Exploring the Final Frontier of PCI

Despite its challenges, CTO PCI has a powerful draw for those who see its promise.

PCI for chronic total occlusion has been shown to provide multiple benefits, including relief of angina, improved exercise tolerance, improvement in left ventricular function and improved mortality rates. Yet, the complexity of such procedures, which require specific training, has served as an obstacle to their widespread use.

“Many interventional cardiologists, while they are very skillful in conventional interventions, have not systematically been trained in CTO interventions,” said Ken Fujise, MD, director of the division of cardiology at University of Texas Medical Branch. “It is also recognized that CTO techniques are sometimes counterintuitive to standard interventional techniques. So, at first, some [interventionalists] may not feel comfortable doing CTO cases.”

Other issues such as significant cath lab time, exposure to radiation and historically low success rates have also served as deterrents to the use of PCI in CTO. According to Gregg W. Stone, MD, director of cardiovascular research and education at Columbia University, New York, these low success rates can be partly attributed to a longtime lack of innovations in technology and technique.

“In general, the success rates are traditionally in the 50% to 60% range, and for many years, there have not been any new techniques or advances in technology to help improve those success rates,” Stone said.

However, recent developments in CTO intervention have yielded improved success rates and with them a renewed interest in tackling such cases. By learning and frequently utilizing these new techniques and devices, previously reluctant cardiologists can begin to undertake CTO interventions with confidence. And for those who have mastered this challenging procedure, CTO intervention is nothing short of a calling.

“It’s something I’m passionate about, and it’s something my colleagues are passionate about,” said M. Nicholas Burke, MD, director of cardiovascular emergency programs at Minneapolis Heart Institute, Minneapolis. “It’s absolutely the right thing to do for our patients.”

Innovations in Technique

The evolution of CTO PCI techniques from the traditional antegrade wire escalation approach has made it easier to enter the distal true lumen, even in cases where lesions are fibrous or heavily calcified. Techniques like antegrade dissection/re-entry and retrograde crossing are useful in preventing wires from being misdirected into the subintimal space, Burke said.

“A successful CTO is predicated on the presence of a wire in the true lumen, both proximal and distal to the lesion. And it’s traditionally difficult to get a wire into the distal vessel; the wires follow the path of least resistance, which is generally between the layers of the artery, into the subintima,” Burke said. “So, very long, calcified or tortuous CTOs were once predictors of failure, but they aren’t anymore, because we now have techniques where we can dissect past the blockage and re-enter the true lumen. And we do that both antegrade or retrograde, through collateral channels.”

In the retrograde technique, which was pioneered in Japan, the wire goes through the contralateral vessels and through a small collateral, and is advanced through the back end of the occlusion, according to Emmanouil S. Brilakis, MD, PhD, director of the cardiac catheterization laboratory at the VA North Texas Health Care System, Dallas, and author of the “CTO Corner” column for Cardiology Today’s Intervention.

“In the largest retrograde CTO PCI registry published to date, good success and low complication rates were observed with this technique at three US sites,” Brilakis said.

The antegrade dissection/re-entry approach involves forming a “knuckle” with a wire or using a dedicated CTO crossing device (CrossBoss, Bridgepoint Medical/Boston Scientific) that is advanced subintimally through the CTO, with subsequent re-entry into the true lumen.

“With this, we use devices that travel alongside the occlusion, without exiting the vessel and causing a perforation,” Brilakis said.

For cardiologists without experience, this approach may feel unnatural at first, according to Barry D. Rutherford, MD, director of interventional cardiology at Saint Luke’s Mid America Heart Institute, Kansas City, Mo.

“Up until this point, most cardiologists have only been comfortable working in the true lumen of the vessel. So when they get out into the subintimal space, they will be concerned about that,” Rutherford said. “This technology requires some experience to become accustomed to it, and for a cardiologist to be very comfortable working in the subintimal space.”

Stone said for those who have mastered this technique, the success rates have been very impressive.

“There has been a group of users — a dozen or so — who have gotten very good at this technique,” he said. “They are getting success rates of about 90% with CTOs going extraluminal and then re-entering.”

Recent, Upcoming Trials

The advancement of CTO PCI has, to some extent, been hindered by a lack of randomized trial data. To date, there have been no prospective, randomized trials evaluating CTO intervention vs. medical therapy or bypass surgery.

“It’s been difficult to do any randomized trials. Nobody stands to gain economically, so there’s no industry behind a randomized trial,” Rutherford said. “And some of the CTO PCI naysayers will use that as a fallback saying, ‘There are no randomized data.’ My response to that is that the best available data, absent randomized trials, suggest a clear benefit.”

Brilakis said there are currently two trials ongoing in Europe and Korea.

“There’s one trial in Europe performed by the EURO CTO Club and one in Korea called DECISION-CTO that are comparing CTO PCI with medical therapy alone. But those won’t be completed for 3 to 5 years,” he said. “So clinical decisions will have to be based on non-randomized data until then.”

Nevertheless, recent studies continue to support the benefits of CTO intervention, including one in a 2012 study published in the Journal of the American College of Cardiology: Cardiovascular Interventions. The study, conducted by researchers in the United Kingdom, found that successful recanalization of CTOs is linked to improved long-term survival.

