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Patient Safety: Review Article

Coronary Artery Stents: Part I. Evolution of Percutaneous Coronary Intervention

Newsome, Lisa T. MD, DMD*; Kutcher, Michael A. MD; Royster, Roger L. MD*

Editor(s): Brull, Soren J.

Author Information
doi: 10.1213/ane.0b013e3181732049
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Abstract

THE BEGINNING OF INTERVENTIONAL CARDIOLOGY

Grüentzig and Myler performed the first coronary angioplasty during coronary artery bypass graft (CABG) surgery in San Francisco in May 1977.1 Grüentzig later performed the first coronary angioplasty in an awake patient in Zurich, Switzerland in September 1977.1 In a Letter to the Editor of Lancet in February 1978, he described the first series of percutaneous transluminal coronary angioplasty, performed successfully in five patients.2 The technique involved advancement of a balloon-tipped catheter into a narrowed coronary artery, inflation of the balloon to cause plaque compression, and removal of the catheter after balloon deflation. However, in the first 50 patients who underwent percutanueous transluminal coronary angioplasty (PTCA), the primary success rate was only 64% and emergency CABG was required in 14%, with a periprocedural myocardial infarction (MI) rate of 6%.3 As experience with PTCA grew, its success rate increased to approximately 90%.4 Balloon dilation, by virtue of tissue injury/trauma, produces several morphological alterations, which occur individually or collectively.5 These include (1) endothelial denudation with rapid accumulation of platelets and fibrin; (2) stretching, fracturing, fissuring, or disruption of the atheromatous plaque, causing intimal dissection, medial tearing, and aneurysmal dilation of the media and adventitia; (3) elastic recoil; and (4) post-injury arterial shrinkage (constrictive negative remodeling).5–7

Successful PTCA thus induces a “controlled injury” of the diseased arterial segment that accounts for its two major limitations: acute vessel closure and restenosis.7–10 Acute vessel closure occurs within the first 24 h in 6%–8% of cases.8,11 Among patients with periprocedural vessel occlusion, 41% suffered a MI and 72% required CABG; the overall mortality rate was 4.9%. This rate remained constant in subsequent registries.12 Despite improved equipment and experience with PTCA, the incidence of abrupt closure after balloon dilation in the late 1980s and early 1990s remained in the range of 4%–8% with more than 20% of patients requiring emergency CABG.13,14 Although patients may experience ischemic complications (MI, CABG, death) due to intimal dissection not associated with acute vessel closure, this is an infrequent occurrence.15,16

Restenosis often occurs within the first 6 mo after PTCA.8 This process appears to be an exaggerated response to the controlled injury induced by PTCA and involves mechanical, biochemical, and histological factors.5,7,17,18 After initial elastic recoil, adventitial myofibroblasts form vascular scar tissue; this scar contracts, causing constrictive negative remodeling.6,7,18 Endothelial injury triggers an inflammatory response.18–20 Activated white blood cells and platelets migrate and release vasoconstrictors, cytokines, and growth factors.18–20 Consequently, medial smooth muscle cells and adventitial myofibroblasts migrate toward the lumen, hyper-proliferate, and secrete elements to form the extracellular matrix.18 Defined as a more than 50% reduction in postprocedural luminal diameter, restenosis rates have varied from 30% to 50%, with a higher incidence after saphenous vein graft angioplasty (68.2%) and left anterior descending angioplasty (45%).17–22 Target lesion revascularization during 6-mo follow-up was performed in 20%–30% of cases.22 Hirshfeld et al.21 found that restenosis rates were inversely proportional to postprocedural luminal diameter (<2.9 mm, 44%; ≥2.9 mm, 34%; P = 0.036).

In the 1980s, devices specifically designed to remove atherosclerotic plaque were developed.6,8 By reducing vessel wall trauma observed with PTCA, investigators envisaged ablative devices would diminish acute vessel closure and restenosis.22 The clinical efficacies of excimer laser coronary angioplasty and rotational atherectomy were evaluated relative to PTCA in the Excimer Laser, Rotational Atherectomy, and Balloon Angioplasty Comparison study of 620 patients with high-risk angiographic lesion morphology.23 Despite significantly improved procedural success with rotational atherectomy, restenosis rates increased in patients treated with laser angioplasty (46%) and rotational atherectomy (46%) compared with PTCA (35%) (P = 0.04). The Coronary Angioplasty Versus Excisional Atherectomy Trials and the Canadian Coronary Atherectomy Trial evaluated the efficacy of directional coronary atherectomy relative to PTCA.24–26 None of these trials demonstrated this technique to be superior to PTCA in reducing restenosis; in fact, abrupt vessel closure and non-ST segment elevation myocardial infarction (non-STEMI) increased with atherectomy. Further, 1-yr follow-up revealed a significant excess mortality rate in the atherectomy group (2.2% vs 0.6%; P = 0.035).27

