ABSORB Trials: Bioresorbable Vascular Scaffold Still Not Up to Snuff

Neil Osterweil

October 02, 2018

SAN DIEGO — Results from two randomized controlled trials of a bioresorbable vascular scaffold (BVS) that has been withdrawn from the market call into question the wisdom of continued development of the technology.

The ABSORB IV trial — a rigorously controlled study designed to overcome problems that may have marred results of earlier trials of the Absorb everolimus-eluting BVS (Abbott Vascular) — showed Absorb was noninferior to Abbott's metal Xience everolimus-eluting stent for the primary end point of target lesion failure (TLF) at 30 days and the secondary end points of TLF and angina at 1 year.

But despite the more careful patient selection and improved implantation techniques used in ABSORB IV, both 1-month and 1-year rates of myocardial infarction (MI), ischemia-drive target lesion revascularization, and device thrombosis were all higher with Absorb.

"These data are largely consistent — although a little better, but largely consistent — with those from the earlier ABSORB trials, emphasizing the need for further advancements in device technology and improvements in technique, such as routine intravascular imaging, to further improve the early safety profile of BVS if the benefits of late-scaffold bioresorption are to be realized," said coprincipal investigator, Gregg W. Stone, MD, New York–Presbyterian/Columbia University Medical Center, New York City, at a briefing here at Transcatheter Cardiovascular Therapeutics 2018.

Details of the trial were published online in the Lancet to coincide with Stone's presentation of the data in a late-breaking abstract session.

In the COMPARE-ABSORB trial, pitting the same two stents against each other in high-risk patients with complex lesions, Absorb also met the primary end point of noninferiority for TLF at 1 year, but at the cost of significantly higher target-vessel MI and definite/probable scaffold thrombosis.

The higher event rate seen with Absorb occurred despite the use of rigorous patient selection and operational protocols, reported Pieter C. Smits, MD, Maasstad Ziekenhuis, Rotterdam, the Netherlands.

Renu Virmani, MD, CVPath Institute, Gaithersburg, Maryland, was a discussant at the briefing. "I think it's possible to make better stents, but should we put all our money into this? I'm not convinced," she commented.

"I can mold it also into a thinner strut, but will it work is the question, and do I want it in my arteries?" she added. "I would tell you, I don't want it in my artery; so if I don't want it in my artery, I don't want it in my patient's artery

Briefing moderator Ajay J. Kirtane, MD, SM, New York–Presbyterian/Columbia University Medical Center, said that the two trials show that better implantation technique is not sufficient to overcome underutilization of intravascular imaging, especially in complex lesions.

ABSORB II-III: Implantation Could Have Been Better

"These devices are designed to improve long-term outcomes after their complete bioresorption, by restoring normal structure and function without having a permanent metal stent there, but we've never even gotten to that point, because that's after 3 years, and we had this increase in event rates before 3 years," Stone told theheart.org | Medscape Cardiology.

At least some of the events seen in earlier studies could be explained by poor or suboptimal technique, including implantation in vessels smaller than intended for the device, he said. Absorb was approved for patients with a reference vessel diameter (RVD) 2.5 mm to 3.75 mm and lengths of 24 mm or less.

"About 19% of the patients had lesions by core lab analysis with a reference diameter of less than two-and-a-quarter millimeters," Stone said. "If you put a thick strut device that can't expand well in a tiny little vessel then you're just set up for thrombosis, and most of the adverse events have been excess device thrombosis."

Stone also noted that earlier studies were unblinded, did not always use predilatation, sizing, and postdilatation (PSP) scoring, and excluded patients with recent MI for whom a BVS device may be appropriate.

An unexpected finding from the ABSORB II trial — not replicated in ABSORB III — was a lower incidence of recurrent angina with Absorb than Xience, but the trials looked at angina as a safety event rather than a clinical end point.

ABSORB IV: Rigorous Protocol

ABSORB IV randomized 2604 patients with stable ischemic heart disease or acute coronary syndrome and one to three target lesions with an RVD diameter of 2.5 mm to 3.75 mm and lengths of at least 24 mm. The investigators describe in the published study the steps they took to ensure proper patient selection and device implantation.

