Next-Generation Stent Technologies: Shedding the Metal

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The Absorb bioresorbable vascular scaffold stent is currently CE marked, but not available for sale in the U.S. Source: Abbott Vascular.
Second-generation drug-eluting stents (DES) are working better, but they are not perfect, especially in sicker patients. Therefore, a variety of models are being developed and tested, but most likely, it won't result in a one-size-fits-all solution.

What's missing now?

"Deliverability has improved with the second-generation DES with respect to the ability to cross a lesion. But there is a movement toward even thinner struts and more flexible designs, which could allow stent delivery to be more similar to that of balloons," explains Jeffrey J. Popma, MD, director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston.

Currently, the deliverability of a stent changes proportionately and inversely to lesion length. "Deploying stents in more difficult, longer lesions requires the implantation of multiple stents," Popma says.

To assess DES in these complex cases, the FDA is "actively engaging" trial sponsors and investigators to broaden inclusion criteria to treat a wider spectrum of more complex patients and lesions, says Andrew Farb, MD, medical officer and senior reviewer at the Office of Device Evaluation at the FDA's Division of Cardiovascular Devices.

However, in terms of stent design, Patrick W. Serruys, MD, PhD, an interventional cardiologist at Thoraxcenter, Erasmus Medical Center in Rotterdam, the Netherlands, suggests a metallic scaffold is a "transient need, only required for approximately six months to prevent restenosis. The permanence of metal in coronary arteries is detrimental, and once the metallic cage is implanted, the patient has permanent boundaries of the vessel."

Restenosis is an ongoing clinical concern that newer stent profiles need to address. "Restenosis with second-generation stents has improved, but it still occurs, particularly in complex lesions," says Popma. Restenosis rates are between 5 and 8 percent with the current second-generation stents—an improvement over bare-metal stents (BMS), but "we'd still like to see improvements in efficacy," he adds.

Soon, there may be fiscal incentives to reduce restenosis if the healthcare reform debate continues to push providers toward bundled payments. "Under the current fee-for-service model, restenosis results in another treatment for the patient, but the hospital collects reimbursement on the second procedure," Popma says. "However, the potential plan for a managed care model may create a financial incentive—in addition to a clinical benefit—to lower restenosis rates over the lifetime of the patient. Health plans may eventually be responsible for the entire cost of the patient over a multi-year period, so payors are going to expect a very durable effect from DES."

For safety considerations, patients who receive DES are required to be on dual-antiplatelet therapy (DAPT) for up to one year following PCI. "While Plavix [Bristol-Myers Squibb/Sanofi-Aventis]  will be cheaper when it goes off-patent in the U.S. in 2012, there will always be an adherence problem," Popma says. "Therefore, our newer stent designs must release the shackled dependence on DAPT, a therapy which is currently keeping the patient safe."

The rates of stent thrombosis have improved with the second-generation stents, especially with SPIRIT IV that showed a 0.17 percent rate with the everolimus-eluting stent (Xience V, Abbott Vascular) at one year (N Engl J Med 2010;362:1663-1674). Serruys says that these second-generation DES have "set the bar quite high because of the low stent thrombosis rates."

"We've been encouraged by the overall clinical event rates in recent trials with newer-generation DES, but we need to see adequate long-term follow-up that demonstrates continued safety and effectiveness," says Farb. "With such low event rates, we acknowledge that there are significant challenges to conducting studies that require large numbers of patients to show differences in safety and/or effectiveness between competing DES platforms."

However, Popma had been hoping that the very late stent thrombosis rates would have been closer to zero. "While the rates of stent thrombosis were promising in SPIRIT IV in the first year, all the patients were on DAPT, and new solutions need to present a way to suspend this dependence," he says.

BVS paves the way; questions abound

In January, the bioresorbable vascular scaffold (BVS) stent (Absorb, Abbott) became the first bioresorbable DES approved in Europe, based on data from the ABSORB trial, which showed its feasibility and safety. At two years, the stent was bioabsorbed, demonstrating that vasomotion was restored and restenosis was prevented, "suggesting freedom from late thrombosis" (Lancet 2009;373:897-910).

The trial outcomes lead Serruys, who was ABSORB's principal investigator, to hypothesize that the next decade could be dedicated to the "elimination of the metal."

Farb says that bioabsorbable stent platforms are "an innovative concept, which may have an array of desirable properties associated with the disappearance of the scaffold, including potential beneficial healing effects and restoration of normal vessel motility."

His optimism is matched with caution: "The proof of benefit derived from bioabsorbable stents will ultimately lie in well-designed and executed clinical trials. It is hoped that complete arterial healing will be associated with adequate luminal expansion with acceptable arterial remodeling." Farb adds that the negative arterial remolding with bioabsorbable stents could become an important issue as the stent disappears and its scaffolding function diminishes.

However, Serruys suggests "if a bioabsorbable stent can produce the same deliverability, safety and efficacy outcomes as the second-generation DES, but it disappears with time—allowing the vessel to respond naturally—then physicians will move in that direction for the benefit of their patients."

Currently, the BVS stent has been tested in a limited number of patients in relatively straightforward lesions, says Popma, adding that the proof-of-concept results show that it is safe (with no cases of stent thrombosis) and the vessel appears to return to its normal physiologic state approximately two years after implantation.

"Bioabsorbable stents have taught us that it is reasonable to leave only the natural vessel over the long term, but questions remain about whether it will reduce the long-term risk of stent thrombosis or reduce the need for long-term DAPT," says Robert Schwartz, MD, an interventional cardiologist at Minneapolis Heart Institute.

