerotic plaque from within stenosed vessels, rather than simply pushing the plaque into the vessel wall, as with angioplasty. It involves the use of a catheter with a powered cutting mechanism that either shears the plaque from specific areas into small pieces, which are aspirated back into the device (directional atherectomy), or abrades the plaque into small particles, which are then carried away in the bloodstream (orbital atherectomy, which can be applied to the entire length of the vessel).

Some 69,000 mechanical atherectomy procedures are expected to be carried out in the US this year, with the figure only rising to 72,000 by 2017, according to Medtech Insight estimates. One possible reason for the low uptake of mechanical atherectomy compared with balloon angioplasty may be a dearth of evidence to support its use. A recent survey by the Cochrane Peripheral Vascular Diseases Group analyzed four separate trials that compared atherectomy with established treatments. In no case was the study deemed to be properly powered or the assessors blinded to the procedures, resulting in a high perceived risk of reporting bias. The survey's authors concluded that evidence in support of atherectomy as an alternative to angioplasty in maintaining patency was of poor quality, and recommended that properly powered trials be carried out.

Leading companies in the atherectomy sector include Boston Scientific, whose Rotablator rotational atherectomy systemincludes catheters featuring exchangeable advancers and diamond-coated burs, a console for monitoring bur rotation speed and procedure time, and other ancillary items; Cardiovascular Systems Inc., with its Diamondback 360, Predator 360 and Stealth 360 systems, which have an orbital action and create a smooth surface within the treated vessel; Covidien/Medtronic, probably the largest player in the sector, with the SilverHawk and more recent TurboHawk directional systems; and Bayer with the Jetstream arthrectomy system.

In April 2015, Medtronic launched the HawkOne Directional Atherectomy System in the US, following the receipt of 510(k) approval the previous October on the basis of its substantial equivalence to Covidien’s earlier TurboHawk system. The HawkOne incorporates a small cutting assembly in its tip with a rotating inner blade contained within a tubular housing, and is indicated for use in the peripheral vasculature, specifically in conjunction with the SpiderFX Embolic Protection Device (which effectively captures and removes debris that becomes dislodged during an interventional procedure) for use in the treatment of severely calcified lesions. Medtronic notes that calcium in atherosclerotic plaque is “a prevalent real-world treatment challenge” that is often linked to lower procedural success and poorer long-term outcomes. The technology incorporated into the HawkOne allows calcified lesions to be treated more predictably, it says.

Development of the HawkOne was based on physician feedback and collaboration. Mark Fugate, MD, of University Surgical Associates in Chattanooga, TN, the first surgeon to use the HawkOne in the US, said at the device’s launch that its improved ability to cross atherosclerotic plaque and cut through calcified deposits means that it can be used to treat practically any patient with PAD, irrespective of lesion morphology.

Last November, Medtronic announced it had begun the REALITY Study (DiRectional AthErectomy + Drug-coAted BaLloon to Treat Long, Calcified FemoropopliTeal ArterY Stenoses) to evaluate the effectiveness of directional atherectomy combined with IN.PACT Admiral DCB treatment in patients with symptomatic PAD in long, calcified lesions in the SFA and/or popliteal artery. The announcement followed the publication of promising results from the DEFINITIVE AR pilot study of the effectiveness of directional atherectomy prior to DCB use in PAD patients.

Cardiovascular Systems is also investigating the use of mechanical atherectomy in combination with a DCB. At the end of last October it announced that the first two patients had been enrolled in its OPTIMIZE, peripheral Orbital Atherectomy System (OAS) study. The study, which is taking place in Europe, will evaluate the short- and long-term outcomes of orbital atherectomy with adjunctive DCB angioplasty versus DCB angioplasty alone for the treatment of PAD. Specifically, the study will look at patients with calcified below-the-knee lesions.

Earlier last year, Cardiovascular Systems received 510(k) clearance to market its new 4 French (4F) 1.25 Solid Diamondback 360 Peripheral Orbital Atherectomy System for the treatment of PAD, using the company’s new 145-cm long 1.25-mm Diamondback 360 Solid Crown (4F sheath compatible) and the modified 1.25-mm Diamondback 360 Micro Crown (4F sheath compatible). The approval complemented the existing approval of the company’s 60-cm peripheral devices and expanded the ability of physicians to treat PAD below the knee through small access sites in the groin (or to treat the upper leg from foot access sites).

