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March 2009
The Scope of Stent Thrombosis
An analysis of the importance and occurrence of stent thrombosis.
At the introduction of coronary stents, the significant risk of acute stent thrombosis was prohibitive for a widespread use. Dual-antiplatelet therapy and stent implantation using high pressures minimized the risk of acute thrombotic events and made stenting an essential part of percutaneous coronary intervention (PCI).
A further expansion of coronary stenting occurred after the advent of drug-eluting stents (DES). Combining scaffolding and antiproliferative properties, DES effectively prevented acute vessel closure and virtually eliminated the risk of restenosis. Unfortunately, the introduction of DES was based on angiographic follow-up studies that were underpowered to detect infrequently occurring, but potentially severe, clinical problems such as stent thrombosis. The interventional community had an unpleasant wake up when secondary analyses1 and a large registry study2 indicated a mortality risk due to late-occurring thrombotic events after DES implantation. Evidently, there was an urgent need for commonly accepted definitions of stent thrombosis, and an expert group agreed on the Academic Research Consortium (ARC) definitions of stent thrombosis.3
Stent thromboses in existing randomized clinical bare-metal stent (BMS) versus DES trials were reassessed, and the results were compared in meta-analyses.4,5 Furthermore, a number of registries6,7 evaluated the DES versus BMS problem using the ARC definitions of stent thrombosis.
According to ARC definitions, stent thrombosis was characterized as definite, probable, and possible, and the time frame for the event was defined as acute, subacute, late, and very late (Table 1 and Figure 1).
DEFINITE STENT THROMBOSIS
Definite stent thrombosis requires angiographic or pathological evidence of thrombus in a patient with an acute coronary syndrome. Unfortunately, the pathological finding is less relevant in clinical practice because a minority of fatal cases will have an autopsy. Therefore, definite stent thrombosis is almost always diagnosed by angiography. These patients usually present with a coronary artery occlusion, and it may be difficult to distinguish between a thrombotic occlusion related to the stented segment and another part of the vessel. Also, the distinction between a severe restenosis with complicating acute thrombotic occlusion and a primary stent thrombosis (ie, a stent thrombosis without restenosis) may be problematic. In the two situations described, the underlying reason may be quite different. Thus, the primary stent thrombosis is likely to be related to the antiproliferative effects or to the polymer coating of the DES, resulting in secondary malapposition or in a peri-stent inflammatory process (Figure 2),8 whereas the restenosis is caused by myoendothelial hyperplasia.9
Definite stent thrombosis may occur acute (<24 hours), subacute (1 day to 1 month), late (1 month to 1 year), or very late (>1 year). Furthermore, acute and subacute thrombosis may be described as early stent thrombosis.3
EARLY STENT THROMBOSIS
Early stent thrombosis is much more common than late-occurring stent thrombosis, encompasses 60% of all stent thromboses, and usually occurs during admission for the index PCI. Early stent thrombosis is not a new entity; it is not related to the type of stent used but rather to inadequate stent implantation and to lesion complexity, especially calcification. Other predictors of stent thrombosis are acute coronary syndrome, diabetes, stent length, and the number of implanted stents.11 Also, problems with dual-antiplatelet therapy may be involved, such as lack of patient compliance or resistance to aspirin or clopidogrel. Somehow, early stent thromboses are considered a more benign entity than late stent thromboses, possibly because we have been accustomed to the problem, which usually is an in-hospital event. However, early stent thrombosis may be associated with severe clinical problems, such as ST-elevation myocardial infarction (STEMI) or cardiac death. Therefore, it is relevant to focus on these early thrombotic events because the problem may be reduced by proper implantation techniques and adequate antiplatelet therapy.
LATE STENT THROMBOSIS
In the Western Denmark Heart Registry, we found similar and low rates of late stent thrombosis in DES- and BMS-treated patients.6 It is likely that dual-antiplatelet medication does inhibit stent thrombosis during this period, but the scientific evidence is limited, and the optimal length of dual-antiplatelet therapy is basically unknown.12 However, both the Swedish Coronary Angiography and Angioplasty Registry2 and data from Western Denmark6 show an increase in the rates of MI and stent thrombosis at the end of the recommended clopidogrel treatment period (after 6 months in Sweden and after 12 months in Denmark) (Figure 3).
During this period, patients with BMS, and probably also patients implanted with "high late loss" DES, will have an increased risk of restenosis, which may have the clinical characteristics of stent thrombosis.14
VERY LATE STENT THROMBOSIS
Meta-analyses of randomized clinical DES versus BMS trials and large registries indicate that very late stent thrombosis is a rare event and is associated with the use of DES. Very late stent thrombosis has been described after BMS implantation, but the relation to the implanted BMS is doubtful. By now, data on this entity are entirely based on the first-generation DES devices (the sirolimus-eluting Cypher stent and the paclitaxel-eluting Taxus stent). It is a matter of debate if there are differences between the Cypher and the Taxus stents concerning risk of stent thrombosis.
