Vascular Closure Market Makes Room For Innovative Solutions

The $1 billion vascular closure market is primed for growth. It comes on the back of intensive R&D that has spawned a range of alternatives to the traditional manual/compression approach, giving SJM and the sector’s other heavyweights cause to look over their shoulders.

• Vascular closure devices fall into three categories: hemostasis pads, mechanical closure products that employ a clip or suture, and products that apply a sealant plug to the arteriotomy.
• Major progress in techniques for sealing arteries following percutaneous procedures has been made over the past two decades.
• More-targeted approaches are gradually replacing the still widely used technique of direct manual compression.
• The innovative technologies being developed are potentially faster and easier to use or require no pre-use assembly or separate deployment device, or are based on new biomaterials.

According to the American Heart Association, 1.3 million percutaneous coronary interventions such as angioplasty are carried out in the US each year, mainly via the femoral artery. Although such procedures are generally regarded as relatively safe and complication-free, this has not always been the case.

Percutaneous interventions involve the use of a trocar to puncture the artery and create a conduit through which a device such as an angiography catheter can be passed. Prior to the 1950s, complications caused by this procedure were relatively common.

That began to change in 1953 when a Swedish radiologist, Sven-Ivar Seldinger, introduced a new and improved technique. In the Seldinger procedure, the artery is punctured by a trocar as previously, but then a round-tipped guidewire is advanced through the lumen of the trocar, and the trocar itself withdrawn. A “sheath,” which is essentially a blunt cannula, is then advanced over the guidewire into the vessel. The guidewire is then also withdrawn, leaving just the sheath in position.

The inherent weakness is that when the sheath is withdrawn, there remains a puncture in the artery wall that must be sealed.

This basic procedure, with some minor variations, has now been successfully performed on millions of patients around the world. However, it still has one inherent weakness, which is that, at the end of the procedure when the sheath is withdrawn, there remains a puncture in the artery wall that must be sealed. Complications that can arise if this is not performed correctly include hematoma, bleeding, arteriovenous fistula, and pseudoaneurysm. The incidence of such complications has been put variously at between 1.5% and 9%, with as many as 40% of affected patients requiring surgical repair.

Manual/Compression Devices

For many years, sealing of the puncture in the arterial wall was achieved by the application of pressure, either manually or by means of a compression device, together with bed rest, thus allowing the normal clotting process to take its course.

A number of manufacturers offer devices designed to facilitate or replace manual compression, possibly the best known of which is St. Jude Medical Inc.’s FemoStop. This device employs an inflatable transparent dome fastened via a belt over the sheath insertion site. The latest iteration of this device, FemoStop Gold, features an integrated manometer that allows pressure to be adjusted based on patient status. Hemostasis may be facilitated via a hemostatic dressing. St. Jude also offers the RadiStop device for post-cannulation compression of the radial artery.

St. Jude currently holds the number one position in the highly competitive vascular closure device market, with companies like Abbott Laboratories Inc., Cordis Corp. (now part of Cardinal Health Inc.), and AccessClosure Inc. snapping at its heels. Furthermore, St. Jude says that it expects further companies to enter the market in coming years.

Other companies offering compression systems specifically include Advanced Vascular Dynamics. Its line includes: ComfortPress, designed to facilitate the application of manual pressure; the CompressAR System, which comprises an adjustable stand and a sterile, disposable CompressAR Disc that attaches to the arm of the stand; the ExpressAR System, a mobile compression device comprising a durable ExpressAR frame and a disposable Belt Kit assembly that allows the clinician to regulate pressure by turning a dial; and the RadAR adjustable strap for use on the radial artery. Vascular Solutions Inc. markets the Vasc Band, a clear plastic compression band for radial artery procedures: it features a single compression balloon that is inflated to maintain hemostasis. Vasc Band was introduced in 2013, and in 2014 achieved sales of $3.4 million.

The compression approach has a number of shortcomings: it occupies the time (up to half an hour) of medical personnel who could be doing other things, it is uncomfortable for the patient, and it may be of limited effectiveness in obese patients or those receiving anticoagulants.

