BBI Contributing Editor

NEW ORLEANS The market for devices used in interventional radiology is one of the most diverse within the medical device industry. The market spans applications ranging from cancer therapy, treatment of vascular disorders, and orthopedic treatment devices to imaging and biopsy products. Interventional radiology addresses a wide range of diseases, many of which typically afflict the expanding elderly population, creating a strong underlying demand that is expected to grow rapidly over the next decade. The 30th annual scientific meeting of the Society of Interventional Radiology (SIR; Fairfax, Virginia), held here in early April, provided a forum for presentation of a wide range of diagnostic and therapeutic modalities from suppliers in the interventional radiology market.

Cancer is emerging as one of the most important diseases that can be treated by interventional radiology techniques, and clearly is a major and growing public health problem in the U.S. and most other developed countries. It is the second-leading cause of death in the U.S., based on the most recent data from the American Cancer Society (Atlanta). Trends in U.S. incidence for the major cancer types targeted by interventional radiology treatment are shown in Table 1 below. An additional group of target patients consists of patients with metastatic bone cancer, who can realize significant reductions in pain when treated with interventional radiology ablation techniques. Worldwide, the annual number of new cases for the cancer types listed in Table 1 ranges from two-fold to as much as 28-fold higher than for the U.S., with liver cancer having a much higher incidence rate worldwide than in the U.S.

Embolization therapy is another growth segment of the market, with interventional radiology providing a new, less invasive alternative to surgical treatment for conditions such as uterine fibroids and vascular aneurysms. Another growing application addressed at the SIR conference is treatment of spine disorders using minimally invasive techniques, a rapidly growing segment of the market that addresses a large and expanding patient population. New approaches for the management of stroke and other cerebrovascular disorders also were discussed, an important application that continues to prove challenging for any type of therapeutic modality.

Venous ablation, for treatment of varicose veins, was discussed in numerous sessions at the SIR gathering and represents a large, mostly untapped market opportunity. Other important segments within the interventional radiology market discussed at the conference include carotid stents, peripheral stents, endovascular grafts, vascular closure devices, vena caval filters, new imaging and guidance modalities, and biopsy devices.

Growing demand in oncology

Ablation therapy for cancer can use a number of interventional radiology modalities, including cryo-ablation, radiofrequency and microwave ablation, and chemical ablation coupled with embolization (chemo-embolization). Cryoablation is showing increasing promise for cancer treatment because of its effectiveness in rapidly ablating tissues, the ability to precisely control and visualize the treated regions, the wide range of tumor types that can be treated, and the minimal levels of pain associated with the technique.

Endocare (Irvine, California) is the leading supplier of cancer cryoablation devices with its Cryocare CS cryotherapy generator and probes. The Cryocare probes are priced at $1,000 each, and the generator unit is typically placed at no cost. Matthew Callstrom, MD, of the Mayo Clinic (Rochester, Minnesota), described use of cryoablation for treatment of metastatic bone tumors at the SIR conference. Some 40% of cancer patients develop bone metastasis, and 50% of those have poorly controlled pain due to bone metastases.

Other modalities for treatment of bone tumors are not optimal. Radiation, the most effective therapy, does not benefit 20% of patients who are treated, and 50% of the patients who show some reduction in pain have recurrent pain within six to 10 weeks. Most patients with metastatic bone cancer have already failed chemotherapy, and surgery is reserved only for patients with isolated disease who may be cured. Most patients with bone metastasis eventually fail treatment, leaving increased doses of narcotics as their only option, resulting in a reduced quality of life. Radiofrequency ablation is another treatment alternative, but six weeks are required in order for pain to be reduced following treatment, and the first 24 hours after therapy are often characterized by increased pain.

In contrast, as described by Callstrom, cryoablation using the Cryocare system provides immediate pain relief, with 54% of patients experiencing complete elimination of pain at some point, and 85% experiencing a drop of three or more points on a standardized pain scale.

