Abstract
Interview by Louise Rishton, Commissioning Editor
Gregg Stone is Professor of Medicine at Columbia University, Director of Cardiovascular Research and Education at the Center for Interventional Vascular Therapies at Columbia University Medical Center, and Co-Director of Medical Education and Research at the Cardiovascular Research Foundation in New York (NY, USA). He has served as the principle investigator for more than 70 national and international multicenter randomized trials, has authored >1000 book chapters, manuscripts and abstracts published in peer-reviewed journals, and has delivered >2000 invited lectures around the world. His areas of expertise include interventional therapies of acute coronary syndromes and myocardial infarction; drug-eluting stents; adjunct pharmacology; new device angioplasty including distal embolic protection, thrombectomy, vascular brachytherapy and stent grafts; intravascular imaging; saphenous vein graft therapies; chronic total occlusions; vulnerable plaque; contrast nephropathy; mitral valve therapies; clinical trial design and regulatory issues. Along with Martin Leon, Stone is the director of Transcatheter Cardiovascular Therapeutics, the world’s largest symposium devoted to interventional cardiology and vascular medicine. Stone’s medical practice is devoted to interventional cardiology procedures at Columbia University Medical Center.
You currently serve as the Director of Cardiovascular Research and Education at Columbia University Medical Center. Could you tell us a little bit about your background and how you ended up in New York City?
Following undergraduate education at the University of Michigan (MI, USA), medical school at Johns Hopkins (MD, USA) and internal medicine training at New York Hospital–Cornell Medical Center (NY, USA), I completed cardiology training at Cedars Sinai Medical Center (CA, USA). For advanced angioplasty training, I worked at the Mid America Heart Institute at St. Luke’s Hospital in Kansas City (MO, USA) with one of the pioneers of the speciality, Geoffrey Hartzler. Following this, I went to practice on the west coast at El Camino Hospital (CA, USA) and Stanford University Medical Center (CA, USA) for 9 years. I then joined Martin Leon, initially in Washington DC, after which we moved to New York City where I have been for the last 15 years, first at Lenox Hill Hospital (NY, USA) and then at Columbia.
Are there any people who you feel have particularly influenced the progression of the field of interventional cardiology?
Interventional cardiology is a complex subspecialty and there are too many people to acknowledge. Obviously, there is Andreas Gruentzig, the originator of coronary balloon angioplasty. There is also Geoff Hartzler, with whom I was fortunate enough to train in Kansas City, who brought angioplasty to very complex patients, including those experiencing heart attacks, multivessel disease and chronic total occlusions. More than anyone else, he was the force behind the globalization and widespread use of angioplasty in increasing numbers of patients with coronary disease. He and his colleagues Barry Rutherford, David McConahay, Warren Johnson and Lee Giorgi educated a generation of interventionalists around the world.
Bill O’Neill, Cindy Grines and Felix Zijlstra demonstrated the safety and efficacy of primary angioplasty in patients with acute myocardial infarction, perhaps the area where we are greatest to able to benefit patients. Eric Topol and Rob Califf ushered in the era of interventional pharmacology, highlighting the importance of adjunct pharmacotherapy for intervention to be performed safely.
Julio Palmaz, Richard Schatz, Gary Roubin and Ulrich Sigwart deserve extraordinary recognition for ushering in the stent era.
Martin Leon and Patrick Serruys are two key leaders who have been fundamental in the so-called new-device angioplasty era, which includes a variety of techniques and devices ranging from atherectomy to lasers and to stents. Their contribution to the evolution and maturation of the subspecialty cannot be overemphasized.
Antonio Colombo’s pioneering efforts were seminal in improving the safety of coronary intervention and further expanding the scope of interventional cardiology. Barry Katzen and numerous other luminaries paved the way for peripheral vascular intervention. And now with physicians such as Martin Leon, John Webb and many others leading the way, the interventional cardiologist and the subspecialty have moved well beyond coronary and vascular intervention for the treatment of valvular and structural heart disease. There are so many others who have been seminal to interventional cardiology that I apologize to those whom space limitations preclude acknowledging.
Expert Review of Cardiovascular Therapy turns 10 years of age in May this year. Interventional cardiology – in particular percutaneous revascularization – has progressed a great deal in this time. Could you discuss the most important trials and findings that you have been involved in?
