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Circulation. 1996;94:882-890

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(Circulation. 1996;94:882-890.)
© 1996 American Heart Association, Inc.

Articles

Intracoronary Stenting

From Concept to Custom

Peter N. Ruygrok, MB, ChB, FRACP; Patrick W. Serruys, MD, PhD

the Catheterization Laboratory, Thoraxcenter, Erasmus University, Rotterdam.

Correspondence to Patrick W. Serruys, MD, Catheterization Laboratory, Thoraxcenter BD 432, University Hospital Dijkzigt, Dr Molewaterplein 40, 3015 GD Rotterdam, Netherlands.


Key Words: stents • angioplasty • atherosclerosis • coronary disease


*    Introduction
up arrowTop
 *Introduction
down arrowPreclinical Evaluation
 down arrowClinical Development
 down arrowRandomized Trials
 down arrowThe Flow and Ebb...
 down arrowWhy Should We Stent?
 down arrowThe Future
 down arrowNew Developments
 down arrowConclusions
 down arrowReferences
 
When Charles Stent, a 19th century English dentist, developed a mold with which to form an impression of the teeth and oral cavity, he would never have imagined that his name would become synonymous with the management of obstructive vascular disease, in particular coronary artery disease (Fig 1Down).1 The term "stent" became associated with a device that held a skin graft in position, a support for tubular structures that were being anastomosed, and, more recently, an endovascular scaffolding to relieve and prevent vascular obstructions.



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  		Figure 1. Charles Stent (1845-1901), an English dentist who lent his name to a tooth mold (bottom) and more recently to endoluminal scaffolding devices.

The management of coronary atherosclerosis has shifted from "masterly inactivity" to medical therapy, coronary bypass surgery, and, more recently, percutaneous techniques introduced by Gruentzig et al in 1977.2 Intracoronary stenting with continuing refinements appears poised to become the mainstay of the mechanical treatment of obstructive coronary disease.


*    Preclinical Evaluation
up arrowTop
 up arrowIntroduction
 *Preclinical Evaluation
down arrowClinical Development
 down arrowRandomized Trials
 down arrowThe Flow and Ebb...
 down arrowWhy Should We Stent?
 down arrowThe Future
 down arrowNew Developments
 down arrowConclusions
 down arrowReferences
 
In his 1912 Nobel lecture, laureate Alexis Carrel described experiments with glass and metal tubes covered with paraffin that were introduced into canine thoracic aortae. Coagulation did not occur provided the aortic wall was not ulcerated, with one animal surviving for 90 days with a glass tube. He concluded that the presence of foreign bodies within vessels did not necessarily produce thrombus.

The concept of using an implantable prosthetic device to maintain the luminal integrity of diseased vessels was reintroduced by Charles Dotter in 1964, when he suggested that the temporary use of a silicone elastomer endovascular splint could maintain an adequate lumen after the creation of a pathway in a previously occluded vessel.3 In 1969, he reported the results of the nonsurgical endarterial placement of spiral springs, mounted coaxially on a guidewire and positioned with a pusher catheter in the femoral and popliteal arteries of healthy dogs.4 Although these early stents were able to be positioned satisfactorily, secondary dislocations occurred because only small devices could be used, and significant narrowing within the stents occurred. These findings appeared to suppress any optimism that such a device might have a role to play in atherosclerotic vascular disease, until the early 1980s, when Dotter et al5 presented the work of further canine experiments with a modified stent. Dotter placed coils made of the "memory metal" nitinol in peripheral vessels and injected heated saline solution through the catheter, allowing the coil to enlarge to its predetermined form with a luminal diameter approximately equal to that of the adjacent blood vessel. He suggested that this device might be of potential therapeutic use not only in arteries and veins, but also in the cerebral aqueduct, bladder neck, biliary system, and tracheobronchial tree. Initial experiments with this stent in nonheparinized dogs proved promising, with no episodes of subacute thrombosis, and vessel patency was maintained at 4 weeks.6

The potential for the use of such a device in the nonsurgical treatment of vascular disease had become evident, and experimentation with a variety of innovative devices had commenced. Maass and coworkers7 reported the results of implantation of spiral springs in the aortae and vena cavae of dogs and calves. When torque was applied, the springs decreased in diameter, allowing distal delivery, and on release of the torque, they expanded to their predetermined dimensions.7 Although the spirals remained stable and did not produce stenosis, thrombosis, or perforation, target lumen access remained a limitation. An expanding zigzag-shaped stainless steel stent was developed by Wright and coworkers, and the results of initial studies in dogs were reported.8 It was appreciated that the diameter of the fully expanded stent had to be larger than the recipient vessel to prevent migration.8 The above devices were all reliant on the inherent recoil properties of the metal used, which, on release or positioning, returned to a predetermined diameter, desirably a little greater than the vessel proximal and distal to the treated segment (Fig 2Down).



