No Stent Left Behind

Bioresorbable scaffolds hold great appeal as DES alternatives, but need to stand the test of time.

In treating CAD, bioresorbable scaffolds are widely anticipated as a potential successor to traditional drug-eluting stents. These temporary polymeric structures are designed to optimize the revascularization and mechanical support of a DES before dissolving and eliminating unnecessary and potentially undesirable vessel constraints.

According to Dean J. Kereiakes, MD, FACC, FSCAI, medical director of the Lindner Research Center at The Christ Hospital, Cincinnati, the eventual disappearance of a bioresorbable scaffold leaves behind a natural environment for the vessel, which is then liberated from caging and able to undergo remodeling and restoration.

“These arteries can normally grow and accommodate atherosclerosis, and they can’t do that if they have a metal girdle in them. So the bioresorbable scaffold dissolves and frees the artery,” Kereiakes said. “These arteries have the ability to autoregulate and increase blood flow to meet demands, and that doesn’t happen if they’re caged with metal, either. So there are multiple potential advantages.”

Whether bioresorbable scaffolds (BRS) will deliver on their promise as a practice-changing alternative to permanent stenting, however, largely remains to be seen. Although the technology is not yet approved for use in the United States, it is available in many other countries. Yet, according to Ron Waksman, MD, associate director of the division of cardiology at MedStar Heart Institute, Washington, D.C., this technology has not yet been widely adopted.

“The scaffold technology is approved in many countries in the world, and it is being used, but the penetration at this point is not very high,” Waksman said. “The reason for that is there has been a differential in price, and also, there are limited sizes and lengths. Because of these considerations, and without the data to support massive use, the penetration so far is under 5% worldwide.”

Devices Approved in Europe

Currently, two BRS devices have obtained CE mark approval — the Absorb bioresorbable vascular scaffold (BVS, Abbott Vascular) and the DESolve scaffold system (Elixir Medical). A third BRS, REVA Medical’s ReZolve coronary scaffold, is currently undergoing clinical trials in Australia, Brazil, Europe and New Zealand. REVA Medical also plans to initiate first human implants of its Fantom sirolimus-eluting BRS in late 2014.

The Absorb BVS consists of a bioabsorbable poly-L-lactide (PLLA) foundation with a poly-D, L-lactide coating that regulates the delivery of everolimus in a dose comparable to that of the best-in-class Xience V/Prime (Abbott Vascular) DES. Within 30 days, most of the drug has been dispensed, and the scaffold is designed to dissolve within 2 years.

In July, 6-month data from the GHOST-EU registry yielded encouraging early and midterm results with the Absorb device, with rates of cardiac death, target vessel MI and target lesion revascularization all less than 5%.

Additionally, the Absorb BVS is being studied through the ABSORB clinical trial program, which is currently being conducted in pursuit of regulatory approval in the United States, China and Japan.

The DESolve Scaffold system is a novolimus-eluting device made from PLLA material and featuring a narrow strut profile of 100 mcm. The device is designed to dissolve within roughly 12 months.

“The DESolve is perhaps the second most promising scaffold device,” said Alexandre Abizaid, MD, chief of coronary interventions at Institute Dante Pazzanese of Cardiology in São Paulo, Brazil. “In the CE mark study of 126 patients, it achieved very good results, with low rates of late lumen loss and MACE, and only one patient with probable stent thrombosis.”

Benefits over Traditional DES

According to Abizaid, although traditional DES technology confers important benefits in terms of controlling negative remodeling and neointimal hyperplasia, some of these features cease to be necessary over time.

“After 6 months, you do not need the mechanical force or the drug,” he said. “So, if after 6 months, we can trigger the resorption of the scaffold, that is fantastic. We never had that solution in the past, and it could be a reality with scaffolds.”

Additionally, because there is no foreign body left behind with BRS, this technology may obviate the need for long-term dual antiplatelet therapy and its attendant risks, Abizaid said.

“If we have a device that will slowly disappear after 1 year, the very long-term use of DAPT could be avoided,” he said. “This could definitely be a potential benefit in reducing bleeding risks associated with DAPT.”

Abizaid said the use of a dissolvable, polymeric device will also allow for the noninvasive imaging of the vessel during follow-up.

“Metal creates a big artifact on an X-ray, and you can’t evaluate the lumen or the amount of tissue growth,” Abizaid said. “We generally catheterize this patient again to be able to see and evaluate the anatomical appearance of the vessel. Because the scaffold is polymeric, we are able to evaluate these patients noninvasively.”

According to Kereiakes, BRS devices offer the advantage of larger coronary lumen area, particularly late lumen enlargement.

