EDITORIAL COMMENT
The "Vulnerable" StentWhy So Dreadful?*
Fernando Alfonso, MD, PhD, FESC*
Interventional Cardiology, Cardiac Department, Cardiovascular Institute, San Carlos University Hospital, Madrid, Spain.
* Reprint requests and correspondence: Dr. Fernando Alfonso, Interventional Cardiology, Cardiac Department, Cardiovascular Institute, San Carlos University Hospital, Plaza de Cristo Rey, Madrid 28040, Spain. (Email: falf{at}hotmail.com).
In a new era where the clinical manifestations of acute coronary syndromes are just considered to be the peak of the iceberg of an underlying systemic inflammatory process, terms such as "vulnerable plaque" have lost appeal in favor of more comprehensive terminology such as vulnerable blood, vulnerable myocardium, and vulnerable patient (1). Ultimately, all of them emphasize the need for implementing global preventive therapeutic strategies in the management of these patients.
Coronary interventions, however, are increasingly being used in unstable patients, and stent implantation is currently considered the best possible intervention to effectively tackle discrete coronary lesions. In this scenario, drug-eluting stents (DES) emerged and quickly revolutionized the field of interventional cardiology. As compared with bare-metal stents (BMS), DES are able to dramatically reduce neointimal proliferation and restenosis rate, leading to a major reduction in the need for target vessel revascularization and an improved long-term clinical outcome (2,3). Drug-eluting stents, however, have been unable to reduce the incidence of stent thrombosis. Their potent anti-inflammatory and antiproliferative properties might, in fact, constitute a double-edged sword, delaying endothelization and promoting vessel remodeling and late acquired malapposition that, in turn, might favor stent thrombosis (4). We need to acknowledge that the concern that DES could be more vulnerable to thrombosis than BMS has always been there and, in fact, from their early implementation prolonged dual antiplatelet regimens were systematically recommended in these patients. In addition, some controversial and provocative preliminary studies suggested that DES might be associated with a poorer clinical outcome, likely as the result of an increased risk of stent thrombosis (5,6). For a while, it was difficult to differentiate the fire from the smoke, and the complete field of coronary revascularization was temporarily destabilized. Definitions of stent thrombosis were revisited, and new recommendations were issued regarding extended (1 year) dual antiplatelet regimens.
Fortunately, subsequent systematic and exhaustive scrutiny of all pivotal randomized clinical trials (using patient-level data from the raw databases and independent analyses) failed to identify any potential increased risk for major adverse cardiac events (death and myocardial infarction) associated with the use of DES (2,3). Later on, additional well-designed analyses of large "real world" registries, where DES were often implanted for "off label" indications, confirmed the long-term clinical safety of DES and, in some cases, even their superior safety profile compared with BMS (7,8). Eventually, after the storm the calm prevailed, and it is expected that all of these reassuring data will generate a second wind effect in the clinical use of these new devices, refueling their market penetration.
In all of these analyses, however, a clear distinct temporal pattern of stent thrombosis emerged: whereas most episodes of BMS thrombosis clustered early after the procedure, the distribution of DES thrombosis was relatively late skewed with a certainly small but sizeable number of episodes occurring very late (>1 year) (9). Moreover, we still do not know how to reconcile some conflicting findings stemming from these studies, namely the risk for very late DES thrombosis (up to 0.6% annually in some reports) (9) and the unaffected myocardial infarction and mortality rates (2,3). This apparent paradox is particularly striking considering the adverse clinical outcome experienced by most patients suffering this complication (10–14). Could it be that the slight increase in the incidence of late thrombosis would require larger series of patients or much longer periods of follow-up to be clinically recognizable? Alternatively, a more optimistic explanation would be that the reduced need of repeated revascularization obtained with DES might eventually pay off, because restenosis (formerly presented as an innocent nuisance) could actually be associated with a marginal risk of untoward clinical events.