THE DEVELOPMENT OF BARE-METAL STENTS

The idea of using foreign bodies to maintain arterial luminal integrity was introduced by the Nobel laureate Alexis Carrel in 1912 when he described experiments in which paraffin-covered glass and metal tubes were implanted into canine thoracic aortae.28 Dotter and Judkins reintroduced the concept of using an implantable prosthetic device to maintain the luminal diameter of diseased vessels in 1964; Dotter continued developing devices, such as self-expanding coils, over the following two decades.29,30 Rousseau et al.31 developed flexible, self-expanding, stainless-steel mesh tubes, which were implanted in canine coronary arteries. In 1985, Palmaz et al.32 introduced the use of balloon-mounted stents in peripheral arteries. Interest in stent implantation in human coronary arteries intensified after Schatz et al.33 reported the results of successful percutaneous implantation of Palmaz-type stents in canine coronary arteries. With the hope that acute occlusion and restenosis could be alleviated, Jacques Puel in Toulouse, France, and Ulrich Sigwart in Lausanne, Switzerland, deployed the first human coronary stents after PTCA in 1986.34 Twenty-four self-expanding mesh devices were implanted in 19 patients (17 restenosis, 4 acute closure, and 3 venous bypass grafts).34 Sigwart et al.34 also first described the use of this stent for arterial dissection. The stent, acting as a scaffold, optimized lumen integrity by tacking down dissection flaps against the vessel wall, and providing mechanical support to offset elastic recoil during PTCA.22,35 In 1993, bare-metal stents (BMS) were approved in the United States to treat acute and threatened vessel closure after failed PTCA.20,36 Subsequent studies confirmed the efficacy of percutaneous coronary intervention (PCI), with stenting as an alternative to avoid emergency CABG surgery after failed PTCA.37

In 1993, two landmark trials, the Belgium Netherlands Stent Arterial Revascularization Therapies Study (BENESTENT) and the North American Stent Restenosis Study (STRESS), confirmed coronary stenting significantly improved angiographic and clinical outcomes, thus establishing elective coronary stent implantation as an accepted standard of care.38,39 These studies also prompted the Food and Drug Administration (FDA) to approve BMS for elective use in the United States.22 Restenosis decreased from 42% to 32% (P = 0.04) in the STRESS trial and from 32% to 22% (P = 0.02) in the BENESTENT trial.38,39 The incidence of target-lesion revascularization decreased from 25% to 35% with PTCA alone to 10%–15% with stenting.38–40 By 1999, 84.2% of all interventions involved stent insertion.5,41 Although BMS implantation effectively eliminated acute vessel closure, initial trials reported acute (<24 h) and subacute (24 h to 30 days) stent thrombosis rates of 16%–24%.10,22,36,42 Thrombosis had long been recognized as a serious complication of stent implantation in both animal and early clinical studies; aggressive anticoagulation attempts were implemented to prevent this.32–36

The BENESTENT and STRESS studies reported subacute stent thrombosis rates of 3.5% and 3.4%, respectively, despite the use of a complex anticoagulation regimen consisting of dextran, aspirin, dipyridamole, heparin, and warfarin.38,39 The incidences of stent thrombosis, MI and death were higher than with PTCA alone.38,39 Thrombosis is the most devastating complication of stent placement and manifests itself as a STEMI in 90% of patients; 20% of patients die.43,44 Moreover, extensive anticoagulation in these patients was associated with a 15%–18% bleeding incidence and extended hospital stays.42,44–46 Two practices led to a dramatic reduction in the incidence of stent thrombosis in BMS: (1) the use of intravascular ultrasound and high balloon pressures to optimize apposition of the stent struts to the vessel wall, and (2) the replacement of anticoagulation with dual-antiplatelet therapy.47,48 The combination of a thienopyridine with aspirin became the cornerstone of antithrombotic prophylaxis. Their combined effects resulted in superior antithrombotic activity when compared to conventional anticoagulation in initial studies.46–49 Initially, ticlopidine was prescribed with aspirin. Clopidogrel later replaced ticlopidine owing to its better safety profile, including less frequent incidences of rash, neutropenia, and thrombotic thrombocytopenic purpura.50 These advancements effectively reduced the incidence of BMS thrombosis to the current rate of 1.2%.51–53

The thienopyridines and aspirin selectively inhibit platelet activation by different mechanisms. The thienopyridines inhibit the adenosine diphosphate (ADP) pathway, whereas aspirin inhibits the arachidonate-thromboxane A2 (TxA2) pathway. The complementary mechanisms illustrate their importance in the amplification of platelet activation.

Ticlopidine and clopidogrel are prodrugs, which are oxidized to active metabolites via the hepatic cytochrome P450-dependent CYP3A4 pathway.54 These active moieties are reactive thiol derivatives and are antagonists of the platelet P2Y12 ADP receptor. The metabolites irreversibly inactivate the P2Y12 receptor subtype by covalent binding (Fig. 1). The P2Y12 receptor is negatively coupled to adenylyl cyclase through the Gi protein, and is expressed on the platelet membrane.55 ADP-P2Y12 downregulation of adenylyl cyclase causes (1) amplification of the response to ADP, thromboxane, thrombin, and collagen, and (2) enhanced platelet activation and aggregation.56,57 P2Y12 plays a central role in thrombus formation and stabilization.57 Covalent binding of P2Y12 by thienopyridines inhibits both mechanisms that are otherwise essential for platelet aggregation and stabilization58: (1) ADP-mediated activation of glycoproteins IIb/IIIa and Ia/IIa, and (2) binding of fibrinogen to glycoprotein IIb/IIIa.58 Although the t1/2 of clopidogrel is 4 h, its irreversible inhibition requires platelet regeneration to normalize platelet function (a 7–10 day process).

