CDU Contributing Editor

ORLANDO, Florida – Transcatheter therapy is now the dominant modality employed in the U.S. and most other developed countries for the treatment of occlusive coronary artery disease. Percutaneous transluminal coronary angioplasty (PTCA) and coronary stents are used in over two-thirds of all coronary revascularization procedures performed in the U.S., and procedure trends indicate that the role of interventional, as opposed to surgical, therapy will continue to expand. One reason for the increasing popularity of transcatheter techniques is the ongoing improvement of underlying technologies, including balloon catheters, delivery technologies, stents, anti-restenosis technologies, and atherectomy catheters. Those technologies are not only improving outcomes by reducing the rate of re-intervention, but also by allowing patients with more complex forms of coronary artery disease to be treated with minimally invasive techniques, reducing procedural morbidity and avoiding the adverse effects of surgical therapy.

As described by investigators at this year's scientific sessions of the American College of Cardiology (ACC, Bethesda, Maryland), held here in March, advanced transcatheter diagnostic technologies are likely to play a major role in helping to further expand the role of interventional treatment. The detection of unstable plaque is an important area of research, and a number of new devices show promise for allowing patients with such plaques, who are at higher risk for an acute coronary event, to be identified.

The integration of unstable plaque detection devices with therapeutic catheters will potentially allow cardiologists to ensure that the highest-risk lesions are treated in real time, concurrent with performing the angioplasty or stent procedure. Noninvasive angiography techniques are also advancing, and could allow improved identification of the approximately 50% of individuals who now suffer a myocardial infarction each year who have no identified risk factors.

Other important improvements in interventional technology that are driving growth in the market include puncture site closure devices, which streamline both diagnostic and therapeutic procedures; new devices and drugs to minimize complications arising from transcatheter treatment; and, longer term, advanced catheter-based revascularization technologies such as in situ bypass and delivery of angiogenesis drugs.

Unstable plaque detection draws investment

A variety of technologies are under investigation for the detection of unstable plaque. As described by Patrick Serruys, MD, of the Thoraxcenter (Rotterdam, the Netherlands), intravascular ultrasound (IVUS) can be used as a first step to characterize the hardness of plaques within an artery. An intravascular elastogram can be measured using IVUS that shows the percentage strain existing in the plaque. Based on studies performed by Serruys, strain levels above 2% indicate the presence of dangerous plaques that are prone to rupture. Another approach, studied by Tomokazu Okimoto and others at Tsuchiya General Hospital (Hiroshima, Japan), uses IVUS to identify the presence of macrophages and lymphocytes in plaque. Such cells play a prominent role in plaque formation, progression and rupture. Initial studies indicate that IVUS may prove useful to identify vulnerable plaque by allowing regions with high macrophage and lymphocyte content to be imaged. Key suppliers of IVUS catheters and equipment include Boston Scientific (Natick, Massachusetts) and Jomed NV (Helsingborg, Sweden), which acquired Endosonics and its line of IVUS products.

Studies by other research groups have shown that unstable plaques also exhibit elevated temperature and reduced pH levels, as well as elevated lipid content. A number of companies are now developing catheters and other technologies for detection of unstable plaque using temperature mapping, pH analysis, and other approaches, as shown in Table 4.

Table 4: Technologies Under Development for Unstable Plaque Detection
Company/Institution Technology Details/Status

Remspec (Charlton, Massachusetts)/University of Massachusetts(Worcester, Massachusetts)and University of Texas(Houston, Texas) 3 Fr 360 side-viewing near-infrared spectroscopic catheter Monitors metabolic activity of plaque via spectroscopic determination of temperature and pH. Sensor also under development for lactate. Early-stage development.

InfraReDx (Cambridge, Massachusetts) Fiber optic catheter for identification of lipid-rich plaque 1.5 mm diameter catheter made by MedVenture (Louisville, Kentucky) uses both sampling and reference channels to measure plaque lipid content via spectroscopic analysis. In animal studies.

Magna-Lab (Syosset, New York) Cardiac View Transesophageal MRI Coil Coil used with standard MRI machine to enhance signal from coronary arteries for noninvasive detection of vulnerable plaque; 510(k) filed February 2001.

Temperature Specialist(St. Francis, Minnesota) Thermosensor Basket Catheter 4 Fr catheter with configurable basket containing nine thermocouples for detailed (0.01 C) temperature map of vessel wall. Adding ultrasound elastography. In animal studies.

Thermocore Medical (Ghent, Belgium) Combination IVUS/thermography catheter Simultaneous mapping of temperature and morphology of arterial wall with 3 Fr catheter; scans at 0.3mm per sec with one minute off-line data analysis; clinical trials planned within six to eight months.