A Brief Who’s Who

The sector’s major players and those committing R&D dollars to new solutions include:

Abbott – nitinol circumferential, flexible clips

AccessClosure – polyethylene glycol sealant

Advanced Vascular Dynamics – hemostatic pads

Biotronik – sodium alginate-based hemostatic pads

Cardiva Medical – collagen plug and intra-arterial anchor

Cordis (Cardinal Health) – bioabsorbable plugs

Essential Medical – anchor/plug sealing approach for large- and small-bore punctures

Marine Polymer Technologies – hemostatic pads using microalgae for accelerated platelet activation

Morris Innovative Research – Small Intestinal Submucosa extracellular patch that is gradually remodeled when surgically implanted

Perclose – suture-based mechanical closure system

Scion BioMedical – chitosan-based hemostatis

St. Jude Medical – manual and adjustable compression, sealant plugs

Vascular Closure Systems – bioabsorbable closure, nitinol clips

Vascular Solutions – compression band/balloons

The Quest For Alternatives

The early 1990s saw the emergence of alternative vascular closure devices that addressed many of these limitations, and the market for such devices is now thought to be worth in the region of $1 billion. Even so, the current market is estimated to be only 30% to 35% penetrated.

The newer types of devices can be broken down into three categories:

• External hemostatic devices that are placed over the puncture and that augment the physiological clotting mechanism.
• Devices that physically close the puncture with a clip or suture.
• Devices that deploy a sealant plug at the site of the puncture.

Hemostasis Pads

Advanced Vascular Dynamics’ offering in the hemostatic segment is the Celox Vascular Hemostatic Pad, which contains chitosan, a natural polysaccharide that works independently of the body’s physiological coagulation mechanisms to clot blood even when normal clotting is slow or impaired.

According to Advanced Vascular, in clinical trials the product was able quickly and reliably to stop even deep arterial bleeds. Furthermore, it can be used on femoral, radial, or brachial puncture sites utilizing introducer sheaths up to 16 French (16F) as its flexible backing allows better "feel" of the puncture site and placement on virtually any anatomy.

Scion BioMedical also offers a chitosan-based approach with its Clo-Sur P.A.D. products. The Clo-Sur P.A.D. is claimed to allow earlier ambulation compared with manual compression alone as well as to reduce vascular complication rates; using the Clo-Sur P.A.D., hemostasis may be achieved in approximately 10 minutes post-procedure. The Clo-SurPLUS P.A.D. builds on the chitosan platform by additionally incorporating an antimicrobial barrier to prevent bacterial colonization of the dressing.

Another major player in the vascular closure market, Abbott Vascular was formerly active in this segment with its Chito-Seal device, but the product was retired several years ago.

Marine Polymer Technologies Inc.sells the Syvek line of hemostatic pads that utilizes poly-N-acetyl glucosamine fibers derived from microalgae to accelerate platelet activation, erythrocyte aggregation, and vasoconstriction. As well as bringing about rapid control of bleeding, the Syvek line is suitable for use in patients taking anticoagulants including heparin, clopidogrel, and aspirin. The Syvek product line includes SyvekExcel, which is particularly effective for controlling bleeding in hemodialysis patients as well as those undergoing various catheterization procedures.

A similar product is Biotronik SE & Co. KG’s Neptune Pad, which is based on sodium alginate.

Product offerings from Vascular Solutions, meanwhile, include the company’s D-Stat 2 Dry, D-Stat Rad-Band, and D-Stat Dry Silver systems. The D-Stat 2 Dry topical hemostatic bandage incorporates thrombin and is used as an adjunct to manual compression. The D-Stat Rad-Band is used at radial artery sites and features a thrombin-containing pad attached to an easy-release clasp for single-operator pressure adjustment. It is designed to prevent ulnar artery compression and allow the patient a full range of motion at the wrist. The D-Stat Dry Silver product is a topical hemostatic pad containing thrombin and silver chloride to help prevent microbial colonization of the access site.

In 2014, overall sales of the D-Stat line of products were in the region of $20 million. The market for hemostat patches for the control of bleeding after femoral artery punctures is a mature one, according to Vascular Solutions, with multiple competitors and constant pricing pressures. The company also identifies two trends that are negatively affecting the demand for D-Stat patches: a movement toward greater use of radial artery as opposed to femoral artery procedures, and a slowdown in the growth of catheterization procedures in general.

Mechanical Closure Products

An altogether different approach is taken by Abbott Vascular with its StarClose vascular closure system, which is designed to deliver a small, circumferential, flexible clip that holds the cut surfaces of the femoral artery together. The clip is made of nitinol, a nickel and titanium alloy whose properties allow the clip to return to its original shape once released from the device. Application of the clip is a four-step process: the procedural sheath is replaced with the StarClose sheath, the precise location of the puncture is confirmed angiographically, the clip is delivered to the site, and then the clip is deployed to achieve hemostasis. The system features numbered windows for visual guidance in step completion and, because the clip is placed externally to the artery, there is nothing on the inside to cause potential blockages later.

The StarClose system gained FDA approval in 2005, although it had been in use in Europe since 2004. It is claimed to reduce times to hemostasis, ambulation, and dischargeability.

