Author + information
- Received September 14, 2015
- Accepted October 24, 2015
- Published online February 22, 2016.
- Jeffrey D. Wessler, MD, MPhila,
- Philippe Généreux, MDa,b,c,
- Roxana Mehran, MDb,d,
- Girma Minalu Ayele, PhDb,
- Sorin J. Brener, MDb,e,
- Margaret McEntegart, MD, PhDf,
- Ori Ben-Yehuda, MDa,b,
- Gregg W. Stone, MDa,b and
- Ajay J. Kirtane, MD, SMa,b,∗ ()
- aNewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York
- bCardiovascular Research Foundation, New York, New York
- cHôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada
- dIcahn School of Medicine at Mount Sinai, New York, New York
- eNew York Methodist Hospital, Brooklyn, New York
- fGolden Jubilee National Hospital, Glasgow, Scotland
- ↵∗Reprint requests and correspondence:
Dr. Ajay J. Kirtane, Center for Interventional Vascular Therapy, Columbia University Medical Center/New York-Presbyterian Hospital, 161 Fort Washington Avenue, 6th Floor, New York, New York 10032.
Objectives This study sought to determine the extent to which individual components of intraprocedural thrombotic events (IPTEs) are associated with adverse events.
Background IPTEs occurring during percutaneous coronary intervention (PCI) are associated with adverse in-hospital and late outcomes in patients with acute coronary syndromes.
Methods A total of 6,591 patients who underwent PCI for non–ST-segment elevation acute coronary syndromes/ST-segment elevation myocardial infarction in the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) and HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trials underwent detailed frame-by-frame core laboratory angiographic analysis to assess for IPTEs. The associations of IPTE components with death, major bleeding, and major adverse cardiac events at 30 days were assessed using univariable analyses and multivariable models.
Results The overall incidence of IPTEs was 7.7%, with a greater incidence in ST-segment elevation myocardial infarction patients (12.2%) compared with non–ST-segment elevation acute coronary syndromes patients (3.5%). Specific components of IPTEs included no-reflow/slow reflow in 58.0%, new/worsened thrombus in 35.3%, distal embolization in 34.9%, abrupt closure in 19.8%, and intraprocedural stent thrombosis (IPST) in 9.5% of patients. Each IPTE component was independently associated with 30-day death, major bleeding, and MACE in multivariable models, with the strongest association observed for IPST (MACE hazard ratio: 7.51 [95% confidence interval: 4.36 to 12.94]).
Conclusions The occurrence of IPTEs is not infrequent among high-risk acute coronary syndromes patients undergoing PCI, and each IPTE component was associated with subsequent adverse events. Although IPST represented <10% of IPTE events overall, it was the component with the strongest association with adverse events.
The occurrence of intraprocedural thrombotic events (IPTEs) has been demonstrated to be a powerful and independent predictor of both early and late adverse clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) (1–6). In analyses conducted with patients experiencing both non–ST-segment elevation acute coronary syndromes (NSTEACS) and ST-segment elevation acute coronary syndromes, IPTE was independently associated with ischemia and bleeding (5,7). Compared with patients experiencing ST-segment elevation myocardial infarction (STEMI), those with NSTEACS had a reduced incidence of IPTEs compared with those with NSTEACS, but in both groups of patients, IPTEs were associated with major adverse cardiac events (MACE) (all-cause death, myocardial infarction, target vessel revascularization, or stroke), major bleeding, and mortality (5,7).
Although IPTEs overall are clinically challenging and are prognostically important, the extent to which individual components of IPTEs are associated with adverse events is unknown. Several smaller studies have demonstrated worse clinical outcomes with various complications of PCI including intraprocedural stent thrombosis (IPST), distal embolization, and no-reflow/slow flow (2,4,8–14); however, no study has assessed the relative importance of various IPTE components on the subsequent development of clinical outcomes. This is, in part, due to the large sample size necessary to conduct such analyses and because systematic objective assessments of IPTEs require frame-by-frame assessments of a large cohort of patients undergoing PCI. In this study, we sought to further characterize the extent to which individual components of IPTEs, including new or worsened thrombus, abrupt closure, no-reflow/slow flow, distal embolization, and IPST, were associated with adverse events using pooled core laboratory–adjudicated data from the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) and HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trials.
