Dr. James B. Hermiller can be contacted at herms2@gmail.com.

Disclosure: Dr. Hermiller reports he is a consultant for Abbott, Boston Scientific Corporation, and Medtronic.

ABSORB II trial data were released at TCT this past fall, from 501 European and New Zealand patients randomized 2:1 to the Absorb bioresorbable scaffold or Xience stent. Before looking ahead to ABSORB III and IV, can you summarize what we learned from ABSORB II?

There are some high points from the ABSORB II data. First, angiographically, the Absorb bioresorbable vacular scaffold (BVS) (Abbott Vascular) looks very similar to a metallic platform in terms of stent restenosis and recoil. Second, there was no significant difference in terms of early safety between the control and the BVS. Third, in terms of clinical efficacy, target lesion revascularization for the BVS was not higher than with the metallic stent. The BVS patient-centered outcomes are, at least numerically, better than the control. Finally, reduced angina was seen in the BVS group. The BVS group also demonstrated less use of nitrates and less revascularization, which may have been driven by the reduction in angina.

Had any signals been observed prior to ABSORB II regarding reduced angina with BVS?

Operators had noticed it clinically, but it had never been tested in a randomized fashion. There are many hypotheses to potentially explain a lower rate of angina, but this was the first study to really bring it to everyone’s attention.

Why might angina be reduced with the BVS?

I don’t think anybody knows, but there are a few hypotheses. One clear difference between metallic platforms and the BVS platform is in how much the vessel is straightened once the device is implanted. Coronary arteries are naturally very curved structures. When we implant metal stents inside a coronary artery, the artery is straightened. The BVS is a much more flexible scaffold, so the straightening is much less. Also, because the BVS is biodegradable, the vessel actually is able to dilate once it is absorbed. Metallic-stented vessels are unable to dilate; they have no vasomotion. However, that wouldn’t explain the reduced angina in the first year. I think the best hypothesis is the one of vessel straightening, but honestly, we just don’t know.

How much more flexible is the BVS than your standard metallic stent?

Substantially. It is significantly more flexible than a metallic device, and you can measure that by how much the vessels straighten once the platform has been implanted. That was one of the studied targets for ABSORB II, and the level of straightening that occurred was quantitated. It was visible and fairly obvious.

Once the BVS resorbs, does the vessel return to its original formation or does it maintain that little bit of difference?

That is a great question. I have not seen anyone address the late geometry.

It may not matter.

It may not, and it may. There is 3- to 4-year data available, and we should be able to go back and look.

Can you give us a brief overview of ABSORB III and IV, and how these two trials are connected?

ABSORB III is basically a much larger randomized trial than ABSORB II, with a clinical primary endpoint of target lesion failure, including cardiovascular death, myocardial infarction related to the target lesion, or ischemic-driven target lesion revascularization. It is a standard endpoint in pivotal trials for U.S. approval. The trial has enrolled over 2000 patients randomized to metallic drug-eluting stent (DES) (Xience, Abbott Vascular) or a BVS. At this point, we are just waiting for the primary outcome to be released. ABSORB III is a pivotal trial, with a much larger cohort of patients. Thus, the power to detect differences in either efficacy or safety between the control metallic platform and BVS is going to be much greater. The complexity of lesions is also going to be greater than in ABSORB II, which looked at a relatively vanilla group of lesions. ABSORB III is going to have more complex lesions and it is also going to include multivessel interventions. As most of these studies have gone along, we start with very early, very safe, simple lesions, and then as the trials move forward, the lesions get more complex. This isn’t to say ABSORB III is a real-world study taking all comers. Although it is more complex than ABSORB II, III is still going to exclude lesions that are heavily calcified. There will be no total occlusions in this study or patients presenting with ST-elevation myocardial infarction. So it is not real world, but on the other hand, it is going to include more complexity than we saw with ABSORB II. Next is ABSORB IV, which is going to be very different for stent studies, because the primary endpoint is related to angina and quality of life metrics. ABSORB IV will enroll another 3000 patients. ABSORB IV is an extension of ABSORB III, and so there will be a total of 5000 patients that will have been enrolled and randomized. These two studies will be combinable in terms of the analysis. Getting stents approved in the United States has typically followed a straightforward pathway. Randomized trials have more or less stuck to the same trial design, with target lesion failure as the primary endpoint. ABSORB IV has a very different endpoint looking at angina and quality of life measures, and it is a different kind of trial than we have seen before. In a very objective, blinded way, this trial will evaluate whether a newer design and a newer stent platform increases the number of patients that remain asymptomatic. Metallic DES have been extraordinarily effective, but still about a quarter of patients have residual angina after stenting that reduces their quality of life. Angina is also expensive. If people experiencing chest pain after stenting come to the emergency room, they are then admitted to the hospital, and either have non-invasive testing or are frequently re-cathed. Once you relook after stenting with angiography and start  examining  these arteries, there is a much higher probability that another stent will be placed somewhere else.

