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Late Angiographic Stent Thrombosis (LAST): The Cloud Behind the Drug-Eluting Stent Silver Lining?
The widespread popularity of drug-eluting stents (DES) had a dramatic impact on the modern interventional therapy of coronary artery disease; accordingly, the cardiac surgical volume has experienced a corresponding decrease. Like the introduction of bare-metal stents (BMS) during the balloon angioplasty era, DES represent yet another quantum advancement towards overcoming the challenges of restenosis. The promises of this potential panacea, however, have been recently attenuated by the looming specter of late angiographic stent thrombosis (LAST). The usual time frame for stent thrombosis is believed to be the initial few months, as reflected by the 3- and 6-month recommendations for dual antiplatelet therapy (DAT) for sirolimus- and paclitaxel-eluting stents (SES [Cypher™, Cordis Corp., Miami Florida], and PES [Taxus®, Boston Scientific Corp., Natick, Massachusetts]), respectively. However, there is now increasing recognition of prolonged risk for LAST, especially in the setting of DAT cessation. We hereby present a case of DES LAST-associated acute myocardial infarction (AMI) 14 months after implantation and review the current literature regarding this controversy.
Case Report. A 70-year-old male was transferred to our hospital for an inferior AMI. Fourteen months previously, he had undergone elective DES placement with a 3.0 x 16 mm PES in the ostial right coronary artery. The patient had continued on DAT with clopidogrel (CLOP) 75 mg and aspirin (ASA) 325 mg daily until 4 days prior, when both agents were held for an upcoming colonoscopy.
Upon arrival, the patient was angina-free, with resolution of the ST-elevations. He was on heparin and integrelin infusions. Emergent cardiac catheterization revealed severe triple-vessel disease; previously noted noncritical stenoses in the left coronary system have progressed significantly. The ostial right coronary artery contained a 95% eccentric in-stent thrombosis, with excellent TIMI 3 flow (Figure 1). His left ventricular ejection fraction was estimated at 45%, with inferobasal akinesis.
A 6 Fr RBU 3.5 guide catheter (Medtronic, Inc., Minneapolis, Minnesota) was engaged in the superiorly-oriented right coronary ostium. Immediately, ventricular fibrillation ensued, requiring several defibrillatory shocks. Repeat angiography with a diagnostic Judkins right-4 catheter revealed no change in the thrombotic stenosis, with normal flow. The patient recovered without incident, remained angina-free and had a stable electrocardiogram. Given the previous event, as well as the lack ofongoing clinical ischemia, percutaneous coronary intervention (PCI) was cancelled, and an intra-aortic balloon pump was placed. He was referred for complete surgical revascularization and underwent quadruple bypass surgery 3 days later. The patient’s postoperative course was remarkable only for transient atrial fibrillation, and he was discharged 4 days subsequently. He has remained event-free for over 6 months.
Discussion and Review
In his keynote address to the Texas Heart Institute, Patrick Serruys stated that as of January, 2005, over 1 million and 1.5 million PES and SES, respectively, have been implanted. At an average cost of $2,000 each, the cumulative price tag exceeded $5 billion.1 Ever since the seminal RAVEL2 and SIRIUS3 trials, which reported dramatically superior restenosis rates of SES over control BMS, DES have overtaken the stent market. The TAXUS trials demonstrated similarly impressive major adverse cardiovascular events (MACE) reductions for PES versus BMS controls.4–8
The safety and efficacy of DES therapy in AMI were demonstrated in the TYPHOON trial. A 49% statistically significant relative decrease in target vessel failure (TVF) versus BMS was observed, with no difference in stent thrombosis at 1 year.9 The ARTS-II study compared SES therapy in multivessel disease patients to historical data from patients assigned to the coronary bypass arm in ARTS-I. The investigators found no difference in MACE, mortality, repeat revascularization or stroke at 1 year.10
The initial enthusiasm for DES was further bolstered by the lack of differences in early thrombosis (ET, < 24 hours) or subacute thrombosis (SAT, 1–30 days) versus BMS. Ong and others reviewed 2,512 patients, of whom 506 received BMS, 1,017 SES, and 989 PES. There was a uniform 1% SAT seen in all 3 groups, with a 12% SAT mortality rate (3/26 patients). Most SAT occurred with 11 days, suggesting a possible mechanical or technical etiology.11 This observation was confirmed in the E-Cypher registry for SES.12 A major risk of stent thrombosis was found to be premature discontinuation of dual DAT with ASA and CLOP. Accordingly, Spertus and co-authors found predictors of early DAT discontinuation to include advanced age, single marital status, lack of high school graduation, preexisting coronary history, lack of discharge instruction and lack of cardiac rehabilitation referral. These patients had a 10-fold mortality increase in the initial 12 months.13 Ajzenberg and co-investigators found that patients with SAT exhibited greater shear-induced platelet aggregation while on DAT, as compared to those free of thrombosis.14 Brachytherapy for in-stent restenosis (ISR) has previously been demonstrated to increase the SAT rate,15 especially with concomitant new stent implantation.12 Heparin-coated stents, however, may decrease this risk.16