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  		Figure 2. Four early endovascular stents. The upper left panels show Dotter's early nitinol coil wire stent compacted for placement and after heat-induced expansion to its predetermined dimensions.5 The zigzag expanding stainless steel stent described by Wright et al8 shown in the upper right panels in both its sheathed and unsheathed forms. The lower left panel shows the stents developed by Maass et al.7 The lower right panel shows the balloon expandable stainless steel Palmaz stent.9

The concept of a stent mounted on a balloon was introduced by Palmaz. In 1985, he described the initial results of implantation of a woven stainless steel graft mounted on angioplasty balloon catheters and placed in the aortae and peripheral arteries of dogs by balloon expansion9 (Fig 2Up). The following year, Palmaz et al10 published the data of an extended group of 18 balloon expandable stent implantations and provided a unique and accurate insight into the problems that would torment stent implantation for the subsequent decade. Stents were placed in the iliac, femoral, renal, mesenteric, and carotid arteries of normal dogs via arteriotomies. Procedural heparinization was used without long-term anticoagulation or antiplatelet therapy only in the last 9 cases. Four thrombotic occlusions occurred, all in nonheparinized animals, and thus motivated the use of heparin in the latter experiments. Palmaz recognized that "heparin does not prevent occlusion of grafts with low flow and the best results were obtained in those without flow restriction,"10 a canon of contemporary stenting. Additionally, the overall stent patency at 35 weeks was 77%, giving a restenosis rate of 23%, a prelude to the findings of more recent studies.

With refinement and miniaturization of equipment, smaller and more distal vessels could be accessed, and stents began to be implanted in the coronary system. Rousseau and coworkers11 developed and tested a flexible, self-expanding stainless steel mesh tube, restrained by a sheath. Forty-seven devices were implanted in 28 dogs, 21 in the coronary arteries, without the use of anticoagulation or antiplatelet agents. Partial or total thrombosis was seen in 8 of 28 animals (29%), which was partly attributed to the earliest of several models of prostheses used during the study. Thrombosis was recognized to occur at points of rapid reduction of vessel diameter, when the end of the prosthesis was engaged in a side branch of a major vessel and when there was a high ratio of unconstrained to implant device diameter.11 It was found that the process of endothelialization, incorporation of the stent into the vessel wall by neointimalization, had occurred by the third week after implantation, consistent with the findings of others.8 9 These results, particularly in the second part of the series, which predominantly involved implantation in coronary arteries, primed this group of investigators for the beginnings of stent implantation in human atherosclerotic vessels.

Interest in stent implantation in human coronary arteries intensified after reports of successful implantation of balloon-expandable stents in canine coronary arteries. Schatz et al12 reported the results of percutaneous implantation of 20 Palmaz-type stents, and Roubin et al13 described implantation in 39 animals of a new interdigitating flexible coil stent mounted on a balloon. With the appearance of these reports in Circulation in 1987, the divorce of coronary stenting from vascular radiology had occurred.


*    Clinical Development
up arrowTop
 up arrowIntroduction
 up arrowPreclinical Evaluation
 *Clinical Development
down arrowRandomized Trials
 down arrowThe Flow and Ebb...
 down arrowWhy Should We Stent?
 down arrowThe Future
 down arrowNew Developments
 down arrowConclusions
 down arrowReferences
 