As discussed by Gary Onik, MD, of Florida Hospital/Celebration Health (Celebration, Florida), cryo-ablation also is an effective therapy for prostate cancer. Onik has pioneered a technique called male lumpectomy for prostate cancer that provides a less-invasive option as compared to radical prostatectomy and involves focal cryoablation of identified lesions in the prostate gland, sparing normal prostate tissue. About 60% to 64% of prostate cancer patients are candidates for local lumpectomy based on a literature analysis performed by Onik. Cryoablation has been FDA-approved for use in prostate cancer treatment since 1999, and is the only approved treatment for failed radiotherapy in prostate cancer. Onik has achieved 10-year disease-specific survival rates of more than 98%, and has observed very few long-term failures, with some patients now disease free at 10 years post-treatment. In particular, 95% of patients who had not previously failed radiation therapy are disease free after cryoablation treatment at a mean follow-up of 3.5 years. About one-quarter of the patients treated by Onik are classified as medium- to high-risk.

In addition to its treatment effectiveness, cryoablation has the advantage of allowing retreatment if some tumor foci are missed on initial treatment, and adverse side effects are considerably reduced vs. surgical treatment. About 78% of cryotherapy patients in Onik's experience have maintained sexual function, vs. only 25% with surgery and 50% with radiotherapy or brachytherapy, and no incontinence has been observed in any of the cryotherapy patients.

The advantages of cryoablation for treatment of cancer and other diseases have driven sales of cryoablation products to significant levels, as exemplified by sales data from Endocare, shown in Table 2 below. Use of cryoablation in cancer treatment has expanded significantly as a result of the development of improved imaging methods that allow the ablation zone to be precisely visualized during the procedure by using CT to identify the ice ball created by the cryogenic probe, and due to the introduction of smaller insulated probes that allow precise localization of treatment.

Other types of ablation therapy delivered via interventional radiology techniques for cancer treatment include radio frequency ablation, using systems such as the CoolTip RF Ablation System from Valleylab (Boulder, Colorado), a unit of Tyco Healthcare (Mansfield, Massachusetts), and the Starburst probes and Rita Model 1500X RF generator from RITA Medical Systems (Mountain View, California); microwave ablation, using systems such as the VivaWave system from Vivant Medical (also Mountain View); and focused ultrasound, with the new InSightec system introduced by GE Healthcare (Waukesha, Wisconsin) at the SIR meeting, now FDA-approved for uterine fibroid therapy and under investigation for a variety of applications in oncology. Ablation therapy can be combined with other treatment modalities, and, unlike many other therapies, can be repeated as necessary if a tumor recurs.

At present, indications for use for devices such as the CoolTip and the RITA Starburst are mainly limited to treatment of non-operable liver tumors, where probes can be placed percutaneously to treat a tumor that would otherwise not be amenable to therapy. In such cases, improvements in survival of up to 50% have been achieved as compared to no additional therapy. But interventional radiologists are now studying additional applications of ablation therapy in lung cancer, breast cancer, and brain cancer. According to suppliers, penetration of the potential market for interventional ablation devices is only about 6% to 9% in the U.S., with RITA Medical claiming a 70% share and shipping 10,000 to 12,000 disposable RF needles annually priced at $1,000 to $2,000 each.

Microwave ablation is another option for interventional treatment of tumors developed by Vivant Medical. Promising results were reported at the SIR conference by clinicians using the company's VivaWave microwave ablation system in lung cancer patients. Damian Dupuy, MD, of Rhode Island Hospital (Providence), discussed results with the VivaWave in 24 patients with thoracic malignancies. The tumors were early stage lesions with a diameter in the range of 2 cm.

Multiple lesions can be treated in the same patient, although the procedure time becomes at issue at about five lesions. A 50% improvement in survival was observed as compared to patients who did not receive the added therapy, and complication rates were low at 3% for hemoptysis and 7% for chest tube drainage. In all, 43% of the patients developed pneumothorax. As compared to RF ablation, microwave ablation has the advantage of not requiring grounding pads, a relatively large induced thermal zone (although currently limited to about 4cm), and the ability to use multiple applicators simultaneously.

Another study with the VivaWave, presented at the SIR conference by Melinda Mortenson, MD, of the University of California Davis Medical Center, found that microwave ablation generally requires less time to perform than RF ablation. Vivant received FDA clearance for the VivaWave system in 2002 but has mainly focused on performing long-term studies to accumulate data for marketing purposes, and it is not yet actively selling the system. Pricing will be similar to that for RF ablation systems, at $1,500 to $2,000 per procedure.

