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FDA Panel Recommends Abbott's Absorb Bioresorbable Vascular Scaffold for Approval
Part One of a Two Part Feature on This New Technology
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Abbott's "Disappearing Stent": the Absorb Bioresorbable Vascular Scaffold |
March 21, 2016 -- Last Tuesday, the 10-member FDA Circulatory System Devices Panel conducted a day-long session, filled with presentations, questions, and testimony from industry representatives, interventional cardiologists, and patients, to determine whether to recommend approval of Abbott's "disappearing stent": the Absorb GT1™ Bioresorbable Vascular Scaffold (BVS).
Much of the discussion revolved around the data generated by the ABSORB III pivotal trial of BVS compared to the Xience second-generation drug-eluting stent (DES), the one-year results of which were presented at October's annual TCT meeting and published simultaneously in the New England Journal of Medicine. This was a non-inferiority trial, and the BVS met those criteria: this novel device that acts as a stent, but then fully resorbs over time, was statistically "non-inferior" to the Xience permanent metal stent, even though the raw numeric outcomes in all performance measures were slightly worse for the BVS.
A Unanimous Vote for Stated Indications
At the end of the day, and it was the end of a very long day, the panel voted to recommend approval. Manufacturer Abbott's proposed indications for were for use in de novo native coronary artery lesions, not longer than 24mm, and between 2.5mm and 3.75mm in diameter. These limits exclude much of what is known as "complex angioplasty," meaning that on-label indications for the BVS would be for relatively straight-forward cases. Given these parameters, the panel voted 9-1 that the BVS was safe, 10-0 that it was effective, and 9-0 (with one abstention) that the benefits outweighed the risks. The FDA usually follows the recommendations of its advisory panels, although the Agency alone makes the final decision which, as Abbott stated in a press release, is expected later this year.
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This is the first installment of a two part feature regarding current thinking about the Bioresorbable Vascular Scaffold. Part One discusses the history and some general background issues surrounding the device; Part Two (to be posted at a later date) consists of comments from leading interventional cardiologists about the current and future implications, predictions, critiques, and recommendations for the utilization of BVS.
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BVS: A Decade in the Making
The year was 2006. The "paradigm-shifting" drug-eluting stent (DES) had been introduced only three years earlier, significantly lessening the problem of restenosis, or reblocking of the artery. But reports from Sweden and other European centers showed that, in a small number of cases, these devices were causing late stent thromboses: blood clots that could lead to a heart attack or death a year or more after stent implantation. These reports were labeled a "firestorm" and prompted a two-day FDA hearing on stent safety, attended by all the device manufacturers, mainstream media, and cardiologists from around the world. As a quick fix, dual antiplatelet therapy (DAPT) to reduce blood clots was extended from a three-or-six month regimen to a year minimum.
In the same year, Abbott began its first-in-man study of the Absorb stent. The idea was that the stent would disappear over time, that DAPT could be shortened, and that, since a permanent metal stent restricted movement of the artery (a.k.a. vasomotion), outcomes would be better if the stent could be resorbed and was no longer present after it did its job.
The product was refined a bit and another study was started. Around 2009, Abbott began referring to the Absorb as a "scaffold" instead of a "stent." (We at Angioplasty.Org would like to think that it was because of our blog post "Is the Scaffolding Coming Down?") In any case Absorb received the CE Mark approval for Europe and other markets in 2011, and the company launched the device in 2012. Abbott has reported that to date over 125,000 patients have received the Absorb BVS. However, over 50% of the market for these devices lies in the United States, Japan, and China, so approval in these countries would be critical. Therefore in 2013, Abbott launched ABSORB III as a "non-inferiority" trial, targeted at getting FDA approval.
