CDU Contributing Editor
WASHINGTON – Although dramatic progress has been made in the past several years to improve the clinical outcomes of the approximately 1 million Americans annually receiving a coronary intervention – either angioplasty or coronary artery bypass graft (CABG) – the cardiology community remains frustrated by the high percentage of cases that require another intervention. That frustration and various efforts to ease it were very much in evidence during this year's Transcatheter Cardiovascular Therapeutics (TCT) conference, held here in the latter part of October.
TCT, sponsored by the Cardiovascular Research Foundation and Lenox Hill Heart and Vascular Institute (New York), is now regarded as the world's premier interventional vascular conference. It provides attendees with the opportunity to view numerous live cases from cath labs around the world, as well as attend a plethora of symposia and lectures discussing the latest clinical trial results. This year's TCT gathering drew an international audience of more than 10,000 interventional cardiologists and company representatives.
The broad question of "re-do" procedures, and efforts to avoid them, was a major focus of the conference. Several factors contribute to the re-closure of revascularized coronary arteries, but injury to the vessel wall clearly appears to be the most prominent culprit. An early reaction to wall injury can trigger abrupt re-closure while the late reactions are caused by the stimulation of new tissue growth (neointimal hyperplasia), which develops over several months.
Coronary stents have been a tremendous addition to the interventionalist's armamentarium, nearly eliminating episodes of emergent abrupt re-closure by acting as a prop against vessel recoil. However, stents still are not the final solution, since numerous clinical trials have established a post-stenting restenosis rate in the 25% to 30% range.
Vascular brachytherapy (VBT), recently approved by the FDA for treating in-stent restenosis, will be marketed by Novoste (Norcross, Georgia) and the Cordis Cardiology (Miami Lakes, Florida) division of Johnson & Johnson (New Brunswick, New Jersey). While VBT has exhibited solid benefits for post-stenting restenosis, the jury is still out on whether this somewhat expensive and cumbersome technology will be widely adopted in preventing de novo lesion restenosis.
For the latter problem, in recent years many pharmaceutical agents have shown initial promise then have seriously disappointed in larger clinical trials. However, the search for a "magic bullet" has continued. A session titled "Stent-Based Local Drug Delivery" noted that, while the data is preliminary, polymeric, surface-coated stents may mitigate or perhaps even eliminate neointimal hyperplasia and thus solve one of the most troublesome issues in the field of interventional cardiology.
Studies eye paclitaxel, rapamycin
In particular, two agents that are currently FDA-approved for other applications were the subject of several talks at TCT. Paclitaxel, sold by Bristol-Myers Squibb (Princeton, New Jersey) under the brand name Taxol, is an outstanding and widely sold drug for the treatment of breast cancer. Several speakers noted that paclitaxel is a proven, potent immunosuppressive agent that in animal trials has shown that it can blunt the growth of neointimal hyperplasia. Delivery of this compound as a coating on a coronary stent thus may be an elegantly simple method of reducing in-stent restenosis.
Two large interventional cardiology companies – Boston Scientific (Natick, Massachusetts) and Cook (Bloomington, Indiana) – are now in the midst of clinical trials in Europe. The former has just released its paclitaxel-coated coronary stent, while the latter has already implanted this promising device in several hundred European patients. Both companies have licensed this technology from publicly-traded Angiotech Pharmaceuticals (Vancouver, British Columbia, Canada) on a co-exclusive, worldwide basis and will market these products directly assuming that the clinical trials are successful and the relevant regulatory hurdles are met.
Another company, privately-owned Quanam Medical (Santa Clara, California), has developed a novel drug delivery device, which features a non-biodegradeable proprietary polymer that is impregnated with a derivative of paclitaxel called taxane. This device has been implanted in both Argentina and Germany, the latter site under the auspices of the highly-regarded interventionalist Dr. Eberhard Grube of the Heart Center Siegburg (Siegburg, Germany). Grube had presented his initial, promising results at this year's annual scientific sessions of the American College of Cardiology (Bethesda, Maryland), indicating that there was no evidence of neointimal hyperplasia evident after an average of eight months of follow-up. At TCT, Dr. Jeffrey Popma, director of interventional cardiology at Brigham & Women's Hospital (Boston, Massachusetts), provided updated results on this device, noting that "these highly promising results warrant further investigation."
Two significant clinical trials will be conducted; one is called the Study to Compare Restenosis Rate between Quest and Quad QP-2 (SCORE) trial with 200 (of 400 total to be enrolled) in Europe already enrolled and a second called the Quanam Trial to Reduce Restenosis (QUATTRO) trial, with 1,000 patients in the U.S.