TLF occurred in 4.9% of patients with Absorb and 3.7% of patients with Xience at 30 days (hazard ratio [HR], 1.35; P for noninferiority = .02) and in 7.6% and 6.3%, respectively, at 1 year (HR, 1.22; P for noninferiority = .0006).

The 30-day and 1-year rates of device thrombosis were numerically but not statistically higher with Absorb, at 0.6% vs 0.2% (P = .06) and 0.7 vs 0.3% (P = .016), respectively.

Recurrent angina, a major secondary end point, was virtually identical throughout follow-up with superimposable curves, at 21.3% with Absorb vs 21.2% with Xience (P for noninferiority = .0008). The rate of recurrent angina was about four times higher than the 1-year revascularization rate (4.9% vs 3.9%), Stone noted.

"Two big lessons from that: first of all, what PCI does in most patients with stable disease, it doesn't prolong life but just reduces symptoms," Stone told theheart.org | Medscape Cardiology. "The angiogram restenosis rates have always been similar with Absorb compared to Xience, and now we know that any recurrent angina, despite any trend toward increasing events, is almost identical with Absorb and Xience. So that's actually favorable."

The second lesson comes from the observation that approximately 66% of patients with recurrent angina had a recurrence within the first 2 months after device implantation, before restenosis typically occurs.

"That reflects incomplete revascularization, underlying small vessel disease, microvascular disease, vasospasm, or something else," Stone said.

The remaining patients with recurrent angina experienced it within 8 to 12 months, which coincides with the expected time of restenosis.

"If we're going to continue to improve the symptoms and the quality of life for patients after PCI and coronary disease, we're going to have to understand recurrent angina better and all of its mechanisms," Stone said.

COMPARE-ABSORB

This trial was an investigator-initiated, prospective, single-blind, randomized controlled trial comparing Absorb with Xience in high-risk patients with complex lesions. In addition to showing non-inferiority to Xience at 1 year, the trial had a secondary objective of showing the superiority of Absorb on TLF between 1 and 5 years in a landmark analysis.

Investigators at 44 European centers enrolled patients with at least one high-risk characteristic for restenosis, including known diabetes and/or multivessel disease in which more than one de novo target lesion was to be treated with a study scaffold or stent, or a complex de novo target lesion, defined as lesion length greater than 28 mm, small vessels (diameter, 2.25 - 2.75 mm), lesions with a pre-existing total occlusion, or a bifurcation lesion.

"We hypothesized that patients who are at high risk for restenosis might benefit most with the BVS technology and vascular restoration on the long term," Smits said in his presentation of the data.

Investigators followed a strict PSP protocol, with mandatory predilatation with a 1:1 balloon–artery ratio, treatment of target vessels smaller than 2.75 mm on QCA, intravascular ultrasound or optical coherence tomography, mandatory high pressure postdilatation (>16 ATM), and recommended postdilatation with noncompliant balloons up to 0.5 mm larger than the scaffold.

The original trial protocol called for 2100 patients, but was amended after 1670 patients were enrolled and the trial was put on hold in August 2017 at the advice of the data safety monitoring board and the subsequent withdrawal of Absorb from the market. A total of 848 patients with 1242 target lesions were randomized to Absorb, and 822 with 1213 target lesions were assigned to Xience. Absorb patients underwent a total of 962 procedures, and Xience patients 904 procedures.

The TLF rate at 1 year, the primary end point, was 5.1% with Absorb and 4.2% with Xience (P for noninferiority < .001).

Two of the three components of the composite TLF end point — cardiac death and clinically indicated target vessel revascularization, were numerically but not statistically more frequent with Absorb than with Xience, but the third component, target vessel MI, was significantly higher with the Absorb device, at 4.0% vs. 2.1% (HR, 1.96; P = .02).

The incidence of 1-year scaffold/stent thrombosis was 2.0% for Absorb vs 0.6% for Xience.

The investigators plan to follow patients out to 7 years, Smits said.

Good Concept, Wrong Device?

At the briefing, discussant Deepak L. Bhatt, MD, MPH, Brigham & Women's Hospital, Boston, said that although he doesn't see a future for this iteration of the BVS, the studies provide lessons for future stent development, and that he anticipates future generations of safer, effective bioresorbable devices.

"I think it was an error to approve this stent at the time it was, when a lot of smart folks, such as Dr Virmani and Dr [Elazer] Edelman [Massachusetts Institute of Technology, Cambridge], were saying wait for 5 years of human follow-up before approving," he said.

