Author + information
- Received October 11, 2011
- Revision received January 19, 2012
- Accepted February 7, 2012
- Published online May 15, 2012.
- Margaret B. McEntegart, MD, PhD,
- Ajay J. Kirtane, MD, SM,
- Ecaterina Cristea, MD,
- Sorin Brener, MD,
- Roxana Mehran, MD,
- Martin Fahy, MS,
- Jeffrey W. Moses, MD and
- Gregg W. Stone, MD⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Gregg W. Stone, Columbia University Medical Center, Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022
Objectives The purpose of this study was to assess the prognostic impact of intraprocedural thrombotic events (IPTE) during percutaneous coronary intervention (PCI).
Background Ischemic complications of PCI are infrequent but prognostically important. How often these events are a consequence of intraprocedural complications is unknown, with only limited data assessing the occurrence and importance of IPTE.
Methods A total of 3,428 patients who underwent PCI for non–ST-segment elevation acute coronary syndrome in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial underwent detailed frame-by-frame core laboratory angiographic analysis. An IPTE, defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow, slow reflow, or distal embolization at any time during the procedure, occurred in 121 patients (3.5%).
Results Patients with IPTE had higher in-hospital, 30-day, and 1-year major adverse cardiac event rates than patients without IPTE (25.6% vs. 6.3% in-hospital, 30.6% vs. 9.3% at 30 days, and 37.0% vs. 20.5% at 1 year; p < 0.0001 for each). An IPTE was strongly associated with Q-wave myocardial infarction and out-of-laboratory definite/probable stent thrombosis (in-hospital 3.3% vs. 0.5%, p = 0.006; 30 days 5.8% vs. 1.3%, p < 0.0001; and 1 year 6.7% vs. 2.0%, p = 0.0002). Unplanned revascularization, target vessel revascularization, and major bleeding not associated with coronary artery bypass graft surgery were also increased among patients with IPTE, as was overall 30-day mortality (3.3% vs. 0.7%, p = 0.002). Moreover, IPTE was an independent predictor of 30-day and 1-year composite death/myocardial infarction, stent thrombosis, and major adverse cardiac events.
Conclusions Although infrequent among patients undergoing early PCI for moderate and high-risk non–ST-segment elevation acute coronary syndrome, IPTE was strongly associated with subsequent adverse outcomes including death, myocardial infarction, and stent thrombosis.
- non–ST-segment elevation acute coronary syndrome
- percutaneous coronary intervention
Acute ischemic complications in the modern era of percutaneous coronary intervention (PCI) are infrequent, but when they occur, are often severe and affect future prognosis. The ischemic complications of PCI that have garnered most extensive study are periprocedural myocardial infarction (MI) and stent thrombosis. How often these adverse events develop directly as a consequence of intraprocedural complications is unknown, and few studies have assessed the occurrence and importance of intraprocedural thrombotic events (IPTE) such as slow flow, vessel closure, distal embolization, and new thrombus formation (1–4). Indeed, the frequency and implications of IPTE have not previously been reported from a dedicated core laboratory-based angiographic study, in part because such analysis requires detailed assessment of all procedural cineangiographic frames, a time-intensive and expensive process. Moreover, as the standard Academic Research Consortium (ARC) definitions (5) of stent thrombosis exclude intraprocedural events, the frequency and implications of intraprocedural stent thrombosis (IPST) have never been reported.
We, therefore, sought to determine the incidence of IPTE (including IPST), to describe the patient, lesion, and procedural characteristics associated with their occurrence, and to assess their impact on early and late clinical outcomes from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, a large-scale contemporary study that investigated different antithrombotic regimens in patients with moderate- and high-risk non–ST-segment elevation acute coronary syndrome (NSTEACS) who were undergoing an early invasive strategy (6).