Thoraxcenter (Rotterdam, the Netherlands) Intravascular capacitometry Intracoronary 3 Fr catheter with multiple metal rings at tip for assessment of electrical capacitance of vessel wall. In vitro testing stage.

University of Texas (Galveston, Texas) MRI combined with super paramagnetic iron oxide particles Noninvasive detection of inflamed plaques; polysaccharide-coated particles are taken up by macrophages in vulnerable plaque.

Source: Cardiovascular Device Update

An important thrust of the studies now being conducted by those suppliers is to identify the characteristics of plaque that are the most reliable indicators of propensity to rupture. Lipid-rich plaques can be imaged using near-infrared spectroscopy, as demonstrated in animal studies performed by Moreno, et al., at the University of Kentucky (Lexington, Kentucky) using a laser-based catheter developed by InfraReDx. The company is now working to further refine its catheter to reduce noise levels in preparation for studies in humans. In addition, inflamed plaques, believed to be the most vulnerable to rupture, typically exhibit elevated temperature and different metabolic characteristics as compared to normal tissues or stable plaque. Technologies are now being studied to determine if they can be used to reliably identify unstable regions by measurement of local temperature differences or pH.

Noninvasive approaches to detecting the presence of unstable plaque have obvious appeal, opening up the possibility of developing screening tests that could identify individuals who are progressing to an acute coronary syndrome, even though classical risk factors are normal. Technologies that are being evaluated for non-invasive detection of vulnerable plaques include magnetic resonance imaging (MRI), CT scans, electron beam CT, and, for a more general indicator of risk, blood tests. MRI approaches appear particularly promising because of the technology's ability not only to detect the presence of lesions but to also ascertain plaque composition. Magna-Lab (Syosset, New York) recently filed a 510(k) for marketing clearance for its Cardiac View MR system for coronary imaging. The Magna-Lab system uses two coils, an esophageal coil plus a surface coil. The company believes better resolution is possible with that approach than is achievable with intravascular coils, for example. Magna-Lab hopes to launch the Cardiac View coil system in the third or fourth quarter of 2001 to allow physicians to image coronary artery lesions.

The use of MRI during catheterization procedures has been demonstrated for peripheral revascularization procedures, allowing viewing of vessel characteristics as well as the balloon catheter with resolution and image quality equivalent to an angiogram. Surgi-Vision (Columbia, Maryland) is another supplier developing technology with applications in intravascular MRI imaging. Improved intravascular imaging methods are expected to allow therapy to be applied more effectively, and to allow clinicians to better evaluate what type of treatment is most appropriate.

Optimizing percutaneous intervention

A variety of other advances are helping to improve outcomes for transcatheter procedures and making treatment more efficient, as well as allowing physicians to deal with procedural complications more effectively. Technologies for restenosis prevention are advancing rapidly, with the most recent advances dropping restenosis rates to near zero, at least in the short term. In addition to widely publicized positive results with drug-coated stents and brachytherapy, other approaches are being evaluated.

One described at the conference by Christodoulos Stefanadis of Hippokration Hospital (Athens, Greece) uses alternating magnetic fields applied from an external source to heat implanted stents to 45 C and thereby inhibit neointimal proliferation and restenosis. Initial animal studies demonstrated a 50% reduction in intimal thickness vs. controls when heat was applied for a period of 45 minutes. In principle, the technique would avoid issues with radiation shielding and the logistical issues of handling radioisotopes that complicate the use of brachytherapy, and would be noninvasive. It might also prove less expensive than coating of stents with anti-restenosis agents, although a temperature-monitoring catheter is also required to ensure that the proper temperature is maintained over the entire exposure period. Further studies are being performed to assess long-term complications of the procedure.

Based on the major reduction in restenosis rates observed with sirolimus drug-coated stents, a number of research groups are now investigating other coating agents for preventing restenosis. However, so far none of the alternative agents have produced effects equivalent to those seen with sirolimus. A group led by Jose Suarez de Lezo at the Negrin Hospital (Las Palmas, Spain) evaluated both intermittent and prolonged administration of methatrexate for restenosis prevention. The findings, although preliminary, did not show any benefit compared to controls in terms of lower restenosis. Another study, described by Josef Dirschninger and conducted at the Med Klinik of Munich (Munich, Germany), evaluated a new biodegradable stent coating that releases Hirudin and Iloprost. However, no statistically significant benefit was observed in patients, in spite of promising results in animal trials. Other compounds being evaluated include paclitaxel, an anti-cancer agent being used by Cook (Bloomington, Indiana) as a stent coating to prevent restenosis. So far, the Cordis BX Velocity stent, coated with Sirolimus, has produced the best results, with no restenosis observed at six months follow-up. Sirolimus, a cytostatic agent, has the unique capability to both inhibit proliferation of neointimal cells and to allow the growth of endothelial cells around the struts of the implanted stent.

