Late Stent Thrombosis
2007; Lippincott Williams & Wilkins; Volume: 115; Issue: 11 Linguagem: Inglês
10.1161/circulationaha.106.666826
ISSN1524-4539
AutoresPatrick W. Serruys, Joost Daemen,
Tópico(s)Cerebrovascular and Carotid Artery Diseases
ResumoHomeCirculationVol. 115, No. 11Late Stent Thrombosis Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBLate Stent ThrombosisA Nuisance in Both Bare Metal and Drug-Eluting Stents Patrick W. Serruys and Joost Daemen Patrick W. SerruysPatrick W. Serruys From the Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands. and Joost DaemenJoost Daemen From the Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands. Originally published7 Mar 2007https://doi.org/10.1161/CIRCULATIONAHA.106.666826Circulation. 2007;115:1433–1439Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 7, 2007: Previous Version 1 Late stent thrombosis (ST) is for us an old foe that we have tracked repeatedly throughout the history of interventional cardiology. In 1991, we made headlines by publishing in the New England Journal of Medicine a rate of early and late ST of 20% among the first 151 patients having received a wall stent.1 A few years later, when some believed that they had discovered the universal panacea for restenosis (vascular brachytherapy), we were the first to report in the literature 6 cases of late ST in 100 patients having undergone brachytherapy after stent implantation.2 At that time, this seminal observation triggered a wave of observations; the cases of late ST after brachytherapy accrued month after month until the pioneer in the field, Ron Waksman, courageously admitted in an editorial that we were "sitting on a time bomb."3 Five years later (2004), in the beginning of the drug-eluting stent (DES) era, we reported, together with Waksman's group, the first 4 cases of late ST.4 In the following 2 years, the incidence of late ST, scrutinized by alerted clinicians, was publicized in reports that included >25 000 patients treated with DES; the incidence ranged from 0.2% in a postmarketing surveillance trial to 1.8% in a small series of multivessel stenting.5–10 Around this period, we realized that Bern and Rotterdam had somewhat diverging incidences of late ST, 0.4% and 0.9%, and we joined efforts to retrospectively assess the rate of late ST over a period of 4 years. A steady rate of 0.6% per year was detected without abatement over a follow-up period of 3 years.11 What makes the experience of these 2 groups unique is that both tertiary institutions embraced the technology of eluting stents at the time of their commercial introduction and decided to treat all comers with this new promising therapeutic approach. Of 8146 patients, we saw 61 patients coming back to our catheterization laboratory with symptoms and angiographic signs of late ST. Of these 61 patients, 3 died in hospital from late ST, and 44 sustained a myocardial infarction (MI). At the 6-month follow-up, an additional 2 patients had died and 2 sustained a reinfarction. In summary, 5 of 8146 patients died as a result of this dreadful complication of ST. These numbers were largely confirmed by the 3 years of follow-up of the Arterial Revascularization Therapies Study Part II, showing a similar annual increase of definite ST of 1.7%, 0.6%, and 0.4% at 1, 2, and 3 years, respectively, in a population with a majority of 3-vessel treatment and with an average stented length of 73 mm. By reporting these figures, we are not trying to minimize the phenomenon, and we recognize that we are describing only the tip of the iceberg by disregarding fatal MI and unexplained death as clinical surrogates of ST, but we do not believe that 0.6% per year could, by any means, be compared with the 6% late ST seen after vascular brachytherapy. In other words, we are not facing a new "vascular brachytherapy syndrome."Response by Camenzind et al p 1439After this introduction on the history of ST, we will analyze more judiciously the contentions by Camenzind et al that DES increase deaths, as headlined by the European Society and World Congress of Cardiology (ESC) newsletter at the congress in Barcelona 2006.12Are There Physiopathological Reasons to Have Late ST?Camenzind and coauthors referred to the classic triad of Virchow (altered blood constituents, flow pattern, and endothelial lining). This is without a doubt appealing to the readers, but let us analyze critically their arguments and the validity of their analogical comparison when they equate a stenotic lesion covered by a DES to an atherothrombotic phenomenon in the general circulation.Their first argument suggests that implantation of DES with concomitant but transient administration of dual platelet therapy would generate at the time of the discontinuation a thrombogenic milieu. Using common sense, we have to point out that ≈99% of the patients worldwide discontinue their thienopyridine medication without experiencing ST within days. We were the first to link the interruption of aspirin with ST in DES.4 In that respect, the relationship between platelet therapy and thrombosis is not unique to DES. In a study