With the hope that the two problems that continued to trouble coronary balloon angioplasty, namely, acute occlusion and restenosis, could be alleviated or at least attenuated, Jacques Puel in Toulouse, France, and, shortly afterward, Ulrich Sigwart in Lausanne, Switzerland, implanted the first stents in human coronary arteries in the spring of 1986. The results of implantation of 24 self-expanding mesh stents (Medinvent) in 19 patients (17 restenosis, 4 acute closure, and 3 venous bypass grafts) were reported subsequently.14 Three complications (15.8%) related to stent thrombosis occurred. No cases of restenosis were observed within the stented segment 9 weeks to 9 months after implantation. By early 1988, 117 Wallstents, as these self-expanding stents became known, had been implanted in the native coronary arteries (94 stents) or saphenous bypass grafts (23 stents) of 105 patients. The results were daunting, with complete occlusion of 27 stents occurring in 25 patients, resulting in controversy and a diversity of anticoagulation regimens. However, with the expectation that a solution to the problem of thrombotic occlusion would be found, optimism in the future clinical utility of the technique remained, because the rate of restenosis in those stents that were patent at follow-up was 14%.15

The early clinical implantation of coronary stents remained largely limited to situations of acute and threatened closure after balloon angioplasty, with a diminishing proportion of patients proceeding to semielective coronary bypass surgery. Roubin and coworkers16 reported the results of Gianturco-Roubin stent implantation in 115 patients with acute or threatened closure in 119 vessels in the years 1987 through 1989. Stenting produced an optimal result in 93% of the cases. Given the emergent nature of the procedure, the number of complications was acceptably low, with a hospital mortality rate of 1.7%, a bypass surgery rate of 4.2%, an overall myocardial infarction rate of 16%, and a subacute stent thrombosis rate of 7.6%.16 Although it appeared that the stent had come to the rescue in the acute closure situation, a restenosis rate of 41% was observed in those patients (76%) who had undergone restudy at the time of publication of the study, indicating that the long-term solution had yet to be found.

During the same period (1987 through 1989), Schatz maintained a multicenter registry of elective Palmaz-Schatz stent implantations in native coronary arteries. Delivery of the device was successful in 213 (94%) of 226 attempted lesions.17 Early optimism that this stent was less thrombogenic than others,18 and thus required little if any anticoagulation therapy, was quashed when a subacute closure rate of 16% was observed in the first group of 39 patients who received only aspirin and dipyridamole after the procedure. In addition, the second group of 174 patients received warfarin for 1 to 3 months, with a dramatic reduction in subacute thrombotic stent occlusion to 0.6%.17 One must question whether patients were even more carefully selected after the discouraging findings in the first group of patients. Nevertheless, the notion was being entertained that the complication rates and perhaps even the long-term results of elective stenting were significantly less than those obtained after the bailout situation, in which the artery had undergone multiple and often prolonged dilations.

The role of stenting a restenotic lesion after a previous balloon angioplasty was also being explored. The Wiktor stent, a single interdigitating tantalum wire, was implanted in 50 consecutive patients with restenosis as part of a European registry. The implantation success rate was 98%. Acute or subacute occlusion occurred in 5 patients (10%), and restenosis according to the >=50% diameter criterion was observed in 13 patients (26%) 5.6±1.1 months after stent implantation.19

A number of fundamental questions were raised by the findings of these and other studies. Were the variable results from the growing number of stent registries related to the clinical situation (elective versus bailout stenting), the inherent properties of the device, the deployment strategy, or the anticoagulation regimen? The characteristics the ideal stent should possess had become clear (Table 1Down). The feeling of excitement surrounding the use of stents in obstructive coronary disease, despite the hurdles, prompted Spencer King III to ask a number of searching questions.20 Was there a problem for which stenting could provide a solution? Was the proposed stenting strategy efficacious? Was stent implantation safe? Could stents be made sufficiently foolproof for widespread clinical use? It was clear that countless questions remained and that thousands of patients had to be studied carefully before the clinical domain of intracoronary stenting could be clearly defined.


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  		Table 1. Desirable Stent Characteristics


*    Randomized Trials
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 up arrowIntroduction
 up arrowPreclinical Evaluation
 up arrowClinical Development
 *Randomized Trials
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 down arrowWhy Should We Stent?
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Two landmark randomized trials have been performed and reported,21 22 perhaps once and for all determining the fate of coronary stent implantation. The European-based Benestent and the North American–based STRESS studies both began patient recruitment in 1991. In both studies, patients were randomized to receive conventional balloon angioplasty or Palmaz-Schatz stent implantation in a primary lesion of a native coronary artery with a diameter stenosis of 50% and 70% in the Benestent and STRESS studies, respectively. The target lesion was required to be <15 mm long and the reference diameter >=3 mm. The presence of thrombus, ostial stenosis, a lesion spanning a major bifurcation, diffuse disease, severe tortuosity, and abnormally functioning myocardium subtended by the lesion, along with intolerance of anticoagulants and ineligibility for coronary bypass surgery, were exclusion criteria. Five hundred sixteen patients (257 balloon and 259 stent), all of whom had stable angina, were recruited in the Benestent study and 407 patients (202 balloon and 205 stent), of whom 47% had unstable angina, were randomized in the STRESS study.