F1-31
Figure 1.:
The activation of complex intracellular signaling processes causes the production and release of various stimuli, including thromboxane A2 (TxA2), thrombin, and adenosine diphosphate (ADP), which act by binding to their respective G protein-coupled receptors. Therapies targeted at inhibiting these receptors and also the integrins and proteins involved in platelet activation include the thromboxane inhibitors, the ADP receptor antagonists, the GPIIb/IIIa inhibitors, and the novel PAR antagonists and adhesion antagonists. (Reprinted from Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100:1261–75. Fig. 2, p 1263).
F2-31
Figure 2.:
Illustration depicting complications of coronary artery stents: restenosis of bare metal stent (left) and acute stent thrombosis in drug eluting stent (right).

Aspirin affects the arachidonate-TxA2 pathway by irreversibly binding the enzyme cyclooxygenase-1 (COX-1).59 Aspirin acetylates a serine residue on the enzyme at position 530, thereby preventing the conversion of arachidonate to the unstable prostaglandin intermediate PGH2, which is converted to TxA2, a potent vasoconstrictor and platelet agonist (Fig. 1). A single dose of 160 mg completely eliminates platelet TxA2 production (measured as its stable analog TxB2).59 The same effect can be progressively achieved with daily doses of 30–50 mg, or maintenance dose as low as 0.5 mg · kg−1 · day−1 to provide more than 95% inhibition of TxA2 synthesis during 24 h.59,60 High doses of aspirin may have antithrombotic effects independent of platelet COX-1 inhibition: increased fibrinolytic activity, depressed prothrombin synthesis, improved endothelial function, and antiinflammatory effects.60–62

CLINICAL EFFECTIVENESS OF DUAL-ANTIPLATELET THERAPY IN BMS

Multiple studies confirmed the clinical superiority of combined thienopyridine and aspirin therapy to prevent stent thrombosis in patients undergoing PCI. Schömig et al. performed the first randomized controlled study comparing the safety and efficacy of aspirin/ticlopidine with aspirin/warfarin in patients undergoing stent implantation. The Intracoronary Stenting and Antithrombotic Regimen Trial reported significantly lower incidences of death, MI, and target vessel revascularization with aspirin and ticlopidine at 1-mo (1.6% vs 6.2%).49 Major vascular and/or bleeding complications were also reduced (0% vs 6.5%). Leon et al.63 reported similar results, randomizing patients to receive (1) ticlopidine and aspirin, (2) aspirin alone, or (3) aspirin plus warfarin. The 30-day end point for the composite of death, target lesion revascularization, angiographic-evident stent thrombosis, and MI, in the ticlopidine/aspirin group reported a 0.5% event rate, as compared with aspirin alone (3.6%), and to aspirin/warfarin (2.7%) (P = 0.001). However, both ticlopidine/aspirin (5.5%) and warfarin/aspirin (6.2%) were associated with higher rates of bleeding and vascular complications than aspirin alone (1.8%) (P < 0.001). The Full Anticoagulation Versus Aspirin and Ticlopidine trial found patients undergoing elective or unplanned stenting had fewer adverse cardiac events (2.4% vs 9.9%; P = 0.01), a 41% reduction in bleeding complications, and significantly shorter hospital stays (4.3 ± 3.6 vs 6.4 ± 3.7 days; P = 0.0001) when receiving dual-antiplatelet therapy.46

Subsequent research delineated the most effective antiplatelet regimen. Moussa et al.64 compared the combination of clopidogrel/aspirin with ticlopidine/aspirin in patients undergoing PCI. At 1-mo, both treatment regimens were equally effective, with similar rates of stent thrombosis (1.4% vs 1.5%; P = 1.0) and major adverse cardiac events (2.4% vs 3.1%, P = 0.85). However, the incidence of side effects was lower with clopidogrel (5.3% vs 10.6%; P = 0.006). Additional studies confirmed the efficacy of clopidogrel in the treatment of acute coronary syndrome with PCI. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial showed patients with unstable angina or non-STEMI who received clopidogrel/aspirin experienced 20% fewer cardiac complications (cardiac death, MI, and stroke) than patients treated with placebo after PCI.65 Minor bleeding was significantly more frequent in the clopidogrel/aspirin group (5.1% vs 2.4%; P < 0.001). Significant bleeding complications were not observed. The PCI-CURE substudy reported death and MI decreased by 31% at 30 days in patients receiving long-term clopidogrel/aspirin after PCI with BMS versus aspirin/placebo (P = 0.002).66 No difference in bleeding was observed. Additional studies suggest prolonged therapy with clopidogrel/aspirin improves long-term outcome. Data from the Clopidogrel for the Reduction of Events During Observation trial revealed treatment after PCI with clopidogrel/aspirin beyond 30 days reduces the combined risk of death, MI, and stroke by 26.9% at 1-yr as opposed to remaining on aspirin alone.67 The Clopidogrel for High Atherosclerotic Risk and Ischemic Stabilization, Management, and Avoidance trial demonstrated combined clopidogrel and aspirin were beneficial in patients with established cardiovascular disease, although no benefit was derived in patients with risk factors for developing vascular disease.68 The current antithrombotic regimen for BMS implantation involves an initial dose of clopidogrel 300–600 mg and aspirin 325 mg several hours before the procedure. Aspirin 75–325 mg and clopidogrel 75 mg are prescribed daily for 4–6 wks to allow stent endothelialization.69,70 Aspirin is then continued for life as secondary prevention.69,70