Extremely promising results were provided on the compound rapamycin, another potent immunosuppressant and anti-proliferation agent. Known by the brand name Rapamune and sold by the Wyeth-Ayerst Laboratories (Radnor, Pennsylvania) division of American Home Products (Madison, New Jersey) as a post-kidney transplant immune suppressant, this drug is delivered as a coating on the BX Velocity stent, a recent addition to the stent portfolio of Cordis Cardiology. This combination device elicited a tremendous response at TCT after the stellar results of 45 human cases, followed for six months, were presented. Fifteen patients were treated at the Thoraxcenter (Rotterdam, the Netherlands) by noted interventionalist Dr. Patrick Serruys and 30 were treated at the Institute Dante Pazzanese of Cardiology (San Paolo, Brazil) by Dr. Eduardo Sousa and his colleagues. The complete absence of restenosis or other major adverse coronary events in the several months of follow-up prompted Serruys to joke, "don't pinch me, don't wake me; I want to keep dreaming about these results." Dr. Alexandre Abizaid of the Institute Dante Pazzanese, in an equally ebullient mood, gushed that "if the preliminary promise of rapamycin is realized, this could become the next revolution in percutaneous coronary intervention."
Enrollment for the Randomized Velocity Lesions (RAVEL) trial, a randomized, multicenter pivotal European trial, is expected to be completed by year-end, with possible CE-mark approval by late 2001. In the U.S., the pivotal Sirolimus United States (SIRIUS) trial is expected to commence in early 2001, with 1,100 patients to be enrolled at 55 centers. If all goes well, final FDA approval is possible in late 2002 or 2003.
Several other promising anti-restenosis technologies were discussed at TCT. Privately-owned, venture capital-backed Pharmasonics (Sunnyvale, California) gained significant prominence, as two live cases were performed using its proprietary Intravascular Sonotherapy (IST) technology. This catheter-based, therapeutic ultrasound approach, based on the use of non-ionizing (safe) ultrasound has shown excellent results in clinical trials for both de novo and in-stent restenosis therapy.
In early 2000, the company initiated its first human studies, the Sonotherapy for In-Lesion Elimination of Neointimal Tissue (SILENT) trial, which demonstrated short-term safety and procedural feasibility. Based on this success, the FDA recently granted Pharmasonics approval to expand to a larger, pivotal trial called Sound Wave Inhibition of Neointimal Growth (SWING), which will enroll 1,200 patients in 60 U.S. centers. This trial is targeted toward the prevention of stent restenosis in patients undergoing de novo stent placement in a single native coronary. The company also is planning to submit an application for the treatment of in-stent restenosis with another study called Sonotherapy Prevention of Late Arterial In-Stent Hyperplasia (SPLASH). It expects to enroll 500 patients in most of the same centers as the SWING trial.
Angiosonics (Morrisville, North Carolina) also is pursuing ultrasound technology to treat restenosis. It is collaborating with the Cleveland Clinic (Cleveland, Ohio). Its main thrust is to reduce the restenosis rate in the setting of acute myocardial infarction, with six-month follow-up results showing significant benefit in reducing the restenosis rate. Angiosonics' data suggests that applying therapeutic ultrasound energy, which the company calls the Acolysis Ultrasound System, can inhibit the restenosis process and optimize vessel wall healing through the process of apoptosis, or programmed cell death.
Another company whose technology shows excellent results for treating restenosis is privately-owned Interventional Technologies (San Diego, California). Its Cutting Balloon device features a non-compliant balloon with three or four microsurgical blades mounted longitudinally on its outer surface. This produces a controlled incision of atherosclerotic plaque, allowing for dilatation of the target lesion with less force and a reduction in trauma to the artery. The Cutting Balloon was favorably featured in numerous live TCT cases, as well as discussed in a plethora of oral abstracts. The device, which received FDA-approval earlier this year, showed excellent results in treating in-stent restenosis, ostial and other hard-to-treat lesions in an elegant way. In particular, the Cutting Balloon significantly reduces the rate of repeat revascularizations for in-stent restenosis, and is especially adept in treating small vessel lesions.
Trial results a setback for TMR
Whereas there is considerable hope and promise for myriad new anti-restenosis approaches, two technologies that heretofore have been highly regarded by many interventionalists have suffered a decline in their clinical credibility. Transmyocardial revascularization (TMR), an approach to coronary revascularization that uses laser energy to create tiny channels in the myocardium, has gained FDA approval in the surgical arena either as sole therapy mainly for very-late-stage "no option" patients or as adjunctive therapy to a CABG procedure. The interventional cardiology community has been optimistic that a percutaneous TMR or PTMR (femoral artery to access the myocardium) approach could attain FDA approval. Indeed, results of the PACIFIC (Potential Angina Class Improvement From Myocardial Channels) trial showed that the treatment arm enjoyed significant benefits vs. the medical management cohort in the reduction in angina class and improved exercise tolerance.
At TCT, the 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. This trial, which included 298 patients from 14 centers and used the Biosense Webster (Diamond Bar, California; a division of Johnson & Johnson) holmium YAG laser system, 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.
TMR skeptics, who have long insisted that its benefit was heavily related to a placebo effect, felt vindicated by this study. Dr. Martin Leon, TCT's program director and principal investigator of the DIRECT trial, noted that the trial "indicates no clinical benefit associated with laser myocardial revascularization procedures. The blinding process clearly demonstrates a profound placebo effect in 'no option' patients with severe angina when exposed to a new, innovative technology with presumed therapeutic actions."