Is there any economic aspect to ABSORB IV that will evaluate cost?

Yes, there will be a full profiling of the costs throughout the system. That will actually be a very big part of the trial as well.

How far out will the trials be following patients?

These will be long-term studies out to five years, just looking at BVS versus metallic platforms. I don’t think anybody predicted that chest pain would be an issue before these studies started to roll out. Most of the benefits were thought to occur down the road, since three to four years later, the BVS is gone. Where we originally anticipated seeing a difference was in the long-term follow-up.

Angina is patient-reported, not a hard clinical endpoint. How did that aspect impact the trial design?

A critical aspect of ABSORB IV is that both the patient and the physician conducting the post procedure evaluation will be blinded. This will avoid concerns about the placebo effect.

How long does it take the BVS to fully dissolve?

It is an interesting question. What we know from the old balloon angioplasty days is that you only need about 3-6 months of having a scaffold in the artery. That is how long it takes for the artery to re-narrow, and after a balloon angioplasty, it re-narrows because the artery constricts; it negatively remodels. Having something around for at least 6 months that is a full-blown stent is the ideal for these kinds of devices. With the Absorb BVS, by a year, there is a loss of some of the radial strength. By two years, we start to see loss of the scaffold itself, meaning the mass and structure of the device, and by three to three and a half years, the BVS is gone. There is probably some variability. Certainly by four years, in vessels examined with high-resolution optical coherence tomography, the scaffold is gone and what is left behind looks like a fairly normal neointima. The other observation is that the vessel remodels positively. The lumen enlarges over time. Furthermore, it demonstrates vasomotion, meaning that the vessel can now expand in response to stimuli. When we exercise, increased flow that is a stimulus for our arteries to expand and allow greater blood flow. With a metallic platform in place, the vessel can’t do that, and it may be part of why some people have long-term angina.

What are other potential advantages of a BVS?

It has been clear that one of the downsides of metallic DES is the occurrence of atherosclerosis beneath the stent struts. Stents may actually enhance long-term atherosclerosis. Stented segments renarrow early because of intimal hyperplasia, which is like a scar, but in the late term, out to 5 or 10 years, there is accelerated atherosclerosis. Very late stent thrombosis is probably in part due to rupture of atherosclerotic plaque that has developed underneath these stents. One hope is that by getting rid of that nidus, fewer late events will occur in that territory, because there is no accelerated atherosclerosis in a caged segment of the vessel.

Will the BVS eventually move to the peripheral system?

I think the superficial femoral artery is an ideal location for the BVS. A device that is flexible would be good early on, and then if it completely disappeared, leaving an unconstrained vessel, that would be an ideal situation. It may be good for other applications as well, such as behind the knee in the popliteal arteries, which get huge flexion, and potentially below the knee, in limb salvage procedures. Metallic stents are suboptimal, because it has been difficult to get anything to conform to what happens when the knee is bent. Physicians in the peripheral vascular space would love to have something that would disappear and is very flexible. Particularly for the superficial femoral artery, which is the bane of the peripheral interventional practice.

Any final thoughts?

Looking back over many years of doing interventions, I see an amazing progression. When the first bare metal stents came out, delivering the stent was difficult and there was a high restenosis rate. Next, first-generation DES arrived and we thought, these are fantastic! Then we found very late stent thrombosis was higher than with bare metal stents, which caused an initial scare. The current DES are very good. We still have people that restenose and we still have issues with diabetics, although we are much better than before. But the future will be in bioabsorbable devices. We will need to determine whether bioabsorbable platforms can be expanded into use for new applications, whether in the peripheral vascular arena or in new anatomic subsets. It may be that these new devices will allow us to take on more complex disease. For example, we will soon see results from the EXCEL trial, looking at left main disease and how stenting compares to surgery. Chronic total occlusions (CTOs) are also a huge unmet need. A very large number of patients either get surgery because of CTOs or are not treated with percutaneous coronary intervention because we can’t get through the CTO. We are going to get better at treating these patients. We are certainly better today than we were five years ago, and the field will continue to advance and expand transcatheter therapy to many more patients.