"I think as a field we've got to learn that, yeah, things might look exciting, but don't approve them until there are good safety data and preferably good efficacy data," he added.

Referring to the COMPARE-ABSORB data, David J. Cohen, MD, MSc, University of Missouri–Kansas City, said that long-term follow-up of patients who received the Absorb BVS is important.

"We need this proof that there's some light at the end of the tunnel," he said. "That's been the challenge I think with the whole bioresorbable scaffold concept: we know the challenges, we know it's harder to implant, you have to be more compulsive to use it well. There is this early penalty with respect to scaffold thrombosis at a minimum and possible acute-related MI, and the benefit was all promise. It's hard to sell promise," he said.

Stone said at the briefing that two competing devices, both bioresorbable sirolimus-eluting scaffolds (Fantom, REVA; and Magnitude, Amaranth) are likely to improve BVS technology and results further. Both scaffolds have thinner struts than ABSORB, with thicknesses approaching those of current metal stents, and the Fantom device is radiopaque, allowing it to be seen during implantation imaging, unlike ABSORB.

"The scaffolds are getting better and better, and hopefully that will eliminate most of these early differences," he said.

Virmani, however, expressed doubts about the integrity of poly-L-lactic (PLLA)-based BVS devices such as ABSORB and Magnitude. (Fantom is composed of a different material, tyrosine polycarbonate.)

"I don't think PLLA stents necessarily have a future," she said. "I personally think that because they don't have the strength, fracture is really a problem, and that if you do micro CT on these in normal arteries, we see fracture within 3 months. That is when there is not dismantling at that time — at least with the ABSORB — that we've seen."

During the formal presentation, discussant Antonio Colombo, MD, Columbus Hospital/San Raffaele Hospital, Milan, Italy, said, "I think this study is a nice step forward, confirms the value of vessel selection, but to me, it is not sufficient to justify bringing back all the devices unless a new iteration is put forward."

Asked by moderator Patrick W. Serruys, MD, PhD, Imperial College London, whether in retrospect Smits thought that he and his coinvestigators started COMPARE-ABSORB too early, Smits agreed.

"In the beginning, we were very encouraged by the results shown in registries," he said. While it was prudent to start the trial when they did, given the data they had at the time, he added, "I think definitely for those patient populations that will have a worse outcome in the long term with metallic stents, I think we should try to find something new to approve."

In an editorial accompanying ABSORB IV in the Lancet, Colombo and Francesco Giannini, MD, San Raffaele Scientific Institute, Milan, write that ABSORB IV results show progress compared with other trials evaluating BVS devices, but that further development is needed.

"Which conditions justify a comeback of BVS? We need to acknowledge that the immediate and long-term advantages of BVS are neither clear nor well defined," they write. "We should accept the need to avoid any additional procedural complexity compared with metallic stents when implanting BVS."

Another issue, they note, is dual antiplatelet therapy (DAPT) duration.

"At a time when the clinicians would like to decrease the dependence of stents from DAPT, we now offer devices that might require DAPT to be extended. The optimum duration of DAPT, particularly DAPT after BVS implantation, needs to be studied more deeply," they conclude.

ABSORB IV was funded by Abbott Vascular. COMPARE ABSORB was sponsored by the European Cardiovascular Research Center . Stone reports personal fees from Claret, Ablative Solutions, Matrizyme, Miracor, Neovasc, V-Wave, Shockwave, Valfix, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore; and other renumeration from the MedFocus family of funds, Ancora, Cagent, Qool Therapeutics, Aria, Caliber, SpectraWave, and the Biostar family of funds. His employer, Columbia University , receives royalties from Abbott. Smits reported grant/research support and fees from Abbott Vascular. Serruys disclosed fees from Abbott Vascular. Bhatt reports grants/research supports from Abbott Vascular and others. Cohen reports grants/research support from Abbott Vascular and others. Virmani reported having nothing to disclose. Colombo and Giannini reported no competing interests.

Transcatheter Cardiovascular Therapeutics (TCT) 2018: ABSORB IV and COMPARE-ABSORB. Presented September 25, 2018.

Lancet. Published online September 25, 2018. ABSORB IV abstract, Editorial

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