Other mechanical closure systems employ a suture rather than a clip. One of the earliest to be approved was Perclose Inc.’s Prostar XL Percutaneous Vascular Surgical (Prostar XL PVS) device, which uses two braided polyester sutures and four nitinol needles to help create a secure closure, and which has an integrated pre-dilator to facilitate device placement. The ProStar system was originally developed for use on larger punctures created during therapeutic procedures, whereas the related Techstar device was designed for use on smaller vessel punctures associated with diagnostic procedures. Perclose became part of Abbott Vascular in 1999.

The Prostar and Techstar devices feature needles that are deployed within the arterial lumen and directed out through the arterial wall. This approach was reversed in a subsequent product, the Closer, which deploys its needles outside of the artery and directs them inwards. More recent suture-mediated product developments include the Perclose A-T, intended for closure of 5F to 8F vascular access sites and which features simplified knot delivery with pre-tied knots, and the ProGlide system that shares a similar platform and is indicated for the closure of 5F to 21F femoral artery access sites.

In its financial reporting, Abbott does not split out individual products. However, vessel closure products, along with carotid stents and other peripheral products, make up the company’s endovascular segment, which had sales in 2014 worth $527 million (equivalent to 20.5% of the company’s total vascular products segment).

Sealant Plugs

The third group of closure devices comprises those that position a plug, gel, or some other type of sealant at the puncture site. These are sometimes held in place by a resorbable anchor that is placed in the artery lumen. The earliest such devices were based on a collagen plug that is deployed in the subcutaneous tissues over the arteriotomy, where it expands to close the wound. More recently, other materials such as polyethylene glycol or polyglycolic acid have been employed. Collagen plugs also work by accelerating the physiological clotting cascade.

The most widely used product in the sealant plug category is St. Jude’s Angio-Seal, which made its market debut some 18 years ago. The product was originally developed by the Dutch concern DSM Biomedical, but is exclusively licensed to and manufactured, marketed, and distributed by St. Jude. It comprises three resorbable components: a polymer anchor, a collagen plug, and a suture that are deployed in a rapid, three-step procedure. The resorbable polymer anchor and suture act within the artery as a pulley to position the collagen plug adjacent to the outside of the arterial wall. This results in rapid sealing of the puncture site and quick and efficient hemostasis. The latest version of the product is the Angio-Seal Evolution, which features automated collagen compaction, making it easier for the clinician to deploy the device.

Since its market introduction more than 22 million units of the Angio-Seal device have been sold. However, although sales volumes increased during 2014, the company reported an overall net sales decrease as a result of average selling prices declining in response to competitive pressures.

Cardiva Medical Inc.’s Vascade also employs a collagen plug and an intra-arterial anchor, although in this case the anchor is collapsible and is removed after placement of the plug. The device is placed via the existing procedural sheath. The anchor, in the form of a collapsible nitinol disc, is deployed and the sheath removed over the Vascade device. The disc is maneuvered against the intimal aspect of the vessel wall at the arteriotomy site, where it provides temporary hemostasis while simultaneously properly positioning the collagen plug in the tissue tract for release. Its location is verified fluoroscopically.

The collagen plug is then released by inserting a "key" into the sleeve of the device. The sleeve is retracted proximally to expose the plug in the tissue tract at the arteriotomy site. The device is then removed by collapsing the disc and stripping the collagen from the device shaft. Final hemostasis is achieved through the application of gentle pressure.

The Vascade system was approved by the FDA in January 2013 on the basis of the results of the RESPECT (Rapid Extravascular Sealing Via PercutanEous Collagen ImplanT) trial. In a total of 420 patients, time to hemostasis was 3 minutes for Vascade compared with 20 minutes for manual compression. Time to ambulation was 3.2 hours for Vascade versus 5.2 hours for manual compression. No major access site-related complications were recorded in either group, although the incidence of minor events was lower in the Vascade group (1.1% vs. 7%). Cardiva is a private company, and no Vascade sales data are available.

Companies offering vascular closure products based on non-collagen materials include AccessClosure and Cordis. AccessClosure was founded as a private company in 2002 and acquired by Cardinal Health in 2014: Cardinal acquired Cordis from Johnson & Johnson in spring 2015, consolidating its position in this segment of the market. [See Deal] (See (Also see "Cardinal Health Builds On Generic Device Strategy With Cordis Deal" - Medtech Insight, 2 Mar, 2015.).)

AccessClosure is responsible for the Mynx line of vascular closure devices that are currently sold in the US and increasingly in other countries. Mynx devices employ polyethylene glycol as the sealant: this material is delivered through the original procedural sheath and absorbs blood and other fluids, swelling to conform to the contours of the arteriotomy site, thus sealing it and preventing bleeding. It is absorbed within 30 days. In addition, the devices incorporate Grip Technology, which increases the volume of the sealant and increases adherence of the plug to the arteriotomy.

