CDU Contributing Editor

According to statistics from the American Heart Association's (AHA; Dallas, Texas) 2001 Heart and Stroke Statistical Update, more than 60 million Americans suffer from one or more types of cardiovascular disease (CVD). Of this total, 12.4 million people in the U.S. suffer from coronary artery disease (CAD), with 6.4 million suffering from angina pectoris. Since 1900, CVD has been the No. 1 killer in the U.S. in every year but 1918. It is the leading cause of death and disability in the U.S., directly causing nearly 1 million deaths annually. CAD, characterized by a narrowing of the coronary arteries that supply blood to the heart muscle, caused roughly one-half of those deaths and is a huge cause of morbidity as well.

The magnitude of CVD in the U.S. is amply demonstrated by the recent release of 1997 hospital data from the Agency for Healthcare Research and Quality (AHRQ; Rockville, Maryland), which noted that nearly 9 million hospital admissions a year, or one of every four hospital stays, involve use of a diagnostic imaging test, surgery, or other procedure for heart and circulatory system problems. According to AHRQ, the four most common cardiovascular procedures for adults are cardiac catheterization (3.9 million patients per year), open-heart surgery (739,000 patients); echocardiograms (641,000 patients) and coronary angioplasty (608,000 patients).

The advances in treating CVD in general and CAD in particular over the past two decades have been truly remarkable, with major technological improvements on numerous fronts. Yet, despite this progress, a significant number of CAD patients reach the stage when all available or applicable therapeutic options have been exhausted. As shown in Table 1, the domestic market size of this group of patients, who are euphemistically referred to as "no option" patients, is believed to be in the 52,000 to 70,000 range per year.

One of the therapeutic alternatives for this desperate group of patients is transmyocardial revascularization (TMR), a surgical procedure that is aimed at improving the perfusion of oxygenated blood to the myocardium. This is achieved by using laser energy to create numerous (from 15 to 50) channels or pathways through the myocardium directly into the left ventricle. TMR first attained FDA approval in August 1998, when PLC Systems (Franklin, Massachusetts) gained marketing clearance for its CO₂ laser. This was followed by a February 1999 FDA approval for the Eclipse Surgical Technologies (Sunnyvale, California) solid-state holmium YAG laser. Cardiovascular Device Update estimates that PLC Systems has an installed base of approximately 160 lasers worldwide (roughly half in the U.S.), while Eclipse Surgical Technologies has an installed base of about 260 lasers in the U.S. and an additional 65 elsewhere. An estimated 15,000 to 20,000 TMR/PTMR procedures have been performed worldwide since human use began.

Trials show TMR as efficacious and safe

A plethora of clinical trials conducted worldwide over the past five years have consistently demonstrated that TMR is a very efficacious and safe procedure, as 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. TMR's sustainable, long-term benefits were presented at the American Heart Association's annual scientific sessions in November 2000, when Dr. Keith Horvath of Northwestern University Medical Center (Chicago, Illinois) presented a paper titled "Sustained Angina Relief Five Years After Transmyocardial Revascularization with a CO₂ Laser," using the PLC Systems laser. The average pre-TMR angina class for the 78 patients at the eight clinical sites in the study was 3.7. Pre-TMR, 66% had unstable angina, 73% had suffered at least one myocardial infarction, 93% had undergone at least one coronary artery bypass graph, 42% had at least one angioplasty, 74% were in angina class IV and 26% were in class III. One year after TMR, the average angina class was recorded at 1.5. More impressively, at 4.6 years, the average angina class remained virtually unchanged at 1.6. Some 17% of the patients had no angina after five years and 64% were in class I or II. By this criterion, 68% of the patients had successful long-term angina relief. Table 2 provides a description of the delineation between the four classes of angina.

Following the release of this study, Horvath noted, "The significance of the study has a global impact on TMR. The findings establish CO₂ TMR as a revascularization technique that achieves long-term angina relief for patients. Also, the long-term data validates the use of CO₂ TMR for the surgical community as a standard of care when treating patients with diffuse vessel disease, which is currently an obstacle when treating severe angina patients."

Despite these inspiring results, TMR has long been and continues to be a highly controversial procedure. The skeptics attribute TMR's benefits to a placebo effect, point to the minimal or absence of improvement in myocardial perfusion and assert that since its exact mechanism of action has never been completely understood, it cannot become a mainstream therapy for "no option" patients.