Late Angiographic Stent Thrombosis (LAST). Stent thromboses are subdefined by the relative certainty of the diagnosis. Definite thrombosis includes angiographic confirmation of total occlusion of the target vessel or intrastent thrombus. Probable thrombosis is defined as AMI in the target vessel territory, while possible thrombosis is any unexplained death in a patient with a previously implanted DES.17
Recent concerns have arisen regarding the increased risk of LAST (beyond 30 days) following DES implantation. Henderson and Gunalingam reported a patient with LAST 41 months after SES implantation. The patient had continued DAT for 6 months postprocedure, with ASA monotherapy thereafter. Reintervention with a PES was successful and followed by indefinite DAT.18 In a series of 2,006 DES patients (1,017 SES and 989 PES), 8 cases of LAST (0.35%, 3 SES and 5 PES) were observed from 2–26 months. Of note, none of these patients were on DAT at the time of event, including 3 who had discontinued therapy during the preceding 5–7 days for upcoming surgery. Five patients were on ASA therapy alone, with 2 and 3 patients having discontinued CLOP within and beyond the previous month, respectively.19
The available data indicate an increased risk of LAST after termination of DAT. Liistro and Columbo reported LAST in a patient 7 months post-DES implantation after cessation of ticlopidine therapy.20 In another large series, Kuchulakanti and colleagues found 38 cases of DES thrombosis in 2,974 patients (1.27%). Of these, 5, 25 and 8 were early, subacute and late, respectively. Stent thrombosis conferred a mortality rate of 31%, as compared to 3% for the comparator nonthrombosis group. In addition to early CLOP discontinuation, they found chronic renal failure, bifurcation lesions, Type C morphology and treatment for ISR to be predictive of thrombosis.21 Moreover, a similarly dramatic 45% thrombosis-associated mortality incidence was observed in another large series involving 2,229 DES patients.22 Stabile and associates reported 2 cases of DESLAST at 11 and 12 months postimplantation, after DAT cessation. Ironically, in both patients, preexisting BMS in other vessels were widely patent.23
Recent Belgian data suggested that while DES posed no increased risk over BMS for SAT, its potential for LAST beyond 1 year was of concern.24 The BASKET-LATE trial found an increase in MACE from 6–18 months post-DES implantation when compared to BMS controls. However, no difference in cumulative MACE was observed, owing to the early (< 6 months) benefit conferred by DES. Of note, DAT was continued for only 6 months in these patients. In a large meta-analysis of 9 major DES trials, the Cardiovascular Research Foundation found an 86% decrease in ISR, with no differences in combined death or MI for either SES or PES versus BMS controls. However, there were nonsignificant mortality excesses of 5 versus 0, and 9 versus 2, for SES versus BMS and PES versus BMS, respectively.25
Baim presented data pooled from randomized trials involving 3,445 PES patients demonstrating a 0.5% increase of LAST over BMS patients (p = 0.02) without increases in MI or in cardiac or noncardiac deaths. He theorized that this small excess was offset by the morbidity and mortality benefit from the 10% absolute reduction in reintervention.26
In a meta-analysis involving 10 DES trials, Moreno et al found that longer stent lengths completely accounted for the increased risk of LAST in the DES-treated patients.27 In their 3-year follow-up analysis of RAVEL, Fajadet and others reported only 1 possible SAT in 120 patients. Freedom from target lesion revascularization (TLR) and overall MACE rates was significantly improved at 93.7% versus 87.9% and 16.7% versus 34.5%, for SES versus BMS, respectively. Additionally, no differences were seen for rates of death or MI.28
A meta-analysis of all 4 randomized SES trials (RAVEL, SIRIUS, C-SIRIUS and E-SIRIUS) revealed no significant differences in thrombosis for any time interval or cumulatively. Similarly, no increased thrombosis was seen for the premarket zotarolimus-eluting stents (ZES, Endeavor, Medtronic, Inc.).25 In a 2-year follow up of the RESEARCH study, overall MACE was 15.4% versus 22.0% (p = 0.01) for SES versus BMS, respectively. No cases of LAST and no differences in mortality or cumulative death and MI rates were observed.29 Weisz and co-authors likewise reported no increased ET, SAT or LAST associated with SES over control BMS at 2- year follow up of the SIRIUS trial patients.30
Pathophysiology of LAST. The 3 major determinants of thrombosis are endothelial injury, alterations in blood flow and hypercoagulability, collectively known as Virchow’s triad. Endothelial damage can occur from trauma, inflammation, infection or hypertension-induced sheer stress. Furthermore, static or turbulent flow can promote platelet-endothelial contact and aggregation, as occurs in areas of atherosclerotic plaques or aneurysmal dilatation. Disturbances in the coagulation cascade such as antithrombin III or protein C/S deficiency, as well as decreased activity of the endogeous fibrinolytic system, are yet another less common cause of pathologic thrombosis.31
Intracoronary stent implantation satisfies two, and potentially all three, of the above criteria. By definition, stent deployment is direct mechanical intimal trauma. Plaque disruption thus created, subsequently releases prothrombotic cytokines and promotes platelet adhesion and aggregation. Lastly, while successful stent deployment certainly increases overall coronary flow, it is possible that small, local pockets of turbulence or even stasis can form around the struts.