Following the endovascular procedure, temporary hemostasis is achieved by introduction of an intra-arterial balloon, followed immediately by delivery of the Mynx Grip sealant, which is positioned on the surface of the artery. The sealant is compressed, which accelerates expansion and adhesion to the vessel wall, the balloon is deflated, and the device removed. Platelets and blood cells collect inside the sealant’s porous matrix causing it to swell, thus providing a platform for natural vessel healing.

The original Mynx device was CE-marked January 2007 and received initial FDA approval later that year. The Mynx product family is now claimed to be the leading extravascular solution in the US and includes the MynxGrip, launched in 2012, and the new Mynx Ace, launched in 2013.

Cordis’ Exoseal vascular closure device was approved by the FDA in May 2011. It consists of a bioabsorbable plug made of polyglycolic acid (the same material used in resorbable sutures) and a plug delivery system. Like the Mynx device, the Exoseal system is deployed through the existing procedural sheath, which helps make it quick and easy to use, but unlike the Mynx device it incorporates two markers that provide the surgeon with visual targets to determine the location of the plug relative to the outside of the vascular wall, prior to initiating and deploying the plug. This visual feedback is also claimed to promote patient comfort by minimizing tugging and pulling during positioning.

US company Vascular Closure Systems Inc. is developing a bioabsorbable closure system that has undergone first-in-human clinical testing, with positive results so far. The FastSeal system requires no assembly prior to use, and no separate deployment device is needed to be inserted into the puncture site. Also, it does not require an expandable internal vessel support component to deploy the sealing element.

The system is designed to enable hemostasis within 60 seconds after the non-collagen sealing element has been deployed, and once the sealing element has been deployed, no external compression is required. The inner vessel section of the sealing element is absorbed within 14 days, with the remainder of the sealing element completely absorbed in less than 30 days.

Vascular Closure Systems is currently in the process of securing funding to complete the regulatory and clinical requirements to enable the commercialization of its vascular access closure technology. It expects to receive CE mark for the FastSeal system in the near future. It is also understood to be developing other types of closure devices, including a self-closing nitinol clip system designed for either temporary use or as a permanent implant.

Meanwhile privately held medical device company Essential Medical Inc. has developed two femoral artery closure devices for use following vascular access procedures. The MANTA device is designed to close large-bore punctures (10F–18F) following procedures such as transcatheter aortic valve replacement (TAVR), abdominal aortic aneurysm (AAA) repair, and balloon aortic valvuloplasty, all of which are among the fastest growing segments within interventional cardiology. The X-Seal device is designed for smaller-bore arterial punctures following procedures such as angiography, angioplasty, and stenting. Both devices employ the "anchor/plug" sealing approach using common absorbable biomaterials, with the added advantages of X-ray visibility and improved deployment control. The X-Seal device received CE mark approval last October.

Lastly, Morris Innovative Research Inc. has developed two vascular closure devices that do not fit well into the above classification. These are the CombiClose and ControlClose devices, in which an extracellular matrix closure patch is premounted onto the access sheath. This combines access and closure on the same device, with the potential for simplification of these two steps, the company claims.

The extracellular patch comprises SIS (Small Intestinal Submucosa), a new biomaterial that does not encapsulate when surgically implanted, but is gradually remodeled, leaving behind organized tissue. SIS is extracted from the intestine in a manner that removes all cells, but leaves the complex extracellular matrix intact and available for new cell ingrowth. The SIS device originally received Premarket Approval (PMA) from the FDA in 2007.

Market Leaders – But For How Long?

For the moment, St. Jude Medical and Abbott Vascular, closely followed by AccessClosure, continue to dominate the vascular closure market. But this could be about to change. As already discussed, the sector has seen considerable innovation over the past 20 years, and this level of innovation continues, with new entrants poised to enter the market, challenging the dominance of the big three.

This high level of innovation is also driving the growth in the value of the sector, with cardiologists in East Asia in particular reportedly keen to adopt new technologies. Additional factors include the aging of the population and an increase in the incidence of cardiovascular disease, leading to more investigatory procedures being carried out.

The upshot of all this? Growth in the region of 5% per annum is expected to continue in the next few years. On that basis, the $1 billion market this year will be worth about $1.05 billion in 2016 and almost $1.160 billion by 2018.

Although the market is currently dominated by companies that are major players in other sectors of the cardiovascular market, there are still opportunities aplenty for smaller, innovative companies to enter the market with newer devices that can offer benefits to patients and interventionists alike.