ABSORB III: BVS Non-Inferior to Xience
For the ABSORB III study, 2,008 patients at 193 sites were randomized 2:1 from March 2013 to April 2014: 1,322 patients received the Absorb BVS and 686 got the Xience second-generation drug-eluting stent. At one year the primary end point of target lesion failure was 7.8% for BVS and 6.1% for Xience, statistically insignificant for the pre-defined non-inferiority comparison. The other secondary end points were also numerically worse for the BVS, but statistically insignificant for non-inferiority. Of some concern, however, were the rates of device thrombosis: 0.7% for the Xience, but for the BVS, it was 1.5%, more than double. This increased ST rate, along with other issues, was the subject of a critical editorial by Dr. Robert Byrne that accompanied the publication of ABSORB III in the New England Journal of Medicine. Unfortunately, regardless of whether the BVS achieved non-inferiority, the hope that it could reduce the duration of DAPT was not supported; in fact, due to the increased thrombosis rate, DAPT duration would probably need to be prolonged.
BVS Shows Worse Outcomes in Smaller Vessels
Further examination of the ABSORB III data showed that, as one would expect, adverse events increased for both BVS and Xience in smaller vessels, those less than 2.25mm in diameter. This is typical of all devices; the narrower the vessel, the greater the chance for a problem. However, the BVS showed a much higher dependence on vessel diameter. For example, when only arteries less than 2.25mm were looked at, the device thrombosis rate of 4.6% for BVS was more than triple that of the Xience; the myocardial infarction rate of 10% was more than double.
These less than optimal results may be due to the fact that the Absorb BVS has thicker struts, or that it was not optimally placed and expanded. The BVS is a marvel of biochemical engineering, but this first generation scaffold is not unlike the early drug-eluting stents: these scaffolds are more difficult to maneuver to distal, small vessels, their thicker struts are more prone to thrombosis. Additionally, because they are not as strong as metal, they have a tendency to fracture when over-expanded, which can cause adverse events. Conversely those events can also occur if the BVS is not expanded enough, leaving a gap between the scaffold and vessel wall. All these issues become more critical in smaller vessels. Given this data, the FDA panel agreed with Abbott that the BVS should not be used in vessels smaller than 2.5mm.
How Small is Small?
But by what modality does the physician determine the vessel diameter. Measurement of vessel size is one of the long-standing issues in interventional cardiology. As we at Angioplasty.Org have written about for many years, "angiography alone is not enough." The only accurate way to measure the diameter of a coronary artery is by using intravascular guidance, either IVUS or OCT (read about these modalities more in our Intravascular Guidance Center).
In ABSORB III, only 11% of the procedures utilized intravascular imaging guidance, which mirrors usage in the U.S. But the conclusions of the sponsor Abbott and agreed to by the FDA panel were that any vessel that is visually estimated via angiography at 3.0mm or less should utilize additional imaging (presumable IVUS or OCT) to measure more accurately the vessel diameter, to ensure that the BVS is not implanted in an artery less than 2.5mm. Needless to say, this would greatly increase the need for intravascular imaging, increasing cost and procedural time.
Pre and Post-Dilatation
To ensure proper seating of the scaffold, Abbott is emphasizing proper lesion preparation, possibly pre-dilating the blockage or using a scoring balloon, so that the scaffold device can be inserted smoothly. Once the device is expanded and the delivery balloon is withdrawn, an additional step of post-dilatation may be needed: a non-compliant balloon may be used to further expand the scaffold so that it sits firmly against the vessel wall. Under-expansion of any stent is associated with increased adverse events, especially stent thrombosis. Because the of thicker struts and sizing issues with the BVS, Abbott has asked that the labeling for the device include a reference to the need for post-dilating the scaffold. Again, this requires another balloon.
Potential Labeling and Precautions
The bottom line is that, if approved, labeling for the Absorb BVS will probably indicate a limited size range, a recommendation for enhanced intravascular imaging, pre-and/or-post-dilatation balloons, and finally, additional training so that interventional cardiologists
understand how the BVS may have differences in implantation techniques from the standard DES currently in use.
Commentary by Interventional Cardiologists
In light of the panel's recommendation, Angioplasty.Org queried several interventional cardiologists to get a "real world" read on what a potential approval of the Absorb BVS might mean for physicians, patients, and hospitals in the U.S. We talked to Drs. Ajay Kirtane, James Blankenship, and Dan Simon. Read their comments in Part Two, to be posted at a later date.
Reported by Burt Cohen, March 21, 2016 - revised July 15, 2016 regarding posting of Part II
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