Figura 1. Abrupt closure of the right coronary artery after elective PTCA. The patient experienced s...

Figura 2. A 3 mm by 20 mm Gianturco-Roubin stent is advanced to the PTCA site with restoration of T...

INTRODUCTION

If Andreas Gruentzig’s balloon catheter was the launchpad for coronary and vascular intervention, then the metallic stent was the rocket engine that thrust interventional cardiac and vascular therapies into orbit. Once confidence about the fate of metallic stents in the coronary arteries was established, the entire field flourished1. Rigorous evidence based outcomes were established by scientific work, unparalleled in medicine up to that time. There was an overwhelming commitment to rigorous,randomized, prospective clinical studies, an enlightened advance that continues to this day. Progress in establishing clear, superior clinical outcomes for patients with wide ranging vascular conditions lead to massive clinical adoption and enthusiastic and aggressive investments by commercial entities and entrepreneurs.

Today’s large and impressive array of percutaneous interventional technologies and procedures largely depend on placing stent based devices in the cardiovascular system. Start with the undeniable and hugely important treatment of STEMI in patients with coronary disease. Move forward to the management of unstable coronary syndromes and unremitting angina in patients with stable disease. Then on to stroke prevention in stenting the carotid artery. And to the stent clot retriever for treating intracranial embolic stroke and the stent flow dividers for intracranial aneurysms. Or “covered stenting” the opening of the clot filled left atrial appendage to prevent stroke in patients with atrial fibrillation.

The entire amazing field of structural cardiac intervention, notable percutaneous valve replacement is largely based on balloon expandable and self-expanding stents. Then comes the clinically invaluable covered stents for aortic and arterial aneurysm, dissection and rupture. And the peripheral stents that are now used to maintain side branch and especially renal and mesenteric artery patency.Last but certainly not least, is the array of stent technologies that, despite exciting alternative revascularization technologies, ultimately underpin safe and reliable revascularization of the the lower extremities in treating severe claudication and critical limb ischemia.

The metallic stent was the engine that informed the future that was to become interventional cardiac and vascular work. No one individual was responsible for this turn of events. Many extraordinary individuals, over a generation of innovation, clinical experience and scientific validation were responsible.

ORIGINS OF THE STENT

Investigation into intra-vascular prostheses dates to work in the late 19th century and notably vascular radiologists and surgeons in the mid 20th century2. Robert Ersek patented an expandable mesh stent device in the 1950’s to assist in aorto-iliac graft surgery and Charles Dotter, the grandfather of all percutaneous vascular intervention, placed coil stents in animal arteries in the 1960’s. Dotter was the first to use the term stent to describe the metallic intra- arterial prosthesis. Dotter borrowed the term from the dental surgical literature after Charles Stent developed a technique using Gum Arabic to hold tissue “in place” – Stents’ Compound. There were multiple innovative surgeons, angiologists and radiologists in the 1970’s that proposed stenting techniques of various types in order to expand tubular structures in the body. But the one individual to actually advance his ideas to clinical practice was Cesare Gianturco. A retired radiologist from Champaign Illinois, Gianturco developed a self-expanding, Z shaped stainless steel stent device that could be collapsed into a delivery catheter and deployed by a push-pull release technique. The device was manufactured by Cook Inc. (Bloomington IN) and used in patients with encroaching malignant tissue obstructing the vena cava. In retirement, Cesare Gianturco worked part time at the MD Anderson Cancer Center in Houston TX. His self-expanding Z design was to become, in time, the fundamental design of all the forthcoming stent graft technology for large arterial work. But Gianturco is recognized for much more. Along with Dotter, Eberhardt Zeitler and other pioneering radiologists of that time, Gianturco was fascinated by Andreas Gruentzig’ inflatable balloon technology. In 1979 at MD Anderson Hospital Gianturco wrapped a clever interwoven coil on a “Gruentzig balloon” and successfully deployed the device in the iliac artery of a dog.

As the 1980’s progressed others around the world were working on arterial stenting. Hans Wallsten, an engineer was working in Switzerland on a clever woven nitinol device he named the Wallstent. This was to become the first metallic device used clinically in the coronary arteries. In the Soviet Union, Iosif Rabkin an interventional radiologist placed a “Dotter like” coil in a patient’s iliac artery and also reportedly did a similar procedure in a carotid artery.