The ACUITY and HORIZONS-AMI study designs, protocols, and results have been previously described in detail (15–18). Briefly, ACUITY was a large, multicenter, prospective trial of 13,819 patients with moderate- to high-risk NSTEACS randomly assigned to either heparin plus glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin plus GPI, or bivalirudin alone. All patients underwent angiography within 72 h followed by PCI, surgical revascularization, or medical therapy at the treating physician’s discretion. In the HORIZONS-AMI trial, 3,602 patients undergoing primary PCI for STEMI were randomized to bivalirudin plus GPI versus heparin plus GPI; patients were subsequently randomized to a paclitaxel-eluting stent compared with an identical bare metal stent. The present analysis included the 6,591 patients who underwent stent implantation in these 2 trials.
Detailed frame-by-frame angiographic analyses were performed in PCI patients at an independent angiographic core laboratory (Cardiovascular Research Foundation, New York, New York) by technicians blinded to treatment randomization and clinical outcomes. Standard definitions were used for lesion morphology, thrombus, and Thrombolysis In Myocardial Infarction (TIMI) flow grades (19–22). Each angiographic film underwent quantitative and qualitative assessment of pre- and post-procedural images as well as independent assessment of each cine angiographic frame for intraprocedural complications.
IPTE was defined as the development of a new or increasing thrombus, abrupt vessel closure, no-reflow/slow flow, distal embolization, or IPST (defined as new or increased thrombus within the deployed stent during PCI) occurring any time during the procedure and not present at baseline. Each event was assessed relative to the angiographic appearance of the previous frame, such that interval growth of a baseline thrombus or interval resolution followed by recurrence were both considered an IPTE. The clinical outcomes in each trial, including MACE, major bleeding, and mortality, were evaluated at 30 days and adjudicated by an independent clinical events committee blinded to treatment randomization.
Continuous variables were compared using the Kruskal-Wallis test and are expressed as medians with interquartile ranges. Categorical variables were compared using the chi-square or Fisher exact test, as appropriate, and are expressed as proportions. A separate multivariate Cox regression model of 30-day outcomes was constructed for each IPTE component. Candidate covariates included those previously identified as independent predictors of outcomes within these datasets (age, sex, history of diabetes, history of hypertension, hyperlipidemia, current smoking, previous myocardial infarction, baseline hematocrit, baseline white blood cell count) as well as other baseline demographic characteristics and pre- and post-PCI characteristics selected using stepwise selection with p < 0.05 for entry into the models. The analyses were similar when trial was included in the model as a random effect. Final models were refitted after elimination of nonsignificant covariates to avoid overfitting due to missing covariates.
Frame-by-frame core laboratory angiographic analysis was completed for 6,591 patients in the combined cohort, including 3,428 patients with NSTEACS from the ACUITY trial and 3,163 patients with STEMI from the HORIZONS-AMI trial. The overall incidence of IPTEs was 7.7%, with a greater incidence among STEMI patients (12.2%) compared with NSTEACS patients (3.5%). Patients experiencing IPTEs had a lower prevalence of diabetes, hypertension, previous myocardial infarction, previous PCI, and previous coronary artery bypass grafting but were more likely to have had elevated baseline cardiac biomarkers (Table 1). Previous use of thienopyridines was more frequent among patients without IPTEs, and patients with IPTEs more likely to have been randomized to bivalirudin rather than to heparin and GPI.
Compared with patients without IPTEs, patients with IPTEs had significantly higher 30-day rates of MACE (12.7% vs. 6.5%, hazard ratio [HR]: 2.09, 95% confidence interval [CI]: 1.60 to 2.72; p < 0.0001) and death (4.0% vs. 1.2%, HR: 3.35, 95% CI: 2.04 to 5.50; p < 0.0001) (Table 2). Patients experiencing IPTEs additionally had significantly increased 30-day rates of definite or probable stent thrombosis (4.2% vs. 1.7%, HR: 2.49, 95% CI: 1.56 to 3.98; p < 0.0001) and noncoronary artery bypass grafting major bleeding (10.6% vs. 5.3%, HR: 2.06, 95% CI: 1.54 to 2.75; p < 0.0001) compared with patients without IPTEs. Target vessel revascularization was modestly increased in patients with IPTEs compared with those without IPTEs (3.8% vs. 2.2%, HR: 1.84, 95% CI: 1.14 to 2.98; p = 0.01).