The complication of LAST and the benefit of decreased ISR represent the two extremes in the spectrum of the DES double-edged sword of neointimal inhibition. Neointimal proliferation is triggered by loss of contact inhibition from adjacent endothelial cells. Within 3 days of BMS implantation, fibrin deposition, inflammatory cells such as polymorphonuclear cells, and a thin thrombus layer are formed. At 2 weeks, a matrix-poor neointima is observed; and increased extracellular matrix with accompanying smooth muscle infiltration and a paucity of inflammatory cells are evident at 1 month.31 Neointimal thickness peaks at 6 months post-BMS therapy, with reduced growth subsequently. In contrast, DES neointima increases slowly but steadily to 2 years, at which time it plateaus. At 6 months, pathological specimens demonstrate surface areas of 30 mm2 and 10–15 mm2 for BMS and DES, respectively.1 In one series, angioscopic evaluation at 6 months demonstrated complete endothelialization in 100% of BMS, but only a striking 13.3% of DES.32 Guagliumi and coinvestigators found that at 16 months, DES exhibit only 80% endothelial coverage, with significant platelet and fibrin deposition. Conversely, BMS are 90% endothelialized with virtually no platelet or fibrin visible.33 Proinflammatory cytokines thought responsible for SAT, such as interleukins-1 beta and -6, are released in response to mechanical vessel injury. Surprisingly, these are found at equivalent levels in BMS and DES patients at all time intervals.34
Hypersensitivity is increasingly recognized as a crucial component of stent thrombosis, especially LAST. Allergic reactions can occur with both the anti-inflammatory agent sirolimus as well the antineoplastic compound paclitaxel. The bonding polymer and even stent material itself may be allergenic. The Kounis syndrome involves an almost identical pathophysiology, whereby acute coronary syndrome results from hypersensitivity reactions to anti-inflammatory, antineoplastic, thrombolytic or even steroid-containing compounds. The mechanism is postulated to involve vasoactive compounds such as arachidonic acid metabolites, chymase, tryptase or histamine.35
The RADAR project, which tracks adverse drug reactions, has identified 262 suspected cases of hypersensitivity in over 2 million DES-treated patients. Of these, 4 autopsy confirmations revealed eosinophilic and thrombotic infiltration accompanied by a lack of intimal healing in the DES segment. None have been observed with BMS, however; this finding certainly argues against the metallic component as a potential allergen.36 Virmani and colleagues previously reported autopsy findings of a 58-year-old male from the E-SIRIUS trial who succumbed to fatal LAST 18 months post-SES placement. Aneurysmal dilatation and local hypersensitivity reaction were evident in the stented segment; the polymer matrix was postulated to be the culprit compound, as sirolimus is nondetectable beyond 60 days. Of note, antemortem intravascular ultrasound at 8 months had previously revealed progressive vessel enlargement.37 Panja and associates presented a case of giant SES-induced aneurysm which necessitated bypass surgery.38 Other less dramatic, allergic symptoms include: itching, hives, fevers and rash.39
CLOP or ASA resistance is likely underdiagnosed as a cause of DES and BMS thrombosis. Matetzky and copresenters followed 60 AMI patients who underwent primary PCI with stent placement. On day 6, the patients were assessed for CLOP effect on adenosine diphosphate-induced platelet aggregation studies and divided into quartiles accordingly. Nonresponders were allocated to the first quartile and subsequently experienced 8 events, including ACS and MI. One event was reported in the second quartile, and none were observed for the high responders in quartiles 3 and 4.40 In a pathological series, Farb et al identified anatomic and histological predictors of stent thrombosis. In addition to impaired intimal healing, these included: traversing of a side-branch, disruption of adjacent vulnerable plaque, concomitantbrachytherapy and significant interstrut plaque prolapse.41
