CDU Contributing Writer

BOSTON, Massachusetts The 83rd annual meeting of the American Association for Thoracic Surgery (AATS; Beverly, Massachusetts) provided one of the first forums for cardiac surgeons to discuss the future impact of the new drug-eluting coronary stents on patient management. In addition, advances in anastomotic devices and experimental coronary artery disease (CAD) were presented at an afternoon forum during the four-day AATS meeting held in early May at Hynes Convention Center.

Bruce Lytle, MD, of the Cleveland Clinic Foundation (Cleveland, Ohio), highlighted key benefits of coronary artery bypass graft (CABG) surgery in terms of longer life expectancy for those groups of patients with severe coronary artery disease (such as LAD lesions, multi-vessel disease, abnormal left ventricular function [LVF]) and superior angina relief in comparison with medical therapy.

Complete revascularization was presented as a key factor in positive long-term outcomes for CABG. For example, from the CASS study, for patients with abnormal LVF, survival rates at five and six years were superior for patients who had complete revascularization rather than incomplete revascularization. Lytle emphasized that out to 20 to 25 years, the difference in survival rates between patients with complete vs. incomplete revascularization is significant and continues to widen.

"We also know from those early days that vein graft failure is the Achilles' heel of bypass surgery," he said. Solving this dilemma was the development of the left internal mammary artery (IMA) graft to the left anterior descending (LAD) coronary artery, a technique Lytle believes to be the best anatomic treatment of any kind in coronary artery disease.

He said that the left internal thoracic artery (ITA) to LAD graft the "gold standard" procedure for coronary bypass surgery does not just stay patent more often but leads to better survival rates. Patients undergo fewer re-operations, have less angina and have fewer cardiac events than treatment with vein grafts or percutaneous therapy. "That is a major incremental benefit over any type of percutaneous therapy and always has been," he said of benefits seen in patients with single-, double- or triple-vessel disease.

In the BARI trial, using first-generation balloon angioplasty, by one year more of the patients with PTCA had angina and about half underwent re-intervention. Results with the second-generation PTCA, or bare-metal stents, were improved at 20% to 25% in the SoS trial but are still higher compared with bypass surgery. "Percutaneous therapies have improved," Lytle said. "However, they still did not and do not produce revascularizaton as well as surgery."

Still, despite the superiority in revascularization with surgery, the application of these percutanous technologies has increased, with a resulting decrease in the use of bypass surgery. "We have two decades of IMA to the LAD that basically has been without any problems at all," he said. "But instead the most often chosen form of therapy is to have some type of percutaneous intervention," a therapy he cites as delivering up to a 20% chance of re-intervention.

Drug-eluting stents and the long term

According to Lytle, the third generation of percutaneous intervention, drug-coated stents, have yet to confirm their ability to prevent restenosis. He agrees that the 10% in-segment restenosis rate at nine months followup in the SIRIUS drug-eluting stent trial is an improvement compared with bare metal stenting, but he is concerned over the long-term patency and survival results with drug-eluting stents. "We really have no concept whether this is going to extend from one year to 10 years or how it affects survival," he said.

Lytle acknowledged that use of drug-coated stents would decrease referrals for bypass surgery even though he believes patients would be trading superior long-term outcome to avoid having surgery. He said he believes the cardiac surgeon's response to decreasing referrals is to make bypass surgery a better operation. Examples include multiple interior grafting with two ITAs instead of one. Other strategies include making it less invasive, though he acknowledges surgery will never be less invasive than a femoral artery puncture. "We have to make certain we do not give up the long-term outcomes, though," he said, which can be achieved with ITA grafts, complete revascularization, alternative arterial grafts and the use of statins.