Currently, the dilemma might be summarized as follows: either we choose DES to overcome the risk of restenosis (still the Achilles' heel of BMS) or rather we select BMS to avoid the long shadow cast by the fear of very late stent thrombosis (still the Damocles sword of DES). Because of the major implications in clinical decision making of this yet unsolved dilemma, it is quite surprising that the term "vulnerable stent" has not yet gained widespread acceptance. Can we identify clinical and anatomic factors increasing stent vulnerability? Should we consider all DES as "vulnerable" stents? Should we obtain more in vitro or in vivo insights to confirm adequate platelet inhibition in patients with vulnerable stents? Why should we keep struggling to identify vulnerable plaques, if eventually our stents are also vulnerable? Finally, why is the prognosis of stent thrombosis so dismal despite timely and adequate management? This latter question is beautifully addressed in an elegant piece of work reported in this issue of the Journal (15).
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The "Vulnerable" Stent
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Table 1
summarizes clinical, procedural, anatomic, and biological factors associated with the risk of stent thrombosis (10–14). Most of these factors apply both to BMS and DES. Mechanical factors are clearly implicated in the pathophysiology of vulnerable stents (10–14). Patients suffering from BMS thrombosis frequently present underexpanded stents, significant inflow/outflow disease, uncovered dissections, and incomplete stent apposition (10). The same mechanical factors seem to play a major role in patients suffering DES thrombosis (11). In addition, the profound ability of DES to inhibit neointimal proliferation seems to be closely linked with a delayed process of endothelization, at least with the first generations of these devices. Pathologic, angioscopic, and optical coherence tomography studies have clearly demonstrated that DES, in contradistinction with BMS, might remain incompletely endothelized after 6 months, and this finding has been related to fibrin deposition and stent thrombosis (4). Furthermore, in DES the polymer might occasionally elicit inflammatory and allergic reactions that favor DES thrombosis (4). Finally, these bioactive stents might alter the normal healing process of the vessel wall and also trigger positive vessel remodeling leading to acquired malapposition. Indeed, this finding is more frequently found after DES than after BMS implantation. We should keep in mind, however, that suboptimal stent deployment and even malapposition is relatively common but, fortunately enough, stent thrombosis remains very rare. However, the other side of the same coin is also of interest, and different studies have demonstrated that underexpansion and malapposition are frequently detected in patients suffering stent thrombosis (10,11). Which face of Janus is telling the truth? Is there any important information missing in the equation?
The previous discussion leads us to speculate that—similar to the pathophysiology of many arrhythmias—3 complementary and potentially interrelated factors should be considered in patients suffering from stent thrombosis. These 3 key factors would include: 1) a predisposing underlying anatomic substrate (i.e., stent underexpansion, malapposition, subtle mechanical problems, incomplete endothelization); 2) an unfavorable thrombogenic milieu (i.e., drug discontinuation, resistance to aspirin or clopidogrel, genetic polymorphisms, thrombophilia, rheologic problems); and 3) the trigger (i.e., any potent stimulus for platelet activation). We propose that these 3 aspects comprising the "vulnerability triangle" should be systematically investigated and eventually corrected in all patients experiencing stent thrombosis.
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Consequences of Stent Thrombosis
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Why is stent thrombosis so dreadful? One would be tempted to anticipate that episodes of stent thrombosis would have a better—or at least a similar—clinical outcome than that seen in the general population of patients treated with primary angioplasty. Although most of these stents are implanted in relatively large proximal vessels, the same is true for most patients presenting with ST-segment elevation myocardial infarction. Episodes of stent thrombosis are relatively easy to identify, potentially leading to an early treatment. In fact, many of them occur when the patient is still in the hospital and can be expeditiously treated. These patients should readily recognize their symptoms, and personnel at the emergency department should quickly suspect the diagnosis and forward the patient for urgent cardiac catheterization. Finally, before reintervention, coronary anatomy might be carefully reviewed to anticipate any difficulties and also to select the most appropriate strategy to optimize results. Paradoxically, however, most studies suggest that, despite early and aggressive management, episodes of DES thrombosis are systematically associated not only with large Q-wave myocardial infarctions but also with a higher-than-expected mortality rate (12,13). In an early study (13), in-hospital and 9-month mortality rates were 24% and 45%, respectively. This is, by far, higher than that seen in patients with ST-segment elevation myocardial infarction caused by de novo lesions. However, selection biases might help to explain some of these previous findings.
