Translation Pathway for Coronary Stent Development
Future of Coronary Stents
Mitchell W. Krucoff, MD
Chuck Simonton, MD
Ideally, with primary prevention, the need for revascularization would disappear from the spectrum of public health concerns. Realistically in our aging population, the future of stents is driven by the relatively long list of currently unmet needs associated with secondary prevention.
Present stent technology, particularly drug-eluting stent (DES) technology, represents a mature device space. Technical performance and clinical outcomes are excellent, which has supported the widespread and aggressive use of these devices in more complex anatomy and in fragile patients. With more than one million patients a year being treated and many patients expecting a 20 to 40-year survival, even relatively small design advances continue to have enormous public health impact. With this comes some novel challenges not only in design, but in how we accrue data to define whether indeed a “newer” DES is actually better. Mindful of the present, there are four major areas where we might consider the future of stents with most excitement: 1) stent design objectives; 2) coronary lesion characterization; 3) patient-oriented focus; and 4) “better, faster, cheaper” early feasibility, benefit/risk and safety evidence collection in the 21st century.
Stent Design Objectives Heading Into the Future
DES design objectives are related to the fundamental components of a “combination product,” for example, a device that delivers a drug. These components include: 1) the struts or scaffolding that restrains tissue fragments and overcomes elastic recoil at the percutaneous coronary intervention (PCI) site; 2) the polymer that facilitates control of drug loading and the kinetics of drug release into tissue; and 3) the drug, currently almost all in the limous-analogues class of m-tor inhibitors.
Interest in more high-risk and complex coronary anatomy such as left main PCI continues to challenge certain specific niche designs, such as bifurcation stent platforms. One bare-metal system (Tryton) is now approved in the United States, and there is interest in advancing this design challenge into a DES design. For PCI in general, however, with deliverability of thin strut stents now very high, and restenosis rates of limous-eluting DES very low, engineering objectives have primarily shifted to enhanced safety objectives, in particular reduction of stent thrombosis rates with dependence on adjunctive antithrombotic (dual antiplatelet) therapies, as well as on the potential to restore vascular metabolic and mechanical properties over time. Mechanistically this includes design features conceptually related to short- and long-term healing of the procedural trauma related to implantation, to the endothelialization of the stent prosthesis, to the conformity of the strut/cell architecture into the vessel tissue without fracture, and even to the complete resorption of a scaffold over time.
Advanced contemporary designs available in the United States, including very thin platinum-chromium struts (Platinum, Boston Scientific), biocompatible durable perfluorocarbon- (Xience, Abbott Vascular) and Biolynx polymers (Resolute Integrity and Onyx, Medtronic), and abluminal bioresorbable polymers (Synergy, Boston Scientific), have shown particular impact on long-term healing, with reduced stent thrombosis rates even with shorter-duration dual antiplatelet therapy (DAPT) in randomized and historical comparisons to first-generation DES (Cypher, Taxus). Zero polymer design using etched surface craters to contain the highly lipophilic new molecular entity biolimus A9 (Biofreedom, Biosensors) was recently reported with 30 days of DAPT in high bleeding risk patients, showing safety when randomized against bare-metal stenting (BMS). Work to date thus maps a path of success into the future with continued improvements in DES safety, even with the risk of bleeding that is associated with extended DAPT duration, and even in very high-risk patients. Nonetheless, stent thrombosis within the first 30 days of implantation, primarily related to acute implantation trauma and technique, appears more independent of contemporary stent design. Long-term stent thrombosis reduction with ongoing DAPT, despite added bleeding, is still an important potential risk for patients after PCI. Finally, patients who undergo repeated PCI and accumulate large numbers of metal stents over time may represent a growing patient population also at increased risk even with current DES.
As a continued focus for novel design, short- and long-term safety have produced further innovative directions for current and future evolution and evaluation. One innovative design example is the addition of a biological endoluminal anti-CD34+ antibody designed to attract circulating CD34+ endothelial progenitor cells to the PCI site to more rapidly and completely cover traumatized tissue and stent struts while maturing into healthy, functional endothelium (Combo, OrbusNeich). To date, clinical results have been noninferior to existing DES, while proof that this novel design feature conveys superior safety benefit is still under study. Another area of breakthrough innovation has been targeting the longer-term limitations of permanent metallic stents through development of completely bioresorbable polymer or metallic-matrix scaffolds. Despite concerns emerging with the first-generation Absorb BVS about late fragmentation and resorption promoting increased rates of very late stent thrombosis and its de facto withdrawal from the market, further work and design innovation in this exciting area is a clear target in the near future.