The study design, protocol, and primary results of the ACUITY trial have previously been described in detail (6,7). In brief, 13,819 patients were prospectively randomized to 1 of 3 antithrombotic regimens, heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin plus a GPI, or bivalirudin alone. Angiography was performed in all patients within 72 h, followed by triage to PCI, coronary artery bypass graft surgery (CABG), or medical therapy at the discretion of the physician. Aspirin loading was administered before catheterization while clopidogrel was given to all patients before catheterization or within 2 h post-PCI. Aspirin was continued indefinitely and clopidogrel for 1 year after hospital discharge.
A pre-specified angiographic substudy was undertaken in 6,921 consecutive patients from U.S. centers, with all analyses performed at an independent core laboratory (Cardiovascular Research Foundation, New York, New York) by technicians blinded to randomization and clinical outcomes. From this group, PCI was performed in 3,428 patients, who represent the present study cohort. In addition to routine pre- and post-procedural quantitative and qualitative assessment, additional analyses of every cineangiographic frame was performed. Intraprocedural complications were independently assessed for each angiographic run.
An IPTE was defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow or slow reflow, or distal embolization occurring at any time during the procedure. An IPST (a subset of IPTE) was defined as new or increased thrombus within the deployed stent during the PCI procedure. Each complication was assessed relative to the status of the previous frames. Thus, if thrombus was present at baseline but then resolved only to recur later, this was coded as an IPTE. Similarly, thrombus at baseline that qualitatively “grew” in subsequent frames was considered an IPTE. Conversely, baseline thrombus that persisted in size without growing, diminished, or resolved was not considered an IPTE.
The pre-specified primary clinical endpoints of major adverse cardiovascular events (MACE) [death from any cause, MI, or unplanned revascularization for ischemia]), major bleeding (not related to CABG), and net adverse clinical events (MACE or major bleeding) were assessed at hospital discharge, 30 days, and 1 year. Definitions of these endpoints have previously been described in detail, and were adjudicated by an independent clinical events committee blinded to treatment assignment (6). Stent thrombosis was adjudicated by the ARC criteria (5).
Categorical variables were compared using the chi-square test. Continuous variables are expressed as mean ± SD and median (interquartile range), and compared using analysis of variance or Kruskall-Wallis tests, as appropriate based upon the distribution. Univariate analysis was performed to identify factors associated with IPTE, and to determine which of its components were associated with ischemic outcomes. Multivariable analysis by logistic regression was performed to determine independent predictors of IPTE, and whether IPTE was an independent predictor of outcomes at 1 month; Cox models were used for 1-year outcomes. Candidate covariates for multivariable models were selected using stepwise selection and included IPTE event, randomization group, age, sex, medically treated diabetes mellitus, insulin-treated diabetes, hypertension, hyperlipidemia, current smoker, previous MI, previous PCI, previous CABG, renal insufficiency, baseline biomarker elevation (troponin or creatine kinase–myocardial band), baseline ST-segment deviation ≥1 mm, Thrombolysis In Myocardial Infarction (TIMI) risk score, baseline hematocrit, baseline white blood cell count, left ventricular ejection fraction, number of diseased vessels, total extent of disease, time from randomization to study drug, time from study drug to PCI, pre-procedure thienopyridines, and pre-procedure statins. After initial variable selection, models were refitted using a limited number of covariates to prevent model over-fitting and loss of data due to missing data.
Of the 3,428 patients treated with PCI, 121 (3.5%) had an IPTE, including 10 (0.3%) with IPST. The individual components of IPTE are listed in Table 1. There were no significant differences in the rates of IPTE or IPST among the 3 antithrombotic treatment arms of the trial (3.6% with heparin plus GPI, 3.1% with bivalirudin plus GPI, and 4.0% with bivalirudin alone; p = 0.51).