The incidence of restenosis according to the 50% diameter stenosis criterion and a per protocol basis was significantly lower after stent implantation (Benestent, 22%; STRESS, 32%) than after balloon dilation (Benestent, 32%; STRESS, 42%) and was associated with a more favorable long-term clinical outcome in patients who received a stent. The 7-month event-free survival was 79.9% and 70.4% after stenting and balloon dilation, respectively, in Benestent (P<.05) and 80.5% and 76.2%, respectively, in the STRESS study (P=NS). This was largely because of a reduced need for reintervention in the stented group. The 1-year follow-up of the Benestent patients has subsequently been published23 and shows a continued benefit for stented patients, with a 1-year event-free survival of 76.8% compared with 68.5% in the balloon angioplasty patients. Of the 12 additional events that occurred between 7 and 12 months (8 in the stent group and 4 in the balloon group), 8 involved a revascularization procedure.23

The STRESS investigators also reported a superior procedural success rate in the stent group (stent, 96.1%; balloon, 89.6%). There was no significant difference in acute closure or stent thrombosis between the two treatment groups in either study. These encouraging results were at the cost of significantly increased bleeding and vascular complications and a longer hospital stay in those patients who received a Palmaz-Schatz stent. The clinical results of both trials are displayed in Table 2Down. In addition to these two multicenter trials, enrollment in the Spanish START (STent versus Angioplasty Restenosis Trial) trial continues. A total of 564 patients with stable angina pectoris and a new native coronary artery lesion will be randomly allocated to balloon angioplasty alone or Palmaz-Schatz stent implantation, with the primary end point being the 6-month restenosis rate. The results, when available, are expected to provide data complementary to those of the Benestent and STRESS studies, which have demonstrated a reduced restenosis rate, an improved event-free survival, and an abrupt occlusion rate similar to that of balloon angioplasty but an unacceptable incidence of bleeding and vascular complications, urging the next generation of stenting trials.


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  		Table 2. Clinical Results of the Benestent and STRESS Studies

Perhaps one of the most promising developments is the design of stents with improved thromboresistant properties,24 thus alleviating the need for systemic anticoagulation therapy and thereby reducing, if not abolishing, bleeding and vascular complications. In the pilot phase of the Benestent II trial, 207 patients in four equal groups received a heparin-coated stent, with an increasing delay to the commencement of anticoagulation therapy of up to 36 hours after implantation. There were no episodes of acute or subacute occlusion, and the overall 6-month restenosis rate was 13%.25 On the basis of these compelling results, the Benestent II trial has commenced. Eight hundred twenty-four patients with primary coronary artery lesions in a native vessel will be randomized to receive a heparin-coated Palmaz-Schatz stent, followed by treatment with aspirin and ticlopidine, or conventional balloon angioplasty. A subrandomization will occur to allocate patients to only clinical or clinical and angiographic follow-up. Additionally, a detailed account will be kept of the medical costs related to coronary artery disease in all patients. This trial aims to prove that primary coronary stenting not only will reduce the rates of subacute occlusion and restenosis and improve event-free survival but also will reduce the economic burden of a coronary intervention on society and its psychosocial burden on the individual patient.

The role of stenting for acute or threatened vessel closure after coronary angioplasty has also been studied in a randomized fashion. Much of the early stenting experience was for bailout after failed balloon angioplasty, usually with restoration of normal coronary flow and resolution of chest pain and ECG changes.14 It appeared that patients fared favorably after bailout stenting compared with emergency bypass surgery or conservative management.26 However, a more recent case-control study27 revealed that the clinical outcome after bailout stent implantation was no better than conventional treatment despite rapid restoration of blood flow and a good angiographic result. Bailout stenting has also been identified as one of the most powerful independent predictors of subsequent subacute stent thrombosis.28 One should bear in mind that in these earlier studies, bailout stents were often implanted after closure proved to be refractory to prolonged attempts at therapy with various modalities including autoperfusion balloons and thrombolytic agents.