“Thus, we now have some evidence that the opening of chronically occluded arteries improves overall prognosis,” Fujise said.

Studies have also shown positive initial data for the use of collagenase (Matrizyme Pharma Corporation), enzymes that soften the cap in CTO lesions and facilitate easier crossing. Brilakis cited the phase 1 Collagenase Total Occlusion-1 (CTO-1) trial, which reported that delivery of collagenase into CTOs is “feasible and safe, with encouraging guidewire crossing results in previously failed cases.”

“They’ve been working on this for years, and this paper has shown encouraging initial results,” Brilakis said, adding that planning is currently under way for a second collagenase (CTO-2) trial in the United States and Canada, with enrollment likely to begin this year.

Burke said there is currently a trial ongoing in Europe testing the impact of recanalization of a CTO on LV function in patients after primary PCI for acute STEMI. This trial is called the Evaluating Xience V and LV function in percutaneous coronary intervention on occlusions after ST-elevation myocardial infarction (EXPLORE).

“I hope to start this trial in the United States, pending an application for an investigational device exemption,” he said. “In this study, people who have had a STEMI and also have a CTO are randomized to opening the CTO or standard medical therapy.”

Enrollment is currently finishing for the EXPERT-CTO trial, which will study Xience everolimus-eluting stents (Abbott Vascular) as well as HT Pilot Coronary Guide Wires (Abbott Vascular), Brilakis said.

Everolimus-eluting stents yielded promising recent data from the Florence CTO PCI registry. This study found that everolimus-eluting stents were linked to significantly lower reocclusion rates than other types of drug-eluting stents.

Burke said DES are a noteworthy development in treating CTOs.

“One problem with CTOs has been not just getting them open, but keeping them open,” Burke said. “Now, with the advent of DES, we have a reliable mechanism for keeping them open.”

Emerging Technologies

Many of the innovations made in CTO intervention techniques have become possible due to the development of new devices designed for these techniques. Most notably, the devices made by BridgePoint Medical play a key role in the antegrade dissection/re-entry approach, according to experts interviewed here. Recently acquired by Boston Scientific, BridgePoint Medical has introduced the CrossBoss CTO catheter and the StingRay CTO Re-Entry System.

“One of the biggest problems of CTO angioplasty is that it’s very frequent that the wire will go subintimal by the true lumen, and then it is very difficult to get back into the true lumen,” Stone said. “The BridgePoint technology is a system that actually almost encourages you to go extraluminal, using the CrossBoss Catheter.”

The StingRay CTO Re-Entry System facilitates the next part of the process, using an orienting balloon and a re-entry guidewire, Stone said.

“It’s a special flat balloon catheter with two little holes in the balloon, and the concept is that the StingRay will align itself parallel to the vessel in the subintimal space,” he said. “Then you take a specially designed re-entry guidewire with a very sharp, very low-profile tip, and use the balloon to orient yourself so that the wire is perpendicular to the true lumen. You can then re-enter the true lumen.”

Brilakis said there has also been some progress in the development of the Forward Looking Intravascular Ultrasound Systems (FL-IVUS, Volcano Corp.). These systems, which are designed both with and without radiofrequency ablation devices, allow interventionalists to image the proximal cap of the CTO and direct the guidewires into the occluded lumen or create a channel through the lesion using radiofrequency energy.

“The system is not yet commercially available, but it’s being developed with initial studies being done in peripheral CTOs,” he said.

Stone added that FL-IVUS has the potential to eliminate many of the obstacles to successful CTO intervention.

“One of the biggest limitations of CTO angioplasty is that you can’t see ahead of you because you can’t get dye past the occlusion, so we don’t often know when the wire is extraluminal vs. intraluminal,” he said. “To be able to see in advance with a forward-looking ultrasound or optical coherence tomography would be very useful.”

Currently under development in Japan, Asahi’s Gaia guidewires are also expected to be a promising new generation of guidewires for CTO, Brilakis said.

“They have a dual core construction, which makes them much more resistant to deformation,” he said.

Fujise said other CTO innovations include the Corsair and Tornus microcatheters (Asahi Intecc), and guidewires such as the Fielder (Asahi Intecc), Choice PT (Boston Scientific) and Confianza (Abbott Vascular).

“We now have much better equipment available to address CTOs,” he said.

Mastering the New CTO

Although the new techniques and technologies will ultimately make CTO interventions easier and more successful, becoming comfortable with them requires some training and adjustment. According to Fujise, even the most experienced non-CTO interventionalists will likely need a transition period.

“As Dr. Brilakis has said, lifetime non-CTO interventional experience does not immediately translate into better CTO technique,” Fujise said.

Rutherford said in order to gain confidence in CTO intervention, a cardiologist would need to establish and maintain a high volume of cases.

“An individual would have to do at least 100 to 200 CTOs before he or she would be comfortable going ahead with these new technologies,” he said. “And then you have to continue to have significant exposure to these patients. So you can’t just do one of these a month and expect to be comfortable.”

