Coronary Stenting

Limitations of balloon angioplasty and development of the coronary stent

The performance of the first successful balloon angioplasty by Andreas Gruentzig on September 16, 1977, in Zurich, Switzerland, was a landmark event heralding the inception of percutaneous management of obstructive coronary artery disease. Although this initial procedure set the stage for the millions of PCI procedures that have since taken place, stand-alone balloon angioplasty was a highly unpredictable experience. While the majority of vessels tolerate the focal plaque dissections caused by balloon dilatation and heal sufficiently to result in an adequate lumen, the injury to the vessel wall may unpredictably result in severe dissections, which along with acute recoil and chronic constrictive remodeling, result in balloon angioplasty’s two major limitations: abrupt closure (occurring acutely, or within the first several days after angioplasty) and restenosis (occurring later, within months, and, rarely, years after the procedure). The coronary stent was thus devised as an endoluminal scaffold to create a larger initial lumen, to seal dissections, and to resist recoil and late vascular remodeling, thereby improving upon the early and late results of balloon angioplasty.

The first implantation of stents in human coronary arteries occurred in 1986 when Ulrich Sigwart and Jacques Puel and colleagues placed the Wallstent-sheathed self-expanding metallic mesh scaffold (Medinvent, Lausanne, Switzerland) in the peripheral and coronary arteries of eight patients. Further experience with this device demonstrated high rates of thrombotic occlusion and late mortality, although patients without thrombosis had a 6-month angiographic restenosis rate of only 14%, suggesting for the first time that stenting could improve late patency in addition to stabilizing the acute results obtained after conventional balloon angioplasty. Contemporaneously, Cesare Gianturco and Gary Roubin developed a balloon-expandable coil stent consisting of a wrapped stainless steel wire resembling a clamshell. Completion of a phase II study using the Gianturco-Roubin stent to reverse postangioplasty acute or threatened vessel closure led to United States Food and Drug Administration (FDA) approval for this indication in June 1993. However, high rates of restenosis with this device relegated its use mainly for bailout of occlusive dissections and recoil after balloon angioplasty.

While these stents were being developed and tested, in 1984 Julio Palmaz designed a balloon-expandable stainless steel “slotted tube stent.” In this stent design, rectangular slots were cut into a 15-mm-long, thin-walled stainless steel tube, such that balloon inflation within the stent deformed these rectangular slots into diamond-shaped windows or cells. While this design allowed for relatively straightforward deployment (and greater resistance to recoil than the clamshell design), the rigidity of this stent made it difficult to deliver in the coronary vasculature. In 1989, a design modification was suggested by Richard Schatz, consisting of the placement of a 1-mm central articulating bridge connecting two rigid 7-mm slotted segments, creating the 15-mm Palmaz–Schatz stent (Johnson and Johnson Interventional Systems, Warren, NJ) ( Fig. 15.1 ). The first coronary Palmaz–Schatz stent was placed in a patient by Eduardo Sousa in São Paulo, Brazil, in 1987. The Palmaz–Schatz stent was subsequently investigated in two landmark randomized trials comparing balloon angioplasty to elective stenting. In the STent REStenosis Study (STRESS) and Belgian Netherlands Stent study (BENESTENT)-1 studies, routine use of the Palmaz–Schatz stent was associated with a 20% to 30% reduction in clinical and angiographic restenosis within 6 to 12 months compared with conventional balloon angioplasty ( Fig. 15.2 ). The Palmaz–Schatz stent also resulted in markedly improved initial angiographic results, with a larger postprocedural minimal luminal diameter and fewer residual dissections, which translated into a lower rate of subacute vessel closure. These results led to approval of the Palmaz–Schatz Stent by the FDA in 1994. Long-term follow-up up to 15 years has subsequently demonstrated a low (but not zero) rate of clinical angiographic recurrences from years 1 to 5 after coronary stent implantation, with slight and progressive decrements in luminal size thereafter extending beyond 10 years. The mechanisms of this late progression of disease are not entirely known, but, as discussed later, is usually described as atherosclerotic transformation of neointimal hyperplasia, known as neoatherosclerosis.

Despite the success of the Palmaz–Schatz stent in improving the early and late results of conventional balloon angioplasty, widespread adoption of stent technology was initially hindered by high rates of subacute stent thrombosis necessitating an intense antithrombotic and antiplatelet regimen (consisting of aspirin, dextran, dipyridamole, heparin, and warfarin). Further refinements in the stent procedure and periprocedural pharmacotherapy regimens were thus required. Antonio Colombo and colleagues demonstrated reduced rates of stent thrombosis with more aggressive intravascular ultrasound (IVUS)-guided deployment techniques including routine high-pressure adjunctive dilatation (>14 atmospheres), along with the use of aspirin and a second antiplatelet agent (thienopyridine ticlopidine) rather than prolonged warfarin therapy. These modifications significantly reduced the incidence of stent thrombosis to ∼1% to 2%, along with a marked reduction in bleeding and femoral arterial complications. The confirmation of these initial findings in several randomized clinical trials definitively established the superiority of dual antiplatelet therapy (DAPT) (with aspirin and ticlopidine) over anticoagulation with warfarin for prevention of stent thrombosis, and facilitated widespread adoption of coronary stenting by the late 1990s.