THE UNMET CLINICAL NEED

Clinical device development requires more than clever ideas and one off ‘heroic’ procedures. As Andreas Gruentzig demonstrated to the world and taught, the process requires dedicated, rigorous and scientific validation – first in bench top and in vivo animal studies – and then rigorous prospective clinical studies. Most importantly, there needs to be a well-defined, unmet clinical need. And then detailed engineering, product development and regulatory support.

As Gruentzigs’ balloon angioplasty gained acceptance around the world, the development of coronary stenting was driven by an obvious, unmet clinical need. By the mid 1980’s thousands of anatomically suitable patients were benefiting from acceptable balloon outcomes. But Andreas Gruentzig and the cardiology community were acutely aware of the shortcomings of PTCA. The overwhelming problem was the risk of abrupt closure of the artery either during the procedure or in the hours or days after balloon dilatation. Abrupt closure resulted in significant myocardial infarction and death3. Even if emergency CABG was available it resulted in suboptimal outcomes. The need for back up CABG severely restricted the practice of PTCA. And the risk of abrupt closure was significantly higher in severe diffuse, calcified and tortuous lesions and in treating multi-lesion and multivessel disease and this severely limited the application of PTCA. Balloon dilatation alone in this anatomy and even “ideal” lesions invariably resulted in plaque and intimal tearing and dissection. This was often flow limiting and was rapidly associated with thrombus accumulation and occlusion.

It is also worth noting that antiplatelet regimens were as yet poorly developed and limited to aspirin, dipyridamole and dextran infusions.

In the early 1980’s much thought and innovation was being directed towards plaque modification to overcome the shortcomings of simple balloon dilation. The disrupted plaque and in eccentric disease, temporary stretching of the normal vessel wall. Gruentzig’s lab at Emory University was focused on developing a laser catheter and Andreas openly discussed the use of heated balloons. Others, were investigating atherectomy with a variety of approaches including John Simpson’s directional cutting device. None of these approaches were to prevail in solving the problem of abrupt closure and restenosis after balloon angioplasty of coronary stenosis.

ENTER THE CORONARY STENT

Legions of stent designs, innovative concepts and commercial coronary stent products would evolve. But the genesis of all the clinical progress that was to come, arose from 3 groups around the world who were working on the challenge of a safe and effective stent device for the coronary arteries. The obstacles and unknowns were many and those of us developing the first coronary stent devices were, as is often the case with device development, completely naive to the challenges ahead.

In early 1985, Cesare Gianturco visited with Andrea Gruentzig and myself at Emory University. In his hand he had a tiny plastic tube with a braided guide wire “pusher“ inside and compressed in one end, a small self-expanding Z stent. The rudimentary device that he presented us with was a miniaturized version of the large Z stents that Cook Inc (Bloomington IN) had made for his use in IVC stenting. When he pushed on the wire, the stent “sprung out” of the “catheter” on to Andreas’ desk. He handed me the device and said “Gary go and see what happens when you put these into the dog coronary artery”. Easier said than done – as I was to discover. Andreas Gruentzig was to die tragically in an airplane accident some months later and was never to participate in the stent development. The self-expanding Z was a failure in about every way imaginable but it did focus our attention on what would be required for a safe and effective coronary stent. Cesare Gianturco was to return some weeks after Andreas’ passing to offer commiserations and in response to my feedback about the shortcomings of the self-expanding stent approach, we set about improving a balloon expandable design he had conceived and reduced to practice over a half decade earlier!

Now 40 years on it is almost impossible to understand how challenging was the task! To begin, guide catheters, guide wires and PTCA balloons were still “primitive”.

Safety and efficacy involved designing a stent device that could be safely tracked through a guide catheter to the lesion and not be dislodged from the balloon in the process. It had to be deployed precisely in the correct place and be reliably expanded to a predetermined diameter. The stent needed to hold the tissue apart and not migrate, or fracture or perforate or thrombose. Choice of material and biocompatibility was a huge unknown.