Drug-eluting stents to influence referrals

"I am guilty," said Martin Leon, MD, of the fact that he cannot provide 20-year data on stenting. But Leon also said he was proud to be "guilty" of placing the first commercially available drug-eluting stent in the U.S., Cordis' (Miami Lakes, Florida) Cypher, in April at Lenox Hill Hospital (New York). He projects an overwhelming clinical penetration rate such that by the end of this year, 80% of patients who have a percutaneous procedure will be in the cath lab receiving a drug-eluting stent.

"The last thing you want [as a cardiac surgeon] is an interventional cardiologist threatening your livelihood," said Leon. But he also went on to present results of the National Hospital Discharge Survey indicating the numbers for coronary bypass surgery have been steadily declining and in 2001 were the lowest since 1991. And he said he believes that bypass procedures will decrease by as much as 30% to 50% in the next three to five years.

"The goal of intervention always had been that we can achieve a safe procedure that was essentially complication-free, gave consistent procedural results, could be widely applicable and was definitive with no restenosis," Leon said. But the last goal has been elusive. He said he believes restenosis has been the Achilles' heel of the interventional cardiologist for the past 25 years but that drug-eluting stents will have an important impact on changing that perception.

Experimental work on the Cypher stent began in 1995. It is a three-component system integrating a stent with a drug carrier vehicle and the pharmacologic agent, sirolimus, an immunosuppressant agent with specific effects on the cell cycle. The drug elutes from the stent over a period of 30 days, with about half of it eluting in the first week.

The major study leading to the April FDA approval of the stent was the 1,058-patient SIRIUS trial. Among the worst patients in SIRIUS diabetics with a long lesion in a small vessel the repeat revascularization rate was 10.5% at nine months. With simpler patients non-diabetics in larger vessels and shorter lesions the revascularization rate was 1.6%. Leon said that for every 1,000 patients treated, 124 had a clinical event prevented. "I think that restenosis, if not being put to rest, has been dramatically impacted by this therapy," he said.

"To doubt the overwhelming benefits of drug-eluting stents as an anti-restenosis therapy is like burying your head in the sand," Leon noted. But since these are early days with drug-eluting stents, issues remain including the need for more long-term data and more patient data. Peri-procedural adjunctive pharmacology is still under discussion as well. Optimal operator technique issues are still being hotly debated, and the long-term effects, such as late thrombosis, restenosis or progressive disease, still need to be evaluated.

Leon acknowledges that Cypher stent pricing ($3,195 in the U.S. or EUR 2,000 in Europe) currently influences operator strategy and clinical penetration rate. In the SIRIUS trial drug-eluting stent therapy was about $1,200 more expensive at one year. "But as an ethical question, can anyone afford not to use drug-eluting stents for the majority of their patients?" he asked.

"We are about to enter a new era of advanced percutaneous intervention of ultra-complex patients and lesions," said Leon. The first patients to receive a drug-eluting stent will probably be those with single- or double-vessel disease, 2.5 mm to 4 mm diameter vessel disease, up to perhaps 30 mm lesion length. The next tier will be higher restenosis risk patients such as simple diabetics and patients with acute MIs, diffuse disease and more complex double and triple vessel disease. The most challenging anatomic scenarios will be last to receive drug-eluting stents. "This is attacking the unthinkable like left main disease and diabetics with complex multivessel disease," Leon said. He said he hopes to get funding for the FREEDOM trial, designed to address treatment in diabetics with multi-vessel disease.

New devices for anastomoses

Randall Wolf, MD, of Ohio State University Medical Center (Columbus, Ohio), said that until recently, not much had changed in the way surgeons suture blood vessels compared with the technique of Alexis Carrel, the so-called father of vascular anastomosis, who received the Nobel prize in 1912. But anastomic procedures for coronary surgery are big business, with more than 5.1 million anastomoses performed annually worldwide. Of those, 73%, or about 3.5 million, are proximal and distal coronary artery bypass graft anastomoses.

Proximal and distal anastomotic devices have different value compositions, according to Wolf. For the proximal devices, surgeons are interested in decreasing any neurologic deficits. With distal devices, the goal is to enable minimally invasive coronary surgery procedures.

