Author + information
- Received April 2, 2012
- Revision received June 27, 2012
- Accepted August 16, 2012
- Published online January 1, 2013.
- Sorin J. Brener, MD⁎,†,⁎ (, )
- Ecaterina Cristea, MD†,
- Ajay J. Kirtane, MD, SM†,‡,
- Margaret B. McEntegart, MD†,‡,
- Ke Xu, MS†,
- Roxana Mehran, MD†,§ and
- Gregg W. Stone, MD†,‡
- ↵⁎Reprint requests and correspondence
: Dr. Sorin J. Brener, Professor of Medicine, Director Cardiac Catheterization Laboratory, New York Methodist Hospital, KP-2, Brooklyn, New York 11215
Objectives The aim of this study was to examine the incidence, correlates, and consequences of intra-procedural stent thrombosis (IPST) in patients with acute coronary syndromes (ACS).
Background Stent thrombosis (ST) is a rare but serious complication of percutaneous coronary intervention (PCI). The Academic Research Consortium definition of ST excludes events occurring during PCI.
Methods Angiograms from the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) and HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trials were reviewed frame-by-frame at an independent core laboratory for the occurrence of IPST. Patients with versus without IPST were compared to identify baseline characteristics associated with IPST and demonstrate the independent association between IPST and adjudicated events at 30 days and 1 year.
Results Intra-procedural ST occurred in 47 (0.7%) of 6,591 patients. The occurrence of IPST was associated with ST-segment elevation myocardial infarction presentation, high white blood cell count, treatment of thrombotic and bifurcation lesions, bivalirudin monotherapy, bail-out IIb/IIIa inhibitor use, and implantation of bare-metal (rather than drug-eluting) stents. Major adverse ischemic events were markedly higher in patients with versus without IPST, including mortality at 30 days (12.9% vs. 1.4%, p < 0.0001) and 1 year (12.9% vs. 3.1%, p < 0.0001). Out-of-lab Academic Research Consortium definite or probable ST also occurred significantly more often among IPST patients at 30 days (17.4% vs. 1.8%, p < 0.0001) and 1 year (19.9% vs. 2.7%, p < 0.0001). Intra-procedural ST was a significant independent predictor of 1-year mortality (hazard ratio: 3.86, 95% confidence interval: 1.66 to 9.00, p = 0.002).
Conclusions Intra-procedural ST is a relatively rare complication of PCI in ACS but is strongly associated with subsequent out-of-lab ST and mortality. Intra-procedural ST should be considered as a distinct category of ST and routinely reported, particularly for ACS patients.
Stent thrombosis (ST) occurring after percutaneous coronary intervention (PCI) is a rare but serious complication. The incidence of ST is known to be increased in patients undergoing PCI in the setting of an acute coronary syndrome (ACS) and in those with diabetes mellitus or bifurcation stents and in patients who discontinue dual antiplatelet therapy (1–3).
The Academic Research Consortium (ARC) has standardized the definitions of ST by categorizing the specificity of the adjudicated event (definite, probable, or possible) and its timing relative to PCI (acute, subacute, late, and very late) (4). However, all of these categories refer to events occurring after the patient has left the cardiac catheterization laboratory. Intra-procedural stent thrombosis (IPST) (i.e., the development of occlusive or non-occlusive new thrombus in or adjacent to a recently implanted stent before the PCI procedure is completed) is excluded from the ARC ST definitions. As such, little is known about the incidence, predictors, and consequences of IPST.
With 2 recently performed large-scale trials of PCI in ACS (the HORIZONS-AMI [Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction] and ACUITY [Acute Catheterization and Urgent Intervention Triage StrategY] trials)—in which independent adjudication of intra-procedural angiographic events in addition to early and late clinical events were performed—we sought to examine the frequency, correlates, and implications of IPST.
The HORIZONS-AMI and ACUITY protocols and principal results have been described in detail. In brief, in the HORIZONS-AMI trial 3,602 patients presenting with ST-segment elevation myocardial infarction (STEMI) within 12 h of symptom onset were randomized before angiography to bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) (1:1 ratio) (5). Subsequently, 3,006 patients suitable for stenting were randomized again to a paclitaxel-eluting stent or to an identical bare-metal stent (3:1 ratio). In the ACUITY trial 13,819 patients with moderate and high-risk unstable angina and non-STEMI were randomized to 1 of 3 antithrombotic regimens: heparin plus GPI, bivalirudin plus GPI, or bivalirudin alone (6). Angiography was performed in all patients within 72 h, followed by triage to PCI, coronary artery bypass graft (CABG) surgery, or medical therapy at the discretion of the treating physician. All patients in both trials received standard pharmacological therapy to support PCI, including routine dual antiplatelet therapy with aspirin and clopidogrel for at least 1 year. Clinical follow-up was performed through 3 years in the HORIZONS-AMI trial and through 1 year in the ACUITY trial.