For the cardiology and scientific community and FDA regulators and potential industry supporters – the fate of a tubular metal device in the constantly moving, twisting coronary arteries was the primary question. With the assistance of Keith Robinson PhD, I set up the animal Lab at Emory University and acquired the funding to place stents in multiple animal models, short term and long term, normal and atherosclerotic, coronary and iliac. We studied the angiographic outcomes, the histologic and scanning EM responses and the integrity of the devices. We published in multiple peer reviewed journals and sent our primary specimens for independent review by the National Institutes of Health4,5. My colleague Julio Palmaz thanked me for this work as he wrote “I regard your work as objective, honest and smart. This is very important for all of us in this subject”. One “lightbulb moment” occurred during work in the severely atherosclerotic rabbit iliac arteries. Balloon dilatation had completely disrupted the plaque and compromised the lumen. Stent placement completely transformed the angiographic appearance! 6

Progressing to clinical evaluation was the next hurdle. Surgical aortic valve implants had created liability problems and Cook Inc were reluctant to commit. I submitted an investigator sponsored IDE (Investigational Device Exemption). No one in the world at that time had implanted a balloon expandable coronary stent. Today it would be called an investigator sponsored EFS (Early Feasibility Study). The protocol was specifically designed to test the hypothesis that a coronary stent could solve the problem of abrupt closure after balloon angioplasty and turn Andreas’ method of revascularization into a reliable and safe procedure. The first balloon expandable coronary stent in man was implanted in September 1987 (Figures 1 and 2). It opened the artery and reversed the evolving myocardial infarction. The rest is history.

Multiple multicenter studies followed7,8. The FDA were to finally approve the Gianturco-Roubin Stent in 1994, 1 year before the approval of the Palmaz-Schatz stent1.

The availability of the coronary stent facilitated the rapid expansion of coronary intervention. Operators were finally able to approach more complex lesions and multivessel disease and do so with much greater safety.

Rodriguez et al. in Argentina9,10 were the first to study if the luminal improvement brought about by the stent would improve restenosis rates. They showed it did but incompletely. Time was to prove that optimal results required the stent to deliver antimitotic drugs. This ultimately revolutionized percutaneous coronary intervention.

It is noteworthy that before drug eluting stents, a huge effort was devoted to testing systemic agents to reduce restenosis rates. The stent was to provide the ultimate solution. Just as Andrea Gruentzig taught us that we did not need to open the chest to treat a 10 mm coronary stenosis – the stent facilitated focused drug delivery for restenosis, avoiding systemic side effects. This concept was an early element of stent development even before FDA approval11.

In Switzerland, Hans Wallsten was able to miniaturize his self-expanding, nitinol mesh sleeve and design a delivery catheter and retractable sleeve that could potentially track through a coronary guide. He wanted to take this device to a cardiologist Jean Marco in Toulouse France but Jean Marco was not available that day and his colleague Jaques Puel is credited as being the first to implant a self -expanding metallic device in the coronaries. After this initial implant, Ulrich Sigwart in Lausanne took on “the charge” and without much thought to study objectives and prospectively defined endpoints, placed a series of Wallstents after PTCA electively and emergently in a variety of clinical settings. The results were mixed with episodes of stent thrombosis, MI and adverse outcomes. Sigwarts’s work was the first to be published in the New England Journal of Medicine12, but it was a note of caution for those of us coming close behind - albeit with different, balloon expandable stents with less metal and less moving components. Self-expanding stents were never to become effective devices for the coronary arteries. Ulrich Sigwart, to his credit, went on to develop one of the best designed laser cut, balloon expandable, tubular stents to make it into clinical practice.

In San Antonio, TX, Julio Palmaz an innovative radiologist was busy miniaturizing the balloon expandable stent he had conceived for peripheral vessels. The tubular mesh design was inherently too stiff and unyielding for easy placement in the coronaries. Palmaz was ultimately to team up with Richard Schatz to modify his design for a coronary application.The idea was to simply cut the device and link the 2 halves with a single connector.

The Palmaz Schatz stent IDE was an “all comers approach” with elective placement in the majority of appropriate lesions and additional use for threatened (severe dissection) or actual abrupt closure patients. The results of this study were difficult to interpret and the FDA panel decided against PMA approval until I year after the approval of the Gianturco-Roubin stent1. Randomized trial data was to ultimately launch the Palmaz-Schatz12.