One of the newest ablation technologies to be introduced, at least in the U.S. market, is focused ultrasound. A variant of the technology, high-intensity focused ultrasound, or HIFU, is used extensively for treatment of a range of diseases including cancer outside the U.S., particularly in Asia. Focused ultrasound is being launched in the U.S. market by GE Healthcare and InSightec (Tirat Carmel, Israel). InSightec was founded in 1999 when GE Healthcare and Elbit Medical Imaging (Tel Aviv, Israel) transferred their proprietary technology to the company to enable it to concentrate on developing magnetic resonance-guided focused ultrasound surgery that both companies had investigated. InSightec has developed the ExAblate 2000 system, which received FDA approval in 2004 for use in the treatment of uterine fibroids. Applications are under development for the treatment of various cancers including breast, liver, brain, and bone metastases, as well as for applications in prostate disease.

The system uses a unique combination of non-invasive MR imaging for planning, procedural guidance and post-treatment confirmation with non-invasive focused energy (ultrasound) treatment. The technology avoids the use of ionizing radiation, relying on a large array of ultrasonic transducers focused on the target region to generate heat, raising the tissue temperature to 65 C and resulting in tissue ablation. The treatment zone can be reduced to as small as 1 mm to 2 mm, or expanded to as much as 10 mm x 30 mm. Tissue temperature drops off rapidly, within five cell diameters outside the treatment zone, making the treatment highly selective and sparing normal tissue.

Treatment can be monitored in real time using MRI to detect changes in spectral emission patterns. In studies using the device for uterine fibroid therapy, 85% of patients had relief of symptoms within 90 days. Patients experience some pain during the procedure, but not afterwards, as is common with some other types of uterine fibroid therapies. The ExAblate system is priced at $1 million, or can be leased for $20,000 per month. At present, there is no reimbursement for uterine fibroid or cancer therapy using the ExAblate in the U.S. One of the drawbacks of the technology is the long procedure time of 2.5 hours to 3 hours, which can especially be an issue for busy MRI centers. The company is developing new software that will reduce the imaging time.

Orthopedic applications expand

Another rapidly growing segment of the interventional radiology market is osteoplasty devices for use in minimally invasive treatment of bone disorders such as herniated spinal discs and cancer-related bone defects. As shown in Table 3, there is a substantial market for such devices already and significant opportunity for market expansion, particularly when emerging applications for cancer patients are considered. The leading supplier in the market at present is Kyphon (Sunnyvale, California), which focuses exclusively on devices for performing kyphoplasty, one of the restorative techniques used to treat spinal fractures. Kyphon reported worldwide sales of $213 million in 2004, up 63% vs. 2003, and sales have increased at a 43% compound annual rate since the company first entered the market in 2000. According to suppliers in the market, Kyphon currently accounts for about half of the total market in dollar volume but only about one-fourth of unit volume or procedures in the U.S. In Europe, the market is even more unbalanced, with 16,000 kyphoplasty procedures and 24,000 vertebroplasty procedures, but a three-fold higher dollar volume share for kyphoplasty.

In cancer patients, osteoplasty is used primarily to reduce pain related to bone metastases. One in five cancer patients have poorly controlled pain due to bone metastases, which can be reduced significantly by injection of bone cement, typically polymethylmethacrylate, via percutaneous needle injection. Targeting of the injection is critical, mandating the use of interventional radiology techniques such as biplane fluoroscopy. The procedure benefits the patient both by stabilizing the fracture, thus reducing pain, as well as by cauterization of the tumor due to the heat generated by the cement as it cures. As discussed by A.G. Ryan, MD, of Vancouver General Hospital (Vancouver, British Columbia), at the SIR sessions, osteoplasty has produced prompt relief from bone pain in all patients treated with the procedure. The technique represents a significant advance compared to alternatives such as radiotherapy, which can be effective in relieving pain but can require up to 12 to 20 weeks to take effect.