Coronary Lesion Characterization Heading Into the Future
Even the best of DES design may result in clinical complications if lesion selection and implantation technique are suboptimal. Lesion substrate characterization pre-PCI as well as technical results assessment post-PCI continue to emerge as integral components of optimal procedures, and hence also as windows into potential directions for future cath lab, DES, and adjunctive device design. Physiological assessment has become a key criterion for predicting the clinical benefit/risk of PCI with DES in angiographically borderline lesions. Use of intravascular ultrasound (IVUS) and optical coherence tomography (OCT) to assess circumferential calcium prior to PCI as well as strut apposition after DES implantation has gained wider use in selected communities of operators such as in Japan, while for many U.S. sites, the added time and issues with cost recovery continue to limit clinical adoption of these technologies. Integration of imaging and physiological fractional flow reserve/instantaneous wave-free ratio (FFR/iFR) instrumentation into cath lab systems promotes ease of use both prior to and after completion of PCI procedures, and has had some impact on uptake in the United States.
Co-registration of angiographic, IVUS, and OCT images, as well as FFR/iFR pullback gradients constitute the building blocks of future strategies for optimal target lesion and device selection (especially diameter and length), adjunctive device use (for calcific lesions and chronic total occlusions [CTOs]) and for ensuring that final results have technically optimal strut deployment and physiologic normalization of flow characteristics in the entire vessel. Ongoing work with noninvasive anatomic and physiological assessment also has future promise for enhanced spatial resolution and accuracy that could lead to a reduction of need for invasive instrumentation at least for pre-PCI assessments.
Patient-oriented Benefit/Risk Heading Into the Future
Since the advent of percutaneous transluminal coronary angioplasty through to modern PCI with contemporary DES it has been appreciated that while coronary lesion anatomic and physiological substrates are highly predictive of lesion and device behavior, clinical outcomes are also heavily influenced by other cardiac and noncardiac comorbidities and patient characteristics. Comorbidities such as age, diabetes, and renal dysfunction; clinical presentations such as acute coronary syndromes associated with thrombotic events; and behavioral characteristics such as drug noncompliance are all highly interactive with present and future device designs for optimizing outcomes with PCI.
With increased life expectancy, new considerations have emerged and constitute maturing areas of inquiry for future recalibration of benefit/risk scenarios for PCI. Longer survival from first diagnosis means that more patients undergo multiple repeat procedures, with greater likelihood of involving de novo bifurcations and CTOs, degenerated vein grafts, and previously stented coronary segments not simply as isolated interventions but as aggregated procedures with permanent implants and potentially additive risks. Repeated PCI in these settings has traditionally been excluded from the pivotal stages of new device evaluation, making randomized data testing longitudinal therapeutic strategies for these patients relatively rare. As this spectrum of survivors continues to grow, future efforts to better define optimal care and identify areas of unmet need that could become targets for novel device engineering, in addition to advanced optimal medical therapy, could have important public health impact.
Aging alone in many countries such as the United States constitutes an exponentially growing domain of clinical management decision making, particularly with regard to appropriate application of invasive procedures and implantable devices. Discrimination of outcome objectives, such as mortality benefit versus symptom relief, in conjunction with age-related risk profiles associated with the procedures (e.g., kidney injury) or adjunctive medications (e.g., bleeding risk) not only challenge professional best practice recommendations in the near future, but also the need to expand the patient/family role in decision making with regard to PCI as an option. The relative balance of knowns and unknowns available at the time of informed consent are essential for new device studies. Another fascinating area of relatively new science for cardiovascular procedures, the assessment of “frailty” has strongly correlated with outcomes in elderly patients undergoing transcatheter aortic valve replacement procedures, and may have great future relevance in PCI patients, ranging from elective PCI to primary ST-segment elevation myocardial infarction and shock presentations.