reporting on 1236 patients hospitalized for acute coronary syndrome, those who stopped aspirin presented significantly more often with ST-segment elevation acute coronary syndrome. Twenty percent of these cases involved a bare metal stent (BMS) thrombosis on an average of 15.5 months.13 In fact, interruption of aspirin is a risk factor for every patient with atherosclerosis.14 "Noncompliance or withdrawal of aspirin treatment has ominous prognostic implications in subjects with or at moderate-to-high risk for coronary artery disease. Aspirin discontinuation in such patients should be advocated only when bleeding risk clearly overwhelms that of atherothrombotic events." These are the conclusions of a recently published meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50 279 patients at risk for coronary artery disease.14 Similarly, clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes mellitus and coronary artery disease.15 The concern in trials has not been the discontinuation of the antiplatelet therapy but its premature discontinuation, and this concept of premature discontinuation has to be critically discussed.It is relevant to note that the patients included in the FIM (First in Man) and the RAVEL (Randomized Study with the Sirolimus-Coated Bx Velocity Balloon Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions) trials were prescribed 2 months of ticlopidine or clopidogrel. The rationale for the 2-month prescription is that initially (July 1999, trial discussion at the headquarters of Cordis) the First in Man trial was planned as a 60-day safety trial with concomitant use of 60 days of ticlopidine. Later, the protocol was converted into a 4- and 6-month study with quantitative coronary angiography and intravascular ultrasound.After completion of the European pivotal trial, the American pivotal trial, SIRIUS (Sirolimus-Eluting Stent in De Novo Native Coronary Lesions), was initiated, and for reasons unknown to the authors, the prescription of clopidogrel was prolonged to 3 months, although no thrombotic issue was observed in the RAVEL trial in the first 5 years of follow-up. The decision to prescribe 6 months of clopidogrel in the TAXUS-I trial (and in the subsequent trials) was not discussed in the original report. In other words, the duration of prescription of clopidogrel does not seem to be validated by scientific arguments; consequently, the concept of premature discontinuation is arbitrary as well. So far, there is no evidence-based medicine that prolonged dual-antiplatelet therapy could reduce late ST in DES-treated patients. Of note, one quarter of our patients with late or very late ST were on dual-antiplatelet therapy.11 The only evidence of a preventive effect of dual-antiplatelet therapy on late ST stems from the experience with brachytherapy in which prolongation of dual-antiplatelet therapy was effective in preventing late ST, although a rebound phenomenon in ST was observed after cessation of clopidogrel. At 15 months, the incidence of thrombotic occlusion was 15.9% in the Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST-PLUS) versus 13.5% in WRIST.12,16,17The postmortem findings in patients with a DES constitute dramatic and compelling evidence that stented arteries show, in a limited number of patients, impaired reendothelialization with uncovered stent struts as a consequence. However, the eminent pathologist Dr Renu Virmani is the first to admit that in postmortem studies there is no common denominator and that the number of patients treated with DES in whom "uncovered stent struts" do not lead to ST is unknown but undoubtedly very large. Still today, the relative impact of the stent platform with a variety of strut thicknesses, polymers, and drugs on ST remains unclear. In her most recent presentation, Dr Virmani demonstrated a complete endothelialization of the struts with cells exhibiting cd31 (antigen surface marker of good endothelial functionality) at 14 days in rabbit iliac arteries stented with a DES eluting everolimus, a sirolimus analog with a sole and minimal alteration of the molecular structure of sirolimus in the binding domain, without any chemical modification of the mTOR binding domain. With such a subtle difference between sirolimus and everolimus, it becomes unclear whether we have to blame the drug, the polymer, or even the platform for the difference in reendothelialization.18We are aware that DES may induce complex interactions between shear stress and inhibition of neointimal growth, resulting in a peculiar rheological profile that we described early on in Circulation,19 and we have attempted to differentiate delayed neointimal growth (delayed restenosis) from adaptive shear stress–induced growth, which is a long-term physiological process.20,21But before discussing in more detail the impact of vessel wall remodeling on late ST, we should clarify that late acquired malapposition and stent underexpansion are 2 different entities with different possible consequences. In the early days of BMS, Colombo et al22 convinced the world that incorrect deployment and incomplete apposition