BMS AND IN-STENT RESTENOSIS

Despite the advancements made with BMS implantation, restenosis continues to be the “Achilles heel” of this device (Fig. 2).40 BMS are associated with a 20%–25% restenosis rate within 6 mo of implantation. Lesion complexities, comorbidities (diabetes, renal insufficiency) increase this incidence, and restenosis rates approaching 80% have been observed in these subgroups.21,44,71–74 Repeat revascularization occurs in 60%–80% of restenotic lesions.74 Although initial stent placement prevents acute recoil, the stent struts traumatize the vascular wall provoking an inflammatory reaction followed by an exaggerated proliferative response within the media and adventitia, which produces greater neointimal formation when compared with PTCA-induced restenosis.8,20,21,74 In-stent restenosis incidence peaks at 3 mo, reaches a plateau between 3 and 6 mo, but can persist beyond 1 yr after stent deployment.21 The presence of BMS worsened the incidence of restenosis by threefold when implanted in patients ineligible for the BENESTENT and STRESS trials.75,76

In-stent restenosis is not a benign event; approximately 35% of patients present with an acute coronary syndrome requiring reintervention in 12%–20% of patients.77 In 2006, Chen et al.77 reported morbidity and mortality rates of 9.5% and 0.7%, respectively. Reintervention attempts to prevent in-stent restenosis have included PTCA, atherectomy, repeat stenting, and brachytherapy (intracoronary delivery of a radioactive isotope).78,79 Yokoi et al.78 reported a recurrent restenosis rate of 85% when in-stent restenosis is treated with PTCA. Brachytherapy increases stent margin restenosis and delays endothelialization, leading to a 15.6% stent thrombotic occlusion rate.79–81 The overall failure rate is 30%.80

THE ADVENT OF DRUG-ELUTING STENTS

Drug-eluting stents (DES) were developed to prevent neointimal hyperplasia (medial hyperproliferation) and consequent restenosis while preserving vessel architecture compromised by PTCA.82 By coating a BMS with a polymer containing antiproliferative material that inhibits neointimal hyperplasia, cardiologists hoped these devices would eliminate restenosis and the need for reintervention.44,82,83 The first-generation DES locally release either sirolimus or paclitaxel from a nonresorbable polymer. Both agents effectively inhibit vascular smooth cell migration and proliferation, although by different intracellular mechanisms79 (Table 1).

T1-31
Table 1:
Comparison of Sirolimus vs Paclitaxel

DES were approved for use in Europe in 2002. In the United States, the FDA granted expedited review of both DES, and approved sirolimus-eluting stents (Cypher®, Cordis Corporation) for use in April 2003 while paclitaxel-eluting stents (Taxus®, Boston Scientific) were approved in March 2004. Initial approval was based on the results of randomized controlled trials with carefully selected patient populations (Table 2).84–93 These trials demonstrated the superior ability of both sirolimus-DES and paclitaxel-DES to reduce neointimal hyperplasia, restenosis, and reintervention at 6–12 mo when compared with BMS (Figs. 3D and 4D). At 2-yr follow-up using angiography and intravascular ultrasound, the clinical safety of DES was further established with minimal late lumen loss observed in both sirolimus-DES and paclitaxel-DES.94,95 Both types of DES have shown continued efficacy in preventing restenosis (74% reduction) when studied 4 yrs after initial deployment (Figs. 3D and 4D).96,97 Although a meta-analysis of randomized trials comparing paclitaxel-DES with sirolimus-DES revealed significantly higher restenosis rates with the former (P = 0.001), clinical outcomes (death and MI) were similar in both groups.98 In 2005, at the height of clinical enthusiasm, 85% of all stents implanted in the United States and Europe were DES.99

T2-31
Table 2:
Characteristics of the Study Trials Gaining Food and Drug Administration (FDA) Approval
F3-31
Figure 3.:
Comparison of sirolimus-eluting stents to bare-metal stents in randomized clinical trials. (Reprinted from Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus-and paclitaxel-eluting coronary stents. N Engl J Med 2007;356:998–1008. Fig. 1, p 1004).
F4-31
Figure 4.:
Comparison of paclitaxel-eluting stents to bare-metal stents in randomized clinical trials. (Reprinted from Stone GW, Moses JW, Ellis SG, Schofer J, Dawkins KD, Morice MC, Colombo A, Schampaert E, Grube E, Kirtane AJ, Cutlip DE, Fahy M, Pocock SJ, Mehran R, Leon MB. Safety and efficacy of sirolimus-and paclitaxel-eluting coronary stents. N Engl J Med 2007;356:998–1008. Fig. 2, p 1005).

DES AND STENT THROMBOSIS

Despite the effectiveness of DES in reducing restenosis, concerns about stent thrombosis plague these devices (Fig. 2). The overall risk of DES thrombosis is between 0.5% and 3.1%.100,101 When stent thrombosis occurs, it is catastrophic. Fatality and MI rates associated with stent thrombosis have ranged from 45% to 75% and 25% to 65%, respectively.102–106 Of the 1% angiographic incidence of late stent thrombosis observed by Ong et al.,104 75% of these patients presented with a MI, and 12% died. The pivotal clinical trials reported similar early (acute and subacute) stent thrombosis rates for DES and BMS (≤1%) and attributed this complication to mechanical factors.97,107–109 Late (30 days to 12 mo) and very late (beyond 1 yr) stent thrombosis also occur with BMS and DES, but the pathophysiology differs between these devices.110 In DES, late stent thrombosis presents as primary thrombosis.111 It is affected by the degree of endothelial coverage and the intensity of antiplatelet therapy.111–113 In contrast, BMS thrombosis is related to target lesion revascularization, and carries a 0.4%–0.8% incidence.110 However, Ferrari et al.114 reported 10 cases of late or very late stent thrombosis occurring with BMS after aspirin withdrawal. Those events occurred 15 ± 6.5 mo after stent implantation.

