FOCUS ISSUE: DRUG-ELUTING STENTS: STATE-OF-THE-ART PAPER
Late and Very Late Thrombosis of Drug-Eluting StentsEvolving Concepts and Perspectives
Ronen Jaffe, MD1 and
Bradley H. Strauss, MD, PhD, FACC*
Schulich Heart Program, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
Manuscript received February 12, 2007;
revised manuscript received March 30, 2007,
accepted April 2, 2007.
* Reprint requests and correspondence: Dr. Bradley H. Strauss, Reichmann Research Chair in Cardiovascular Sciences, Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Suite A-253, Toronto, Ontario, Canada M4N 3M5. (Email: bradley.strauss{at}sunnybrook.ca).
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Abstract
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Coronary stents are the mainstay of percutaneous coronary revascularization procedures and have significantly decreased the rates of acute vessel closure and restenosis. Stent thrombosis (ST) after percutaneous coronary intervention is an uncommon and potentially catastrophic event that might manifest as myocardial infarction and sudden death. Optimization of stent implantation and dual antiplatelet therapy have markedly reduced the occurrence of this complication. Bare-metal stent (BMS) thrombosis occurs in <1% of the cases, usually within the first month after implantation. The advent of drug-eluting stents (DES) has raised concerns regarding later occurrence of ST, beyond the traditional 1-month timeframe, especially in complex lesion subsets that were excluded from randomized trials that compared BMS to DES. There is widespread controversy regarding the actual incremental risk associated with DES. Recent studies suggest a 0.5% increased long-term thrombosis risk with DES; however, the clinical significance of these events remains under debate. The degree of protection achieved by dual antiplatelet therapy and optimal duration of treatment are under investigation. Novel stent designs might potentially decrease the incidence of this event. In this review, we will describe the current knowledge of the pathophysiology of late DES thrombosis, although many aspects remain incompletely understood.
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Abbreviations and Acronyms
| | BMS = bare-metal stent(s) | | DES = drug-eluting stent(s) | | MI = myocardial infarction | | PCI = percutaneous coronary intervention | | PES = paclitaxel-eluting stent(s) | | SES = sirolimus-eluting stent(s) | | ST = stent thrombosis |
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Coronary stents are the mainstay of percutaneous coronary revascularization procedures and have significantly decreased the rates of acute vessel closure and restenosis. Stent thrombosis (ST) after percutaneous coronary intervention (PCI) is an uncommon and potentially catastrophic event that might manifest as myocardial infarction (MI) and sudden death. Optimization of stent implantation and dual antiplatelet therapy have markedly reduced the occurrence of this complication. Bare-metal stent (BMS) thrombosis occurs in <1% of the cases, usually within the first month after implantation. The advent of drug-eluting stents (DES) has raised concerns regarding later occurrence of ST, beyond the traditional 1-month timeframe, especially in complex lesion subsets that were excluded from randomized trials that compared BMS to DES. There is widespread controversy regarding the actual incremental risk associated with DES. Recent studies suggest a 0.5% increased long-term thrombosis risk with DES (1,2); however, the clinical significance of these events remains under debate (3). The degree of protection achieved by dual antiplatelet therapy and optimal duration of treatment are under investigation. Novel stent designs might potentially decrease the incidence of this event. In this review, we will describe the current knowledge of the pathophysiology of late DES thrombosis, although many aspects remain incompletely understood.
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Definition and Clinical Manifestations
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Historically, diagnosis of ST has been based on angiographic and clinical criteria. Angiographic definition—coronary Thrombolysis In Myocardial Infarction flow grade 0 to 1 in the stented vessel in the presence of thrombus—likely underestimates the true incidence of ST, because patients who are asymptomatic or who sustain cardiac arrest might not undergo coronary angiography. Clinical definitions—target vessel MI or urgent target lesion revascularization and unexplained sudden death when the stent was not known to be patent—might overestimate the actual occurrence of ST. The recently proposed "Academic Research Consortium" definitions (4) were designed to standardize ST diagnosis and provide consistency in the reporting of future trials (Table 1).
Stent thrombosis is also classified according to the time elapsed since implantation. Acute ST occurs during the stenting procedure or within the subsequent 24 h, subacute ST between 1 and 30 days after implant, late ST between 1 month and 1 year, and very late ST occurs more than 1 year after the procedure. In the BMS era, ST usually presented acutely or subacutely, before neointimal formation. In randomized trials that compared BMS with DES, rates of acute and subacute ST among patients receiving dual antiplatelet therapy were similar for both stent types (<1%) (3,5). Recent attention has focused on delayed occurrence of DES thrombosis beyond 30 days, which might be categorized according to the intensity of antiplatelet therapy administered at the time of the event, while the patient is still receiving dual antiplatelet therapy or after cessation of 1 or both antiplatelet drugs.