To test the efficacy of stenting in this situation, at least three studies randomizing stents against balloons have been performed. In the Stent-by and TASC-II (Trial of Angioplasty versus Stenting in Canada) studies, the utility of Palmaz-Schatz stenting was compared with prolonged balloon angioplasty methods, whereas in the GRACE (Gianturco-Roubin Stent Acute Closure Evaluation) study, a Gianturco-Roubin stent was used. Despite sound protocols, these studies have been hindered by slow recruitment and dilution of results by crossover. It appears that the use of and faith in the stent in the bailout situation is so strong that few interventionists are willing to subject their patients with acute or threatened closure to prolonged and repeated balloon dilation.

A further niche for stenting is in the increasing proportion of patients with aging saphenous venous bypass grafts who return for repeat coronary revascularization. Stent implantation appears to be an attractive option with a high chance of immediate success, an acceptable complication rate, and a favorable late clinical outcome (76.3% 12-month event-free survival) compared with previous balloon angioplasty studies.29 30 31 The results of randomized studies comparing balloon angioplasty with stent implantation in bypass grafts are awaited to determine whether the growing trend to implant stents is justified.

Randomization of balloons versus stents has also been performed for restenotic lesions (the Rest study) and after recanalization of a coronary artery occlusion (Stenting in Chronic Coronary Occlusions [SICCO]). The results of these trials, when they become known, will give more direction to current clinical practice.

With the growing number of publications reporting the results of coronary stenting, generally with favorable results in comparison with balloon angioplasty, a frenzy of activity has pervaded the stent development industry. A diverse variety of stents are becoming clinically available, varying in composition, configuration, and size (Fig 3Down). Although niches for particular stents are evolving, the advantage of one stent over another may never be defined scientifically, and it is likely that market forces will be a major determinant of clinical choice.



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  		Figure 3. Seven coronary stents, clockwise from bottom left: Wallstent, Palmaz-Schatz stent, Wiktor stent, Gianturco-Roubin stent, Cordis stent, AVE stent, and multilink stent.


*    The Flow and Ebb of Anticoagulation Therapy
up arrowTop
 up arrowIntroduction
 up arrowPreclinical Evaluation
 up arrowClinical Development
 up arrowRandomized Trials
 *The Flow and Ebb...
down arrowWhy Should We Stent?
 down arrowThe Future
 down arrowNew Developments
 down arrowConclusions
 down arrowReferences
 
From the very early animal studies, it became clear that implantation of endoprostheses within the vascular system activated coagulation, with resultant thrombosis of varying degree depending on stent composition, configuration, and size.

The finding that the thrombogenicity of metals was related to their surface properties, such as electric charge,32 prompted studies of stents made from various metallic compounds in the hope that the ideal thromboresistant device would be found, with little success.7 11 12 The reported variation of thrombosis within stainless steel stents was thought to be explained in part by configuration. Schatz was encouraged by his early canine studies with the balloon-expandable slotted-tube stent when no instances of thrombosis were encountered.12 His optimism continued after implantation of the stent into the first 17 human coronary arteries. No episodes of abrupt closure occurred in these patients, who were given procedural dextran and heparin and discharged to receive aspirin and dipyridamole alone. However, as the series of patients grew, a significant number of thrombotic episodes occurred, and warfarin was added to the postprocedural regimen.18 Thrombosis within the self-expanding Medinvent stent, which also was composed of stainless steel, was encountered in animal experiments,11 prompting the use of intracoronary urokinase along with heparin, aspirin, dipyridamole, and coumadin in the first coronary implants.14 Despite this aggressive regimen, thrombosis remained a problem, and both dextran and sulfinpyrazone were added.15 The escalation of anticoagulant regimens, with up to seven agents (aspirin, dextran, heparin, dipyridamole, sulfinpyrazone, urokinase, and coumadin) being used and associated bleeding and vascular complications, led to the inevitable question, "Are we the sorcerer's apprentice?"33 and in many centers, stenting was temporarily abandoned except for bailout situations.

