CDU Contributing Editor

According to statistics from the American Heart Association (AHA; Dallas, Texas), more than 12 million people in the United States suffer from coronary artery disease (CAD). This disease is the leading cause of death and disability in the U.S., directly causing nearly 1 million deaths annually. CAD is characterized by a narrowing of the coronary arteries which supply blood to the heart muscle. The progression of the disease results in insufficient blood supply to maintain the optimal functioning of the heart muscle, producing angina pain, which can often be severe and debilitating, and may eventually result in heart failure. The AHA estimates that angina pectoris afflicts more than 6 million Americans, with over 300,000 new cases per year.

Established nonsurgical intervention approaches to treat angina include medications and lifestyle changes that reduce myocardial oxygen demand and prevent further progression of the disease. Over the past two decades, coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) have emerged as the primary means to treat angina when medical management and lifestyle changes are not effective in providing meaningful relief. While these modalities have demonstrated their ability to improve coronary blood flow, reduce anginal symptoms and, most importantly, boost the patient's quality of life (QOL) with an impressive level of efficacy and safety, a significant and growing number of patients remain unavailable to these interventions. This is due to myriad factors, including the patient's age, other co-morbidities, previously failed interventions and severely, diffuse or occluded coronary vessels.

Various estimates of the size of this subset of patients, often referred to as "no option" patients, have been made in recent years as new revascularization technologies loomed on the horizon. An interesting article in the Sept. 1, 1999, issue of The American Journal of Cardiology, titled "Direct Myocardial Revascularization and Angiogenesis–How Many Patients Might Be Eligible?" and authored by Debabrata Mukherjee, MD, et al., of the Cleveland Clinic Foundation (Cleveland, Ohio) noted that between 5% and 12% of patients presenting at a tertiary care center with symptomatic obstructive CAD are not candidates for either PTCA or CABG and are classified as "no option" patients. Note that the wide range between 5% and 12% is solely due to how strictly the inclusion criteria are defined. Further, in an HMO population with even stricter criteria, the authors estimated that 2.3% of the patients would be eligible for alternative technologies. In a talk at this year's annual scientific sessions of the American College of Cardiology (ACC; Bethesda, Maryland), Dr. Ran Karnowski of the Washington Center Hospital (Washington) said that approximately 9% of patients needing revascularization at his hospital are defined as "no option" and would be candidates from the newer revascularization techniques. It is important to note that according to data from the Cleveland Clinic Foundation that was presented at last fall's Transcatheter Cardiovascular Therapeutics symposium, the one-year mortality for "no option" patients is an alarming 16%.

About a decade ago, researchers began investigating a new technique called transmyocardial revascularization (TMR). This procedure is performed on a beating heart, with the laser's energy being used to create numerous (typically 15 to 50) channels directly into the wall of the left ventricle of the heart. Oxygenated blood from inside the left ventricle can then directly perfuse the myocardium, improving the patient's health and well-being. Initially, TMR was performed surgically with a left anterior thoracotomy approach and using an industrial-sized carbon dioxide laser. Several years ago, investigators began using a smaller, less costly holmium YAG laser, which has the crucial advantage of being able to deliver its energy either through the thoracotomy opening into the left ventricle or from a catheter-based fiber optic, which enters the patient percutaneously and creates laser channels into the myocardium from within the ventricular chamber. More recently, the excimer laser, which also can deliver laser energy through a fiber optic, catheter-based system has been under investigation.

PLC, Eclipse have approved products

Two companies have now attained final FDA approvals. PLC Systems (Franklin, Massachusetts) received FDA approval for its carbon dioxide laser in August 1998, while Eclipse Surgical Technologies (Sunnyvale, California) gained approval for its holmium YAG laser in February 1999. Both devices are approved solely for the surgical (thoracotomy or sternotomy) approach alone. Meanwhile, several other laser-based companies are moving through the long and tortuous FDA process. These include Edwards Life Sciences (Irvine, California), the recent spin-off from Baxter International (Deerfield, Illinois), which uses an excimer laser; Biosense Webster (Diamond Bar, California), a division of Johnson & Johnson (New Brunswick, New Jersey), which uses a holmium YAG; and the Cardiodyne division of Trimedyne (Irvine, California), which also uses a holmium YAG.