“There is a larger arterial lumen area with BRS, both from a fixed lumen perspective and a dynamic perspective after 6 to 12 months,” he said. “The BRS loses its radial rigidity, and the artery can then grow or respond to stimuli to make it open up more. So the artery is no longer captive to the diameter of a stent; it’s freed.”

The elimination of mechanical constraints also allows for arterial remodeling.

“This is a very important aspect; the metal platform doesn’t have the ability to grow with the artery if the artery undergoes adaptive remodeling,” Kereiakes said. “Additionally, microcirculatory function can be improved following BRS compared with DES.”

Another possible advantage of BRS is a decrease in angina vs. metal stents, Kereiakes said.

“The angina story is interesting,” he said. “Angina in itself is a challenge following PCI, and the observation has been made, in largely nonrandomized trials, that patients treated with BRS less often complain of angina than those treated with metal platform DES.”

Additionally, BRS technology may be useful in decreasing plaque burden, Kereiakes said.

“There is some evidence that over time, these BRS devices may be associated with plaque reduction, an actual decrease in plaque burden,” he said. “We haven’t proven that yet, but with long-term, meticulous follow-up, we are en route to getting that.”

ABSORB: Noninferiority and Beyond

To date, the Absorb BVS is the most extensively investigated BRS, and is expected to be the first scaffold to obtain FDA approval. The ABSORB clinical trial program is exploring the device through various studies that are powered for different objectives.

Recently, 3-year results from the ABSORB trial were released, and showed that the Absorb BVS was linked to stability in mean lumen and scaffold area, as well as low restenosis rates.

“The idea is we have to show that within 1 year, you can get comparable results [with Absorb BVS], because otherwise, we don’t want to make any compromises,” Waksman said. “Then at 1 year, if it achieves positive results, which is to say, noninferiority to the best-in-class DES, then we can anticipate there will be FDA approval.”

Results from the ABSORB II trial, evaluating the device in 501 patients, primarily in Europe, were presented in September at Transcatheter Cardiovascular Therapeutics in Washington, D.C., as a late-breaking clinical trial. In the study, the Absorb scaffold demonstrated 1-year clinical outcomes comparable to those of the Xience family of DES (Abbott Vascular) in treating CAD. Notably, there was a significant reduction in 1-year cumulative angina episodes with the scaffold.

In addition, Abbott Vascular recently completed enrollment for the ABSORB III US pivotal trial, which includes roughly 2,000 participants and will directly compare the Absorb BVS and the best-in-class DES (Xience, Abbott Vascular). The study’s primary endpoint will be TLF at 1 year.

Similar studies are being conducted in Japan and China that are comparing the Absorb scaffold to Xience with a primary endpoint of 1-year TLF.

The possibilities of the Absorb BVS will be explored even further in the ABSORB IV trial, which will enroll an additional 3,000 patients and will be powered for superiority, Kereiakes said.

“The ABSORB IV trial will run in sequence and will look at TLF between 1 and 5 years, with a landmark analysis to provide the superiority of BVS compared with Xience,” he said. “The second endpoint will be angina to 1 year. The patients will be very carefully monitored to maintain and ensure blinding.”

Kereiakes said the straightforward protocol of the ABSORB III trial is necessary to determine noninferiority and gain FDA approval, but the more inclusive approach planned for ABSORB IV is likely to yield interesting findings.

“So far, my experience with these devices has been very good, but it’s limited by the inclusion/exclusion criteria of the ABSORB III clinical trial,” he said. “I believe the relative benefit of these devices may be more evident with more complex disease, so we will have to wait for the extension into ABSORB IV, where the inclusion/exclusion criteria have been liberalized and will be more complex.”

However, Waksman said it may be some time before ABSORB IV yields these important long-term data.

“This study will look at [outcomes for] up to 5 years and will be powered to show a reduction of clinical events with biodegradable scaffolds vs. DES,” he said. “The problem is, we probably won’t know those results until 6 or 7 years from now.”

The device is also being tested in the ABSORB EXTEND registry, a multicenter, single-arm study. Data from the registry were presented at TCT 2014 and showed low rates of MACE, repeat revascularization and scaffold thrombosis at 3 years with the BVS. Specifically, there was a 1.2% rate of definite/probable scaffold thrombosis at 3 years.

“We don’t expect to see the total elimination of stent thrombosis, but we expect to see less thrombosis with the bioresorbable scaffolds each year,” said Abizaid, who is an investigator in the study.

Abizaid said as these studies progress, additional randomized studies of Absorb are forthcoming in the near future.

“This is the body of evidence we are building,” he said. “Next year, you will see close to 10,000 patients enrolled in studies. Absorb is already approved in many countries, and we all expect to see the big randomized trials for universal use.”