Some stalwarts wondered whether the problem of thrombosis was in fact as much related to the flow through the implanted stent, with adequate expansion, inflow, and outflow, as to the metallic properties of the stent itself, and they continued to implant stents electively, frequently in restenotic lesions.34 With greater attention to optimal stent implantation in perhaps more carefully selected vessels, along with continued stringent anticoagulation therapy, the incidence of subacute occlusion diminished to <5%. Of particular interest was the rate of restenosis, which promised to be lower than that after balloon angioplasty, along with an improved event-free survival. In the Benestent and STRESS studies that ensued, the subacute thrombosis rates were 3.5% and 3.4%, respectively, with an anticoagulation/antiplatelet regimen consisting of dextran, heparin, aspirin, dipyridamole, and warfarin.21 22

The tide began to turn with the introduction of intracoronary ultrasound and high-pressure intrastent dilation to ensure optimal stent deployment.35 The concept of high-pressure stent expansion, thought to be important by the pioneers of stenting, could be tried as a result of the development of balloon catheters able to withstand high pressures and tested with intravascular ultrasound. Anticoagulation regimens began to diminish with ticlopidine or even aspirin alone replacing warfarin and both dextran and dipyridamole being omitted completely without any apparent rebound in the rates of subacute thrombosis.36 37 38 It appears paradoxical that these results can now be achieved without significant changes to the configuration and composition of the stent itself, strongly suggesting that meticulous attention to stent expansion and through flow plays a critical role in successful stent implantation. We are reminded of the words of Julio Palmaz, who made similar observations a decade ago.10 Additionally, stent coatings have been studied, in particular covalently bound heparin. In the fourth phase of the Benestent II pilot study, 50 patients received a heparin-coated stent and were discharged to receive ticlopidine and aspirin with no episodes of subacute thrombosis.25

With the ebb of anticoagulation therapy, bleeding complications and the length of hospital stay have been reduced dramatically to equal those of balloon angioplasty. Continued development of coated and biocompatible stents and attention to optimal deployment will likely mean future postprocedural anticoagulation therapy will consist of aspirin alone.


*    Why Should We Stent?
up arrowTop
 up arrowIntroduction
 up arrowPreclinical Evaluation
 up arrowClinical Development
 up arrowRandomized Trials
 up arrowThe Flow and Ebb...
 *Why Should We Stent?
down arrowThe Future
 down arrowNew Developments
 down arrowConclusions
 down arrowReferences
 
To answer this question, we return to those raised by Spencer King III.20 First, is there a problem for which stenting provides a solution? Balloon angioplasty has been hampered by two major limitations: acute closure and restenosis. Although the proportion of patients experiencing acute closure is small (2.7% and 1.5% in the balloon angioplasty groups of the Benestent and STRESS studies, respectively21 22 ), it is associated with a significant chance of myocardial infarction and death. As the number of patients with complex, diffuse, and multivessel disease increases, so will the chance of acute closure. The availability of more effective antiplatelet agents, thromboresistant stent coatings, and optimal stent deployment will continue to reduce the problem of stent thrombosis,39 making stenting an attractive option. The Achilles' heel of coronary angioplasty remains restenosis, with {approx}30% of lesions renarrowing because of recoil and intimal hyperplasia. This figure has remained static despite a multitude of pharmacological and mechanical attempts to reduce it. It has been suggested that patients should equate coronary angioplasty with dental treatment, regular and benign. But even a dental visit requires time off work, provokes anxiety, costs money, and has a risk of complications. This approach must be regarded as a temporary solution. While awaiting discovery of the "fluoride" of coronary artery disease, new strategies to reduce the rates of restenosis and associated repeated interventions must be sought. The suggestion that restenosis and related clinical event rates may be lower after stenting of primary coronary lesions, gleaned from early registries, has been confirmed by the Benestent I, STRESS, and Benestent II pilot studies,21 22 25 convincing most practitioners that this problem can be alleviated at least in part by stenting.