Baseline and procedural characteristics
Patients with IPTE had had a lower prevalence of prior diabetes, hypertension, hyperlipidemia, and previous PCI, but more often had elevated baseline cardiac biomarkers (Tables 2 and 3).⇓⇓ There were no significant differences in the pre-procedural administration of antithrombotic therapy and antiplatelet therapy among the IPTE and no-IPTE groups. Procedural GPI use tended to be more frequent among patients with IPTE. Bailout GPI use (permitted in the bivalirudin alone arm) was given more frequently to patients with IPTE (28.9% vs. 7.6% without IPTE, p < 0.0001). Baseline TIMI flow grade and myocardial blush scores were significantly worse in the IPTE group, and patients with subsequent IPTE more frequently had a lesion with angiographically apparent thrombus before PCI. Lesions with an IPTE were longer, had smaller minimum lumen diameter and higher percentage diameter stenosis, but a larger reference vessel diameter.
By multivariable analysis, including clinical characteristics associated with IPTE, absence of prior hyperlipidemia (odds ratio: 0.53 [95% confidence interval (CI): 0.35 to 0.78], p = 0.0014) and baseline cardiac biomarker elevation (odds ratio: 3.20 [95% CI: 1.92 to 5.32], p < 0.0001) were the sole independent correlates of an IPTE.
Patients in whom an IPTE developed had markedly higher in-hospital, 30-day, and 1-year MACE rates than did patients without IPTE (25.6% vs. 6.3% in-hospital, 30.6% vs. 9.3% at 30 days, and 37.0% vs. 20.5% at 1 year, p < 0.0001 for each comparison) (Table 4,Fig. 1). Each of the individual components of IPTE was significantly associated with MACE at 30 days and 1 year (with the exception of no reflow and MACE at 1 year) (Table 5).
An IPTE was strongly associated with the development of MI (Table 4). Of note, Q-wave MI was especially common among patients with IPTE (in-hospital 6.6% vs. 0.5%, p < 0.0001). Definite or probable stent thrombosis occurring out-of-laboratory was also strikingly higher among patients with IPTE (in-hospital 3.3% vs. 0.5%, p = 0.006; 30 days 5.8% vs. 1.3%, p < 0.0001; and 1 year 6.7% vs. 2.0%, p = 0.0002) (Fig. 1), as was definite stent thrombosis (in-hospital 3.3% vs. 0.4%, p = 0.002; 30 days 5.0% vs. 0.8%, p < 0.0001; and 1 year 5.9% vs. 1.3%, p < 0.0001). Unplanned revascularization and non-CABG major bleeding were also increased in patients with IPTE (Table 4). Overall, 30-day mortality was greater among patients with IPTE (3.3% vs. 0.7%, p = 0.002).
By multivariable analysis, the development of IPTE was independently associated with the 30-day and 1-year occurrence of MACE, death, or MI, and ARC definite/probable stent thrombosis (Table 6).
An IPST, although uncommon, was strongly associated with death or MI (in-hospital 50.0% vs. 6.4%; 30 days 50.0% vs. 8.1%; and 1 year 50.0% vs. 12.5%; each p < 0.0001), and out-of-laboratory ARC definite stent thrombosis (in-hospital and 30 days 20.4% vs. 0.9%; and 1 year 20.0% vs. 1.4%; each p < 0.0001).
The principal findings of this analysis from the ACUITY trial are that although IPTE in patients with moderate- and high-risk NSTEACS treated with early PCI is uncommon, its occurrence is strongly associated with early and late MACE. Each of the individual components of IPTE was associated with adverse ischemic outcomes, and in aggregate, IPTE was a powerful independent predictor of adverse events, including death or MI (especially Q-wave MI), and subsequent (out-of-laboratory) stent thrombosis. Thus, the occurrence of IPTE identifies patients at high risk for subsequent adverse events, warranting preventive and therapeutic strategies.
The occurrence of IPTE during PCI increases procedural complexity, and is linked to lower rates of angiographic and procedural success. Several prior retrospective and observational studies have linked procedural complications to MACE (1–4). However, none of these studies performed frame-by-frame analysis at an independent core laboratory blinded to patient outcomes. In the present analysis, blinded core laboratory determination of an IPTE was performed, and IPTE was strongly associated with adverse outcomes in both univariable and multivariable analyses. Moreover, all of the individual components of IPTE were associated with the occurrence of independently adjudicated composite ischemic events.