Frame-by-frame angiographic analysis was performed at an independent angiographic core laboratory (Cardiovascular Research Foundation, New York, New York) by trained technicians blinded to randomization and clinical events with standard definitions for lesion morphology, thrombus, and Thrombolysis In Myocardial Infarction (TIMI) flow grades (7–9). Each film was analyzed independently by 2 separate technicians: 1 reader (blinded to intra-procedural events) assessed only the baseline (pre-PCI) images and the final result, whereas a second reader assessed intra-procedural events. All films were over-read for accuracy by the laboratory director or co-director, who were also blinded to randomization and clinical events and have extensive experience in interventional procedures. Core laboratory analysis was performed in all patients in the HORIZONS-AMI trial and in U.S. patients in the ACUITY trial as part of a formal substudy. The complete HORIZONS-AMI and ACUITY databases were merged, and the present analysis was restricted to patients who underwent PCI and in whom angiographic core laboratory evaluation of the index procedure was performed.
Intra-procedural ST was defined as new or increasing (compared with baseline) thrombus within or adjacent to a deployed stent occurring during the index PCI procedure, whether occlusive or nonocclusive. Intra-procedural ST was also deemed present when the baseline level of thrombus was decreasing or resolved after balloon angioplasty or thrombus aspiration but then increased any time after stent implantation (including stent post-dilation). Clinical events in each trial—including death, myocardial infarction (MI), target vessel revascularization, and ST according to the ARC definitions—were assessed at 30 days and 1 year in both studies by an independent clinical events committee with original source documents, blinded to randomized allocation of treatment.
Continuous variables are presented as median with interquartile range and were compared with the Kruskal-Wallis test. Categorical variables are presented as proportions and were compared with chi-square or Fischer exact test. A multivariable stepwise Cox regression model (entry and exit p < 0.1) was developed to identify the independent predictors of 1-year all-cause mortality. The candidate baseline variables considered in the model (on the basis of common predictive variables from the respective models from the ACUITY  and HORIZONS-AMI  trials) were age, sex, baseline hemoglobin, baseline white blood cell count, current smoking, prior PCI, use of aspirin or thienopyridines at any time before ACS, number of diseased vessels, baseline TIMI flow grade 0/1, bivalirudin allocation, thrombus at baseline, final (post-PCI) TIMI flow grade (0 to 2 vs. 3), and IPST. Significance level was set at 0.05. All analyses were performed with SAS (version 9.0; SAS Institute, Cary, North Carolina).
Percutaneous coronary intervention was performed in 6,591 patients in the combined cohort, including 3,428 patients with unstable angina or non-STEMI from the ACUITY trial and 3,173 patients with STEMI from the HORIZONS-AMI trial. Intra-procedural ST occurred in 47 patients (0.7%), in 49 lesions. These included 37 patients from the HORIZONS-AMI trial (1.2%) and 10 patients from the ACUITY trial (0.3%), p < 0.001. Examples of IPST are shown in Figure 1.
The baseline clinical and angiographic characteristics of patients in whom IPST did and did not develop are shown in Table 1. Patients with IPST were more likely to have STEMI presentation, higher white blood cell count on admission, randomization to bivalirudin alone, subsequent bail-out use of GPI, 1-vessel coronary artery disease, an occluded artery at baseline with thrombus, bifurcation lesions, and bare-metal stents implanted. The peak intra-procedural activated clotting time (ACT) was not significantly different between patients with versus without IPST (342 ± 117 s vs. 310 ± 114 s, respectively, p = 0.09).