The clinical results for TMR have been excellent. Virtually every published paper has shown solid results with respect to the relief of angina, improvement in exercise tolerance, freedom from both cardiac events and treatment failure, and reduced hospitalization. Table 1 provides the results from the Transmyocardial Carbon Dioxide Laser Revascularization Study Group, whose results were reported in an article in the Sept. 30, 1999, issue of the venerable New England Journal of Medicine (NEJM). Also in that same issue of NEJM was another article, authored by Keith Allen, MD, et al., who concluded that TMR offers "no option" patients relief from their angina, with 76% of the Class 4 angina patients (as measured by the Canadian Cardiovascular Society Angina Classification) enjoying two classes of improvement (i.e., Class 4 to Class 2), whereas only 32% in the medical management arm improved two classes.

Table 1-TMR vs. Medical Management/12-month Results
TMR Medical Management
2-class angina improvement 72% 13%
Quality of life 143% 39%
Myocardial perfusion +20% -27%
Hospital admissions 2% 69%
12-month survival 85% 79%
Source: Keith Horvath, MD, et al., Northwestwern University Medical School, 1999 American Heart Association Abstract No. 1290.

The results of the above-noted trials relate to the surgical approach to TMR, with the best-known trial, ATLANTIC (Angina Treatment-Lasers And Normal Therapies In Comparison), serving as the basis for the FDA's approval. In addition, consistently solid clinical results have been reported for the less-invasive, catheter-based, percutaneous TMR (PTMR). At this year'sACCmeeting, one-year follow-up data from the PACIFIC (Potential Angina Class Improvement From Intramyocardial Channels) PTMR trial revealed that a higher proportion of the PTMR cohort (163 patients) enjoyed a far larger decline in their angina class and had a highly significant increase (101 seconds) in their exercise tolerance (treadmill test) than did the group in the medical management arm (162 patients). These results formed the basis for the December 1999 PTMR submission to the FDA byEclipse Surgical Technologies, which hopes to receive final clearance by the end of 2000 and become the first company to market PTMR.

Biosense Webster is poised to become the second company to gain PTMR approval. In December 1999, it completed the 300-patient DIRECT (Direct Myocardial Revascularization in Regeneration of Endomyocardial Channels Trial) study, which compared percutaneous treatment with its holmium YAG laser to a medical management group. The company is now in an FDA-mandated follow-up phase, with a premarket approval application likely to be filed later this year. It is interesting to note that whereas the Eclipse PTMR system uses traditional fluoroscopic (X-ray) imaging, the Biosense technique uses active magnetic fields to create three dimensional, real-time replicas of the left ventricle, based upon quantitative measurements for electrical activity and mechanical, contractile function. As the catheter moves within the left ventricle, its movement and location are tracked. The magnetic sensors provides data that calculates the precise location of the catheter tip relative to a fixed point on the patient. Thus, the catheter tip can be visualized on the endocardial surface at all times during the procedure.

Despite excellent clinical results, TMR has been and continues to be a very controversial therapy, with some skeptics suggesting that its results are entirely due to a placebo-based response. Certainly, no truly randomized double-blind trials (where one group receives TMR, the other group receives a "sham" procedure) have ever been conducted, thereby eliminating any potential placebo effect. Perhaps equally important, the exact mechanisms by which TMR exerts its effect and relieves angina are unknown and still open to conjecture.