Leon added, "I believe that all other TMR/PTMR clinical trials should be viewed with caution and skepticism unless proper attention is taken to account for placebo effects of experimental therapies." Moreover, he said he would "argue strenuously" with anyone who says one of the catheter-based systems is different than the others, and that these results would not apply. "I'm going to have a hard time if people say it is apples and oranges. This is an apples-to-apples comparison."
The backlash to these comments from PLC Systems (Franklin, Massachusetts) and Eclipse Surgical Technologies (Sunnyvale, California), the two companies with surgical TMR marketing approval, has been strong. The former has insisted that surgical TMR, using its proprietary carbon dioxide laser, is fundamentally very different than a YAG laser used to perform either surgical or percutaneous TMR. The latter has stated that its approach to the creation of PTMR channels is different from the channels created by the laser used in the DIRECT trial. Eclipse submitted a PMA application for PTMR, based on the PACIFIC trial data, in December 1999 and was hopeful of an approval in 2001. The results of the DIRECT trial clearly have complicated its efforts to attain regulatory marketing clearance in the U.S. PTMR has been available in Europe for several years.
Several problems plague gene therapy
Gene therapy, whose goal is to promote angiogenesis to aid the revascularization of late-stage coronary artery patients, is another therapy whose stock has slumped. Hailed by the American Heart Association (Dallas, Texas) as one of the top 10 research advances in 1998, gene therapy has been plagued with a host of challenges that has set back its clinical and regulatory timelines. In addition to the highly-publicized deaths that occurred in clinical trials in late 1999 and the mixed results reported in the past year for key clinical trials, gene therapy suffers from far more basic problems.
Dr. Mike Simons, a noted gene researcher who is director of the Angiogenesis Research Center at Beth Israel Deaconess Medical Center (Boston, Massachusetts) and associate professor of medicine at Harvard Medical School (also Boston), noted that there are two widely divergent possible viewpoints on angiogenesis. One holds that it is an emerging treatment modality that will have an impact comparable to beta-blockers, coronary bypass surgery and angioplasty combined. The other view, Simon said, "is that it is a fruitless attempt to influence a process we do not understand, with agents that we do not know how to use, relying on the endpoints we cannot assess." The latter statement clearly points out that gene therapy still has fundamental issues that need to be addressed before it can become an important revascularization therapy.
Among the many unresolved issues is what is the optimal method to delivery gene therapy to the target site. While the delivery of viral vectors is relatively efficient, it is associated with significant tissue reactions at clinically relevant dosage levels. Less-toxic plasmid-mediated gene delivery strategies encounter efficiencies too low for an adequate therapeutic effect.
An abstract titled "In Vivo Plasmid-Mediated Gene Delivery Achieves Viral Efficiencies via Intravascular Ultrasound," from Phillippe Amabile, MD, et al., from Stanford University (Stanford, California), was presented at this year's annual scientific sessions of the American Heart Association. This small animal model trial suggests that adding intravascular ultrasound improves the efficiency of both viral and plasmid-mediated gene therapy. This strategy can be used to either decrease viral doses to safer levels or, more promisingly, to employ safer nonviral strategies at tremendous efficiencies. The ultrasound device is manufactured by privately-owned, venture capital-backed EKOS (Bothell, Washington).
Another company focused on the delivery of genetic growth factors is privately-owned, venture capital-backed AngioSense (Cupertino, California), which has developed a needle-free, jet-injection delivery system for cardiovascular gene therapy. This project represents a strategic collaboration that began about a year ago with Bioject Medical Technologies (Portland, Oregon) whereby the latter's needle-free drug delivery systems are being modified to deliver bio-therapeutics, with several proprietary catheters being developed by AngioSense for catheter-based cardiology interventions. This fall, AngioSense and Repair (Boston, Massachusetts) reported that they will jointly pursue clinical applications for the delivery of fibroblast growth factor, with the former supplying its delivery system and the latter providing its proprietary line of therapeutic agents to treat cardiovascular disease. The research which fostered this alliance was conducted at the Angiogenesis Research Center at Beth Israel Deaconess Medical Center.
A novel gene delivery system was reported in the November 2000 issue of Nature Biotechnology. Dr. Robert Levy of the Children's Hospital of Philadelphia (Philadelphia, Pennsylvania) and colleagues have created a gene-polymer mixture coated with circular pieces of naked DNA carrying a green fluorescing protein that is spread onto stents. This permits localized transfer of the gene to the smooth muscle cells of the coronary arteries. The researchers deployed the gene-coated stents in porcine coronary arteries and tested the coated rods in vitro on tissue cultures. Within seven days, the DNA successfully left the steel surface and entered nearby cells to produce the fluorescing protein. The gene transfer was limited and localized, and the majority of cells that fluoresced were located in the media of the stented artery wall. This delivery strategy may be used to either decrease viral doses to safer levels or, more promisingly, to use safer non-viral strategies at tremendous efficiencies.