From Great to Greater: Innovation in Stent Technology Possible, Worth Pursuing
It is becoming increasingly difficult to demonstrate that investigational DES technologies are better than the ones already in U.S. cath labs, but there appears to be a universal belief that incremental gains are still achievable with metallic platforms while waiting for the potential of fully bioresorbable scaffolds (BRS) to be realized.
Inspired by a debate at TCT 2015 on whether current metallic stent systems can be meaningfully improved, TCTMD talked to several experts about whether it is worthwhile to continue focusing on innovations in stent technology and if so, where advances are likely to be made. All said better stent or scaffold technology should be pursued, but noted the difficulty in proving that newer devices have advantages considering how far adverse event rates have fallen with current-generation DES.
“The question is not if it makes any sense to continue developing new technologies. The question is what pathway we need to take to disrupt current technologies that we have right now,” Juan Granada, MD, of the CRF Skirball Center for Innovation (Orangeburg, NY), said. “I think it’s very minimalist to believe that we’ve plateaued on percutaneous coronary intervention based on metallic stents.”
Areas of Need
The primary rationale for newer and better technologies has been concern over the risk of late adverse events occurring 1 year after implantation, such as restenosis and stent thrombosis leading to TLR, particularly in patients with complex lesions or ACS. Compared with results of DES implantation in all-comers populations, results are subpar in diabetics, patients who require oral anticoagulation, and those with small vessels, multivessel disease, saphenous vein grafts, and renal failure, according to multiple experts.
Other problems cited with current systems included deliverability, profile size, and polymer hypersensitivity, as well as the need for long-term dual antiplatelet therapy.
Reducing or Eliminating Polymer the Answer?
One way that late events and extended treatment with antiplatelet therapy might be avoided is by doing away with durable polymer on DES either through gradual degradation after implantation or by the use of stents that elute antiproliferative agents without the use of a polymer.
David Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), said that theoretically a metallic DES with bioresorbable vs durable polymer would be more biocompatible because there would not be permanent polymer inducing impaired healing or late hypersensitivity. That increase in biocompatibility would lessen risk of late events and possibly allow for shorter antiplatelet regimens, he said.
Stephan Windecker, MD, of Bern University Hospital (Bern, Switzerland), agreed, pointing out that there are several clinical scenarios in which the ability to reduce the need for or potency of antiplatelet therapy after stent implantation would be beneficial, citing cases when patients need to stop antiplatelet therapy for active bleeding or urgent surgery. “If you could implant a stent and leave the patient without any aspirin, without any antiplatelet therapy, that would be an important clinical advance,” he said.
Windecker said improvements to the antiproliferative agents used on DES might be able to mitigate the need for antiplatelet therapy, but he and others also pointed to polymer-free metallic stents as a potential way forward.
Such a stent, the BioFreedom drug-coated stent (Biosensors International), was evaluated in LEADERS FREE, which was presented at TCT 2015, comparing the polymer-free stent to a BMS in patients with a high bleeding risk taking just one month of dual antiplatelet therapy post-implantation. At one year, BioFreedom reduced the rate of clinically-driven TLR (primary efficacy endpoint) and of a composite of cardiac death, MI, and definite/probable stent thrombosis (primary safety endpoint), compared to the BMS.
Windecker said, however, that further research is needed to determine whether polymer-free stents are as effective as DES with polymer.
Promise of BRS Still Unproven
Another way to potentially reduce late events is through a fully bioresorbable stent, which performs the drug delivery and support functions of metallic DES within the first year and then degrades within 2 years to leave no permanent implant behind.
This strategy would solve the problem of a permanent metallic stent left behind, which straightens the vessel, causes compliance mismatch, allows for persistent inflammation, introduces the potential for late strut fractures, and allows for the development of neoatherosclerosis. These are issues that no currently available stent technology has addressed, Gregg Stone, MD, of Columbia University Medical Center (New York, NY), observed.
Studies, including ABSORB III, indicate that BRS are noninferior to best-in-class DES in the first year, but a potential advantage for reducing late outcomes—where most interventional cardiologists see the advantage of BRS—will not be apparent for several years. All going to plan, removing metal from the vessel would lessen neoatherosclerosis and the risk of very late stent thrombosis, although that remains to be proven.
“Currently, the clinical benefit of BRS is purely hypothetical,” Philip Urban, MD, of the Hôpital de la Tour (Geneva, Switzerland), who is the principal investigator of LEADERS FREE, told TCTMD in an email. “Surrogate endpoints such as vasomotion, positive remodeling, etc., have not so far been enough to convince operators to switch to a device that is more difficult, expensive, and time consuming than a metallic DES to optimally implant.”
Kandzari also cited potential obstacles to using BRS, including their relatively high profile, limits on deliverability, their thicker struts, and limitations in the ability of radial strength, scaffolding, and expansion. Those issues are being addressed in further iterations of what is still first-generation technology.