Diagnostic Products

At the same time that new therapeutic products for PAD have reached the market, so too have new diagnostic products. In August 2015, Semler Scientific Inc. commercially launched its QuantaFlo plethysmographic PAD diagnostic system (510(k) approval for QuantaFlo, which is predicated on the company’s earlier FloChec device, was granted in March 2015).

Semler, an emerging medical risk-assessment company based in Portland, OR, is engaged in the development and commercialization of products that identify the risk profile of medical patients, thus allowing health care providers to capture full reimbursement potential for their services. So far, its only FDA-approved products are the FloChec and QuantaFlo devices.

QuantaFlo aids in the diagnosis of PAD by measuring blood volume changes in the brachial, posterior tibial and anterior tibial/dorsal pedis arterial distributions. A sensor resembling a pulse oximeter is placed on each upper and lower extremity: the sensor uses changes in the reflection of emitted infrared light to detect changes in arterial blood volume. From these signals proprietary software calculates a result that is predictive of PAD. In addition, the system provides hard-copy waveforms as part of its report, which may be viewed on the system display, printed and/or saved.

Market Outlook

Although there is some evidence of a slowdown in the number of coronary revascularization procedures carried out each year, the number of peripheral procedures continues to show consistent year-on-year growth. This development is being driven by a number of factors, including changes in patient demographics and the continued improvements in outcomes resulting from more effective diagnostic and therapeutic procedures.

For example, although DCBs have only been available in the US for treating PAD for a little over a year, they reportedly account for a growing proportion of interventional cardiovascular procedures. Both the products available so far are based on the slow release of paclitaxel to inhibit neointimal regrowth: research is currently underway to develop systems that will offer a higher tissue concentration of antiproliferative drug over a longer period of time than the currently available products.

As mentioned earlier, the use of a DCB in conjunction with atherectomy, particularly in the SFA is growing. Lesions in the SFA tend to be long and are more likely to be calcified, which makes treatment difficult. The use of atherectomy before the insertion of a stent has improved outcomes in this situation, although it is still prone to in-stent restenosis. Debulking of the lesion prior to DCB deployment removes an effective barrier to homogenous drug uptake throughout the lesion. So far, clinical experience with this treatment combination is limited, although the results so far are promising.

Bioabsorbable Drug-Eluting Stents

The other technique generating some excitement within endovascular circles is the use of bioabsorbable drug-eluting stents. There are two types of bioabsorbable stents: those composed purely of a bioabsorbable material, such as poly-L-lactic acid or polyglycolic acid, and those that have a metallic core coated with a bioabsorbable layer (sometimes called partially bioresorbable stents). Their claimed advantage over "traditional" drug-eluting stents is that long-term exposure to the polymer (which remains after the antiproliferative drug has been released) may cause inflammation, which can delay healing and lead to complications. Clearly, if the polymer is absorbed, this possibility does not arise.

Last October, Boston Scientific’s Synergy became the first bioabsorbable polymer drug-eluting stent system to be approved in the US for use in coronary vessels (although the product received CE marking in the EU in 2012). But while there is a considerable body of evidence to support the use of bioabsorbable stents in the coronary setting, there is much less experience of their use in peripheral vessels and the clinical data available to date are inconclusive. Furthermore, concerns have been expressed on theoretical grounds about the applicability of fully bioabsorbable stents to the peripheral situation, particularly in regard to the greater mechanical stress they must endure compared with coronary stents.

A handful of other companies appear to be investigating the use of bioabsorbable drug-eluting stents in the treatment of coronary disease, including Abbott Vascular, Biotronik SE & Co. KG, Elixir Medical Corp. and Arterial Remodeling Technologies, but the only one that appears to be looking at peripheral applications of this technology is Abbott, which is collaborating with the National Taiwan University Hospital in a study of the feasibility and safety of bioabsorbable everolimus-eluting stents in patients with erectile dysfunction and concomitant internal pudendal artery stenoses.

Looking even further ahead, genetic studies have shown that, not only are certain PAD risk factors such as dyslipidemia heritable, but also that predisposition to PAD may be independently influenced by genetic variants. This would open the door to a whole new generation of diagnostic and therapeutic products.

Market Update: Growth And Opportunities In Peripheral Artery Disease

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