Although the initial randomized controlled trials did not reveal an increased incidence of stent thrombosis, case reports and longer follow-up studies were published suggesting otherwise. In 2003, more than 290 cases of subacute stent thrombosis occurring after sirolimus-DES implantation were reported to the FDA; a 20% mortality rate was also reported.107 Cases of premature discontinuation of clopidogrel were associated with subacute stent thrombosis.115 Jeremias et al.116 reported a 1.1% incidence of subacute stent thrombosis at a mean of 7 days postsirolimus-DES implantation. All patients had prematurely stopped clopidogrel, increasing the risk of stent thrombosis by 30-fold. The first case of late stent thrombosis in a sirolimus-DES was published in 2003.117 Clopidogrel was discontinued after 4 wks of dual-antiplatelet therapy; late stent thrombosis and a nonfatal MI occurred 2 wks later. McFadden et al.118 reported the first case series of late stent thrombosis in 2004. Late stent thrombosis and MI occurred in four patients with DES (two sirolimus-DES; two paclitaxel-DES) after discontinuation (4–14 days earlier) of antiplatelet therapy. In all four cases, the DES had been implanted longer than a year. One patient with a sirolimus-DES stopped both clopidogrel and aspirin; the remaining patients were taking aspirin only. Of interest, three of the four patients were undergoing noncardiac surgery. Karvouni et al.119 reported a case of very late stent thrombosis in a diabetic patient 17 mo after sirolimus-DES implantation; he had taken clopidogrel for 9 mo and remained on aspirin monotherapy. Waters et al.120 published a case of late stent thrombosis in a left circumflex-sirolimus-DES after a 6-mo course of dual-antiplatelet therapy and life-long aspirin therapy. These serendipitous findings created an intense debate, questioning the safety of DES.

Research continues to elucidate the pathophysiology of stent thrombosis. Experimental models of BMS demonstrated complete endothelialization at 28 days, whereas at 6 mo, DES uniformly revealed incomplete healing, fibrin deposition, and inflammatory cells, indicating a hypersensitivity reaction.100,121–123 In late 2003, the FDA notified physicians of possible hypersensitivity reactions to sirolimus-DES associated with stent thrombosis.124 In autopsy studies of DES implanted 1–4 yrs, Virmani et al. found eosinophilic inflammation, thrombus, impaired vessel healing, persistent fibrin deposition and poor endothelialization in 45% of the stents (Fig. 5).115,125–130 Sirolimus and paclitaxel impair endothelial function both within the stent and in the distal coronary artery, leading to delayed arterial healing of the stent itself, as well as enhancing the risk for distal arterial ischemia and coronary occlusion.111 Both antiproliferative agents enhance the expression of endothelial cell tissue factor, creating a prothrombogenic environment.111,131 Sirolimus has also been shown to directly activate platelets, induce local platelet aggregation, and contribute to local thrombus formation at the stent site.131,132 The most powerful histological predictor of stent thrombosis has been incomplete endothelial coverage (P < 0.00005).113 Kotani et al.127 performed angioscopy in sirolimus-DES and BMS 3 to 6 mo after implantation, and compared the extent of neointimal coverage. All of the BMS were completely endothelialized, whereas 86.7% of the sirolimus-DES were not; 50% of these contained thrombi. Investigators analyzed the histology of restenosis retrieved from paclitaxel-DES, sirolimus-DES, and BMS of patients presenting for reintervention.128 DES showed incomplete neointimal healing with fibrinoid deposition two yrs after implantation. Patients with paclitaxel-DES restenosis presented more frequently with unstable angina and showed more pronounced signs of delayed healing than sirolimus-DES. Additional predictors for late stent thrombosis are included in Table 3.115,133–137

F5-31
Figure 5.:
Line chart comparing the percentage of endothelialization in drug-eluting stents (DES) versus bare-metal stents (BMS) as a function of time. Note that DES (solid line) consistently show less endothelialization compared with BMS (dashed line) regardless of time point. Even beyond 40 mo DES are not fully endothelialized, whereas BMS are completely covered by 6 to 7 mo. (Reprinted from Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193–202. Fig. 2, p 195).
T3-31
Table 3A:
Off-Label (Non-Food and Drug Administration [FDA] Approved) Uses of Drug-Eluting Stents (DES)/Predictors of Drug-Eluting Stent Thrombosis