Given the positive results with the Sirolimus-coated stent in inhibiting restenosis, it is possible that other types of drug therapy could have a beneficial effect on restenosis, even if given systemically. Some evidence corroborating that theory was presented at ACC by Guido Schnyder of the Swiss Heart Center (Bern, Switzerland). Schnyder's team had previously documented evidence of an association between elevated plasma homocysteine levels and restenosis after PTCA. In a prospective, randomized study of 553 patients, the group given folic acid, an agent widely shown to reduce homocysteine levels, had a significantly lower composite rate of death, myocardial infarction and target vessel revascularization (12% vs. 19.8%). The use of folic acid supplementation in the manufacture of bread and grain products is now mandated in the U.S. as a strategy to reduce cardiovascular disease. Additional folic acid supplementation of the diet for patients following PTCA could provide a low-cost, safe approach to reducing restenosis rates and other adverse events. The use of the anti-oxidant drug probucol has also been shown to help lower the rate of restenosis after stenting, and a major trial (the PRESTO study) is nearing completion evaluating the drug Tranilast as a preventative agent. Even if effective drug therapies are used to reduce restenosis, the use of stents will still be required in many cases in order to address the issue of elastic recoil and support of the artery post-angioplasty.

Other approaches under investigation for restenosis prevention include cryotherapy, using catheters to deliver a liquid refrigerant to the treated site and ultrasound as a means to inhibit tissue proliferation after stenting. A number of novel therapies, including cryotherapy, are being studied by Paul Yock, MD, of Stanford University Medical Center. Intravascular ultrasound therapy, or Sonotherapy, is being developed by PharmaSonics (Sunnyvale, California), in the Sonotherapy for In-Lesion Elimination of Neointimal Tissue (SILENT) registry. In 37 patients studied so far, a restenosis rate of 13% has been observed.

Another important area of ongoing investigation involves the development of technologies to deal with non-optimal angioplasty and stent results, which are becoming increasingly common as a wider range of patients are treated. Treatment of perforations, which are a particular problem when performing angioplasty and stenting on diseased saphenous vein grafts, is one area of focus. Jomed NV has recently received a humanitarian device exemption in the U.S. for use of its Jostent Coronary Stent Graft for the treatment of free perforations. The device consists of an ultra-thin layer of PTFE sandwiched between two stainless steel stents. The use of IVUS is strongly recommended to help guide placement of the device, since initial evaluations showed that IVUS guidance helped to reduce post-procedure complications significantly. In addition to sealing perforations, the device is used outside the U.S. to help prevent embolization of debris when treating saphenous vein grafts. Another device for the treatment of saphenous vein grafts, the Fibrin Film Stent, is being developed by Medtronic (Minneapolis, Minnesota). As reported at ACC by Charles McKenna, MD, of the Mayo Clinic (Rochester, Minnesota), the stent consists of a small-wave Wiktor stent coated with fibrin isolated from human plasma. An initial safety study on 10 patients demonstrated that the stent can be implanted and that adverse events were no higher than with other methods used to treat diseased saphenous vein grafts. Because the fibrin coating is biodegradable, it appears promising as a vehicle for local drug delivery.

Another recent innovation in transcatheter therapy that has helped in particular to improve the efficiency of angioplasty and angiography procedures is the development of vascular closure devices. Key products now on the market and under development are described in Table 5.

Table 5: Closure Devices for Use in Diagnostic and Interventional Catheterization
Company Product Key Features Status

CardioDex (Tirat Hacarmel, Israel) EpiClose Dual balloon-based closure device; uses proprietary balloon material to provide closure in 10-15 minutes. Comprises positioning anchor balloon and hemostasis balloon. Will be priced at under $100 to end user. Animal trials complete. Initiating human trials at three centers in U.S., one in Europe, and one in Israel.

Datascope (Montvale, New Jersey) VasoSeal VHD Collagen plug for occlusion and sealing of access tract. 5 minutes to hemostasis for diagnostic catheterization; 10-15 minutes for interventional procedure. FDA cleared; more than 350,000 procedures performed with device worldwide.