Other questions also remain unanswered for bioabsorbable stents: Does restoring the vessel to its normal conformation reduce the stress to the vessel wall? Does it return to normal endothelial function over time? Is there a change in inflammation and late restenosis? Will the efficacy be maintained in more complex lesion subsets? Will these stents be as strong in calcified vessels, compared with BMS?

"While there appears to be improved vasoreactivity with the BVS stent, rates of late thrombosis will be the game changer," says Schwartz, who also questions where Absorb will find its niche.

For many physicians, the ABSORB trial was too short to answer the outstanding questions. After the trial, the BVS stent underwent design changes with improved radial scaffolding and radial resistance.  

"It's just too early to tell," Popma says. "With the new design, the BVS stent could be fine in calcified lesions. It hasn't been tested yet. They certainly can design a bioresorbable stent as sturdy as a BMS, but it may result in a tradeoff with flexibility." These considerations will be vetted in the upcoming studies, including the ABSORB EXTEND multicenter single-arm registry, which will aim to eventually recruit 1,000 patients.

However, one practice management concern is that the ABSORB researchers stored the BVS stent at below -20ºC "to prevent physical aging of the polymer and to ensure device stability, which was both inconvenient and resulted in a limited shelf life of eight weeks" (J Am Coll Cardiol 2010;56;S43-S78).

Proliferation of new profiles

For future stent technology platforms, some are seeking thinner filaments and better deliverability, while bioabsorbable polymers and drug-eluting balloons (DEB) also are waiting in the wings.

Research on limus-based drugs mixed with abluminal biodegradable polymers on the outside of metal stents began in 2005. Serruys suggests these profiles may be an improvement on the current second-generation DES with durable polymers because the biodegradable polymer is on the outside of the stent against the vessel wall. Eliminating the coating from the luminal surface could potentially prevent delayed re-endothelialization and enhance strut coverage.

While bioabsorbable polymers on metal stents have shown some early promise, Schwartz questions if it will provide a solution that the industry doesn't already have. "Like bioabsorbable stents, bioabsorbable coatings will need to show improvement with late stent thrombosis," he adds.

The Nevo profile (Cordis) has shown "very interesting early data about the safety and efficacy of a bioabsorbable polymer," Popma says. The Evolve program (Boston Scientific), which has placed a bioabsorbable polymer on the company's BMS, also could be a "big step forward," he says. In addition, there are a number of stent platforms, built on the Biolimus A9 platform, which is a lipophilic sirolimus analogue that is combined with an abluminal PLA biodegradable polymer.

Drug eluting balloons, which Serruys says are more appropriately called a drug-coated balloons, may provide the biggest competition to DES. "Although there appears to be some concerns with stent thrombosis when you combine a BMS with a drug-eluting balloon, the potential for these devices is huge, especially in the peripheral arteries," Schwartz says. "Currently, we don't have a great solution for blockages below the knee or in the superficial femoral artery, so DEB probably will start to gain traction there, and then migrate to use in the coronaries."

"Over the next few years, the competition will get tough for second-generation DES," Serruys says.

Research costs = device costs

Due to the enormous costs associated with conducting long-term clinical studies, companies may need to charge a large premium if the devices are to become approved. These expenses, along with the stringent regulatory considerations, have led much research to be conducted outside the U.S.

"The FDA is tasked with a burdensome congressional mandate to demonstrate safety and efficacy for devices that garner approval," says Popma. "Therefore, it is more difficult to bring new products to U.S. shelves compared with the regulatory process in Europe, and we have the potential to fall behind."

Farb noted that the FDA evaluates safety and effectiveness and does not consider cost in its review process; however, "we appreciate the economic challenges associated with medical device development." Yet, he points to the agency's recently launched Medical Device Innovation Initiative that is seeking to foster development and speed the review of innovative devices that address important unmet needs.

"The FDA has some notable differences in regulatory approaches compared with the EU," Farb explains. "We have a single regulatory body, assessing the safety and effectiveness of medical devices, while the EU has a decentralized system with numerous regulatory notified bodies that review products based on a different standard of safety and performance, which leads to CE mark issuance. The U.S system places a greater focus on clinically significant outcomes."

In the U.S., Popma sees a potential for new funding from the federal government. "During this year's State of the Union address, President Barak Obama expressed an interest in supporting technology development to bring new jobs to the U.S., which is a laudable goal for this industry. Based on the President's speech, I'm hopeful that there will be more than rhetoric around reorganization to allow more studies to be conducted within the U.S. with an assurance of safety and efficacy. If we don't, companies will continue to move development overseas and these products might not become available to the American public in a timely manner, if at all, which could be detrimental to our patients."

The FDA is increasingly looking toward international approaches, according to Farb. "We embrace appropriate international trials, and we are working to improve the consistency of premarket studies and regulatory review through initiatives, such as the Japan-U.S. Harmonization By Doing program."

Farb suggests ongoing initiatives have already begun to have an effect, including continued work in preclinical research, the standardization of cardiovascular definitions for trials, and involvement with multi-sponsored registries and trials, such as the INTERMACS and DAPT. Finally, the FDA is working with professional societies and trial sponsors to develop performance goals for mature technologies that could result in "more feasible and efficient clinical trial designs," he says.  

All this could prove beneficial for research of next-generation stent technologies. "It is clear that no single stent design and polymer type will be suitable for all patients and lesion types," wrote Serruys and Garg. "Therefore, a more individualized choice of stent, taking into account patient characteristics…will be an important factor influencing stent selection" (J Am Coll Cardiol 2010;56;S43-S78).