The main proposed mechanisms include direct blood flow from the ventricular cavity to the ischemic myocardium through laser (or other device) channels and increased myocardial blood flow through neovascularization mediated thermal or mechanical laser injury. However, the theory of patent channels contributing to TMR has been rebuffed by numerous studies showing that, in fact, the channels begin to occlude as early as two days after the procedure. Improved myocardial blood flow has not been accepted as an explanation for TMR's efficacy, as thallium-201 single photon emission computed tomography (SPECT) imaging studies in most TMR clinical trials have demonstrated minimal, if any, gain in blood flow. Although less accepted as a theory explaining its anginal reduction, some have hypothesized that TMR may relieve angina by causing myocardial sympathetic denervation. Indeed, an article authored by Thabet Al-Sheikh, MD, et al., in the July 13, 1999, issue of Circulation, titled "Cardiac Sympathetic Denervation after Transmyocardial Laser Revascularization," concluded that the relief in angina provided by TMR, without concomitant improved coronary blood flow, was due to damaging the nerves that convey angina pain.

It has been common for investigators to equivocate about the benefits of TMR. For example, a study from the April 2000 issue of the Journal of the American College of Cardiology, titled "Transmyocardial Revascularization with Carbon Dioxide Laser in Patients with Refractory Angina Pectoris," authored by Lars Aaberge, et al., of the National Hospital (Oslo, Norway), concluded that TMR "is primarily a symptomatic treatment and so far there is no convincing evidence of either improving myocardial function or a reduced number of ischemic events."

Improved quality of life

While solid evidence of TMR's efficacy – that is, improved coronary perfusion – may be minimal, there is little doubt that the typical TMR patient experiences a meaningful reduction in their angina symptoms and, perhaps far more importantly, enjoys an improved quality of life (QOL). As noted in Table 2, Dr. John Spertus and his colleagues from the Mid America Heart Institute (Kansas City, Missouri) presented impressive QOL data at the 1999 American Heart Association annual scientific sessions. This study represents the largest randomized trial to examine various QOL measures and covers a one year follow-up period. It is this sharp improvement in the quality of life of the patient that has created staunch support amongst some members of the cardiovascular community.

Table 2-TMR Improves Quality of Life (Based on Seattle Angina Questionnaire*)
Medical Therapy TMR
Physical Limitations 72+/-22 233+/-23
Angina Frequency 159+/-30 320+/-34
Quality of Life 167+/-26 376+/-29
* The Seattle Angina Questionnaire is a self-administered, 19-question test that assesses physical limitations, symptom frequency, and quality of life. A higher score demonstrates improved QOL.
Source: John Spertus, MD, et al., Mid America Heart Institute, 1999 American Heart Association Abstract No. 1291.

Laser-based TMR has been investigated for the past decade. In the past couple of years, in response to the high cost of lasers, research has been initiated into other energy forms or creating intramyocardial channels. Radiofrequency (RF) energy, which is extremely cost effective relative to the laser, is currently in an early stage of clinical research.Boston Scientific (Natick, Massachusetts) has partially completed its Phase I feasibility trial, using a 9 Fr catheter and steerable guidewire to deliver RF energy percutaneously. Its RF generator is being supplied byArthrocare(Sunnyvale, California), which has licensed its coblation technology, which enables rapid and precise tissue removal with little or no heat-related damage to surrounding tissue, a cool process similar to that of excimer lasers.Arthrocare will receive licensing fees fromBoston Scientific upon completion of milestones and royalties on sales of resulting products.

Another company working in the TMR space with RF energy is privately-owned Radius Medical Technologies (Maynard, Massachusetts), which uses thermocoupled, temperature-controlled RF energy to heat the tip of a 0.035 inch guide wire that is placed in a 6 F. catheter. Animal clinical trials began at the Phoenix Heart Institute (Phoenix, Arizona), and soon will be completed at Brigham & Women's Hospital (Boston, Massachusetts). The company expects to initiate its human trials during the latter part of 2000 and hopes to receive CE Mark clearance in 2001.

At this year's ACC meeting, a group from the Montreal Heart Institute (Montreal, Quebec, Canada) reported on promising early animal (pig model) results using a novel cryothermic, deflectable percutaneous catheter. Whereas the other revascularization technologies aim to create channels, this approach is targeting the creation of four to eight sites in the myocardium, in order to create controlled cryo-injuries which will then engender an inflammatory response. The analysis of the animal data at both three weeks and six weeks is showing prominent neovascularization, with vessel sizes of between 0.1 and 1.0 millimeters developing. The animal clinical work has been completed, and the first phase of human clinical trials could begin about mid-2000. This catheter was developed by CryoCath Technologies (Kirkland, Quebec, Canada), a privately-owned, venture capital-backed early stage company that is also active in developing percutaneous catheters for the cryoablation of various cardiac arrhythmias.