Burke, who is involved in CTO Fundamentals, a website and educational resource aimed at teaching CTO PCI, said there is currently a wealth of educational tools available for the aspiring CTO interventionalist.

“Currently, there is training provided by Boston Scientific through BridgePoint Medical, and the Society for Cardiovascular Angiography and Interventions is providing training as well,” he said. “BridgePoint is also sponsoring training events where cardiologists come to centers and hear lectures and watch faculty members perform procedures.”

Burke said much of the faculty — himself included — are members of the North American Total Occlusion Society, an organization dedicated to promoting and teaching CTO interventions.

“It’s like a university,” he said. “There’s a series of 13 lectures that are put together, and once you finish those lectures, you’re invited into the community. Then you can share cases on the secure website and get expert advice.”

Once a newly trained CTO interventionalist establishes a center for CTO cases, a CTO Fundamentals faculty member will come to the site to proctor them. BridgePoint Medical sponsors this service, Burke said.

“Our service proctors come in and teach CTO PCI at centers around the country,” he said. “I just spent all day yesterday doing that, and I was training people who you could consider to be my competition. But this is something that they should be able to offer their patients; I wouldn’t begrudge anyone this.”

Rutherford said he, along with colleagues William Lombardi, MD, Craig Thompson, MD, and J. Aaron Grantham, MD, teach CTO recanalization “mini-courses” to classes of between 10 to 20 physicians.

“We happen to run about three of these a year. The physicians come here, and we do four or five cases a day, so they can come in and observe exactly what is done,” he said. “But more important than that, if physicians come to these courses, then one of our instructors will actually go to their cath labs and work with them on some cases.”

However, Rutherford said not everyone who attends these sessions goes on to establish a CTO intervention practice.

“Some will go back home and, either because their cath labs won’t let them or because of the time and technology involved, will not take it on,” he said. “They will send their cases to a referral center like ours. But about a third of these individuals will take it on and build a program for themselves, and that’s what we like to see.”

Weighing Pros and Cons

Even with the new technologies and techniques, CTO intervention has its drawbacks. According to Rutherford, exposure to radiation is a real concern, particularly given the duration of the procedure.

“Radiation exposure is an issue both for the patient and the physician,” he said. “The radiation limits now are around 8 Gy to 10 Gy. Gray is a measurement of the amount of radiation that a person is getting over a period of time. So, 4 Gy to 5 Gy would be comfortable, but when we’re getting up to 8 Gy to 10 Gy, there is a possibility that the patient will develop a radiation burn, so we know to keep it under that limit.”

Rutherford said at his center, technicians are trained to notify the cardiologists at the passage of every 2-Gy interval. This enables the cardiologist to remain aware and vigilant regarding radiation use.

“There is also a whole series of techniques available now to cut down on your fluoroscopy time, so you can make sure you’re using very low frame rates for your radiation,” he said. “There are also settings on the new systems now where you can go to very low radiation levels. So, if you just remain aware of it and keep your radiation levels and time down, then these cases become much more practical.”

Another clear disadvantage of CTO intervention procedures is that they are not financially feasible, Stone said.

“They are still long and complex procedures that require complex skill sets and dedicated time in the cath lab, and for the most part, they are reimbursed the same as standard angioplasty procedures,” he said. “Most hospitals and cath labs probably lose money by doing these procedures.”

Burke and colleagues at the North American Total Occlusion Society have developed an algorithm to instruct cardiologists on how to mitigate these CTO issues.

“Our algorithm has been designed to minimize these problems to make [CTO PCI] not only effective, but also efficient, so we’re not spending an undue amount of time or money, or putting a patient in harm’s way,” he said.

The Quest Continues

Ultimately, the quest for better patient outcomes will continue to drive cardiologists to pursue CTO intervention, Stone said.

“Of course, the people who are expert at them will want to do them, because the patients clearly do benefit in terms of — at a minimum — symptom relief,” he said.

Stone said despite the lack of randomized studies, CTO intervention has demonstrated multiple benefits compared with other alternatives.

“Compared with medical management, successful CTO PCI is clearly associated with decreased symptoms, decreased reliance on anti-angina medications, improved exercise tolerance and improved LV function,” he said. “And in registry studies, at least, successful CTO angioplasty is also associated with improved survival, although we need randomized trials to confirm that. Compared with surgery, of course, it’s less invasive, much faster and much easier for the patient.”

Burke said he is confident that as techniques and technologies continue to improve, more cardiologists will undertake CTO interventions.

“Cardiologists no longer need to be apprehensive about CTO intervention,” he said. “To the contrary — we need to embrace it.” – by Jennifer Byrne

Disclosure: Brilakis receives honoraria from BridgePoint Medical, Terumo and St. Jude Medical, research support from Guerbet, and his spouse is an employee of Medtronic; Burke is a consultant for Boston Scientific and Terumo; Fujise is a speaker for Boehringer Ingelheim and Daiichi-Sankyo/Eli Lilly and a consultant for St. Jude Medical; Rutherford is on the speakers’ bureau for Abbott Vascular, Medtronic and Volcano; Stone is a consultant for Boston Scientific and Volcano.