Acute and subacute thrombosis of both BMS and DES have adverse clinical consequences (6,7). In a registry of patients who underwent DES implantation with 9-month follow-up (8), 24% of ST cases presented as death, 60% as nonfatal MI, and 7% as unstable angina. The case fatality rate for ST in this registry was 45%. In a series of patients who presented with acute coronary syndrome and had angiographically or autopsy proven ST after DES implantation, 6-month mortality was 31% (9). However, in recent meta-analyses of DES trials, modest increases in rates of late and very late ST compared with BMS did not translate into a worse clinical outcome (3,10). These differences might reflect selection bias stemming from different diagnostic criteria for ST or possibly from implantation of DES in small vessels subtending limited myocardial territory. Percutaneous coronary intervention for emergent ST is often suboptimal, and ST recurs in 12% of these patients (11).
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Incidence of Late and Very Late Stent Thrombosis
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Late BMS thrombosis is an uncommon event (12). In an initial report of very late DES thrombosis, the events were associated with cessation of antiplatelet therapy (13). Subsequently, studies of patients who underwent DES implantation for off-label indications in complex anatomical subsets, with prolonged follow-up periods, have documented higher ST rates than previously reported (14–16).
Recently reported registries, randomized trials, and meta-analyses have investigated the relative risk for late ST with either DES or BMS over varying follow-up periods and reported conflicting results. Some studies identified thrombosis-related clinical events, whereas others focused on angiographically proven ST. In a registry of 6,906 patients who received BMS or DES, there was no difference in clinical outcomes or ST rate over 1 year of follow-up (17). In another registry of 8,146 patients who received DES between 2002 and 2005, a persistent excess ST risk of 0.6%/year was found compared with historical control subjects who received BMS (2). A meta-analysis of 8 trials in which 4,545 patients were randomized to sirolimus-eluting stent (SES) or paclitaxel-eluting stent (PES) versus BMS revealed no difference in rates of ST over 4 years of follow-up (5). Conversely, another meta-analysis of 14 randomized clinical trials, in which a total of 6,675 patients were randomized to either SES or PES versus BMS, confirmed a 0.5% excess risk of very late ST with DES (1).
Several recent studies have highlighted the potential adverse clinical significance of late thrombotic events. In a Swedish registry of DES and BMS patients, the adjusted relative risk for death associated with DES implantation from 6 months to 3 years after PCI was 1.32 (95% confidence interval 1.11 to 1.57) (18). The authors hypothesized that ST caused the increased mortality. In the BASKET-LATE (Basel Stent Kosten Effektivitäts Trial–Late Thrombotic Events) study, 746 patients who had been randomized to DES or BMS and were free of major cardiac adverse events after 6 months (when clopidogrel was stopped) were followed for an additional 12 months (19). During this follow-up period, rates of cardiac death and nonfatal MI were higher in the DES than the BMS group (4.9% vs. 1.3%, respectively). However, this increase in major cardiac events in the DES group was much higher than the actual difference in the rates of definite or possible ST (2.6% DES group vs. 1.3% BMS group). Timing of thrombotic events was evenly distributed across the 12 months after clopidogrel discontinuation. Camenzind et al. (20) reported a meta-analysis of randomized trials comparing DES with BMS that included 5,108 patients, with follow-up over 9 months to 3 years; SES were associated with a 60% relative increase in death or MI (p = 0.03), whereas PES were associated with a nonsignificant increase of 15%. Another meta-analysis of 9 trials in which 5,261 patients were randomized to SES, PES, or BMS reached quite different conclusions (3). Over 4 years of follow-up, increased rates of very late ST were found both for both SES (0.6% vs. 0%, p = 0.025) and PES (0.7% vs. 0.2%, p = 0.028) compared with BMS. The increased ST rate was confined to the time interval between 1 month and 1 year after PCI and was not associated with adverse clinical outcomes. Similarly, a meta-analysis of 14 trials in which 4,958 patients were randomized to SES or BMS, with follow-up ranging up to 59 months, showed an increased rate of very late ST with SES (0.6% vs. 0.05%, p = 0.02) without increase in adverse events (10).
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Mechanisms Contributing to ST: Are There Differences Between BMS and DES?
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After both BMS and DES implantation, procedural and technical factors play a major role in determining the occurrence of acute and subacute ST, whereas delayed thrombotic events seem to be influenced largely by the degree of endothelial coverage and intensity of antiplatelet therapy (21). Incomplete endothelization and presence of thrombus were frequent angioscopic findings in a study performed 3 to 6 months after DES implantation but were not found in BMS (22). Presence of lipid-rich plaques abundant in tissue factor within the vessel wall might predispose to late ST (12).