Components of IPTEs
The frequencies of the various components (not mutually exclusive) of IPTEs are shown in Figure 1. Among patients with IPTEs, no-reflow/slow reflow was present in 58%, new/worsened thrombus in 35.3%, distal embolization in 34.9%, abrupt closure in 19.8%, and IPST in 9.5% of patients. Of all IPTEs, 93.4% occurred in a main branch, whereas 17.4% occurred in a side branch. More events occurred after stent placement (68.0%) compared with before stent placement (51.2%). Of note, there was significant overlap among IPTEs in individual patients, with 57% having only 1 IPTE, 23% having 2 IPTEs, and 20% having >2 IPTEs.
Each IPTE component was strongly associated with subsequent 30-day MACE, as depicted in Figure 2. Moreover, each IPTE component was independently associated with 30-day MACE, major bleeding, and death in multivariable models, as shown in Table 3. Although IPST was the least frequently occurring component of IPTEs, the strongest association between an IPTE component and adverse outcomes was observed for IPST (HR: 7.51, 95% CI: 4.36 to 12.94 for MACE; HR: 4.47, 95% CI: 2.44 to 8.20 for major bleeding; and HR: 7.47, 95% CI: 3.21 to 17.39 for death) (Table 3, Figure 2E).
This analysis, using pooled data from the ACUITY and HORIZONS-AMI trials, is the first assessment of the effect of individual components of IPTEs on clinical outcomes, using frame-by-frame core laboratory angiographic analyses of 6,591 patients undergoing PCI for NSTEACS and STEMI. The principal findings of this analysis are the following: 1) IPTEs occurred in 1 of every 13 patients undergoing PCI for high-risk acute coronary syndromes; 2) although multiple IPTEs frequently occurred in an individual patient, each individual component of an IPTE was independently and strongly associated with adverse outcomes; and 3) the IPTE component with the strongest association with adverse events was IPST.
Complications of PCI including IPTEs result in increased procedural complexity that can increase the risk of subsequent adverse outcomes. In previous analyses of patients undergoing PCI for NSTEACS and STEMI, IPTEs were strongly associated with the occurrence of 30-day MACE, major bleeding, and death (5–7,13). Previous studies assessed several components of IPTEs including no-reflow, distal embolism, and IPST—demonstrating worse clinical outcomes with these individual events (2,4–6,8,9,11–13); however, no previous study has assessed the associations of multiple IPTE components at once in a large cohort.
The ability to characterize the effects of IPTE components has the potential to add significant value to the understanding of the mechanism underlying the relationship between IPTEs and adverse outcomes. Component analyses offer insight into the most significant mediators of clinically significant outcomes. In this study, IPST yielded the highest risk of 30-day clinical outcomes, with HRs approximately 3-fold higher than those of the other individual components. As IPST is increasingly recognized as an important complication of PCI, this finding may have important implications for future studies of various interventions during PCI. In the CHAMPION-PHOENIX (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trial, for example, the rate of IPST was significantly lower in the cangrelor group than in the control group (0.6% vs. 1.0%, odds ratio: 0.65, 95% CI: 0.42 to 0.99; p = 0.04), which may explain in part the improved outcomes seen in this group (6).
Each of the other components of IPTE, including new/worsened thrombus, abrupt closure, no-reflow/slow flow, and distal embolization were also highly predictive of MACE, major bleeding, and death at 30 days. Thus, therapeutic strategies targeted at preventing and minimizing these events have the potential for a significant clinical impact.