In this issue of the Journal, Chechi et al. (15) sought to unravel the reasons explaining why stent thrombosis is associated with such an adverse prognosis. Clinical and angiographic results of primary angioplasty in these patients were thoroughly compared with those seen after conventional primary angioplasty procedures. Eighty-six patients treated for definitive stent thrombosis (64% early thrombosis, 72% DES) were retrospectively compared with 98 consecutive patients with ST-segment elevation myocardial infarction treated for "de novo" lesions. Because patients with stent thrombosis had more adverse baseline characteristics, logistic regression analyses (with propensity-adjustment) were performed to account for confounders. Time to intervention was similar in both groups. Notably, however, a significantly large angiographic thrombus burden was identified in the cohort of patients with stent thrombosis. Successful reperfusion—the primary outcome measure—was significantly lower, and in-hospital mortality was significantly higher in these patients. After adjustment, stent thrombosis emerged as an independent predictor of unsuccessful coronary reperfusion. In addition, the cumulative rate of major adverse cardiac events at 6 months was significantly higher in patients with stent thrombosis, although these differences disappeared after adjustment. Stent type was not related to prognosis, but specific analyses to identify predictors of adverse outcome in this setting were not performed. The authors eventually concluded that management strategies should be improved in these patients (15).
The in-hospital mortality rate of this series was 17.4%, which favorably compares with initial reports of patients treated for stent thrombosis but is in line with the results of more recent studies (10–12,14). Interestingly enough, despite the larger thrombus burden detected in patients with stent thrombosis, the use of adjunctive antiplatelet medications and thrombus removal devices was similar to that seen in the control group. This could explain the lower rate of adequate reperfusion and the higher rate of distal embolization detected in the stent thrombosis group. Moreover, after intervention the residual angiographic stenosis was more severe in patients with stent thrombosis (final minimal lumen diameter of only 2 ± 0.7 mm). Maximal inflation pressures were not reported, but it is likely that residual thrombus rather than underexpanded stents would account for these poorer angiographic results. In 2 previous prospective intravascular ultrasound studies we demonstrated that, despite all optimization efforts (aggressive balloon dilation and stents for residual dissections, together with a systematic use of glycoprotein IIb/IIIa platelet inhibitors, thrombectomy devices, and intravascular ultrasound-guided stent optimization), a significant amount of "resistant" thrombus is consistently visualized after the procedure in patients treated for either BMS or DES thrombosis (10,11). These findings could help to explain the suboptimal angiographic findings found by Chechi et al. (15) at the epicardial vessel level, which together with the severe derangement of the microvascular bed would jeopardize the results of these rescue procedures. In contrast, whether thrombus in patients with stent thrombosis is not only larger but also qualitatively different (i.e., more resistant to mechanical and pharmacological interventions) than that encountered during standard primary angioplasty procedures remains to be elucidated.
Treatment of patients suffering episodes of stent thrombosis constitutes not only a medical emergency but also a uniquely challenging procedure. Currently, no information exists regarding the best interventional strategy for this entity, and most recommendations remain empirical. Furthermore, individual responses of intracoronary thrombi to interventions remain unpredictable (16). However, owing to the catastrophic clinical consequences potentially associated with this complication, we believe that particularly aggressive measures are clearly warranted. First of all, mechanical flow restoration should be achieved immediately. Then, potent adjuvant antiplatelet and antithrombotic drugs, together with thrombus aspiration devices, should be systematically used, owing to the large amount of thrombus occluding the stent. Furthermore, intravascular ultrasound guidance should be indicated to tackle any potential mechanical predisposing factor and to guarantee stent optimization (10,11). Lastly, ensuring the long-term maintenance of a dual antiplatelet regimen might not be sufficient in these patients, because many of them are indeed resistant to these medications. Detailed studies of platelet reactivity, confirming adequate platelet inhibition under the selected antiplatelet regimen, could be of paramount importance in these patients who are at very high risk for recurrences (17). This is of special interest in light of recent information suggesting that larger maintenance doses or even new antiplatelet agents might be particularly effective in selected high-risk patients (17).