A lower-cost, non-laser approach

Privately-owned, venture capital-backed Angiotrax (Sunnyvale, California) has developed a novel, non-laser mechanical myocardial channeling technology that will address both the interventional cardiology and cardiothoracic surgery markets. Its device is guided by a sophisticated and proprietary imaging system which allows the interventional cardiologist to target ischemic areas of the myocardium, create channels and establish visualization to reduce procedural time.

The 7 Fr, high-speed mechanical coring and vacuum extractor catheter device typically creates 12 to 14 channels in less than 30 minutes and has several attractive features and benefits. First, it is a low-cost and small device, particularly relative to the $300,000 to $400,000 price tag and bulkier size of TMR lasers. Second, it produces a clean channel that stays open longer than the heat-induced channels created by a laser, allowing the formation of thrombus and growth factors. Third, its coring capability can be used for gathering myocardial tissue, which may be valuable in treating the underlying disease. Finally, its technology may be used to deliver growth factors to the areas of the myocardium suffering from ischemia.

At this year's ACC gathering, Dr. Fayaz Shawl of Washington Adventist Hospital (Washington) reported on the first human clinical trials of 11 patients. He noted that the average patient enjoyed a better than two-class drop in his or her angina class and nearly two minutes improvement in an exercise tolerance test. Shawl, who has been a strong proponent of alternative revascularization technologies, concluded that mechanical percutaneous myocardial revascularization with the Angiotrax device system is safe and feasible and may prove to be an inexpensive substitute for laser revascularization. Angiotrax hopes to begin a larger clinical trial later this year.

In the past couple of years, there has been enormous hoopla about gene therapy and its potential to foster angiogenesis and improve the health of severe angina patients. Indeed, in the year-end American Heart Association "Top Ten Research Advances in Heart Disease and Stroke" report, four important gene discoveries were cited. But at this year's ACC meeting, disappointing results were reported for the largest gene therapy trial to date, known as the FIRST (FGF-2 Initiating Revascularization Support Trial). This trial was sponsored by Chiron (Emeryville, California) and used a genetically engineered protein called fibroblast growth factor-2 (FGF-2) to test whether exercise tolerance could be improved with this protein. Patients in the FGF-2 group did not show any improvement relative to the placebo arm, although angina pain was reduced.

Better results were enjoyed by patients in the VIVA (VEGF in Ischemia for Vascular Angiogenesis) trial, who experienced both a reduction in their angina, as well as better exercise tolerance scores. Amid controversy over the death of a patient in a gene therapy trial, the FDA has halted some of these trials. The co-principal investigator of this study, Dr. Michael Simons of Beth Israel Deaconess Medical Center (Boston, Massachusetts), noted that he is encouraged by the early results of this trial, which demonstrate safety and some efficacy but noted that there appears to be a large placebo effect at work in these patients, and that many other confounding issues must be resolved before this therapy can be widely used.

Close on the heels of the ACC meeting, Collateral Therapeutics (San Diego, California) announced preliminary positive findings of a double-blind, placebo-controlled Phase I/II clinical trial of its adenoviral-based Generx gene therapy product for the treatment of patients with stable exertional angina. In the company's AGENT (Angiogenic Gene Therapy) trial, 67 patients received a one-time, non-surgical, intracoronary administration of either a placebo or Generx. The drug was safe and well-tolerated and most importantly, substantial improvements were observed at multiple dosage levels in treadmill exercise time. Based on these solid results, Collateral Therapeutics and its development partners, Schering AG (Berlin, Germany) and the latter's U.S. subsidiary, Berlex Laboratories (Wayne, New Jersey), plan to initiate large-scale pivotal trials later this year.