Much of the research I have been involved in throughout my career has involved patients with acute myocardial infarction (AMI), including leading numerous studies that have resulted in widespread dissemination of and improvements to the technique of angioplasty in the patient with AMI. I have also spent years investigating new interventional devices, from balloon angioplasty to bare-metal stents to drug-eluting stents (DES), and also to adjunct devices such as distal protection devices, aspiration catheters, embolic protection stents, and so on. I led the studies that led to the approval of three of the five drug-eluting stents approved in the USA. I have also heavily focused on adjunct pharmacology, including GPIIb/IIIa inhibitors and, most recently, the direct thrombin inhibitor bivalirudin, which has shown a reduction in mortality among patients undergoing primary angioplasty. We have demonstrated the importance of preventing iatrogenic bleeding complications from drugs if the maximum benefits from their use are to be obtained. I have also spent decades investigating optimal ways to use intravascular imaging to guide procedures, most recently culminating in the first demonstration that vulnerable plaques can be identified before they become symptomatic.
Looking forward to the next 10 years in the field, what do you feel will be the most important areas of research?
Currently I am very excited about DES in patients with unprotected left main disease – a condition that has always previously been the province of the cardiac surgeon. We believe that current generation DES are as good, if not better, than bypass graft surgery for selected patients with left main disease. However, this must be proven and, along with additional surgeons and interventionalists in the USA and Europe, we are leading a large trial examining this issue. We are also exploring the role of a novel atherectomy catheter, the CSI Orbital Atherectomy System, in ablating calcium to improve the long-term prognosis of patients with calcified plaque.
Over the next 10 years, I am hopeful that fully bioresorbable vascular scaffolds (BVS) may represent the next revolution in coronary devices, resulting in improved late outcomes compared with permanent implants. We have just started pivotal clinical trials with one of these devices.
Exciting work is ongoing to further improve outcomes for patients with AMI, either by prevention of distal embolization of friable atheromatous material and thrombus, or prevention of reperfusion injury with approaches such as mild hypothermia or supersaturated oxygen therapy. One such device that is about to enter a pivotal approval trial is the MGuard stent (Tel Aviv, Israel), which excludes thrombus and friable atheroma behind a mesh net on the stent, preventing its embolization. There are numerous other pharmacologic approaches being explored to improve myocardial salvage after reperfusion therapy – still a major issue. The potential for cangrelor, a novel, rapidly acting, potent intravenous ADP receptor antagonist agent, in concert with bivalirudin, is particularly exciting in patients with STEMI undergoing primary PCI. In addition to exploring this agent, we will also investigate the role of new stents with bioabsorbable polymers, such as SYNERGY (Boston Scientific, MA, USA), in STEMI, which may further improve late outcomes. In addition, cell therapy approaches are starting to appear more promising, with pivotal trials just beginning.
Our work with vulnerable plaque is continuing, looking at novel imaging modalities, such as near infrared spectroscopy and optical coherence tomography, and soon we will hopefully begin a randomized trial to determine whether BVS can safely passivate vulnerable plaque. This approach offers the potential to prevent death and MI in patients at risk.
Finally, we have just initiated a major study called COAPT with the MitraClip® (Abbott Vascular, IL, USA) to determine whether transcatheter repair of mitral valve regurgitation in patients with severe heart failure can reverse their otherwise dismal prognosis.
Mitral valve therapies seem to be an upcoming focus within the intervention field. Why do you think this is?
Mitral regurgitation (MR) affects several hundred thousand people in the USA as well as around the world, and when moderate or severe, significantly affects quality of life and longevity. MR is very complex, with numerous etiologies. It can be primary (a diseased valve) or secondary (due to left ventricular remodeling in heart failure). Until recently, only surgery could repair a diseased mitral valve. Mitral surgery is a great procedure in patients with primary MR, but has not clearly been shown to be beneficial in secondary MR – and in these patients, it is a riskier procedure with greater morbidity. Many of us are very excited about the potential of a less invasive catheter-based approach to secondary MR.
What do you predict for the continued evolution of the catheter laboratory over the next 10 years?
