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DENVER -- As new 3- and 4-year data emerged from the ABSORB clinical trials, the FDA updated its cautions to healthcare professionals about continuing risk seen with the first-generation Absorb bioresorbable vascular scaffold (BVS) stent.

"The interim results continue to show an increased rate of major adverse cardiac events and BVS scaffold thrombosis in patients receiving the Absorb GT1 Bioresorbable Vascular Scaffold (BVS), when compared to patients treated with the approved metallic XIENCE drug-eluting stent," the said.

"The FDA's recommendations for healthcare providers outlined in our previous letter remain unchanged. Although healthcare providers with available inventory may continue to implant the BVS, they should carefully consider its safety and effectiveness and only use it if they believe it is in the best interest of their patients."

However, chairman of the ABSORB global clinical trial program Gregg Stone, MD, said, "I think this is not a major issue right now. There are very few being implanted."

Abbott Vascular stopped selling the device in September, which a statement from the company reemphasized was a business decision based on low sales.

"The ABSORB III study was conducted prior to the use of current implantation technique, and as with any first-of-its-kind technology, implantation guidance for Absorb evolved based on learnings from the medical community. We believe that bioresorbable technologies offer patients the possibility of life without permanent metallic implants, and will continue to work on a second-generation device while monitoring long-term outcomes in Absorb clinical trials after stent resorption," the statement said.

The FDA update was in response to interim study results through 3 years from the pivotal ABSORB III trial reported at the Transcatheter Cardiovascular Therapeutics (TCT) meeting and simultaneously online in the Journal of the American College of Cardiology.

Building on the risk seen at 2-years that caused the FDA to send the initial "Dear Doctor" letter in March, the curves continued to separate at 3 years for target lesion failure (13.4% with Absorb versus 10.4% Xience, HR 1.31, P=0.056) and device thrombosis (2.3% versus 0.7%, HR 3.12, P=0.01).

The 3-year mark is when the device is supposed to have been reabsorbed, but only now is adequately powered data becoming available to answer the most important question -- how it impacts patient outcomes, noted Stephen Ellis, MD, of the Cleveland Clinic, who presented the results at a press conference for the TCT late-breaking clinical trial session.

When asked if there's any prospect for the trends to reverse and actually show benefit of Absorb, Ellis said "It's hard to imagine that this device will eliminate adverse events for target lesion revascularization and target lesion failure. I would guess, you're [an absolute] 3% behind right now, to get better it's 10-years plus. So I think the 3% upfront cost, if you will, is insurmountable to be honest with you."

"I still think the idea to find out scientifically whether patients who have a bioresorbable do better than patients with a permanent metallic starting at year 3 is an important issue to try to address," he added.

The FDA reiterated what Abbott has said previously, that it "will continue to monitor patients currently enrolled in the ABSORB III and ABSORB IV US clinical studies through five years following BVS implantation. Patients enrolled in these studies will be followed through standard practice and care after five years."

But from the standpoint of many clinicians, there may be a high hurdle for any future device to meet. Allen Jeremias, MD, of St. Francis Hospital in Roslyn, New York, and a discussant at the TCT press conference, was skeptical.

"I don't think there is any good data at this point that indicates that in fact we will get there," he said. "We need to have that signal at some point to say, 'Okay, there is benefit and this is a technology we should pursue long term.'"

Four-year data from the ABSORB II trial was also presented at TCT and likewise showed a widening of adverse thrombotic event curves between about year 3 and 4, albeit not significant.

However, with 501 patients, Jeremias cautioned it was underpowered to say much about whether a signal was present or not.

Late Impact of Bioreabsorption

Despite the appeal of the idea of a disappearing stent, the mechanics of actually doing so may be part of the explanation for Absorb's spectacular flop.

For one thing, the strut is twice as thick as a conventional drug-eluting stent, Ellis noted. But the late events are probably best explained by the "dismantling" seen on optical coherence tomography, he said. "If the device is not well-embedded into the wall of the vessel at the beginning so that healing can embrace the device, when device begins to lose its structural integrity, it can flop into lumen, if you will, dragging tissue with it. And that is inherently thrombogenic."

Wayne Batchelor, MD, MHS, of Southern Medical Group in Tallahassee, Florida, noted that, "We saw that inflection between 30 and 42 months, whereby there's a 0.5% absolute increase in thrombosis risk with BVS. Most of the dismantling I would have thought would have occurred 1 to 2 years. By 3 years, it virtually all the stent should be gone by then."

Ellis noted that there was no imaging during that period to show what happened. "It may be that the tissue that was dragged in is still there and is thrombogenic. I don't know ... Clearly, there is something wrong between year 1 and year 3."

Better Technique

Previously, the key to the thrombosis rate was claimed to be not the device but how operators implanted it and vessel selection.

And indeed, those aspects seemed to make a difference. An analysis across the ABSORB study program except ABSORB IV, released at TCT and in JACC, showed the following:

• Appropriate sizing (including no use in vessels smaller than 2.5 mm) independently predicted freedom from target lesion failure through years 1 and 3 as well as freedom from scaffold thrombosis through year 1
• Optimal pre-dilation with balloon diameter the same as the vessel diameter was an independent predictor of scaffold thrombosis between years 1 and 3
• Optimal post-dilation independently predicted freedom from target lesion failure from 1 to 3 years

In the ABSORB IV trial, that recommended or strongly recommended these precautions, patterns of thrombotic risk were similar but dialed down in magnitude compared with ABSORB III, Stone reported in a separate presentation at the conference.

The 2,6404 patients randomized in the trial to Absorb or a Xience everolimus-eluting stent showed noninferiority for the primary endpoint of 30-day target lesion failure (5.0% versus 3.7%, P=0.02 for noninferiority).

While device thrombosis was 4.05-fold more common with the BVS than Xience (0.6% versus 0.2%, P=0.06), a comparison of "ABSORB III-like" patients between the two trials showed a lower device thrombosis rate of 0.4% compared with the 1.1% rate seen in ABSORB III.

"We have reduced it, we still haven't eliminated it, and I think we will never eliminate it with this first generation of the device," Stone said. "We need better generation of scaffolds, which are thinner, have better mechanical properties, expansion characteristics, recoil, etc. Technique will take you so far, you need a scaffold-specific technique to improve outcomes, and then we need better scaffolds, then we can get the 2- to 3-year event rates similar to drug-eluting stents to allow the potential late benefits of bioabsorbable scaffolds to emerge."

However, Ellis argued in discussing his findings that dismantling is likely to be problem with any BVS, although perhaps less so with thinner struts, and such. "The field is probably not closed," he said, but the first generation ABSORB was "clearly a dampener on field."

Perhaps the biggest problem, Batchelor said, is the "extremely safe and efficacious effect of just an everolimus-eluting stent. We're looking at 0.7% stent thrombosis rates out to 4 years."

"Whatever we do in the future in this arena is going to be extremely difficult," he concluded, "because the gold standard has become so golden."