of stents were major contributors to subacute ST. This older generation of interventional cardiologists was painstakingly educated to postdilate the stent to avoid this incomplete deployment. Today, the lesson of the past seems to have been forgotten by a new generation of interventional cardiologists who rely too much on the antirestenotic properties of DES and do not care enough for correct mechanical deployment of the "metallic endoprosthesis." In an extensive and retrospective analysis of BMS patients treated in the previous decade, stent underexpansion (minimum stent area 24 h–30 d after stent implantation Late ST*: >30 d–1 y after stent implantation Very late ST*: >1 y after stent implantationThree categories of evidence in defining stent thrombosis Definite stent thrombosis Angiographic confirmation of stent thrombosis TIMI flow grade 0 with occlusion originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus* TIMI flow grade 1, 2, or 3 originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of a thrombus* and at least one of the following criteria has been fulfilled within a 48-h time window: new onset of ischemic symptoms at rest (typical chest pain with duration >20 min), new ischemic ECG changes suggestive of acute ischemia, or typical rise and fall in cardiac biomarkers (refer to definition non–procedure-related MI Confirmation of stent thrombosis Evidence of recent thrombus within the stent determined at autopsy or via examination of tissue retrieved after thrombectomy Probable stent thrombosis Considered to have occurred after intracoronary stenting in the following cases: any unexplained death within the first 30 d and, regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause Possible ST Clinical definition of possible ST is considered to have occurred with any unexplained death from 30 d after intracoronary stenting until end of trial follow-upPuzzled by these observations, we started looking for heterogeneity of the treatment effect and discovered that the slight excess in mortality in the total population was due exclusively to the diabetic population. In the 428 diabetic patients enrolled in the 4 pivotal randomized trials, the 3-year survival was 96% in the BMS control group and 87.8% in the Cypher group, with a value of P=002. Because the nondiabetic Kaplan-Meier curves were nicely superimposed, our first reflex was to analyze the incidence of ST in these diabetic patients as a specific cause of mortality. The rate of definite or probable ST was 1.0% (2 of 195 patients) in the Cypher group versus 2.1% (5 of 233) in the control group. However, there was an imbalance between the Cypher (5.6%, 10 of 195) and control (1.7%, 4 of 233) groups in possible ST defined as any unexplained death from 30 days after the procedure. This intense scrutinizing exercise in comparing the death rate in these 428 diabetic patients boiled down to a difference of 6 unexplained deaths in the Cypher group and an excess of 3 cases of definite or probable ST in the control group, whereas the 3 categories of ST were very well balanced in the total population (Table 2). TABLE 2. Academic Research Consortium Definitions of ST in a Pooled Meta-Analysis of the Randomized RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS TrialsVariablesCrude Event Rates, %PSirolimus-Eluting Stent (N=878 patients)BMS (N=870 patients)Total population: n=1748.Any thrombosis by Academic Research Consortium definitions, % (n/N)3.4 (30/878)3.2 (28/870)0.89Acute ST (within 24 h)0.0 (0/878)0.0 (0/870)…Subacute ST (between 1 and 30 d)0.5 (4/878)0.3 (3/870)1.00Late ST (between 30 d and 1 y)0.3 (3/878)1.3 (11/870)0.034Very late ST (after 1 y)2.6 (23/878)1.6 (14/870)0.18Definite ST1.1 (10/878)0.8 (7/870)0.63Probable ST0.3 (3/878)0.9 (8/870)0.14Possible ST1.9 (17/878)1.5 (13/870)0.58However, a chronological analysis of the occurrence of these thromboses revealed some subtle differences in timing. In the DES group, the incidence of very late (n=23) primary ST (not a sequela of reintervention) was prominent, and the occurrence of ST after target lesion revascularization was not observed mainly because of the very low incidence of target lesion revascularization in the DES group. In the BMS group, 9 late and 6 very late ST events were documented, of which 10 occurred after reintervention. These incidences of late ST in BMS are not uncommon and have been previously documented in the literature in >9000 patients, with rates of late ST (>30 days) ranging from 0.4% and 0.8%.27–29These numbers emphasize the fact that restenosis with BMS is not just a nuisance but has potentially severe consequences. In 2006, Chen and colleagues30 reported on the clinical presentation of 1186 consecutive episodes of in-stent restenosis in patients treated with BMS. Whereas 26.4% of the patients required hospitalization for unstable angina, an additional 9.5% presented with MI, and 0.7% died. Nayak et al31 reported a similar 10% incidence of MI resulting from in-stent restenosis, and an additional 12% presented with a 2-fold increase in troponin. Additionally, 2 recent studies proved a