Other suppliers of osteoplasty devices exhibiting at SIR included the U.S. orthopedics unit of Smith & Nephew (S&N; Memphis, Tennessee), Arthrocare (Sunnyvale, California), and Advanced Biomaterial Systems (Chatham, New Jersey). Smith & Nephew Orthopaedics is about to launch a new discography system that will provide improved diagnosis of the source of disc or back pain. The system will provide a more controlled injection of contrast to allow improved measurement of intradisc pressures. S&N also markets the 20S Spine System, an electrothermal device that applies heat to a herniated disc causing contraction of collagen as well as de-enervation to reduce pain.

Arthrocare markets the Parallax device for vertebroplasty, which allows use of low dynamic pressure during injection of cement, resulting in improved control, as well as the PERC DC Spinewand, used in more than 30,000 disc treatment procedures, employing electrosurgical ablation.

Advanced Biomaterial Systems markets the Plexis bone void-filling system, employing a specially formulated cement mixture that provides improved consistency, leading to more precise localization of the injected material. The Plexis system can be used either for vertebroplasty or kyphoplasty. Another supplier, OptiMed (Ettlingen, Germany) has developed a new bone cement designed specifically for use in vertebroplasty called CementoFixx.

Technologies for stroke therapy

One of the most pressing unmet needs in interventional radiology is new technologies for the treatment of, and ultimately for the prevention of, stroke. Advances in preventive therapy are now beginning to appear in the form of carotid stents that provide a minimally invasive, non-surgical alternative to carotid endarterectomy for treatment of carotid artery stenosis. For stroke therapy, the only treatment at present is delivery of Genentech's (South San Francisco, California) tissue plasminogen activator (tPA) from within three hours of onset. But thrombolysis with IV tPA is not always effective: only 26% of patients with type M1 or M2 clots, which comprise a major type of thrombosis observed in stroke patients, are recanalized with tPA therapy. In addition, clinical studies using IV tPA thrombolysis in stroke patients have shown that it requires between three and four hours to achieve recanalization, and when that time interval is added to the typical delay in reaching the hospital and initiating therapy, most patients are beyond the time window in which optimal efficacy is achievable.

Another issue in stroke therapy is that techniques for definitive rapid diagnosis of stroke are lacking, as are methods to allow identification of brain tissues than can be salvaged following a stroke. While clinical studies indicate that, on average, initiation of tPA therapy must occur within three hours of stroke onset in order to achieve maximum benefit, there also is considerable evidence that certain patients will benefit from treatment beyond the three-hour window. However, methods to definitively identify those patients are lacking. Modalities under development for assessment of brain tissue viability following a stroke include PET imaging, to assess oxygen consumption in compromised tissues; MR diffusion imaging; and assessment of cerebral blood flow, cerebral blood volume and other hemodynamic parameters using CT imaging. Due to the problems with existing techniques for stroke diagnosis and treatment, only about 10% of stroke patients receive thrombolytic therapy even in the most advanced medical institutions, and overall the percentage is considerably lower, at around 2% by some estimates.

As discussed at SIR by Ajay Wakhloo, MD, professor of radiology, neurological surgery and biomedical engineering, and director of the section of neuroendovascular surgery and neurointerventional radiology at the University of Miami School of Medicine (Miami, Florida), the lack of more effective stroke therapies is not due to an absence of research and development activity in the field. More than 65 intracranial devices have been evaluated in various stroke trials, according to Wakhloo, including clot suction catheters, recanalizing wires, PTA balloon catheters, snares, and clot maceration and emulsification devices.

One promising technology that may improve treatment of thromboembolic stroke is ultrasound-assisted thrombolysis using the MicroLysus Infusion Catheter from EKOS (Bothell, Washington). The device is being evaluated in the Interventional Management of Stroke (IMS) study directed by researchers at the University of Cincinnati and sponsored by the National Institutes of Health (Bethesda, Maryland) and EKOS. The trial was recently expanded from six sites to 12. The MicroLysus catheter combines high-frequency (1 MHz to 2 MHz), low-power (0.45 watt) ultrasound with infusion of a thrombolytic drug to accelerate thrombolysis by mechanically dispersing the drug into a clot and increasing clot permeability. An embedded thermistor in the 2.8 Fr catheter monitors temperature to allow automatic control of the power level and also allows detection of recanalization due to the rapid temperature change that results when blood flow is restored. Initial studies conducted with the device have demonstrated a seven-fold higher rate of recanalization within one hour of starting treatment as compared to rates achieved with intra-arterial tPA infusion alone in separate trials.