Several studies and registries have identified predictors of DES thrombosis. Of these, acute coronary syndrome, left ventricular ejection fraction ≤30%, bifurcation treatment, renal insufficiency, diabetes, and premature or standard discontinuation of antiplatelet therapy were the strongest predictors of cumulative stent thrombosis.106,130,133,134,138–148 Premature discontinuation of clopidogrel remains the strongest independent predictor of stent thrombosis in multivariate analysis.106,138–148 Iakovou et al.106 found a more frequent prevalence of diabetes, multivessel disease, small reference-vessel diameter, and complex lesions in 2229 nonrandomized patients who prospectively received DES. Again, the strongest independent predictor of stent thrombosis remained premature clopidogrel discontinuation (P < 0.001). Park et al.139 reported a 7.8% stent thrombosis rate in patients who prematurely stopped clopidogrel, aspirin, or both. An analysis from the Prospective Registry Evaluating Myocardial Infarction: Events and Recovery (PREMIER) Registry, which studied 500 patients with acute MI treated with DES, reported a 7.5% mortality rate among patients who had prematurely discontinued thienopyridine therapy; patients who remained on clopidogrel and aspirin experienced a 0.7% mortality rate (P < 0.0001).140 Ellis et al.141 recently performed a meta-analysis of the Taxus II–VI trials to determine the incidence of late and very late stent thrombosis in patients followed 3 yrs after paclitaxel-DES implantation. In the initial 6 mo, an incidence of 0.8% was observed with both paclitaxel-DES and BMS. Beyond 6 mo, there was a 0.4% absolute increased risk of stent thrombosis in patients with paclitaxel-DES, and all patients who were diagnosed with late or very late stent thrombosis had discontinued clopidogrel. Time from clopidogrel termination to stent thrombosis ranged from 42 to 800 days. One case of very late stent thrombosis occurred when aspirin and clopidogrel were discontinued 5 days before surgery.

Kuchulakanti et al.142 evaluated the correlates of angiographically proven stent thrombosis from a cohort of 2974 consecutive patients treated with DES. In this prospective registry with 12-mo follow-up, the mean duration to late stent thrombosis was 152.7 ± 100.4 days. The incidence of late stent thrombosis was higher in patients who discontinued clopidogrel therapy than in patients who continued clopidogrel (36.8% vs 10.7%; P < 0.0001). The 6-mo mortality rate in patients with late stent thrombosis was 31% (P < 0.001). In addition to clopidogrel discontinuation, independent predictors of stent thrombosis included renal failure, bifurcation lesions, and increased degree of restenosis. The authors concluded that strict adherence to clopidogrel compliance is paramount in patients with increased risk factors for stent thrombosis after DES implantation. Eisenstein et al.143 observed continued clopidogrel use at 6, 12, and 24 mo was associated with a significantly lower rate of cardiac death and MI as compared with patients who had discontinued clopidogrel at 6 or 12 mo (Fig. 6).

F6-31
Figure 6.:
Six-month landmark analysis of patients who discontinued clopidogrel use at 6 and 12 mo versus continuing to 24 months. Drug-eluting stents (DES) 7.2 vs 3.1, P = 0.02; bare-metal stents (BMS) 6.0 vs 5.5, P = 0.70 (Reprinted from Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297:159–68. Fig. 2, p 164).

Resistance to antiplatelet therapy has been cited as a risk factor for developing stent thrombosis.149 Four percent to 30% of patients respond inadequately to clopidogrel on in vitro testing, and 4%–45% respond inadequately to aspirin.150,151 Evidence suggests patients with stent thrombosis have abnormally high rates of excessive platelet activity.152,153 Wenaweser et al.149 reported 48% of patients with stent thrombosis had impaired in vitro responses to aspirin compared with 32% of patients without stent thrombosis (P = 0.01). Although clopidogrel resistance was similar between patients with stent thrombosis and patient controls, combined aspirin/clopidogrel resistance was significantly higher in patients with stent thrombosis (52%, P < 0.05).149

Most cases of aspirin and clopidogrel resistance result from patient noncompliance and improper physician dosing.151,154 Alternatively, compliant patients may have poor intestinal absorption or decreased receptor binding secondary to drug interactions.151,155–160 Studies suggest response variability to clopidogrel may be dose-dependent.153,161 Multiple cellular etiologies have been described.55,150,162 Increased levels of urinary 11-dehydro TxB2 (a marker of thromboxane generation) have been associated with heightened risk of MI and cardiac death.156 Genetic etiologies include polymorphisms of COX-1, P2Y12, and CYP3A4.150,155,163–165 However, there is no universally accepted test for antiplatelet resistance, and consequently its prevalence varies among studies.155 Moreover, there is no consensus as to the role antiplatelet resistance may play in late stent thrombosis.166

THE CONTROVERSY INTENSIFIES

The current firestorm regarding DES was ignited by the findings of two meta-analyses presented at the American College of Cardiology’s 55th Annual Scientific Session in March 2006 and the European Society of Cardiology/World Congress of Cardiology meeting in September 2006.144 These studies confirmed that late stent thrombosis occurs more frequently than reported in randomized controlled trials. The Basel Stent Kosten Effektivitäts Trial-Late Thrombotic Events (BASKET-LATE) study presented in March 2006 sought to determine the true incidence of late stent thrombosis, MI, and death in 746 patients randomized to receive DES or BMS who had remained on dual-antiplatelet therapy for 6 mo. The patients had not experienced an adverse cardiac event during that period.147 At 6 mo, clopidogrel was stopped and patients were followed an additional 12 mo. In addition to a 19% mortality rate and an 88% composite rate of death or MI, the researchers found the following: (1) late stent thrombosis-related events (death and MI) occurred two to three times more frequently in patients with DES than those with BMS (Fig. 7); (2) late stent thrombosis carried a four times higher risk of cardiac death/MI (P < 0.0001, Fig. 8); and (3) late stent thrombosis and its complications occurred up to 1 yr after clopidogrel discontinuation. The authors concluded that while DES use in 100 patients avoids five target lesion revascularization events at 6 mo, it unfortunately leads to 3.3 late deaths or MI. Camenzind et al. presented in September 2006 a meta-analysis of all company-supported randomized trials (RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS, and TAXUS I-VI) comparing sirolimus-DES and paclitaxel-DES with BMS controls for an average 3-yr follow-up.145,146 Sirolimus- DES were associated with a 60% relative increase in death or MI (P = 0.03), whereas paclitaxel-DES demonstrated a statistically insignificant 15% increase. The authors concluded late stent thrombosis and discontinuation of antiplatelet therapy caused the higher rates of death and MI.