Data regarding risk factors for DES thrombosis are derived from selected case reports, non-randomized registries (Table 2), and randomized clinical trials (23–27) (Table 3). Evidence for increased long-term ST risk with DES is primarily from patient registries and not from randomized clinical trials, suggesting that part of the incremental risk is associated with treatment of complex coronary lesions in real-world patients (Table 4).
Patient variables.
Angioplasty in the setting of acute coronary syndromes could theoretically predispose to ST owing to the large thrombotic burden already present, suboptimal stent expansion to avoid the risk of no-reflow, or DES implantation on a thrombus that eventually disappears leading to malapposition. An SES registry reported increased risk of ST in patients who presented with acute coronary syndromes (28). However, 3 randomized trials comparing BMS and DES for primary angioplasty in acute MI found no difference in ST rate between the stent types (29–31). Some registry reports have suggested increased ST rates in diabetic patients and patients with renal failure (8,9,28).
Procedural variables.
Small vessel size, long stents, suboptimal stent expansion, residual dissections and thrombus, and slow coronary flow are associated with DES thrombosis (9,28,32,33), similar to BMS. A 1.03-fold greater ST risk for every 1-mm increase in stent length has been calculated (34). Reports of higher ST rates in bypass grafts treated with DES compared with BMS (19) were not confirmed in a randomized trial (35). Drug-eluting stents have permitted an aggressive approach to angioplasty of bifurcation lesions, which is associated with higher rates of ST (36). In a registry of patients undergoing stenting with BMS or DES, bifurcation stenting in the setting of acute MI was an independent risk factor for ST (odds ratio 13) (7). In another DES registry, bifurcation stenting was associated with a 3.6% to 3.9% ST rate, depending on whether 1 or 2 stents were implanted (8). A registry of "crush" bifurcation stenting with DES reported that 4.3% of the patients had an event consistent with possible ST over 9 months of follow-up (16). In a randomized trial that compared implantation of 1 versus 2 SES in coronary bifurcations, 3.5% of the patients had ST and another patient died suddenly, all of whom had undergone implantation of 2 stents (14).
Antiplatelet therapy.
Cessation of antiplatelet therapy is a major risk factor for late BMS thrombosis. In a series of angiographically documented cases of late DES thrombosis, no cases occurred in patients who were receiving dual antiplatelet therapy (37). In another study of DES thrombosis within 9 months of stenting (14 subacute ST, 15 late ST), the most important independent predictor of ST was premature antiplatelet therapy discontinuation (hazard ratio 90) (8). In a registry of bifurcation "crush" stenting with DES, premature discontinuation of dual antiplatelet therapy was associated with occurrence of subacute and late ST (odds ratio 17) (15). In a registry of 4,666 patients who underwent PCI, prolonged use of clopidogrel was associated with decreased risk of death or MI after implantation of DES but not BMS (38).
Premature discontinuation of antiplatelet agents might be relatively common: among 500 patients who received DES after MI, 13.6% stopped thienopyridine therapy within 30 days (39). Patients who prematurely stopped thienopyridine therapy had more comorbidities, lower socioeconomic status, and were less informed about the importance of long-term therapy than patients continuing therapy. These patients were also more likely to die during the next 11 months (7.5% vs. 0.7%) and be rehospitalized (23% vs. 14%).
Inadequate response to antiplatelet therapy might be caused by patient non-compliance, underdosing, drug interactions, comorbidities that affect the drug-response, genetic polymorphisms at the receptor level, or upregulation of other platelet activation pathways (40,41). Several studies have suggested a role for clopidogrel resistance in the pathogenesis of subacute ST in BMS (42,43). In a cohort of patients undergoing non-emergent PCI (75% DES), high preprocedural platelet aggregation was associated with an increased risk for postprocedural ischemic events over 1 year of follow-up (44). Cross-resistance to aspirin and clopidogrel might be common (45). In a study of elective PCI patients, 12.7% were aspirin-resistant and 24% were clopidogrel-resistant (46). Aspirin-resistant patients were more likely to be women and have diabetes, and 47.4% of them were clopidogrel-resistant. An additional concern regarding antagonism of cytochrome P450 3A4 metabolism of clopidogrel by statins (47) has not been substantiated (48).
Response of the vessel to DES.
The intact endothelium separates the thrombogenic vessel wall and stent struts from the blood stream and secretes a variety of antithrombotic and vasodilator substances. Drug-eluting stents expose the vessel wall to antiproliferative drugs and drug-eluting platforms, with variable effects on endothelial regeneration and function. Rabbit iliac arterial segments in which overlapping SES and PES were implanted exhibited delayed healing compared with proximal and distal non-overlapping sites and compared with overlapping BMS (49). However, in human studies, overlapping SES were not associated with increased ST risk (50). Studies performed 6 months after PCI have examined endothelium-dependant arterial vasomotion in response to acetylcholine (51) and exercise (52). Arterial segments adjacent to SES but not BMS demonstrated reduced endothelial function, although the clinical significance of this finding is unknown.