Finally, an exciting area of current unmet needs now gaining attention is the exploration of DES safety with shortened DAPT in high bleeding risk patients. Historically, PCI with BMS has been coupled with very limited (30-day) duration of DAPT. Actual benefit/risk and safety-related outcomes in these patients has been sparse as they are almost universally excluded from pivotal randomized trials of both new devices and new adjunctive drug therapies. The prospective, randomized, double-blind Leaders Free study, in the DES arm with 30 days of DAPT, however, has raised concerns that the historically intuitive BMS approach may in fact be suboptimal compared to contemporary DES. These concerns in turn have stimulated great interest into the study of these complex patients and their outcomes, from the definition of bleeding risk factors and quantitative risk scores used to characterize high bleeding risk to the study of how the best balance of bleeding and clotting can be achieved through optimal device design and drug selection and duration strategies.
“Better, Faster Cheaper” Device Evidence, Regulatory and Clinical Science Heading Into The Future
Classical approaches to clinical research traditionally have required dedicated site coordinators to put detailed information into case report forms even as other site-based clinical staff put the identical information into procedural reports for the medical health record, professional society quality registries, and inventory replacement and billing systems. Such duplicative efforts have led to exponentially rising costs and slowing enrollment for American medical device trials. Compounded by the financial crisis around 2008, there was a virtual “exodus” of cutting-edge device research from the United States, combined with a pronounced device “lag” for the availability of new, better, safer devices reaching the bedsides of American patients who needed them.
Over the past decade, contentiousness between stakeholders often blaming one another for device lag has been impressively transformed into a more “ecosystem” focus with collaborative approaches to eliminating precompetitive barriers to innovation. With strong leadership from the U.S. Food and Drug Administration (FDA), this profound shift in efforts to “protect and promote” our public health has been orchestrated through inclusive, transparent public-private partnerships (PPP) such as the Cardiac Safety Research Consortium (CSRC), the Clinical Trials Transformation Initiative (CITTI), the Japan-USA Harmonization By Doing (HBD) Program, the Medical Device Epidemiology Network (MDEPINET), and the Medical Device Innovation Consortium (MDIC). It has been supported by academically based society efforts such as the International Society of Cardiovascular Translational Research and the American College of Cardiology.
With regulators, manufacturers, professional societies, academics, clinicians and patients working together, “better, faster, cheaper” clinical trials and regulatory science have been advanced with important strides in early feasibility studies, global regulatory harmonization, electronic data capture tools and infrastructure, and novel statistical methodologies. In 2015 the Medical Device Registry Task Force (MDRTF) recommendations to FDA for a national medical device evaluation system. In its report, MDRTF recommended moving away from the classical clinical trials model that doubles the work load and costs of research at clinical sites. Instead, MDRTF recommended linking existing site-based clinical work flow to other electronic registries and information systems to enable strategically “coordinated registry networks” (CRNs), connecting complementary sources of procedural data, patient data, device identifiers, and long-term follow-up in a system that dual purposed, rather than doubled, existing site-based and related health care efforts. Concentrating on the integration of consistent core data elements and definitions across relevant systems such as electronic health records, quality registries, and claims data, CRNs constitute an ongoing infrastructure of real-world evidence that can be leveraged for device evaluation at every stage of the total product life cycle, from early feasibility studies to safety surveillance, including registry-based prospective randomized trials and longitudinal studies providing larger, real-world cohorts and longer-term follow-up at reduced cost and less added work for clinical centers.
In 2016 the Center for Devices and Radiologic Health (CDRH) at FDA made enhanced infrastructure and methodologies using of real-world evidence its top strategic priority and adapted the MDTRF recommendations to form the National Evaluation System for Health Technologies (NEST) with an emphasis on scaleable CRN-based models for regulatory science and medical device trials. To execute this mission, FDA provided funding to the MDIC PPP to develop a dedicated coordinating center (NESTcc).
The success of the NEST construct for clinical trials and regulatory science evaluating new coronary stent benefit/risk, safety, and comparative effectiveness represents a truly transformative “better, faster, cheaper” solution to device lag, as well as to global device evaluation. With established programs such as the national real-world registry systems in Sweden and recommendations for essential principles of registry infrastructure and methodologies from regulators representing more than a dozen nations in the International Medical Device Regulators Forum , the move toward structuring real-world data and NEST in the United States also opens the door to a “better, faster, cheaper” future of DES research and development to the global community of cardiovascular care as a whole.