F7-31
Figure 7.:
Outcomes related to late stent thrombosis. MI = myocardial infarction. (Reprinted from Gruberg L. BASKET-LATE: Late clinical events related to late stent thrombosis after stopping clopidogrel: drug-eluting vs bare-metal stenting. Available at: http://www.medscape.com/viewarticle/529648. Accessed June 12, 2007. Fig. 3).
F8-31
Figure 8.:
Incidences of death/myocardial infarction and composite of death and myocardial infarction related to stent thrombosis in patients with drug-eluting stents. (Reprinted from Gruberg L. BASKET-LATE: Late clinical events related to late stent thrombosis after stopping clopidogrel: drug-eluting vs bare-metal stenting. Available at: http://www.medscape.com/viewarticle/529648. Accessed June 12, 2007.)

In response, several investigators performed 4-yr follow-up analyses of the initial pivotal trials to support the safety and efficacy of these devices95,167 (Figs. 3 and 4). Further, as the definition of thrombosis varies among studies, adding to the confusion and disagreement among investigators, the Academic Research Consortium (ARC) recently proposed standardized definitions in an effort to develop uniformity and improve sensitivity for the diagnosis of stent thrombosis.109,168 These subsequent meta-analyses were performed using these definitions. In their examination of the data from the RAVEL, SIRIUS, and TAXUS trials, Mauri et al.109 reported no statistical difference in the cumulative incidence of stent thrombosis (paclitaxel-DES 1.3% vs BMS 0.8%, P = 0.24; sirolimus-DES 1.2% vs BMS 0.6%, P = 0.20), although the power to detect such differences was limited. When compared with BMS, Stone et al.97 detected a small, but significant increase in the incidence of late stent thrombosis for both sirolimus-DES (0.6% vs 0%; P = 0.025) and paclitaxel-DES (0.7% vs 0.2%; P = 0.028) 1 to 4 yrs after implantation. No differences in death or MI were initially observed. However, a reanalysis of the data demonstrated a threefold increase in the composite of death and MI after 1 yr (P = 0.05); the 3-yr incidence was 1.2% with paclitaxel-DES versus 0.7% with BMS.169,170 Although Kastrati et al.171 found an increased rate of very late stent thrombosis with sirolimus-DES compared with BMS (0.6% vs 0.05%; P = 0.02), there was no difference in 5-yr mortality. Spaulding et al.169 also did not detect any difference in the incidence of MI or stent thrombosis after a 4-yr follow-up, but the survival rate for diabetics with BMS was significantly higher than in diabetics with sirolimus-DES (95.6% vs 87.8%, P = 0.008). Babapulle et al.170 performed a meta-analysis of 11 trials, showing DES were effective at decreasing rates of death and MI (DES 7.8% vs BMS 16.4%) by reducing rates of target vessel revascularization.

Nonrandomized registries more representative of clinical practice and additional meta-analyses of pivotal trial data have challenged these findings, particularly when the ARC definitions are not applied. The ARC definitions may introduce bias in favor of DES and are not universally accepted. Iakovou et al.106 observed a 1.3% incidence of stent thrombosis with a 45% mortality rate. In 2005, Bavry et al.108,172 performed a meta-analysis of eight randomized clinical trials, finding no difference in stent thrombosis between DES and BMS; the investigators performed a subsequent meta-analysis of 14 randomized clinical trials in 2006 and found DES increased the risk for late stent thrombosis by four- to fivefold. The median thrombosis time was 15.5–18 mo; a greater incidence of late stent thrombosis was seen with paclitaxel-DES. In 2007, Lagerqvist et al.105 performed a 3-yr outcomes analysis comparing 6033 patients treated with DES versus 13,738 treated with BMS through the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). DES implantation was associated with a 32% relative increase in death from 6 mo to 3 yrs. The absolute risk of death increased 0.5%–1.0% per yr. The authors noted a higher frequency of comorbidities and procedural complexities associated with DES use and hypothesized stent thrombosis caused the increased mortality. Further, the incidence of reintervention was the same for DES and BMS (14.7% vs 14.5%), questioning the benefit of DES. However, when the authors studied data from 2005 (yr 4), they found no difference in the relative risk for death and MI (RR = 1.01 for both groups). The authors attributed this improvement in outcome to better technique and longer duration of clopidogrel therapy. Daemen et al.173 evaluated the incidence of late stent thrombosis in unrestricted use of DES in routine clinical practice. Between 2002 and 2005, a persistent excess stent thrombosis risk of 0.6% per year was found compared with historical control subjects who received BMS. The Evaluation of Active Stent (EVASTENT) study evaluated sirolimus-DES in diabetics and nondiabetics.174 At 1 yr, the stent thrombosis and mortality rates were 1.8-times and 3.1-times higher, respectively, in diabetics (P < 0.001).