Second, King asked, "Is the treatment worse than the disease," raising the issue of safety. In the editorial accompanying the Benestent and STRESS studies, Eric Topol provided some words of caution.40 Although abrupt occlusion rates after stenting were not significantly higher than those after balloon angioplasty in both studies, the need for anticoagulation therapy resulted in significant and unacceptably high rates of bleeding complications in the stented groups (Benestent, 13.5%; STRESS, 7.1%), along with a prolonged hospital stay.21 22 With the current use of intracoronary ultrasound and high pressure postdeployment dilation, warfarin has been successfully replaced by ticlopidine and aspirin or even aspirin alone,25 37 38 maintaining an abrupt closure rate of <3% and reducing bleeding complications and hospital stay to equal those of balloon angioplasty. The introduction of smaller guiding catheters and miniaturization of interventional devices, which allow a smaller arterial puncture via the femoral and, more recently, radial artery approach,41 although not without limitations, have also contributed.24 The potential for other problems, such as metal fatigue, stent migration, and endarteritis, appears to diminish as time passes.

Finally, in an era of escalating healthcare costs, the cost-effectiveness of stenting must be considered. Both the Benestent and STRESS studies have shown a superior 6-month event-free survival in stented patients,21 22 and this benefit has been found to be maintained beyond 1 year.23 The economic impact has been negated in part by the expense of the stent itself, a prolonged hospital stay, and additional costs related to anticoagulation therapy and associated bleeding complications; however, with contemporary antiplatelet regimens, these problems clearly will decline. Furthermore, the cost of a primary stenting procedure is less than that of a bailout procedure both in terms of the amount of material used and subsequent complications.28 A decision analytic model has been used to evaluate the potential cost-effectiveness of a new coronary intervention, and it was suggested that elective coronary stenting may be a reasonably cost-effective treatment for patients with single-vessel coronary disease.42 The Benestent II trial will prospectively evaluate cost data and compare costs for patients randomized to stenting with those for patients allocated to balloon angioplasty. Additionally, one must consider not only the economic burden on society but also the psychosocial cost to the individual patient, for example, days off work, which can be lessened only by a reduced need for reintervention after stenting. We await the results of further studies.


*    The Future
up arrowTop
 up arrowIntroduction
 up arrowPreclinical Evaluation
 up arrowClinical Development
 up arrowRandomized Trials
 up arrowThe Flow and Ebb...
 up arrowWhy Should We Stent?
 *The Future
down arrowNew Developments
 down arrowConclusions
 down arrowReferences
 
Despite the major advances that have been made in coronary stenting over the past decade, this is merely the beginning. All registries and trials of elective stent implantation have acknowledged a varying degree of selection, with inclusion and exclusion criteria, making generalization of the results to the general angioplasty population hazardous. The results of stenting diffuse, complex, and small vessels remain uncertain, if not unfavorable. In both the Benestent and STRESS trials, the mean reference diameter of the carefully chosen discrete lesions was 3.0 mm.21 22 A meta-analysis of these trials has clearly shown that the rates of restenosis and clinical events are higher after stenting of smaller vessels. In stented vessels <2.6 mm in diameter, the 6-month restenosis rate was 38% compared with 22% in vessels <3.4 mm.43 Although some clinics are stenting up to 50% of cases, it is likely that stenting is merited on scientific grounds in a far lesser percentage of their angioplasty population. Further research in a wider range of lesion types and clinical situations, along with continuing developments described below, must be undertaken to reduce the mismatch between evolving clinical practice and scientific foundation.


*    New Developments
up arrowTop
 up arrowIntroduction
 up arrowPreclinical Evaluation
 up arrowClinical Development
 up arrowRandomized Trials
 up arrowThe Flow and Ebb...
 up arrowWhy Should We Stent?
 up arrowThe Future
 *New Developments
down arrowConclusions
 down arrowReferences
 
All currently available stents are made of metal, and in every design, a compromise is made between scaffolding properties and flexibility. Metals induce a varying degree of thrombogenesis, necessitating anticoagulation or antiplatelet therapy, and induce significant intimal hyperplasia, both factors that discourage the use of stents in small vessels or in situations of diminished flow. Additionally, the long-term effects of a metallic prosthesis within the vascular system, although seemingly benign, are unknown.40 Needless to say, the search for the ideal stent continues.