Comparison of PES versus SES. In a meta-analysis, Roir and others identified overall MACE rates of 10.1% versus 19.9%, and restenosis rates of 10.5% versus 31.7% for DES versus BMS, respectively. Between the 2 DES, respective MACE odds ratios for SES and PES were 0.28 and 0.62. Additionally, there was a trend towards higher incidence of Q-wave MI in PES patients.42 In the ISAR-DIABETES trial involving 250 diabetic patients with equal randomization to SES or PES implantation, a significant in-segment angiographic restenosis advantage of 6.9% versus 16.5% (p < 0.03) was reported for SES at 9-month follow up. A nonsignificant reduction in TLR of 6.4% versus 12% was also observed, with no difference seen in death and MI.43
Moreover, SIRTAX found similar 9-month TLR reduction of 4.8% versus 8.3% (p = 0.03), resulting in overall MACE benefits of 6.2% versus 10.8% (p = 0.009) for SES versus PES, respectively.44 The REALITY trial demonstrated a decreased lumen loss of SES versus PES patients (0.09 mm versus 0.31 mm, respectively; p = 0.001).45 In their metaanalysis of 6 randomized trials involving 3,669 DES patients, Kastrati and co-authors observed significantly lower rates of TLR of 5.1% versus 7.8% as well as angiographic restenosis of 9.3% versus 13.1% (p = 0.001 for both) favoring SES. No differences in death or MI were reported.46
Conversely, other trials have suggested apparent superiority of PES. One-year results in the diabetic subgroup from the TC-WYRE registry demonstrated a significantly lower TVR rate of 2.8% in PES versus 8.5% in SES patients (p = 0.004).47 At the joint European Society of Cardiology/World Heart Federation meeting in Barcelona, Spain, 2006, Nordmann presented his SES versus BMS meta-analysis demonstrating no difference in cardiac death, but a 270% increase in risk of noncardiac death (predominantly oncologic).48 At the same conference, Silber demonstrated a statistically significant increase in death/MI of 6.3% for SES versus 3.9% for BMS. Similar rates of death and MI, however, were observed between PES and BMS.49
Adjunct Pharmacologic Therapy. The previously presented data underscore the critical role of DAT with CLOP and ASA in the prevention of stent thrombosis. CLOP has demonstrated superior safety profile over the previously used thienopyridine, ticlopidine, which is associated with thrombotic thrombocytopenic purpura.50–52 Current U.S. recommendations for minimal duration of DAT are 1 month for BMS and 3 and 6 months for SES and PES, respectively. The European Society of Cardiology, however, recommends 6–12 months of dual therapy for all DES.49 Brachytherapy patients should receive a minimum of 1 year of DAT.12 Based on the CREDO results, ACS patients receiving DES therapy may benefit from prolonged DAT of 9–12 months. While not a DES trial, the study demonstrated an overall 26.9% relative reduction of combined death/MI/stroke risk in post-ACS patients over a 12-month treatment period. The benefit was at least partially attributable to stabilization of nonculprit plaques as well as carotid disease.53,54 Similarly, Stone and colleagues recommended DAT for 12 months in all DES patients.55
Increases of up to 2% in major bleeding have been reported in the first year of DAT.32 The duration of DAT in patients requiring chronic warfarin anticoagulation should be individualized; the importance of anticoagulation versus bleeding risk must be weighed. The hierarchy of increasing thromboembolic risk, and hence the need for continued warfarin therapy while on DAT, can be summarized as follows: dilated cardiomyopathy, nonvalvular atrial fibrillation, recent deep venous thrombosis, mechanical aortic valve replacement and mechanical mitral valve replacement.12 Moreover, patient compliance plays a major role in duration of therapy; CLOP, even in its generic form, may be cost-prohibitive for financially challenged patients.
Conclusion
The specter of DES LAST has clearly impacted clinical decision-making for the interventional cardiologist. The projected DES use for 2007 is 81%, a significant decline from 86% for 2006.25 To maintain perspective on this issue, however, we should be reminded that the initial thrombosis rate of intracoronary Wallstent implantation was 24%, as reported by Serruys and coinvestigators in 1991.56 The estimated excess risk of DES LAST beyond the first year appears to be 0.2–0.6% per year.24 This small, but serious, hazard is counterbalanced by the 10–15% absolute TLR reduction seen with DES. This advantage, along with the resultant lower peri-PCI MI rate, confers neutral or slightly favorable MACE rates for DES in most trials and series.