Further studies are urgently required to improve stent selection according to the clinical and anatomic setting, to optimize deployment techniques, to better identify vulnerable stents, and last but not least, to elucidate the best antiplatelet regimen and its duration to prevent stent thrombosis. In patients suffering from this dreadful complication, improved interventional strategies should be developed to ensure optimal results after these challenging procedures. Hopefully, next-generation stents will be able to reduce the rate of restenosis even further while, at the same time, completely abolishing the risk of thrombosis. Only then will "vulnerable stents" no longer be an issue.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I Circulation 2003;108:1664-1672.[Abstract/Free Full Text]2. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents N Engl J Med 2007;356:998-1008.[Abstract/Free Full Text] 3. Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007;356:989-997.[Abstract/Free Full Text] 4. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk J Am Coll Cardiol 2006;48:193-202.[Abstract/Free Full Text] 5. Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. BASKET-LATE Investigators Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of the drug-eluting verus bare-metal stents J Am Coll Cardiol 2006;48:2584-2591.[Abstract/Free Full Text] 6. Lagerqvist B, James SK, Stenestrand U, Lindbäck J, Nilsson T, Wallentin L, SCAAR Study Group Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden N Engl J Med 2007;356:1009-1019.[Abstract/Free Full Text] 7. Tu JV, Bowen J, Chiu M, et al. Effectiveness and safety of drug-eluting stents in Ontario N Engl J Med 2007;357:1393-1402.[Abstract/Free Full Text] 8. Marroquin OC, Selzer F, Mulukutla SR, et al. A comparison of bare-metal and drug-eluting stents for off-label indications N Engl J Med 2008;358:342-352.[Abstract/Free Full Text] 9. Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and placitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study Lancet 2007;369:667-678.[CrossRef][Medline] 10. Alfonso F, Suárez A, Angiolillo DJ, et al. Findings of intravascular ultrasound during acute stent thrombosis Heart 2004;90:1455-1459.[Abstract/Free Full Text] 11. Alfonso F, Suárez A, Pérez-Vizcayno MJ, et al. Intravascular ultrasound findings during episodes of drug-eluting stent thrombosis J Am Coll Cardiol 2007;50:2095-2097.[Free Full Text] 12. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials Circulation 2001;103:1967-1971.[Abstract/Free Full Text] 13. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors and outcome of thrombosis after successful implantation of drug-eluting stents JAMA 2005;293:2126-2130.[Abstract/Free Full Text] 14. de la Torre-Hernández JM, Alfonso F, Hernández F, et al. Drug-eluting stent thrombosis. Results from the multicenter Spanish Registry ESTROFA (Estudio ESpañol sobre TROmbosis de stents FArmacoactivo). J Am Coll Cardiol 2008;51:986-990.[Abstract/Free Full Text] 15. Chechi T, Vecchio S, Vittori G, et al. ST-segment elevation myocardial infarction due to early and late stent thrombosis: a new group of high-risk patients J Am Coll Cardiol 2008;51:2396-2402.[Abstract/Free Full Text] 16. Alfonso F, Rodriguez P, Phillips P, et al. Clinical and angiographic implications of coronary stenting in thrombus-containing lesions J Am Coll Cardiol 1997;29:725-733.[Abstract] 17. Alfonso F, Angiolillo DJ. Platelet function assessment to predict outcomes after coronary interventions: hype or hope? J Am Coll Cardiol 2006;48:1751-1754.[Free Full Text]
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The "Vulnerable" Stent
Consequences of Stent Thrombosis