close correlation between the extent of restenosis and late mortality.32,33 In other words, by preventing 100 restenoses per 1000 patients (clinical restenosis reduced from ≈20% to 10%), DES could prevent 10 restenosis-related MIs (9.5% of 100 prevented restenosis), and we could surmise that a reduction of 10 per 1000 cases of restenosis-related MIs would be sufficient to offset an increase of 5 per 1000 in very late ST–related MIs, leading to similar late death and MI rates for DES and the BMS control.How Do We Interpret the Data in Light of the Academic Research Consortium Definitions?We have 3 options: there is a new problem, and the use of DES results in more (very) late thrombosis than BMS; there is no new problem, and the rate of (very) late ST after DES is similar to that of BMS; and there is a problem, and early and (very) late ST should be abolished. In the near future, we may consider 3 strategies (the Figure). Download figureDownload PowerPointFuture directions of clinical trials. RT indicates randomized trials; ASA, acetylsalicylic acid; EPC, endothelial progenitor cell; and gen, generation.1. Pharmacological and long-term randomized trials will test the antithrombotic properties of current or novel dual-antiplatelet therapy in trials with death and MI as their primary end points and ST as their secondary end point.2. Certain current active and passive coated stents claim to have lower rates of ST and will be compared in dedicated randomized trials with long-term follow-up with as a sole primary end point difference in ST with as secondary end point death and MI (eg, REVOLUTION, PROTECT [Prospective Reinfarction Outcomes in Thrombolytic Era Cardizem CD Trial], and TRIAS).3. The current technology is viewed as imperfect, and the deficiencies should be amended by introducing more biocompatible absorbable coatings and new drugs with biological targets other than smooth muscle cell duplication (eg, thrombotic and inflammatory mechanisms) using dual elution of drugs or a prohealing approach such as the capture of endothelial progenitor cells with or without drug elution.It is clear that abolishing neointimal hyperplasia is no longer the ultimate goal. Development of more biocompatible and bioabsorbable stents facilitating adequate endothelialization is expected in the near future.ConclusionsLate ST exists in both DES and BMS. In an all-comer population, angiographic ST in DES seems to occur at a steady rate of 0.4% to 0.6% per year. Clinicians, regulators, and the device industry now realize that clinical surrogates for ST (death and MI) have to be incorporated into the long-term follow-up of the patient to capture late and very late ST patients who do not reach the catheterization laboratory to have their thrombosis angiographically confirmed. Fortunately, a first consensus on these angiographic and clinical end-point definitions has been reached under the umbrella of the Academic Research Consortium. Retrospective analysis of ST, applying the Academic Research Consortium definitions in randomized controlled trials, does not disclose a different rate of late ST between BMS and DES up to 4 years. However, the chronology and circumstances of occurrence seem quite different. In DES, late ST occurs later than in BMS and seems to appear as primary thrombosis, whereas in BMS, a certain number of late thromboses are related to repeat interventions of the target lesion. Dedicated research is warranted to further elucidate the role of endothelial dysfunction, malapposition, and prolonged antiplatelet therapy. Currently, the second generation of DES is attempting to resolve the issues discovered so far with the first generation of DES.DisclosuresNone.FootnotesCorrespondence to Professor P.W. Serruys, MD, PhD, Thoraxcenter, Ba-583, Dr Molewaterplein 40, 3015 GD Rotterdam, Netherlands. E-mail [email protected] References 1 Serruys PW, Strauss BH, Beatt KJ, Bertrand ME, Puel J, Rickards AF, Meier B, Goy JJ, Vogt P, Kappenberger L. Angiographic follow-up after placement of a self-expanding coronary-artery stent. N Engl J Med. 1991; 324: 13–17.CrossrefMedlineGoogle Scholar2 Costa MA, Sabate M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM, Serrano P, Coen VL, Levendag PC, Serruys PW. Late coronary occlusion after intracoronary brachytherapy. Circulation. 1999; 100: 789–792.CrossrefMedlineGoogle Scholar3 Waksman R. 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J Am Coll Cardiol. 2005; 45: 456–459.CrossrefMedlineGoogle Scholar14 Biondi-Zoccai GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F, Testa L, Sheiban I, Sangiorgi G. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006; 27: 2667–2674.CrossrefMedlineGoogle Scholar15 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Macaya C. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes. 2006; 55: 780–784.CrossrefMedlineGoogle Scholar16 Waksman R, Ajani AE, White RL, Pinnow E, Dieble R, Bui AB, Taaffe M, Gruberg L, Mintz GS, Satler LF, Pichard AD, Kent KK, Lindsay J. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST P
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