St. Jude Medical (St. Paul, Minnesota) Angio-Seal 6Fr and 8Fr Millennium platforms, Angio-Seal STS Comprises Locator, Anchor, and Sealing Plug; seals vascular puncture wound in about 3 minutes. New 6 Fr platform for smaller puncture sites used in cardiac procedures. STS allows complete procedure to be performed in cath lab. Angio-Seal 6 Fr and 8 Fr Millennium on the market worldwide; STS to be introduced in 2001.

Abbott/Perclose (Abbott Park, Illinois) Closer Polyester sutures affixed to seal wound site using nitinol needles. Cleared by FDA for reducing time to discharge; on the market in Europe.

Vascular Solutions (Minneapolis, Minnesota) Duett Balloon temporarily occludes access tract, then thrombin and collagen are injected to promote coagulation within 5 minutes. Drug dissolves in 2-4 weeks. Approved by FDA in June 2000

Source: Supplier interviews

The EpiClose, a dual-balloon closure device that is inserted through the access sheath at the end of a catheterization procedure, was exhibited at ACC by CardioDex Ltd. The physician first inflates the anchor balloon inside the artery and pulls it to seal against the inner wall of the vessel. The introducer sheath is then withdrawn, and the outer hemostasis balloon is inflated. The anchor balloon is deflated and withdrawn from the artery. Blood then coagulates in the recess area of the hemostasis balloon, sealing the puncture hole. There are no materials left in the body, and the procedure relies on simple manipulations (balloon inflation/deflation) that are familiar to the interventionist. EpiClose is now beginning human clinical studies with its device. Marine Polymer Technologies (Danvers, Massachusetts) also exhibited its Syvek Patch, an external cellulosic polymer patch that leaves no subcutaneous foreign matter in the patient, is applicable to various size arterial punctures and remains effective even if the patient is receiving anticoagulation therapy.

The market for vascular closure devices is continuing to grow. Sales of the Datascope VasoSeal device increased 32% to $55.8 million for the fiscal year ended June 30, 2000, although in the most recent quarter ended March 31, 2001, sales were up only 1% over the same year-earlier quarter. Cardiology and vascular access product sales for St. Jude Medical increased 36% in the year ended Dec. 31, 2000, to $103 million. Year 2000 sales for Vascular Solutions increased 333% to $6.2 million. The worldwide market for vascular closure devices increased 39% from $165 million in 1999 to $230 million in 2000. More than 7 million diagnostic and interventional catheterization procedures are performed annually worldwide. As shown in Table 6, diagnostic and interventional catheterization procedures in the U.S. are continuing to increase, driven by growing use of transcatheter treatment vs. surgery, and expanding indications for catheter-based therapy.

Table 6
Trend in Inpatient Diagnostic and Interventional Catheterization Procedures in the U.S.
Year Diagnostic
Coronary
Angiography
Procedures
Diagnostic
Peripheral
Angiography
Procedures
Heart &
Pericardium
Diagnostic
Procedures
Patients
Discharged
with a PTCA
Procedure
Patients
Discharged
with a PTA
Procedure
Total

1989 1,199,000 421,000 998,000 177,000 58,000 2,853,000
1990 1,343,000 392,000 1,046,000 194,000 50,000 3,025,000
1991 1,366,000 353,000 1,057,000 221,000 51,000 3,048,000
1992 1,405,000 366,000 1,084,000 267,000 52,000 3,174,000
1993 1,393,000 338,000 1,078,000 269,000 59,000 3,137,000
1994 1,457,000 347,000 1,122,000 312,000 57,000 3,295,000
1995 1,468,000 365,000 1,137,000 316,000 64,000 3,350,000
1996 1,580,000 385,000 1,241,000 485,000 68,000 3,759,000
1997 1,500,000 400,000 1,194,000 452,000 72,000 3,618,000
1998 1,566,000 395,000 1,291,000 540,000 75,000 3,867,000
1999 1,639,000 394,000 1,359,000 599,000 79,000 4,070,000

Note: Excludes ambulatory procedures. For 1996, the most recent year for which data is available, procedures including ambulatory procedures (in thousands) in the above categories were 2,185; 571; 1,740; 525; and 254, for a total of 5,275.
Sources: National Center for Health Statistics, Health Care Financing Administration, Cardiovascular Device Update