Concerns about BRS

Although the findings on BRS have thus far been positive, some clinicians are not convinced that the current-generation devices are necessarily an improvement over DES.

“Intuitively, a temporary vessel scaffolding should be better than stenting, since the main advantage of scaffolding should be the elimination of late stent thrombosis and the maintenance of native vessel integrity,” said David Antoniucci, MD, head of the division of cardiology and catheterization laboratory at Careggi Hospital in Florence, Italy. “However, there are still several concerns for the routine use of these devices.”

The first concern, according to Antoniucci, is the questionable favorability of first-generation BRS over second- and third-generation DES.

“It seems unlikely that available bioabsorbable scaffolding in ‘real-world’ patients will result in a better performance than second- and third-generation DES,” he said. “A MACE rate of 8% at 18 months shown in ABSORB cohort B is high, considering the very low risk of recurrence in the lesions treated. Similar results are reported in the ABSORB EXTEND Registry, where patients could be included only with a maximum of two lesions of two different vessels.”

Another concern, according to Antoniucci, is that given the timeline needed for total reabsorption of BRS devices, patients may still be at risk for adverse events comparable to DES.

 “The majority of adverse events after PCI with DES occur in the first 12 months, and bioabsorbable scaffolding needs much more time for complete reabsorption,” he said. “Also, the design of available bioabsorbable scaffolding does not provide uniform corrosion over time, and presents the potential of increased late restenosis compared with DES.”

Finally, Antoniucci cited potential issues caused by vessel predilation required with BRS.

“The aggressive predilation of the lesion needed before bioabsorbable scaffolding results frequently in long dissections, with the need for very long scaffolding,” he said. “These concerns might explain the delay of FDA approval in the United States.”

According to Ajay J. Kirtane, MD, SM, chief academic officer and director of the interventional cardiology fellowship program at Columbia University Medical Center, New York, the strut thickness of the current generation of scaffolds is also a concern, potentially causing flow disturbances if the wrong size is used.

“We really have to study [bioresorbable scaffolds] and sort these issues out, particularly because now we’re using the current stent platforms in really complex patients and lesions,” he said.

Kirtane said he believes BRS technology has promise, but emphasized that these devices need to be proven against the known quantity of DES technology.

“The main thing is that current DES have a well-proven track record; prices are coming down, and for many patients, they do offer a really good choice,” he said. “So while there’s definitely appeal to BRS technology, whether that appeal actually pans out and comes to fruition really needs to be tested against the established and safer-than-ever stent platforms.”

Only the Beginning

Abizaid acknowledged that current-generation BRS devices are works in progress that will continue to evolve. He said the promise of this “best-of-both-worlds” technology has spurred a great deal of work toward refining these devices.

“The first-generation BRS devices are 150 mcm, and 150 mcm is thick compared with the metallic stents, which are 80 mcm,” he said. “So now, most of the companies are trying to build devices that are lower-profile workhorses, devices that navigate much better and work like best-in-class DES. When we get to that point, bioresorbable scaffolds will gain more market share.”

Waksman said it will take time and rigorous ongoing study to determine whether BRS technology will ever ascend to the level of the gold standard.

“Right now, we have a lot of small studies with good results, but it’s not definitive,” he said. “The attractiveness of this is to be able to not leave anything behind. There’s also promise in terms of possibly improving the reactivity of the vessel and maybe improving quality of life and angina. But right now, these are all hypotheses.”

He said the results of the ABSORB III study will likely pave the way to FDA approval, but there is more work to be done in terms of large randomized studies.

“If ABSORB III demonstrates noninferiority to the Xience stent, we anticipate FDA approval,” Waksman said. “But we have to be cautious. I would say that it is going in the right direction, but we haven’t hit a home run yet.”

Abizaid emphasized that it is still in the early days for BRS technology. He noted that current DES technology has benefited from years of refinement, evolution and study, and predicted that BRS will undergo similar transformations.

“Currently, there is a lack of randomized studies, and the first generation is a little bit bulkier, and there isn’t evidence to show that BRS is superior to DES,” he said. “Right now, it’s just a promising, fantastic new technology. I think in 2 years, the story will be very different.”

Disclosure: Abizaid’s institution receives research grants for clinical trials from various manufacturers of BRS, including Abbott Vascular, Biotronik, Elixir Medical and Reva Medical. Antoniucci reports no relevant financial disclosures. Kereiakes is a consultant for Abbott Vascular and is co-principal investigator of the ABSORB pivotal trial, and has been on the scientific advisory board of Reva Medical. Kirtane’s institution receives research grants from Abbott Vascular, Abiomed, Boston Scientific, Eli Lilly, Medtronic, St. Jude Medical and Vascular Dynamics. Waksman is a consultant for Abbott Vascular and Biotronik.