Therapeutic interventions addressing the no-reflow component have been studied extensively. Isaaz et al. (23) performed immediate angioplasty with very small balloons followed by maximal antithrombotic therapy in 93 patients with STEMI and an initial TIMI flow grade 0, resulting in immediate and sustained recanalization in the majority of patients. Several studies have additionally examined the effects of pharmacological therapy on the resolution and outcomes of no-reflow. Treatment with systemic nicardipine, nitroprusside, and verapamil was equally effective in restoring normal flow (TIMI flow grade increased from 1.62 to 2.78, p < 0.0001) in 347 patients (24), and intracoronary administration of verapamil significantly improved flow (TIMI flow grade 3) in 201 patients undergoing primary PCI for STEMI (25). Despite these studies demonstrating effective restoration of flow by both pharmacological and mechanical interventions, no studies have shown a beneficial effect in terms of clinical outcomes (26).
In patients experiencing new/worsened thrombus or IPST, both pharmacological and mechanical strategies have also been studied. Antiplatelet and antithrombotic therapies are frequently used for bailout treatment of residual thrombus during PCI; however, this likely contributes to the increased risk of major bleeding observed in patients with new/worsened thrombus or IPST. In a recent analysis of the ACUITY trial, bailout GPI therapy was used 4 times more frequently in patients experiencing IPTEs compared with those without IPTEs (7). Although bailout thrombectomy is often pursued during primary PCI with residual thrombus burden, in a multicenter study of 141 patients with STEMI, randomization to thrombectomy with PCI failed to demonstrate improvements in flow compared with patients undergoing PCI alone (27). Similar to the no-reflow component, the optimal treatment strategy for new/worsened thrombus or IPST remains elusive.
First, patients with IPTEs had differing baseline characteristics compared with those without IPTEs, with more frequent randomization to bivalirudin alone. These variances in baseline characteristics and treatments may have contributed to or influenced the various effects of IPTE components on clinical outcomes, even though an attempt to adjust for them was made. Similarly, the role of unmeasured confounders as predictors of clinical outcomes cannot be excluded, particularly because our study did not assess the determinants of individual IPTE components. Additionally, because this study used pooled data from 2 different cohorts of patients with NSTEACS and STEMI, the specific effects of the IPTE component on each population were not assessed. Although core laboratory angiographic analyses were performed prospectively by technicians blinded to treatment randomization and clinical outcomes, further validation of the findings is warranted. Finally, we found that patients with a significant risk factor burden (diabetes, hypertension, coronary disease) experienced fewer IPTEs, a finding that might be explained by better baseline medical therapy or heightened practitioner awareness in these patients with greater baseline risk.
The results of the present study demonstrate the significant positive association of IPTEs and their individual components (all IPTEs, new/worsened thrombus, abrupt closure, no-reflow/slow flow, distal embolization, and IPST) on adverse outcomes. IPST demonstrated the strongest association with adverse events. The objective assessment of individual components of IPTEs may contribute to future therapeutic strategies aimed at minimizing adverse clinical outcomes.
WHAT IS KNOWN? IPTEs that occur during PCI are associated with adverse outcomes in patients with ACS.
WHAT IS NEW? This study demonstrates that IPTEs are not infrequent (occurring in 1 of every 13 patients undergoing PCI for high-risk ACS) and that IPST is the IPTE component with the strongest association with adverse clinical outcomes.
WHAT IS NEXT? Further studies will focus on validation of these findings followed by therapeutic strategies aimed at minimizing the occurrence of these events and subsequent adverse outcomes.
Dr. Mehran has received institutional research grant support from The Medicines Company, Bristol-Myers Squibb/Sanofi Pharmaceuticals, Eli Lilly and Company, Daiichi-Sankyo, Regado Biosciences, and STENTYS; is a consultant for Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, and Merck & Co.; is on the Advisory Board of Covidien, Janssen Pharmaceuticals, Merck, Sanofi, Endothelix Inc.; and has equity in and is a shareholder in Endothelix Inc. Dr. Kirtane has received institutional research grants to Columbia University from Boston Scientific, Medtronic, Abbott Vascular, Abiomed, St. Jude Medical, Vascular Dynamics, and Eli Lilly. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- glycoprotein IIb/IIIa inhibitor
- hazard ratio
- intraprocedural stent thrombosis
- intraprocedural thrombotic event
- major adverse cardiovascular event(s)
- non–ST-segment elevation acute coronary syndrome
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Thrombolysis In Myocardial Infarction
- Received September 14, 2015.
- Accepted October 24, 2015.
- 2016 American College of Cardiology Foundation
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