Without doubt, TMR has been best accepted in the medical community when performed in conjunction with a CABG procedure. CDU believes that at least 75% of all TMR procedures are employed in this manner. In May, the Blue Cross and Blue Shield Association's Technology Evaluation Center (TEC; Chicago, Illinois) completed a favorable assessment of TMR as adjunctive therapy to CABG surgery. The TEC program is sponsored by the national Blue Cross and Blue Shield Association, whose members include local Blue Cross and Blue Shield plans nationwide, as well as other major managed care organizations. TEC concluded that TMR, in combination with bypass surgery, meets the criteria used to evaluate medical technologies. This includes scientific evidence of improvement in health outcomes, net benefit in health outcomes, health outcomes at least as beneficial with any established alternative and improvements achievable outside investigational settings. TEC's determination that TMR plus bypass meets its criteria is a significant step in obtaining reimbursement for the combined therapy by major insurance payers, which will foster further market acceptance.

Benefit/no benefit battle continues

The longstanding TMR controversy has heated up considerably in the past several months. At the October 2000 Transcatheter Cardiovascular Therapeutics (TCT) meeting held in Washington, the six-month follow-up results of the DMR In Regeneration of Endomyocardial Channels Trial (DIRECT) the first placebo-controlled, blinded study of percutaneous direct myocardial revascularization (DMR), were presented by the principal investigator, Dr. Marty Leon of Lenox Hill Heart and Vascular Institute (New York). This trial, which included 298 patients from 14 centers and used the holmium YAG laser system from Biosense Webster (Diamond Bar, California), a division of Johnson & Johnson (New Brunswick, New Jersey), showed no benefit of DMR on either exercise tolerance or angina assessments among symptomatic patients not candidates for CABG or PTCA, over placebo. Both groups were measurably and significantly better off on both of these endpoints, suggesting an extremely robust placebo effect. Those results were updated at the 50th annual scientific sessions of the American College of Cardiology (ACC; Bethesda, Maryland) in March, when Leon disclosed that the 12-month follow-up showed equally dismal results.

For TMR supporters, this information was hugely disappointing, while for longstanding naysayers, it provided sweet vindication. However, at the same ACC meeting – in fact, later that same day – data from another percutaneous TMR (PTMR) clinical trial showed outstanding benefits. The BELIEF (Blinded Evaluation of Laser Intervention Electively For Angina Pectoris) trial, conducted by Dr. Jan Erik Nordrehaug, who chairs the department of heart disease at University Hospital (Bergen, Norway), was the first double-blinded study of the Eclipse Surgical PTMR laser system. In an interview with CDU after release of this data, Nordrehaug said that he had been very skeptical about PTMR's clinical efficacy and was surprised by these robust results.

The trial's primary endpoint was to determine if PTMR improved angina by one or more functional classes (according to the Canadian Heart Association angina scale) in patients with Class III or IV angina with a secondary endpoint to see if PTMR improved exercise tolerance and oxygen uptake. The study included 82 patients (40 were randomized to PTMR, 42 to the sham or placebo arm) at six sites and there was no crossover allowed from the control group to the treatment arm. The study was double blinded, i.e., the procedure was performed without the patient or physician knowing whether laser energy was actually delivered. At six-month follow-up, 64% of the PTMR patients experienced at least a one-class drop in their angina class, compared to 38% of those receiving the sham treatment. With regard to a two-class improvement in the angina level, the tally was 41% of the PTMR group, vs. just 13% in the control arm. It is significant to note that the number of patients achieving a two-class improvement closely mirrors those of the earlier 221-patient Potential Angina Class Improvement From Intramyocardial Channels (PACIFIC) trial, which is the basis of the Eclipse Surgical premarket approval submission to the FDA for PTMR. While there was no statistically significant difference in exercise duration between the two groups, the time until a patient experienced chest pain during treadmill exercise increased 76 seconds from baseline for the PTMR cohort, but dropped 12 seconds in the sham arm.

Given the wide divergence in the DIRECT and BELIEF trials, it behooves industry observers to ponder how the difference in the two randomized, double-blinded trials can be explained. The most credible explanation is that there are variances in the different properties of the lasers used. Specifically, the Eclipse Surgical system generates four times the energy and four times the number of pulses per second of the Biosense Webster system, thus likely penetrating the myocardium more deeply and causing greater angiogenesis.