Animal work continues on varying the surface charge and texture of stents by galvanization and ion bombardment. Palmaz-Schatz stents coated with platinum, gold, and copper by these two techniques have been implanted in rabbit iliac arteries. It was found that thrombus formation occurred in stents coated by galvanization, which resulted in a higher surface porosity, and not in those treated by ion bombardment or those left uncoated. These processes also influenced the surface charge, with the most electropositive coatings (platinum and gold) inducing markedly less neointimal formation within the stent than copper, which was the least electropositive. Thus, it appears that the surface texture influences thrombogenicity, whereas neointimal hyperplasia is related to charge.44 Although alteration of the coatings and charge of metallic stents appears promising, a relatively rigid device with associated limitations is retained.

Perhaps more exciting is the concept of stents made of materials that can be degraded or absorbed. The fibrin stent appears to have the advantages of being able to cover an angioplasty injury site and provide a healing matrix and may also be of value in vein grafts in which a membrane may prevent the distal embolization of friable material. Animal experiments have shown the fibrin film stent to be biocompatible and absorbable, and it appears to be safe without the use of anticoagulation therapy.45 Uncertainty remains concerning its effects on neointimal proliferation and the immune system.

Another area of intense interest is polymer stents, which can be loaded with antithrombotic or antiproliferative agents (eg, methotrexate) in high concentration for sustained local delivery. Bioabsorbable polymers may also avoid the potential for late complications and thus have the potential to prevent elastic recoil, thrombosis, neointimal proliferation, and systemic side effects. The findings of a marked inflammatory response resulting in significant luminal encroachment after polymer stent implantation in early porcine experiments appear to have been overcome by the use of a stent comprising high-molecular-weight poly-L lactic acid.46

Finally, perhaps the most promising new field is that of radioactive stenting. The antiproliferative effect of ionizing radiation has been used for decades to reduce cancer growth and also to reduce the formation of keloid scars. Restenosis within stents is primarily caused by an intimal hyperplastic response due to vascular smooth muscle cell proliferation, and thus the use of a radioactive stent47 48 or local preirradiation of the lesion before stent implantation appears to be an attractive concept. Porcine experiments have shown that preirradiation of the coronary segment to be stented with {gamma}- and ß-radiation significantly reduced neointimal hyperplasia.49 Palmaz-Schatz stents, made radioactive by ion bombardment in a cyclotron, were implanted into the iliac arteries of rabbits and emitted predominantly ß- but also {gamma}- and x-radiation. Neointimal thickening was suppressed, and delayed stent endothelialization, depending on the radiation dose, was observed without an increase in stent thrombotic events.48 The use of 32P as a ß-particle emitter appears particularly promising.47 It ensures local radiation delivery, because the maximal range of ß-particles is 3 to 4 mm in tissue. It has a desirable half-life of 14.3 days and is undetectable at 4 months. Additionally, it exposes the interventionist to less radiation than that of fluoroscopy scatter. The results of the first human trials are eagerly awaited.


*    Conclusions
up arrowTop
 up arrowIntroduction
 up arrowPreclinical Evaluation
 up arrowClinical Development
 up arrowRandomized Trials
 up arrowThe Flow and Ebb...
 up arrowWhy Should We Stent?
 up arrowThe Future
 up arrowNew Developments
 *Conclusions
down arrowReferences
 
Since the very beginning of interventional coronary techniques, the concept of a stent to scaffold stenotic lesions appeared logical and attractive. The problems of thrombogenicity of the metallic device and the need for anticoagulation therapy and resultant bleeding complications initially hampered its clinical introduction and development. With knowledge gained both clinically and from intravascular diagnostic techniques, it was realized that thrombosis was as much related to inadequate stent deployment and through flow as to the metallic composition of the stent. The rate of restenosis after stenting appeared to be low, particularly in primary lesions. Armed with this information, the first randomized trials were undertaken, providing results that have secured the future of stenting as a mainstay of interventional cardiology. With continued developments and refinements, stenting may well lead the coup of percutaneous transluminal angioplasty over surgical revascularization.

We look forward to the results of the first randomized trials of stenting versus surgical revascularization for multivessel coronary artery disease.

Received November 14, 1995; revision received June 24, 1996; accepted June 24, 1996.


*    References
up arrowTop
 up arrowIntroduction
 up arrowPreclinical Evaluation
 up arrowClinical Development
 up arrowRandomized Trials
 up arrowThe Flow and Ebb...
 up arrowWhy Should We Stent?
 up arrowThe Future
 up arrowNew Developments
 up arrowConclusions
 *References
 

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