A controversial technique in spite of the fact that it has been around for about 40 years, enhanced external counter pulsation (EECP) treatment is gradually emerging as a viable non-surgical alternative to CABG and PTCA. EECP is a non invasive, outpatient procedure that involves the inflation and deflation of a series of compressive air cuffs applied to the patient's lower extremities – the calves, lower thighs, and upper thighs, including the buttocks. Timing for inflation and deflation is regulated by a microprocessor running electrocardiogram signals through sets of algorithms that monitor safety and precision. The theory of why EECP is effective goes as follows: significant obstruction in one or more coronary arteries can create a pressure difference between areas of the heart muscle that receive and those that do not receive enough blood. Repeated and pulsed increases in pressure during diastole may stimulate opening or formation of collateral channels across this pressure gradient within the heart muscle, resulting in increased blood supply to deprived tissues.

Several clinical trials have confirmed the benefits of EECP treatment. They include: symptomatic relief of angina unresponsive to medical therapy, improved blood flow to deprived areas of heart muscle demonstrated by the results of thallium stress testing, elimination or reduction of nitrate use and an improved ability to exercise. The April 2000 issue of Clinical Cardiology, in an article titled "Long-Term Prognosis of Patients Treated with Enhanced External Counter Pulsation: Five Year Follow-up Study," reported excellent long-term results with EECP, demonstrating a remarkably low incidence of adverse events in the EECP and a five-year survival rate among patients similar to those typically seen in CABG and PTCA trials. These favorable results confirm the promising results of earlier studies and support the use of EECP, which is FDA-approved and reimbursed by the Health Care Financing Administration (HCFA; Baltimore, Maryland), for patients who cannot undergo traditional therapies. Two companies participate in the EECP market – Vasomedical (Westbury, New York), a public company, and privately-owned Cardiomedics (Irvine, California).

TransVascular's pioneering approach

Perhaps the most intriguing of all the alternative revascularization technologies is being pioneered by privately-owned, venture capital-backed TransVascular (Menlo Park, California). Its revolutionary approach to revascularization is based on a substantial amount of basic research over the past five decades which has shown that the coronary veins have the potential to act as conduit vessels in patients with advanced CAD. Atherosclerosis is not seen in coronary veins, and their proximity to respective coronary arteries makes them attractive for use in revascularization.

TransVascular is actively developing two percutaneous, catheter-based approaches which are performed in the cardiac catheterization lab; the first is dubbed PICVA (percutaneous in situ coronary venous arterialization) while the second is referred to as PICAB (percutaneous in situ coronary artery bypass). The former allows arterialized blood to flow retrogradely through the anterior descending vein and may be useful for patients with chronic total occlusions in whom viable myocardium existed in the distribution of the occluded artery. PICAB may facilitate revacularization of coronary stenoses and does not require retroperfusion because the coronary vein functions only as a conduit for arterialized blood.

TransVascular has designed a series of instruments to perform these procedures. These can be divided into four basic categories: 1) Specialized sub selective and guide catheters, which are used to access and maintain stability for devices introduced into the coronary sinus and the venous system; 2) Its proprietary TransAccess catheters, which are novel devices to introduce a guide wire from one parallel vessel to another in a precisely-controlled fashion using standard visualization modalities; 3) Flow directing and blocking devices and delivery systems for creating instantaneous total or partial occlusion in an arterialized venous system; 4) Channel creation and maintenance devices designed to be delivered over a veno-arterial guide wire and to create a permanent conduit between the vessels.

At this year's ACC meeting, Dr. Stephen Oesterle, director of invasive cardiology at Massachusetts General Hospital (Boston, Massachusetts), reported on the first human case (which was performed in November 1999 in Germany), as well as his experience with extensive animal (swine) experiments. The procedure was very successful and, overall, appears to warrant further investigation. TransVascular hopes to initiate its U.S. human clinical trials sometime later this year or in early 2001, while an application for CE Mark will be submitted after further clinical trials are completed. The company believes that its patented and proprietary procedures, which it calls Cath-Lab Bypass, has the potential to be used in as many as 500,000 patients per year.