During PCI, certain intra-procedural complications were significantly more common in the IPST group: slow or no reflow −75.5% versus 3.2%, p < 0.0001; distal embolization −49% versus 1.9%, p < 0.0001; and side branch closure −14.3% versus 0.6%, p < 0.0001. At the end of the index PCI, TIMI flow grade 3 in the treated vessel was present in 21 patients (44.7%) in the IPST group, compared with 6,014 patients (90.9%) in the no IPST group (p < 0.0001). Residual thrombus was present within or adjacent to the stent in 31.9% of patients (15 of 47) in the IPST group versus 1.0% (62 of 6,515) in the no IPST group (p < 0.0001). Median peak creatine kinase-myocardial band was significantly higher in the IPST group: 18.3 (4.4 to 38.9) ng/ml versus 7.6 (2.4 to 24.0) ng/ml, respectively (p = 0.02).
As shown in Tables 2 and 3⇓ and Figure 2, adverse events at 30-day and 1-year follow-up were markedly higher in patients with compared with those without IPST. Of note, the out-of-lab rates of ST according to the ARC definitions (recurrent clinical ST events among patient undergoing IPST) were also greatly increased in patients with IPST (Fig. 3), with most of these being angiographically proven definite ST events, and with most occurring by 30 days. Adverse ischemic, hemorrhagic, and out-of-lab ST events were increased even among patients in whom final TIMI flow grade 3 was restored (Table 3).
By multivariable analysis, the occurrence of IPST was an independent predictor of 1-year all-cause mortality (hazard ratio [HR]: 3.86, 95% confidence interval [CI]: 1.66 to 9.00, p = 0.002). Other independent predictors of mortality were diabetes mellitus (HR: 1.99, 95% CI: 1.46 to 2.73, p < 0.0001), final TIMI flow grade 0 to 2 (HR: 0.29, 95% CI: 2.33 to 5.00, p < 0.0001), and baseline creatinine clearance (per ml/min, HR: 0.97, 95% CI: 0.97 to 0.98, p < 0.0001).
The present study is the largest reported experience with IPST to date, the first to employ an independent angiographic core laboratory to assess frame-by-frame events, and the first to correlate IPST with early and late clinical outcomes. The most important observations from this report are: 1) IPST was a rare complication of PCI in ACS, occurring in <1% of patients, even in those presenting with STEMI; 2) IPST was not related to most baseline clinical characteristics, except for STEMI presentation and high white blood cell count, but occurred more frequently in patients with angiographic evidence of thrombus before PCI, in those not treated with a GPI, with bare-metal stent use, and in those undergoing bifurcation stenting; 3) although uncommon, IPST was a strong predictor of suboptimal PCI results. Despite high use of bail-out GPI, TIMI flow grade 3 was restored in less than one-half of patients in whom IPST developed, and residual thrombus was present in more than 1 in 3 patients at procedure end; and 4) IPST was associated with a markedly higher incidence of mortality and other ischemic events within 30 days and 1 year after the procedure, including ARC out-of-lab ST events, even if final TIMI flow grade 3 was restored.
The impact of IPST has been evaluated in 2 prior studies. Biondi-Zoccai et al. (12) reviewed the incidence of IPST in patients undergoing PCI with first-generation drug-eluting stents in Italy. Among 1,320 patients <75 years of age and without cardiogenic shock (55% of whom had ACS), IPST developed in 6 patients (0.5%), a rate similar to our study. Total stent length and lack of GPI treatment were related to IPST, but long-term follow-up was not reported from this study. Similarly, Chieffo et al. (13) evaluated 670 patients undergoing elective drug-eluting stent implantation and documented IPST in 0.7%. Of the 5 patients, 1 had complete resolution of the thrombus, 2 experienced non–Q-wave MI, 1 had Q-wave MI, and 1 died while undergoing emergency surgical revascularization. Total stent length was the only variable associated with IPST. In this regard total stent length was not recorded in the ACUITY trial, but the number of stents placed was higher in patients with IPST in our analysis. Whether the association between stent length and IPST reflects the need for additional stents after IPST develops, represents the presence of more extensive “vulnerable” atherosclerosis, or is truly causal cannot be determined with certainty from our study.