The disparity among the various studies has generated both confusion and controversy. Those who dispute the safety of DES question the validity of the pivotal trial data, which excluded the highest risk patients: the population who are currently receiving DES. The prospective, randomized controlled trials are considered not to have adequate power to reliably detect late stent thrombosis or to evaluate clinically relevant end points (death or MI).175 Moreover, these pivotal trials and their analyses were based on the original indications for which the FDA approved the use of DES, which were defined by the inclusion and exclusion criteria of the original trials themselves.167 Use within these well-defined criteria is termed “on-label.”176 Currently, 40% of DES are implanted for on-label indications (Table 3).167,176 The remaining 60% of use is “off-label,” currently unapproved by the FDA, occurring in patients with comorbidities or with complex coronary lesions (Table 3).138,148,176 This population more accurately reflects those patients represented in nonrandomized trials, registries, and clinical practice. Unfortunately, these same comorbidities and lesion complexities are also predictors of stent thrombosis, suggesting serious complications are higher in off-label populations compared with their less-complex, on-label counterparts (Table 3).148 The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) registry of nonrandomized unrestricted paclitaxel-DES use comparing off- and on-label use found off-label use was associated with higher rates of death (6.5% vs 4.6%; P = 0.08), MI (3.6% vs 2.1%; P < 0.0001), and stent thrombosis (3.0% vs 1.4%; P < 0.0001) at 2 yrs.177 Win et al.138 recently published data from a prospective registry of patients receiving DES for on- and off-label use. At 1-yr, the composite of death and MI occurred more frequently with off-label use (17.5% vs 8.9%, P < 0.001). Similar results have been confirmed in other studies and registries.138–148

Along with the stent thrombosis issue, the subject of the appropriate duration of dual-antiplatelet therapy came under scrutiny. The initial recommendations made for both sirolimus-DES and paclitaxel-DES were completely arbitrary, and the FDA, American Heart Association/American College of Cardiology/Society for Cardiovascular Angiography Interventions (AHA/ACC/SCAI) and the stent manufacturers advised patients to remain on clopidogrel and aspirin for 3 (sirolimus-DES) and 6 (paclitaxel-DES) mo followed by life-long aspirin therapy without validation by scientific arguments (Table 2).128,178–181 However, data from several studies suggest a longer duration of antiplatelet therapy than is currently included in the product labeling may be beneficial.138–148 In 2005, the European Society of Cardiology and the AHA/ACC/SCAI extended the recommended duration of therapy, ideally for up to 12 mo, in patients at low risk of bleeding.182,183 As publications continued questioning the safety of DES, the FDA convened in December 2006 to review then-current data relevant to stent thrombosis, and to address the appropriate duration of dual-antiplatelet therapy in both on- and off-label use of DES. The FDA concluded that (1) when DES are used for their approved, or on-label, indications, the risk of thrombosis does not outweigh their advantages over BMS in reducing the rate of revascularization; and (2) off-label use is associated with a higher rate of stent thrombosis, MI and death.94,115,148 With respect to dual-antiplatelet therapy, the panel concluded there was sufficient data to suggest a prolonged course of clopidogrel was beneficial, but the ideal duration was unknown.148“Premature discontinuation, however, of dual-antiplatelet therapy after DES implantation does appear to be associated with an increased risk of stent thrombosis, death, and MI. These risks may even be higher in the off-label compared with the on-label use of DES.148” After the FDA deliberations, a scientific advisory endorsed by five major professional societies was published in January 2007.183 This advisory, written by the ACC/AHA/SCAI, the American College of Surgeons and the American Dental Association, emphasized the importance of 12-mo dual-antiplatelet therapy and life-long aspirin therapy after DES implantation. However, the ideal duration of dual-antiplatelet therapy is not yet known, and may need to be extended beyond one-year in patients with additional risk factors for stent thrombosis.184–187 The National Heart, Lung, and Blood Institute also convened a panel of representatives from academia, industry, and the FDA in January 2007 to readdress the issues raised during the FDA panel, and emphasized the importance of evidence-based medicine to resolve these continuing controversies.144

CONCLUSION

The progress of interventional cardiology over the last three decades has revolutionized the treatment of coronary artery disease. However, the enthusiasm for each advance has been fraught with unforeseen complications, which subsequently limit its use. This is of benefit, as clinicians must decide the most appropriate procedure for their patients; DES may not be the panacea once thought. In fact, the data accumulated over the last 5 yrs have caused cardiologists to carefully deliberate the most appropriate stent(s) to implant in a patient, with a decline in DES use from 90% to the current rate of 70%. Research is focused on developing more biocompatible absorbable coatings and newer drugs with biological targets other than smooth muscle proliferation.110 Development of more biocompatible and bioabsorbable stents facilitating adequate endothelialization is expected in the near future.110 Second-generation DES, containing everolimus or zotarolimus, are undergoing clinical trials to assess their ability to resolve the issues discovered with the first generation of DES. Virmani188 has demonstrated complete endothelialization in animal models, suggesting a better safety profile with these stents. Despite these new technologies, there must still be focus on the stents already implanted to ensure patient safety and improve outcomes.

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