Stent Design: Impact on Performance and Clinical Outcomes

Limitations of Bare-Metal Stents

By the late 1990s, stent implantation became the predominant treatment for most patients with coronary artery disease as a result of more predictable acute and late angiographic results compared with conventional balloon angioplasty, atherectomy, and laser therapy. Improvements in procedural technique (including IVUS and optical coherence tomography [OCT] guidance), more effective antiplatelet regimens, and the introduction of increasingly lower profile, more flexible and deliverable devices additionally contributed to the ascendancy of stenting. With improvements in stent deliverability and reductions in rates of subacute stent thrombosis to less than 1%, restenosis emerged as the major persistent limitation of coronary stenting. While coronary stents increase acute luminal diameters to a greater extent than balloon angioplasty (greater acute gain), the greater vascular injury caused by stent implantation compared to balloon angioplasty elicits an exaggerated degree of neointimal hyperplasia, resulting in greater decreases in luminal diameter (late loss). Importantly, however, comparing stents to balloon angioplasty, the mean incremental gain in luminal dimensions with stenting is statistically greater than the mean incremental increase in late loss, resulting in a larger net gain in minimal luminal dimensions. This observation led Kuntz and Baim to formulate the “bigger is better” concept: the greater the acute gain, the greater the late gain and the lower the ultimate rate of restenosis. Nonetheless, even with optimal stent implantation, restenosis after BMS implantation still occurred in approximately 20% to 40% of patients within 6 to 12 months, in part due to stenting more complex patient and lesion subsets than in the balloon angioplasty era. As such, coronary restenosis became known as the “Achilles’ heel” of coronary stenting, with significant resources devoted to its prevention and treatment (see Chapter 34 ).

DES, which maintain the mechanical advantages of BMS while delivering an antirestenotic pharmacologic therapy locally to the arterial wall, have been shown to effectively and safely reduce the amount of in-stent tissue that accumulates after stent implantation, resulting in significantly reduced rates of clinical and angiographic restenosis. These devices were designed specifically to prevent the neointimal hyperplasia resulting after conventional BMS placement, and have been highly successful in this regard. In numerous randomized trials, the reduction in neointimal hyperplasia that occurs with DES compared to BMS has been shown to result in a 50% to 75% reduction in binary angiographic restenosis and target-lesion revascularization (TLR). The initial results of the pivotal randomized trials that led to device approval have been replicated and validated in numerous subsequent trials and real-world registries across the spectrum of disease and lesion subtypes.

Components of Drug-Eluting Stents

The three critical components of a DES that must be optimized to ensure its safety and efficacy are (1) the stent itself (including its delivery system); (2) the pharmacologic agent being delivered; and (3) the drug carrier vehicle, which controls the drug dose and pharmacokinetic release rate ( Fig. 15.3 ).

Basic Drug-Eluting Stents Pharmacology

Following promising cell culture and in vitro development, t he antirestenotic properties of a wide range of pharmacologic agents have been tested in humans ( Fig. 15.4 ). Among these, the two most clinically effective classes of agents are the “rapamycin-analog family” of drugs and paclitaxel. The principal mechanism of action of rapamycin (also known as sirolimus), and its analogs (including zotarolimus, everolimus, biolimus A9, and novolimus) is inhibition of the mammalian target of rapamycin (mTOR), which prevents cell cycle progression from the G1 to S phase. mTOR is also localized on platelet membranes where it mediates platelet activation and aggregation. Inhibition of mTOR by sirolimus analogs has been shown to prevent platelet spreading on fibrinogen coating cover slips, can inhibit platelet aggregation, and produce platelet diasaggregation under shear flow conditions. In addition, rapamycin or rapamycin analogs are able to inhibit mTOR-dependent clot retraction. Although somewhat varying in lipophilicity and potency, most rapamycin analogs have been clinically comparable in their safety and efficacy effects. Two other rapamycin analogs that in the past (but not present) have been used on DES platforms—tacrolimus and pimecrolimus—have a different mechanism of action, binding directly to FKBP506, thereby inhibiting the calcineurin receptor with downregulation of cytokines and inhibition of smooth muscle cell activity ; unlike the mTOR inhibitors, these agents have not shown significant antirestenotic potential.

The other agent that has been used effectively not only in DES but also on drug-eluting balloons is paclitaxel. By interfering with microtubule function, paclitaxel has multifunctional antiproliferative and antiinflammatory properties, prevents smooth muscle migration, blocks cytokine and growth factor release and activity, interferes with secretory processes, is antiangiogenic, and impacts signal transduction. At low doses (similar to those in DES applications), paclitaxel affects the G0 to G1 and G1 to S phases (G1 arrest) resulting in cytostasis without cell death.