Another device for mechanical disruption of clots in stroke patients, the Merci Retriever System, has been developed by Concentric Medical (Mountain View, California). The system uses a microcatheter with a corkscrew-type microwire that is first threaded through the clot. A balloon at the tip is then inflated to stop blood flow, and the wire is retracted into the microcatheter to extract the clot. The device was approved by the FDA in August 2004. In a clinical trial with the Merci catheter, a 48% recanalization rate was achieved, which was increased to approximately 60% when tPA infusion was added.

Another mechanical clot-removal device for use in stroke therapy is being developed by IDEV Technologies (Houston). The IDEV device is a miniaturized thrombectomy catheter with a 4 Fr diameter that will be suitable for use in the cerebral vessels.

Thrombectomy devices a growing focus

In addition, advances in device technology for use in the treatment of deep venous thrombosis (DVT), described at the SIR conference, promise to improve treatment for the 200,000 to 300,000 patients who develop DVT in the U.S. each year. Thrombectomy devices for use in the larger peripheral vessels, such as in the leg arteries and in dialysis access grafts, also are a focus for R&D investment in the interventional radiology market. As discussed by Suresh Vedantham, MD, of Washington University (St. Louis) at SIR, new devices using pharmacomechanical thrombolysis techniques are proving highly effective for treatment of deep vein thrombosis (DVT). There are 200,000 to 300,000 new cases of DVT annually in the U.S., and 600,000 total cases including recurrences.

The conventional treatment for DVT is catheter-directed thrombolysis, which is effective but requires one to two days, is costly, and associated with a high risk of bleeding, limiting its utilization. In addition, in about 50% of untreated patients, or in some patients who have residual clot after treatment, post-thrombotic syndrome can occur. Post-thrombotic syndrome affects between 100,000 and 150,000 patients per year in the U.S., and causes significant swelling of the legs as a result of permanent damage to valves in the leg vessels caused by blood clots. In addition to swelling, the resulting impaired circulation in the legs can lead to skin ulcers, affecting 500,000 to 600,000 patients.

Many physicians are not aware of post-thrombotic syndrome, resulting in lack of appropriate therapy in many cases. Pharmacomechanical treatment for DVT promises to reduce the incidence of post-thrombotic syndrome by providing improved removal of clots, and to increase the percentage of patients who receive appropriate therapy by lowering the cost and reducing the time required for treatment. Devices available for use in DVT therapy include the Helix catheter from ev3 (Plymouth, Minnesota), the AngioJet from Possis Medical (Minneapolis) and the Trellis-8 device from Bacchus Vascular (Santa Clara, California).

The Helix catheter operates at 100,000 rpm to create a vortex that breaks up the clot and is used in combination with a thrombolytic drug in the treatment of DVT. Success rates for clot removal with the Helix are 94% vs. 71% with drug treatment alone, and the treatment time is reduced by 40%. Lower bleeding rates also are achieved. Similar success rates of 93% have been achieved using the Possis AngioJet.

With the Trellis-8 device, success rates for clot removal are 89%; but cost is reduced by more than 60%, treatment time is reduced from two days to as little as 30 minutes, and no bleeding episodes have been reported. The 8 Fr Trellis-8 system includes dual balloons that are inflated on either side of the clot both to prevent embolization of clot fragments and to isolate the thrombolytic drug at the site of the clot, thereby reducing systemic exposure and bleeding risk. A wire is then rotated at 3,000 rpm to mechanically disrupt the clot, enhancing the enzymatic action of the thrombolytic agent. The Trellis-8 is a new product from Bacchus specifically designed for use in DVT treatment, and was cleared by the FDA in February of this year. The device was launched in the U.S. market in April.

Another new device, the Eliminator from IDEV Technologies, was cleared by the FDA in mid-March for use in clearing thrombosed dialysis access grafts and native AV fistulas.

Datascope Interventional (Mahwah, New Jersey) also has introduced a new thrombectomy device within the past year, the $595 Prolumen rotational thrombectomy system.