In our study, the maximal ACT level did not significantly differ between the groups with and without IPST, but it is possible that additional doses of heparin were given in response to IPST, elevating a previously low ACT. Of note, although bivalirudin typically results in a higher ACT level than heparin (with or without GPI), anticoagulation with bivalirudin alone was associated with an increased incidence of ST compared with unfractionated heparin, enoxaparin, or bivalirudin plus a GPI. This observation is consistent with our previous report of a higher rate of acute ST occurring within the first 4 to 5 h in STEMI patients treated with bivalirudin alone (14). Nonetheless, treatment of patients with STEMI with bivalirudin alone resulted in reduced 30-day and 3-year mortality compared with heparin plus a GPI, with comparable rates of ST at 3 years (14,15). Of note, ST is a platelet-mediated event (16), and neither prasugrel nor ticagrelor (which are known to reduce early and late ST compared with clopidogrel (17,18) were available during the enrollment periods of the ACUITY and HORIZONS-AMI trials. Thus, future studies are warranted to determine whether combining a more potent adenosine diphosphate antagonist with bivalirudin might reduce IPST as well as acute ST and thereby further improve outcomes in patients with ACS.
The present study does not address the cause of IPST, and with only 47 patients with IPST events, robust multivariable analysis to identify the independent predictors of IPST was not possible. Procedural complications such as IPST can occur because of a variety of causes, such as insufficient anticoagulation, dissection, or distal embolization leading to compromised flow and thrombosis in situ. The association between an elevated white blood cell count and IPST is also intriguing and deserves further study to elucidate whether systemic inflammation plays a role in IPST development. Recognizing the underlying cause might allow targeted therapy to prevent IPST or to rapidly restore antegrade perfusion if IPST occurs. However, it is notable in our analysis that a high subsequent rate of ischemic events (especially definite ST) occurred within 30 days of IPST, even in patients with resolution of the thrombotic episode and restoration of normal (TIMI flow grade 3) antegrade flow. In this regard, the present analysis extends the findings from earlier reports in which intra-procedural complications were associated with greater myocardial necrosis but not recurrent thrombosis (19).
Although IPST was rare (0.7%), this frequency is similar to the rate of out-of-lab ST within the first 30 days or 1 year in most large series (20). Moreover, although IPST is de facto recognized and can be treated immediately in the catheterization laboratory, its occurrence portends nearly the same adverse prognosis in terms of early and late mortality as out-of-lab ST. These observations are further justification as to why IPST should be considered a new classification of ST (ARC or otherwise) and reported in all cases.
It might be difficult to always distinguish between events that started with thrombus and those in which new thrombus developed, even for an expert angiographer performing frame-by-frame analysis. Moreover, the angiographic core laboratory can only evaluate events that were captured on cine-angiography. Although investigators in the ACUITY and HORIZONS-AMI trials were asked during site training to film all intra-procedural adverse events, we cannot exclude the possibility that some events were not recorded or led to misclassification or under-reporting of IPST. Furthermore, the intensity of anticoagulation at the time of angiographic thrombus appearance, such as minimal ACT, is not precisely known. It is possible that the nominally higher ACT in the IPST group reflects additional anticoagulation given at the time of thrombus detection or from bail-out GPI, which is known to increase ACT levels (21). We could also not find a mechanism explaining the association between bare-metal stent and IPST.
Despite these limitations, we conclude that the occurrence of IPST is relatively rare, even in ACS patients, and is related more strongly to clinical presentation and procedural factors (e.g., anticoagulation regimen, lesion type, and presence of thrombus at baseline) than to baseline demographic characteristics. The development of IPST is strongly associated with a substantial excess of ARC-defined out-of-lab ST in the first 30 days after PCI, which implies that these patients might especially benefit from more potent antiplatelet agents, such as prasugrel or ticagrelor. Intra-procedural ST is also a powerful independent predictor of 1-year mortality. Therefore, IPST should be added as a separate category to the ARC definition of ST and be recognized as a high-risk procedural complication portending a poor prognosis.
Dr. Mehran has served as consultant to Abbott, AstraZeneca, Ortho McNeil, and Regado; and has received research grant support from Sanofi/BMS and the Medicines Company. Dr. Stone has received consulting fees from Medtronic, GlaxoSmithKline, Eli Lilly, and Bristol-Myers Squibb and grant support from Boston Scientific, the Medicines Company, and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndromes
- activated clotting time
- Academic Research Consortium
- coronary artery bypass graft
- confidence interval
- glycoprotein inhibitors
- hazard ratio
- intra-procedural stent thrombosis
- major adverse cardiac events
- myocardial infarction
- percutaneous coronary intervention
- stent thrombosis
- ST-segment elevation myocardial infarction
- saphenous vein graft
- Thrombolysis In Myocardial Infarction
- Received April 2, 2012.
- Revision received June 27, 2012.
- Accepted August 16, 2012.
- American College of Cardiology Foundation
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