Progress for transcatheter bypass, angiogenesis

Ultimately, transcatheter techniques may be introduced that allow most if not all coronary revascularization procedures to be performed with minimally invasive technology. TransVascular (Menlo Park, California) is continuing to make progress in the development of its Percutaneous In situ Coronary Venous Arterialization (PICVA) and Percutaneous In situ Coronary Artery Bypass (PICAB) systems, with 10 hospitals in Europe now collaborating with the company, along with investigators at Massachusetts General Hospital, Stanford University Medical Center and the Mayo Clinic. At present, Transvascular has only received approval for limited clinical trials in Europe, which are being conducted at three sites. The company received ISO 9000 certification and clearance to use the CE mark in September 2000. The PICVA and PICAB procedures are intended for use in patients with severe distal disease who are not candidates for conventional PTCA. In addition, the therapy is targeted at patients who cannot undergo the risk of coronary artery bypass surgery, patients with suboptimal results from angioplasty and patients with disease that cannot be treated with angioplasty. Those groups collectively total about 500,000 patients worldwide. PICVA and PICAB use the vessels in the venous system of the heart as bypass conduits and provide a means to access those vessels via catheter techniques. Good patency of the venous bypass conduits has been demonstrated in animal studies, and overall early results are encouraging, according to the company. Procedure time is relatively short, at about 40 minutes.

TransVascular system components include the TransAccess Catheter, a guide wire and special proprietary blocking devices used to close off the existing vessels. The catheter allows the venous system to be accessed via the coronary arteries. In the PICVA procedure, a single anastomosis is created between a coronary artery and an overlying vein upstream from the lesion, allowing the vein to be perfused with oxygenated blood in a reverse manner. The blocking device is used to direct flow to the desired region. The PICAB procedure creates two channels between the coronary artery and the vein, one upstream and one downstream from the lesion, to accomplish a complete bypass of the occluded region. TransVascular also is investigating potential applications of its technology in the treatment of peripheral vascular disease, particularly for diabetic peripheral artery disease for which good treatments currently do not exist. In addition, the TransVascular technology may have important applications in drug delivery, specifically for the delivery of angiogenesis agents for coronary revascularization. The TransAccess catheter provides the opportunity to precisely deliver drugs to multiple locations in the myocardium in a single procedure.

Improved technologies for drug delivery to the myocardium are expected to prove important in the development of successful angiogenesis therapies. According to speakers at the ACC conference, angiogenesis therapy could provide a new option for the 20% to 37% of patients who now have suboptimal results with standard treatments. There have been seven trials of angiogenesis using protein growth factors to date, including the FIRST trial using the fibroblast growth factor (FGF) protein as an angiogenesis agent, and the VIVA trial that used vascular endothelial growth factor (VEGF). While safety has not been an issue in those studies, a significant improvement vs. placebo has generally not been demonstrated. There was a statistically significant improvement vs. placebo in treated patients in the VIVA trial at 120 days, even though the trial's primary sponsor, Genentech (South San Francisco, California), decided to discontinue development. Other studies have used genes coding for growth factors, but again no definitive positive responses have been demonstrated. New angiogenesis drugs that appear promising include AdFGF-4 from Berlex Laboratories (Montville, New Jersey), working in collaboration with Collateral Therapeutics (San Diego, California); and HIV-1a NP16, a drug that induces gene expression, under development by Genentech. However, investigators now believe that multiple factors are likely to be required. One option is to employ cell-based therapy to allow a number of different factors to be produced in vivo. Some initial studies have used autologous bone marrow cells mixed with endothelial cells for angiogenesis, and have found that the cells can be stimulated to secrete VEGF and to proliferate to form tubules that could serve as new blood vessels. In addition, a number of companies are evaluating various drug delivery technologies for angiogenesis applications, since may investigators in the field believe that optimization of the delivery of growth factors or gene therapy agents will be the key to developing clinically useful angiogenesis therapies.

One approach being evaluated by Cordis (Miami Lakes, Florida) uses the NOGA catheter to both map the myocardium to identify ischemic areas and to deliver angiogenesis agents to target regions. The NOGA system is now being evaluated by Dr. Jeffrey Isner of St. Elizabeth's Medical Center (Boston, Massachusetts) and a number of other researchers. The newest version of the NOGA catheter is equipped with an injection needle, and a group at St. Michael's Hospital (Toronto, Ontario), led by Michael Kuliszewski, has shown that both plasmid DNA and cells can be successfully delivered. Another injection device, a needleless injector under development by AngioSense (Cupertino, California) using technology developed by Bioject (Portland, Oregon) also has looked promising in initial animal studies performed by Isner. Genetronics (San Diego, California) is another company involved in the development of drug delivery technologies with applications in angiogenesis. The Genetronics electroporation technology employs pulsed electric fields to enhance the delivery of gene therapy agents into tissues. Animal studies with the Genetronics system of delivery of gene therapy agents in ischemic skeletal muscle tissue have shown that gene expression can be enhanced by four to five orders of magnitude. The company plans to license its drug delivery technologies on a non-exclusive basis.

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