On July 9, Eclipse Surgical will appear at the FDA's Circulatory Systems Device panel meeting and the data will be carefully reviewed by nine cardiovascular medicine physicians from all over the U.S. Should the panel give the FDA a recommendation to approve the Eclipse Surgical PMA submission, it is likely that PTMR final approval will occur before year-end 2001 and an intense marketing campaign will then be directed toward the interventional cardiology community. This will place Eclipse, which in mid-June changed its name to CardioGenesis, in a very enviable position, with the only FDA-approved laser system for performing percutaneous TMR. The PLC Systems CO₂ laser cannot perform PTMR because its energy cannot be delivered percutaneously.

Controversy has limited TMR investment

The longstanding controversy surrounding TMR has discouraged most cardiovascular device companies and some venture capitalists from committing substantial resources to gain market access. The negative publicity from the DIRECT trial encouraged Edwards Lifesciences (Irvine, California), which at one time was in the midst of human PTMR clinical trials, to abandon its PTMR efforts. However, in January Edwards said it would begin domestic marketing of the second-generation (smaller, lighter) PLC Systems CO₂ laser. With a U.S. sales force of about 200, many of those calling on cardiovascular surgeons, Edwards Lifesciences could become a potent force in the still-fledgling TMR surgical market. The company's CEO, Mike Mussallem, has said that while TMR has been a controversial technology, "our physician customers believe that TMR is a very effective and safe procedure."

Although there has been no official word from Biosense Webster or its parent, Johnson & Johnson, CDU suspects that it will relinquish its PTMR development effort. Privately-owned, venture capital-backed Angiotrax (Sunnyvale, California) was in early clinical studies for a novel, non-laser mechanical myocardial channeling technology and reported promising human results from its feasibility trial at the 2000 ACC gathering. However, following release of the DIRECT trial, the company experienced funding problems, and CDU believes that the company may now be defunct or in a reorganization to salvage its assets. Meanwhile Radius Medical Technologies (Maynard, Massachusetts), which was developing a thermo-coupled, temperature-controlled RF energy device to create laser channels, appears to have shifted its resources toward the delivery of gene therapy.

Conversely, Boston Scientific (Natick, Massachusetts) appears to be pressing ahead with its revascularization efforts. Its technology, which uses a 9 Fr catheter and steerable guidewire to deliver RF energy percutaneously, has now been successful in limited human trials and will soon begin a pivotal trial.

Its RF generator is being supplied by Arthrocare (Sunnyvale, California), which has licensed its coblation technology, that 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.

Another company moving forward with a catheter-based revascularization effort is CryoCath Technologies (Kirkland, Quebec), which has developed a cryothermic, deflectable percutaneous catheter to treat severely ischemic patients. In late 2000, the company commenced enrollment of 20 patients in its Pilot study Of Low-temperature Angiogenic Revascularization (POLAR) trial at the Montreal Heart Institute (Montreal, Quebec) and at St. Michael's Hospital (Toronto, Ontario). This feasibility study was expected to be completed by mid-2001. This novel procedure uses cryotherapy to treat multiple points within the myocardium in order to stimulate new blood vessel growth. 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 and angiogenic response.

The sizable TMR market opportunity, as detailed in Table 1, is expected to be derived from several different types of patients, including:

1) Patients who are deemed to be "no option" or end-stage patients who, due to having undergone previous procedures, physical inability to tolerate PTCA or CABG or due to their coronary anatomy, are candidates only for TMR or PTMR.

2) A second group is made up of patients who may benefit from TMR adjunctively in conjunction with a CABG procedure. With the tremendous market growth of minimally invasive coronary surgery, now accounting for an estimated 20% of all CABG procedures, this market niche has become significant.

3) A third subset of patients who could benefit from TMR/PTMR are those who might be candidates for a CABG "re-do," which now accounts for an estimated 20% of total CABGs performed. Many of these patients are old and frail but could tolerate a minimally invasive PTMR procedure.

4) A small subset of angioplasty patients could also be beneficiaries of PTMR, which would be performed adjunctively to a PTCA procedure.