Malapposition of the stent to the vessel wall might result from suboptimal stent expansion ("procedural") or develop months after the PCI ("acquired"). Although procedural malapposition is a recognized risk factor for acute and subacute ST (53), the clinical significance of acquired malapposition is controversial. Acquired BMS malapposition, which is related to positive arterial remodeling, is rare and benign (54). Acquired DES malapposition might result from drug-induced inhibition of neointimal formation, delayed reparative events that usually enable the vessel wall to incorporate the stent, and drug-induced positive remodeling of the vessel wall (55). Some randomized studies (56,57) but not others (58) reported an increased rate of acquired malapposition with DES compared with BMS, which was not associated with adverse events.
Late hypersensitivity reactions to DES seem to be another mechanism contributing to ST. Virmani et al. (59) reported autopsy findings after late ST (18 months after receiving 2 SES). Angiographic and intravascular ultrasound (IVUS) results at 8 months had demonstrated vessel enlargement with absence of neointimal formation. Autopsy showed aneurysmal dilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of T lymphocytes and eosinophils. Because sirolimus is minimally present in the vessel wall after 60 days, these findings likely reflect an effect of the non-erodable polymer (60). A subsequent pathological study revealed that late ST after DES was correlated with delayed healing of the vessel wall, persistent fibrin deposition, and delayed endothelization (55). Nebeker et al. (61) reported 17 cases of hypersensitivity reaction attributable to DES implantation (14 SES and 3 PES) that occurred up to 210 days after the index procedure. Autopsies in 4 patients who died after ST confirmed intrastent eosinophilic inflammation, thrombosis, and lack of intimal healing. In 1 of these patients, concomitantly placed BMS were not associated with these hypersensitivity findings. Clinical manifestations included urticarial and non-urticarial rash, dyspnea, myalgia/arthralgia, itching, and blisters. All urticarial eruptions began within 10 days of implantation. Laboratory findings included eosinophilia and elevated immunoglobulin E titers 5-fold above normal levels in 3 patients. Clinical or laboratory findings did not abate with discontinuation of antiplatelet medications.
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Prevention
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Optimization of stent deployment (62) and dual antiplatelet therapy with aspirin and a thienopyridine (63–65) have achieved the currently accepted 30-day ST rate of <1%. Reports of late DES thrombosis, often in association with cessation of antiplatelet therapy (9,13,19,37,38,59), suggest that long-term combined antiplatelet therapy might be appropriate. A recent science advisory has recommended lengthening the duration of dual antiplatelet therapy to 1 year after PCI and that elective surgery should be postponed for 1 year (66). The efficacy of increasing the maintenance dose of clopidogrel to 150 mg daily in patients with suspected clopidogrel resistance is unknown (67). Triple antiplatelet therapy with aspirin, a thienopyridine, and cilostazol was associated with reduced rate of subacute BMS thrombosis compared with dual antiplatelet therapy (68), although its role in the DES era is unknown.
Innovative stent designs that are polymer-free, bioabsorbable, or coated with monoclonal antibodies that bind circulating endothelial progenitor cells have been proposed to decrease ST rates (69). Their role in preventing late DES thrombosis is unclear.
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Late ST: Is It the Artery or the Stent?
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Drug-eluting stents, by significantly reducing restenosis rates, have expanded the indications for PCI into new complex anatomic subsets (long lesions, small arteries, bifurcations) in high-risk patients (renal failure, diabetes), who are more susceptible to both restenosis and ST. A recent meeting of a U.S. Food and Drug Administration advisory panel concluded that DES seem to carry a greater risk of late ST than BMS, which might be associated with off-label use of these stents, although the magnitude of the risk is unclear (70). This increased risk might be explained both by the complexity of the atherosclerotic substrate currently being treated as well as by intrinsic properties of the DES themselves. By delaying vessel healing in an artery predisposed to thrombosis and inducing a prolonged inflammatory response, DES effectively lengthen and amplify the window of opportunity for ST to occur.
Because of current evidence of the modest increased risk, it is imperative for clinicians to stratify the individual patient’s risk for ST, restenosis, and bleeding when selecting appropriate revascularization strategies. Specifically, if the patient is unlikely to comply with long-term clopidogrel therapy, is likely to require surgery in the near-term, or is at risk of bleeding, alternative treatments are preferred, such as implanting BMS, performing bypass surgery, or managing the patients medically. According to current guidelines, dual antiplatelet therapy should be continued for 1 year (66). Some authorities recommend an even longer duration of dual therapy pending further data (71). Ultimately, innovative pharmacological and device developments to prevent late ST are required to restore full confidence in DES for widespread use.
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Footnotes
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1 Dr. Jaffe is a Research Fellow of the Heart and Stroke Foundation of Canada. 
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Abstract
Definition and Clinical...