The demand by the interventional cardiology community for a device to make PTCA safe was tremendous. Over 100 thousand GR stents were distributed in the first 18 months of availability. Early in the investigation phase of coronary stenting, we were able to show the value of stenting for the treatment of ST elevation myocardial infarction10,14.

But the Palmaz-Schatz stent was a better design in terms of plaque coverage and was to prevail in the market place. It would soon become apparent that the multiple laser cut tubular designs that were to follow, were more ideal for the local drug delivery that would largely solve the second challenge of late restenosis15.

CONCLUSION

There is much more to the story of coronary stent development. The low profile, trackable devices we use today were but a dream during the early work required to validate coronary stenting. Forty years ago we struggled with the bulky devices using 8F and 9F guiding catheters and 0.16” and even 0.18” guide wires to get the stents down the coronaries. Optimal dual antiplatelet therapy (DAPT) was unknown and we struggled with both stent thrombosis and hemorrhagic complications as we first “under shot” then “over shot“ therapeutic efforts. Antonio Colombo in Milan was to direct us to an optimal “DAPT” regimen. Other colleagues including Patrick Serruys in Rotterdam, Marty Leon in the USA and Jean Marco in France made invaluable contributions. Richard Stack at Duke contributed to many stent designs and notably the bioabsorbable platforms that are not yet perfected but will ultimately find their place.

But finally, let us all acknowledge that the coronary stent to this day functions on the basic brilliance of Andreas Gruentzig’s balloon device.

Gary S. Roubin MD PhD FSCAI FACC.

1. The First Balloon-Expandable Coronary Stent: An expedition that Changed Cardiovascular Medicine. Roubin, Gary: University of Queensland Press 2014. (Amazon.com).

2. Dotter CT. Transluminally-placed coilspring endarterial tube grafts: Long-term patency in canine poplitealartery. Investigative Radiology. 1969;4:329–332

3. Ellis SG, Roubin GS, King SB, 3rd et al In-hospital cardiac mortality after acute closure after coronary angioplasty: Analysis of risk factors from 8,207 procedures. J Am Coll Cardiol. 1988;11:211–216

4. Roubin G GC, Brown J, Robinson K, King S. Intracoronary stenting of canine coronary arteries after percutaneous coronary angioplasty (PTCA). Circulation. 1986;74 (Abst).

5. Roubin GS, Robinson KA, King SB, 3rd et al. Early and late results of intracoronary arterial stenting after coronary angioplasty in dogs. Circulation. 1987;76:891–897

6. Robinson KA, Roubin GS, Siegel RJ et al, Intra-arterial stenting in the atherosclerotic rabbit. Circulation. 1988;78:646–653

7. Roubin GS, Douglas JR, Jnr, Lembo NJ, Black AJ, King SB III. Intracoronary stenting for acute closure following percutaneous transluminal coronary angioplasty(PTCA). Circulation. 1988;78:407 (Abst).

8. Roubin GS, Cannon AD, Agrawal SK, et al. Intracoronary stenting for acute and threatened closure complicating percutaneous transluminal coronary angioplasty.Circulation. 1992;85:916–927

9. Rodriguez A, Santaera O, Larribau M, et al. Coronary stenting decrease restenosis in lesions with early loss in luminal diameter 24hours after successful PTCA. Circulation 1995;91:1397– 402.

10. Rodriguez A, Bernardi V, Fernández M et al, In-hospital and late results of coronary stents versus conventional balloon angioplasty in acute myocardial infarction (GRAMI trial). Gianturco-Roubin in Acute Myocardial Infarction. Am J of Cardiol. 1998;81:12861291

11. Cox DA, Anderson P, Roubin GS, Chou CY, Agrawal SK, Cavender JB. Local delivery of heparin and methotrexate fails to inhibit in vivo smooth muscle cellproliferation. Circulation. 1991;84

12. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. The New England Journal of Medicine. 1987;316:701–706

13. Fischman DL, Schatz RA, Savage MP, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. The New England Journal of Medicine. 1994;331:496–501

14. Cannon AD, Roubin GS, Macander PJ, Agrawal SK. Intracoronary stenting as an adjunct to angioplasty in acute myocardial infarction. The Journal of Invasive Cardiology. 1991;3:255–258

15. Stone GW, Ellis SG, Cox DA, et al; TAXUS-IV Investigators. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial. Circulation.2004;109(16):1942-1947.

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