While stent thrombosis is almost always associated with STEMI or death, recent data have suggested that ISR is not necessarily the benign process we previously believed. In their review of the PRESTO database, Assali and associates found that ISR frequently presented as ACS. The baseline characteristics of these higher-risk patients included a greater prevalence of diabetes, hypertension, history of tobacco abuse, previous bypass and heart failure. More importantly, the ISR-associated ACS patients experienced significantly higher rates of TVR and MACE.57 Furthermore, Chen and coauthors reported that 9.5% of patients with BMS ISR presented as AMI.58
Although the subtotal occlusion in our patient clearly appeared thrombotic angiographically, we cannot rule out the possibility that it represented a ruptured restenotic plaque. However, this scenario is true for the vast majority of cases of reported LAST and even SAT. Even when intravascular ultrasound is employed in these situations, it is usually performed after initial measures to aspirate or stabilize the thrombus. Nonetheless, our patient’s angiographic and clinical findings fit the criteria for diagnosis of definite stent thrombosis described previously.17
Innovations in all 3 components of the DES platform are being actively investigated as possible and logical solutions to LAST. The ideal agent(s) would promote and allow onlysufficient endothelialization to prevent thrombosis, yet avoid restenosis. Conor Medsystems (Menlo Park, California) has introduced a biodegradable polymer-bound paclitaxel delivery system. This is imbedded into wells laser-etched into individual stent struts. Another platform from Orbus Medical (Hong Kong, China) embodies CD-34 antibodies which bind circulating endothelial progenitor cells to promote healing.59 In this case, however, if excessive neoendothelialization occurs, the DES restenosis benefit can potentially be compromised. Multiple new platforms involving everolimus/pimecrolimus (Abbott Vascular, Abbott Park, Illinois),60 tacrolimus (Sorin Biomedica, Via Crescentino, Italy), biolimus-A9 (BioSensors International, Newport Beach, California),61 and ABT-578 (Medtronic)62 are presently undergoing bench or clinical research.
Thus, further trials and investigation are needed to define the relative and possibly complementary roles of DES and BMS in the percutaneous treatment of patients with CAD. While results of different analyses vary, the rare, but devastating, complication of LAST appears slightly increased with DES. However, the ISR, TLR and TVR rates are clearly improved. Overall death and MI rates are similar, and there appears to be no definitive advantage between the two domestically available DES. The one exception may be a slightly higher rate of noncardiac, mainly oncologic, death seen with SES. This finding may well represent a statistical anomaly, however, as subsequent investigation revealed that cancer diagnoses in these patients actually predated SES implantation.
Subgroup analyses identifying risk factors, both epidemiologic and angiographic, for DES LAST demonstrate significant overlap with those for BMS restenosis. Unfortunately, as is true in many aspects of medicine, those patients most likely to benefit from a specific therapy also tend to suffer complications from said therapy. Anticoagulation for atrial fibrillation in the elderly, who experience both heightened embolic protection as well as bleeding risk, is a well-recognized example of this paradox.
In December, 2006, the Food and Drug Administration issued an expert concensus panel statement strongly recommending a minimum of 1 year of DAT post-DES implantation, for both brands. They further opined that while DES are associated with a slightly higher risk of LAST, this is offset by the significant reduction in restenosis and TLR, resulting in no net increase in overall MACE. Moreover, careful evaluation for contraindications to prolonged DAT as well as meticulous stent deployment technique were also stressed. In specific, adequate stent strut apposition and appropriate stent sizing allow for maximization of laminar coronary flow and minimization of thrombotic nidus.63 Additionally, judicious use of adjuctive devices such as intravascular ultrasound and debulking therapies can be valuable aides in optimization of DES results.
The issue of pre-PCI informed consent is receiving increasing scrutiny. It is crucial that patients understand the differences in rates and consequences of both ISR and stent thrombosis for DES and BMS. Clearly, patients with a higher likelihood of DAT discontinuation due to upcoming noncardiac surgery, financial limitations or other compliance issues should be considered for BMS implantation. Thus, despite the initial fervor, the exact role of the currently available DES remains unresolved. Further data on patient selection as well as clinical trials involving novel platforms will hopefully dispel or at least diminish the cloud of LAST from the DES silver lining.
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