“There’s a price to pay with these early first-generation designs,” acknowledged Stone, who is the study chair for ABSORB III. “I’m confident those design issues will be overcome over time. In the meantime, though, the question is: once the scaffolds are totally gone in approximately 3 years, will long-term outcomes be improved?”
The answer will not come, he predicted, for another 6 or 7 years.
Ron Waksman, MD, of MedStar Washington Hospital Center (Washington, DC), believes it is worth pursuing BRS despite the uncertainty, assuming 1-year outcomes are comparable. “The promise is huge if it really fulfills expectations, but obviously you don’t want to compromise things with respect to performance at 1 year or 2 years,” he said.
He noted that noninferiority trials, by design, can have wide margins for demonstrating that they are noninferior to a comparator. In ABSORB III, for example, although the Absorb bioresorbable vascular scaffold was shown to be noninferior to Xience (both Abbott Vascular) for 1-year target lesion failure, “if you’re looking numerically at the point estimate, [BRS] were not as good as the existing drug-eluting stent,” Waksman said, acknowledging that BRS are still first generation devices.
“The first-generation of metallic drug-eluting stents also had several limitations which have been overcome, and obviously the same is to be expected with scaffolds,” Windecker commented.
That’s a point stressed by one of the principal investigators of ABSORB III, Dean Kereiakes, MD, of the Christ Hospital (Cincinnati, OH). He argues that because BRS are still first generation, there will be greater strides made in this area than in the area of metallic DES with ultrathin struts and bioresorbable polymers.
Excellent Outcomes Complicate Research
Iterative clinical trials drive device innovation forward, but the size of the gains in clinical outcomes seen over the past few decades with the introduction of newer stents are becoming increasingly difficult to replicate, with rates of repeat revascularization well into single-digit percentages and stent thrombosis rates below 1%.
Thus, contemporary stents are difficult to top in terms of trying to achieve superior outcomes with newer technology. To prove superiority to the already excellent outcomes would require a trial with several thousand if not tens of thousands of patients, which is not practically or financially feasible to do, Kandzari said.
He said that is why noninferiority trials, which require much fewer patients, are used to introduce new devices to the market. Like Waksman, he cited concerns about the wide margins of noninferiority used in such trials. “It raises the issue to clinicians… is ‘as good as’ good enough with a new drug-eluting stent or must we somehow insist that sponsors of clinical trials, device manufacturers, demonstrate some aspect of superiority?” he said.
“Noninferior” technologies with unproven potential benefits also pose a dilemma for practicing interventional cardiologists, Kandzari added.
“With the promise of incorporating bioresorbable technology, whether it’s bioresorbable scaffolds or bioresorbable polymers, I think there is still opportunity for iterative improvement,” he said. “I think the ability to demonstrate it is just increasingly more difficult.”
Granada agreed, pointing to what’s already been achieved with market-approved, permanent polymer, metallic stents. “The platform, the strut thickness, and the mechanism of action of metallic DES have reached the highest level of technological sophistication,” he said.
Stents and Scaffolds in the Future
Granada’s focus in the field of stent and scaffolds is durability over the long term: a patient who is 50 years old could easily have another 30 years of life left or more, potentially with additional coronary procedures down the line. But durability of metallic stents over decades has not really been tested or shown, he said.
“Long-term durability and being able to treat a segment and provide the opportunity for healing and treating that segment again is something that we don’t have right now,” Granada said, noting that BRS have the most potential to address that issue.
“As the technologies get better and better, I do believe they provide a better opportunity for the vessel to recover,” he said. “Therefore, I think [fully bioresorbable devices] would be more desirable for the physician and the patient in the long run.”
In 10 years, Kandzari predicted, interventional cardiologists will be using more BRS, although they will have advanced beyond the technologies still in testing today, in addition to a large number of metallic stents that are either polymer-free or contain bioresorbable coatings.
Regardless of where the technology goes, Kereiakes argued for continued innovation. “When technology stops iterating, I think knowledge stops. And I think that’s darkness, so I don’t go there.”
- Granada reports that the CRF Skirball Center for Innovation performs validation work for all DES commercially available in the United States.
- Kandzari reports receiving research/grant support from Biotronik, Boston Scientific, and Medtronic and minor consulting honoraria from Boston Scientific, Medtronic, and MiCell.
- Kereiakes reports relationships with multiple device companies.
- Stone reports serving as a consultant to Reva.
- Urban reports receiving grant/research support from Biosensors Europe and consulting fees/honoraria from Abbott Vascular, Edwards Lifesciences, and Terumo Corporation.
- Waksman reports serving as a consultant to Abbott Vascular, Biotronik, and Boston Scientific and serving on the advisory board for Medtronic.
- Windecker reports receiving institutional grants from major stent manufacturers, including Abbott Vascular, Biosensors, Biotronik, Boston Scientific, and Medtronic, and having received lecture fees from the same companies more than 6 months ago.