"A lot has happened with proximal connectors in one year," said Wolf. "Not only do we have automatic proximal devices now, but we also have manual assist devices, including the Guidant [Indianapolis, Indiana] Heartstring Aortic Occluder and the Novare [Cupertino, California] Enclose device." He said he believes these devices both FDA-approved have the potential to decrease aortic trauma while allowing the surgeon to perform a conventional anastomosis.

Wolf said the first proximal automatic anastomotic device, the St. Jude Symmetry from St. Jude Medical (St. Paul, Minnesota), now has about 43,000 implants worldwide. The company is working on a second-generation side-to-side device in response to patency and acute failure rumors. Others include Cardiovations' (Somerville, New Jersey) Corlink, FDA-approved and now in the PASSAGE (patency and stenosis study for graft equivalency) post-marketing trial; Cardica's (Menlo Park, California) PASport, which is in European trials and has shown patency of 91% at six-month angiograph follow-up; and Ventrica's (Fremont, California) MagnePort Coalescent Spider, for which clinical implants will begin this summer.

Many distal devices

"If you look at anastomotic devices, the distal devices are really the next big thing," Wolf said. The first distal anastomotic device was the Coalescent Surgical (Sunnyvale, California) Unite clip, a non-automated device that allowed surgeons to do interrupted distal anastomoses without tying knots. "They clearly do work," he said. Other players with at least some clinical data available include St. Jude, Cardica, Ventrica (MVP Series; European trial enrollment just about finished; initial six-month angiograms look very good), Converge (just began clinicals in Europe), Jomed (Beringen, Switzerland), Itech and Vasoconnect (Walnut Creek, California).

"We need to have these disruptive technologies in order to move into a smaller-incision environment," Wolf said. He said he believes the value of anastomotic technology will be greater in small-access coronary bypass grafting, but predicts that when coronary vascular connectors are proven to work reliably and consistently, cardiac surgeons will use them for most cases because they will be faster and more reliable.

Experimental approaches to revascularization

Each year, 350,000 CABG procedures are performed in the U.S. for things like multi-vessel CAD, degenerated vein graft, chronic total occlusions, left main disease, repetitive restenosis and concomitant valve disease. But like Leon, Medtronic's (Minneapolis, Minnesota) Stephen Oesterle, MD, agrees that CABG procedures will decline 50% in the next three to five years. "But there are new things beyond coated stents," he said.

Oesterle, a well-known cardiologist affiliated with Massachusetts General Hospital (Boston, Massachusetts) before joining Medtronic early in 2002 as senior vice president of medicine and technology, said he believes degenerated vein grafts are the major cause of adverse clinical outcomes in the cath lab. Many companies are developing technologies focused on relining vein grafts before they fail, he said. One approach is the use of a covered stent and the other is a series of initiatives to engineer artery-like stent-grafted materials.

Examples of covered stents include the Jomed Jostent and W.L. Gore's (Flagstaff, Arizona) small ePTFE heparin-coated stent graft designed to realign vein grafts before they fail. Oesterle cautioned that no clinical data is available yet.

Percardia's (Merrimack, New Hampshire) novel system for revascularization includes a shunt from the ventricle to a vessel. "It has been demonstrated you can get systolic flow from the ventricle into the coronary vessels, confounding what all of us believed could be possible physiologically," he said.

About $250 million is invested in new techniques for percutaneous valve repair, Oesterle noted. Repairs for mitral regurgitation may include annular dilatation with new devices.

Viacor (Danvers, Massachusetts) has developed new ways for trans-sinus annuloplasty. MitraLife's (Santa Rosa, California) C-Cure is designed to reshape the coronary sinus. E Valve is exploiting the Alfieri stitch with its technology, and Percutaneous Valve Technologies (Fort Lee, New Jersey) is developing a stented valve, now in European clinical testing.