Patients with IPTE less commonly had cardiovascular risk factors or prior PCI, more commonly had elevated baseline cardiac biomarkers, and were less likely to be using cardiac medications. Moreover, patients who had an IPTE had more severe stenoses in larger vessels (often with angiographic thrombus evident), with worse TIMI flow grade and myocardial blush scores. Thus, it is interesting to note that IPTE occurred in some of the highest risk NSTEACS lesions occurring in patients not previously on adequate preventive medical therapies.
The occurrence of IPTE was strongly associated with subsequent ischemic events, including MACE, MI, and stent thrombosis. The vast majority of effect of IPTE upon outcomes occurred early, with parallel event curves for most endpoints after 30 days. A Q-wave MI was particularly likely to develop after IPTE, the occurrence of which has been strongly related to subsequent early and late mortality after PCI. In addition, it is a novel and important observation that angiographically documented thrombotic stent occlusion (ARC definite stent thrombosis) is more likely to subsequently occur in stents patent at the end of a procedure complicated by IPTE . While 1 explanation for this association is the intrinsic link between IPTE and residual thrombus and/or diminished coronary flow, it is also possible that the occurrence of IPTE led operators to perform fewer and/or lower pressure balloon/stent inflations and/or otherwise change their practice to avoid worsening IPTE. Finally, patients with IPTE had notably more non-CABG major bleeding than did patients without IPTE, possibly due to intraprocedural bailout therapy with GPI (bailout GPI in bivalirudin alone patients with an IPTE vs. without an IPTE was 28.9% vs. 7.6%, respectively; p < 0.0001), prolonged anticoagulation therapy, and/or other therapies.
The present study is a post-hoc retrospective analysis from a multicenter clinical trial. Thus, even though core laboratory analyses in the ACUITY trial were prospectively performed blinded to clinical events, these findings merit further validation from other studies. The overall number of IPTE was relatively small, although strongly related to subsequent adverse events. A larger study may have revealed a relationship between IPTE and all-cause mortality, as expected from the increased rates of Q-wave MI and stent thrombosis. Conversely, although IPTE was an important predictor of MACE, MI, and stent thrombosis, after multivariable adjustment for high-risk baseline features, the role of unmeasured confounders cannot be excluded. Additionally, the correlation (and relative predictive accuracy) between site-assessed versus core laboratory-assessed IPTE has never been studied, which is necessary to know whether these results fully translate to clinical practitioners.
The results of the present study suggest that the occurrence of IPTE during PCI for NSTEACS is a strong predictor of subsequent MACE, including Q-wave MI, and subsequent stent thrombosis. Prevention of IPTE by optimizing patient selection, adjunct pharmacotherapy, and technique is, therefore, essential to optimize patient outcomes. Further studies are warranted to determine whether therapeutic measures should be undertaken when IPTE occurs to mitigate their sequelae, such as the use of more potent adenosine diphosphate antagonists to prevent subsequent stent thrombosis (8,9). Finally, the rate of IPTE might be considered an appropriate surrogate endpoint in clinical trials investigating new antithrombin and antiplatelet agents during PCI.
Dr. Mehran is a speaker/consultant for Cordis/Johnson & Johnson, Abbott Vascular, AstraZeneca, Cerdiva, Regado Biosciences, Ortho-McNeil-Janssen, and The Medicines Company; and receives research support from BMS/sanofi-aventis. Dr. Moses is a speaker/consultant for Cordis/Johnson & Johnson and Boston Scientific. Dr. Stone is on the advisory boards of Medtronic, Volcano, Boston Scientific, The Medicines Co., and Abbott Vascular. All other authors have reported they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Academic Research Consortium
- coronary artery bypass graft surgery
- glycoprotein IIb/IIIa inhibitor
- intraprocedural stent thrombosis
- intraprocedural thrombotic events
- major adverse cardiovascular events
- myocardial infarction
- non–ST-segment elevation acute coronary syndrome
- percutaneous coronary intervention
- Received October 11, 2011.
- Revision received January 19, 2012.
- Accepted February 7, 2012.
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