Certain procedures such as coronary angioplasty are now done so well that they have become widespread and have high success rates even in lower volume centers. However, some angioplasty is still very complex and/or high risk (such as chronic total occlusion intervention) and is best done at specialized centers or by expert operators. Similarly, emerging therapies such as transcatheter valve replacement, MitraClip valve repair, left atrial appendage closure, aortic aneurysm exclusion with endografts, novel heart failure therapies, and so on, are very sophisticated and should be mostly performed at speciality centers. In the near future, we will see a hybrid model, a basic catheter laboratory at many hospitals (especially for primary angioplasty in AMI), and then more specialized centers for increasingly complex and high-risk procedures.
With the recent focus on reducing stent thrombosis rates in DES procedures, what effect do you think novel device design will have on the field?
DES devices have markedly improved from their early counterparts a decade ago. The polymers have improved, as have the stents, resulting in improved safety and efficacy. In particular, the everolimus-eluting and slow-release zotarolimus-eluting stents have been proven to have excellent outcomes. On the other hand, stent thrombosis – both early and late – still exists, as does restenosis. Three main pathways are being pursued to further improve stent outcomes:
• First, the durable polymer that controls the dose and elution of the drug can be replaced with a bioresorbable polymer. As polymers are inherently inflammatory and can invoke vascular hypersensitivity reactions, if the polymer has resorbed after a few months, a better long-term safety profile may be seen;
• Second, metallic devices with surface modifications such as etchings, depots or reservoirs, and even hollow drug-filled stent cores, have been developed to eliminate the polymer altogether – perhaps even better if the drug elution can be adequately controlled;
• Third, completely ridding the patient of the polymer and the stent may be the ultimate long-term safety play – this is the concept of a fully resorbable device, or BVS. It is so different from a stent we have a new name for it – a scaffold. These are comprised of a polymer such as PLLA or others (there is even a metallic magnesium version), which can elute a drug such as everolimus either from the device body or a surface coating. The scaffold remains initially to prevent constrictive vessel remodeling within the first year, but then after 18–36 months, the stent completely resorbs, restoring the normal vessel architecture and vascular responses, such as its ability to expand and contract with diastole and systole.
At the same time, there are specialty stents being developed that may have important roles in specific patients and lesions, such as mesh-covered stents to prevent thrombus embolization during primary angioplasty in AMI and dedicated bifurcation stents.
How far off is the clinical utilization of resorbable devices? Do you feel that they will represent the best device for patients?
One such device is already CE marked and thus approved in Europe and other countries. They are currently expensive, but the price should come down with time as competitors emerge. The short-term data look good, but we do not yet have sufficient long-term data to know whether these devices are as good as or better than metallic DES. The 2000- and 4000-patient randomized ABSORB III and IV trials, which I have helped design, are addressing these issues.
Thus, BVS may be considered the ultimate design; however, I do not believe that they will be applicable to all patients and coronary lesions, at least not in the short term, as the polymeric stents are somewhat higher profile, tend to have greater recoil and require more attention to detail to deploy than regular bare-metal stents/DES. Nevertheless, BVS deployment may be applicable to 50–75% of patients. Over time, the design characteristics of these devices will also be improved so they may be applied to all patients and anatomies.
Do you think we will eventually reach an end to cardiac device development?
Yes! In the future, atherosclerosis will be treated without stents at all, with novel pharmacologic agents to prevent the development of vulnerable plaque. There are a variety of fascinating nanotechnology-based approaches being developed that would home in on atherosclerotic plaque and ablate it, without any need for a stent. However, these therapies are 7–15 years away.
As well as being involved in the biggest trials for devices, you have also worked on predicting and reducing procedural-related complications. Could you tell us a bit about your work in this area and what you are trying to achieve?
With every study, there is a trade off between helping the patient versus the side-effect profile and complications from the procedure. For all study analyses, complications are front and center. Regarding stents, most people have focused on stent thrombosis and restenosis, which we have shown can be reduced with optimal technique, pharmacotherapy and intravascular imaging procedural guidance. Other complications can occur such as procedural myocardial infarction, perforations, low flow, and vascular and renal complications. Specifically, we have performed numerous studies demonstrating the trade offs between preventing procedural ischemic complications at the risk of bleeding, the latter of which can affect early and late survival just as adversely as AMI. We must take a personalized approach to each patient based on their clinical and angiographic features and increasingly, their genetic makeup and proteomic expression.
Financial & competing interests disclosure
GW Stone is a consultant for Boston Scientific, InfraReDx, Volcano, Eli Lilly, AstraZeneca, InspireMD, Janssen, VeloMedix, Therox and Daiichi Sankyo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.