Vascular intervention developments

Devices used in vascular intervention, including peripheral vascular stents and stent-grafts, comprise one of the largest segments of the interventional radiology market, and one of the most rapidly growing segments. The first carotid stent, the Acculink from Guidant Vascular Intervention (Santa Clara, California), which is used in combination with the Accunet embolic protection device, was approved by the FDA in August 2004. Carotid stents address a potential target patient population of 150,000 to 175,000 worldwide who now undergo surgical treatment (carotid endarterectomy) for carotid artery stenosis. Development of the market is being paced by the need to train and accredit physicians to perform the stent procedure, and by delays in setting the Medicare reimbursement rate. Physician specialties being targeted by Guidant as users of carotid stents include interventional radiologists, vascular surgeons, interventional cardiologists and interventional neuroradiologists.

Another segment of the vascular device market now undergoing rapid development is stent-grafts for use in a variety of applications, including ane-urysm treatment, improvement of patency in dialysis access grafts and cerebral vessels, and treatment of biliary strictures. A major advance in stent-grafts was described by Ziv Haskal, MD, of New York Presbyterian Hospital (New York) at the SIR meeting using the Fluency device developed by Bard Peripheral Vascular (Tempe, Arizona) in dialysis access grafts. More than 250,000 Medicare patients undergo hemodialysis each year in the U.S., a number that is increasing by about 7% annually. By 2020, an estimated 2 million patients per year will undergo hemodialysis worldwide. A large percentage of those patients have synthetic access grafts implanted in their arm to allow routine dialysis treatment.

About half of patients with a synthetic graft will experience graft thrombosis each year, resulting in a need for repeated angioplasty procedures to restore blood flow through the graft. In a study involving 190 patients led by Haskal, the Fluency stent-graft was used to restore patency in 97 patients as an alternative to balloon angioplasty, with highly positive results. A total of 128 stent-grafts were implanted, and 54% of the stent-grafts remained patent at six months vs. 29% of the grafts treated with angioplasty. Primary patency of the access circuit at six months was 41% vs. 26%. The results could drive a significant expansion of the stent-graft market due to the large and growing number of patients with graft thrombosis and the high cost of maintaining graft patency with existing techniques.

Stent-grafts also are finding increased use in the treatment of abdominal aortic aneurysms (AAAs) and thoracic aortic aneurysms (TAAs). Leading suppliers of stent-grafts for AAA and TAA repair include Medtronic (Minneapolis); W.L. Gore (Flagstaff, Arizona), with the Excluder and TAG devices; and Cook (Bloomington, Indiana). About 43,000 AneuRx stent grafts from Medtronic had been implanted worldwide as of January 2005. In addition, 25,000 Medtronic Talent stent-grafts have been implanted in Europe, and about 10,000 Cook Zenith devices have been implanted worldwide.

The most recent results from clinical studies indicate that procedural mortality is significantly lower with stent-grafts for treatment of AAA as compared to surgery, although there is a higher rate of secondary procedures for stent-grafts. Problems with current-generation devices include endoleaks in 13.9% of implanted grafts at four-year follow-up (for the AneuRx device) and a low (3.3%) but nevertheless significant rate of aneurysm rupture in spite of stent-graft implantation. Most significantly, the latest data from the FDA shows mortality rates increasing over time for stent-graft patients, crossing over the rate for surgically treated patients at about seven years post-procedure.

As discussed by David Williams, MD, of University of Michigan Hospital (Ann Arbor) at the SIR sessions, future generation stent-grafts must have smaller sheath profiles, greater flexibility and more controlled delivery characteristics to reduce trauma and embolisms occurring during implantation, and they must also have features allowing more precise placement. In addition, new devices should be designed to provide higher radial force at anchoring sites, and provide improved fit to the vascular anatomy, particularly for TAA applications, in order to avoid graft migration and endoleaks.

Gore received FDA approval for its TAG stent-graft in December 2004, the first such device to enter the market in the U.S. However, both Medtronic and Cook are about to start clinical trials with new stent-grafts for TAA applications, including the Zenith TX2 from Cook and the Talent TAA graft from Medtronic.