The etiology of very late stent thrombosis is unknown but seems to be associated with an inflammatory reaction to the DES polymer or to the antiproliferative drug. These reactions have been described in both the Cypher and Taxus stents and may be involved in positive vessel remodeling and late stent malapposition. Stent fractures have been described in cases of late stent thrombosis and may be related to late malapposition. With regard to the Taxus stent, an increased persistent hyperplasia has been described in an intravascular ultrasound study.15 The clinical significance of this finding is unknown.
Being numerically small, the problem of very late stent thrombosis will unlikely become prohibitive for the use of DES, but nevertheless it is a problem of clinical significance. It was a major concern when the Bern-Rotterdam registry indicated a linearly growing rate of stent thrombosis (0.6% per year after the first 30 days).16 However, such a linear growth is an unusual phenomenon in biology and will probably not continue, as indicated in a later publication on the research registry with Rotterdam patients treated with Cypher stents.17 In this study, the rate of very late stent thrombosis was found to be 0.1% from year 3 to year 4. Also, it is likely that future generations of DES may perform better than the first-generation DES.
PROBABLE AND POSSIBLE STENT THROMBOSIS
Probable stent thrombosis encompasses patients with unexplained death within 30 days of stent implantation or MI of the territory of the implanted stent, whereas possible thrombosis is defined as any unexplained death beyond 30 days.
Clearly, possible and probable stent thromboses are heterogeneous groups of events. First, there will be little difference between patients with unexplained death before and after 30 days, and unexplained death may not be a cardiac fatality. Second, the diagnosis of acute MI within the stented territory will be problematic in many patients, especially those with posterior wall infarctions. Fortunately, the group of probable stent thrombosis patients with symptomatic infarction will be small in regions with a modern, community-based interventional cardiac service.
The previously mentioned problems in diagnosing possible and probable stent thromboses call into question the pooling of possible, probable, and definite stent thrombosis.
CLINICAL SIGNIFICANCE OF STENT THROMBOSIS
The clinical circumstances of the thrombotic event will determine the clinical outcome: death or MI with varying degrees of permanent myocardial damage. Therefore, stent thrombosis should be seen in the context of its clinical implications. One extreme is the stent thrombosis patient with STEMI resulting in sudden cardiac death or severe impairment of left ventricular function. At the other end of the spectrum, there may be patients with a minor biomarker leakage NSTEMI and near-normal ventricular function or even patients with new onset of chest pain and no impairment of their left ventricular function.
ARC CRITERIA AND CLINICAL PRESENTATION OF STENT THROMBOSIS
The introduction of ARC definitions of stent thrombosis has been extremely helpful in the description of this clinically important entity. However, the heterogeneity of the ARC groups of stent thrombosis may introduce a risk of blurring significant clinical problems. Therefore, it is important not to pool all subgroups of stent thrombosis (definite, probable, and possible) and their occurrence over time (early, late, and very late). Furthermore, data on stent thrombosis should be given together with data on all-cause mortality, cardiac death, STEMI, and NSTEMI. Specifically, I advocate dividing the group of definite stent thrombosis according to the clinical appearance. Detailed outcome description can only be performed in large-scale clinical trials, and such trials should precede marketing of new coronary implants.
CLOPIDOGREL RESISTANCE
Both resistance to acetylsalicylic acid (aspirin) and clopidogrel has been described and seems to occur in about 6% of patients treated with both drugs. It is important to distinguish between conditions resulting in thrombotic events mediated by nonplatelet factors (ie, under dosage or patient noncompliance) and patients with reduced effect of aspirin or clopidogrel. Unfortunately, there is no clear definition of resistance to clopidogrel or a specific test to measure platelet response, although there seems to be a relationship between nonresponse and clinical outcome.
At the present time, there are more questions than answers in the area of aspirin and clopidogrel resistance. However, you may surmize from the Working Group on Thrombosis of the European Society of Cardiology that: (1) routine or even occasional monitoring of platelet function while on therapy with antiplatelet drugs and consequent therapeutic decisions leads to any practical clinically relevant advantages; and (2) assessment of compliance to the recommended drugs should be the immediate consequence of suspected clopidogrel resistance.18 It is likely that upcoming antiplatelet medication may reduce the resistance problems in the near future.19
CONCLUSION
Both early and late-occurring stent thromboses are a major concern in PCI. Many cases of early stent thrombosis may be avoided by optimized implantation technique and antiplatelet therapy. Late-occurring stent thromboses are rare but usually severe events and are primarily related to the tissue reaction to the DES polymer and antiproliferative drug. The risk of these late-occurring thrombotic events may be reduced by new generations of DES.
Leif Thuesen, MD, is the Director of Catheterization Laboratory, Department of Cardiology, Aarhus University Hospital, Skejby, Denmark. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Thuesen may be reached at +45 8949 6105; leif.thuesen@ki.au.dk.
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