Author + information
- Received June 27, 2017
- Revision received August 11, 2017
- Accepted August 14, 2017
- Published online December 4, 2017.
- Tommaso Gori, MD, PhDa,∗ (, )
- Melissa Weissnera,
- Svenja Gönnera,
- Franziska Wendlinga,
- Helen Ullricha,
- Stephen Ellis, MDb,
- Remzi Anadola,
- Alberto Polimeni, MDa and
- Thomas Münzel, MDa
- aZentrum für Kardiologie, University Hospital Mainz, Mainz, Germany; German Center for Cardiac and Vascular Research (DZHK), Standort Rhein-Main, Germany
- bDepartment of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
- ↵∗Address for correspondence:
Dr. Tommaso Gori, Zentrum für Kardiologie, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Objectives The study sought to investigate the incidence, characteristics, predictors, and possible mechanisms of early and 3-year coronary scaffold thrombosis (ScT).
Background An increased incidence of both early and late ScT has been shown in randomized trials.
Methods Consecutive patients were enrolled in a single-center registry. Quantitative coronary angiography was performed. Incidence and predictors of ScT were assessed with Kaplan-Meier and Cox regression analyses.
Results A total of 657 patients (63 ± 12 years of age, 79% men, 21% diabetic, 64% acute coronary syndrome) who received 925 coronary bioresorbable scaffolds (BRS) (Abbott Vascular, Santa Clara, California) between May 2012 and January 2015 were enrolled. Clinical and procedural characteristics and outcome data at 1,076 (interquartile range: 762 to 1,206) days (3-year follow-up rate 93%) were collected. Twenty-eight ScTs were recorded: 14 early (Kaplan-Meier estimate: 2.2%), 5 late (Kaplan-Meier estimate: 0.9%), and 9 very late (Kaplan-Meier estimate: 1.7%). The incidence of ScT followed a U-shaped curve with highest incidence at the extremes of the distributions of reference vessel diameter (RVD) and the ratio of BRS nominal diameter to RVD. At quantitative coronary angiography, RVD (hazard ratio [HR]: 0.14; 95% confidence interval [CI]: 0.04 to 0.49) and BRS oversizing (ratio of BRS nominal diameter to RVD >1.15; HR: 107.40; 95% CI: 9.20 to 1,261.30) emerged as potent predictors of early ScT. RVD (HR: 9.55; 95% CI: 3.90 to 23.42) and BRS undersizing (ratio of BRS nominal diameter to RVD <0.85; HR: 0.0004; 95% CI: 0.0000 to 0.0400) predicted late or very late ScT (all p < 0.0001). The incidence of both early and late or very late ScT were lower (∼80% reduction) when an optimal implantation technique was used. The most important factor appeared to be vessel and BRS sizing.
Conclusions Different mechanisms underlie early and late ScT: although incomplete BRS deployment was a predictor of the former, the latter was associated with large vessel size and BRS undersizing. However, both phenomena are significantly less frequent with an optimized implantation technique. (Mainz Intracoronary Database. The Coronary Slow-flow and Microvascular Diseases Registry [MICAT]; NCT02180178)
An unexpectedly high incidence of scaffold thrombosis (ScT) early following implantation of coronary bioresorbable scaffolds (BRS) was found in single- and multicenter observational studies (1–4). More recently, a risk of late-occurring ScT was reported in randomized clinical trials comparing BRS with newer-generation drug-eluting stents (5,6). The mechanisms of this phenomenon, and whether they differ from those of early events, have not been investigated yet.
Incomplete expansion of the BRS is believed to be the strongest predictor of early ScT, as early ScT has been reported to be more frequent in vessels smaller than 2.25 mm (7) and in poorly expanded lesions (8). Demonstrating that procedural issues are major determinants of early ScT, the application of a BRS implantation technique aimed at achieving full expansion of the device was associated, in both our multicenter registry and in the GHOST-EU (Gauging coronary Healing with biOresorbable Scaffolding plaTforms in EUrope) trial analysis, with a significantly lower incidence of early ScT (8,9). Subsequent multicenter registers demonstrated a marked drop in the incidence of this complication after introduction of adequate vessel or patient selection criteria and implantation techniques (10,11).
Of importance, because the mechanisms of late ScT have not yet been clarified, it also remains unclear whether it can be addressed by applying an optimal implantation technique. The aim of this study was to report on the incidence of early and late ScT following BRS implantation, describe the clinical presentation of these events, and provide a comparative analysis of the predictors of early and late events in a large all-comer population.
Objectives and design
Detailed methods, including follow-up methods, are reported in the Online Appendix.
Clinical characteristics and quantitative coronary angiography (QCA) data of all consecutive patients treated with a BRS (Absorb 1.1, Abbott Vascular, Santa Clara, California) between May 2012 and January 2015 were collected in a single-center retrospective registry. The database was used to search predictors and mechanisms of late ScT and compare them with those of early ScT. The primary clinical endpoint was to test whether an optimal implantation strategy was associated with a reduction in late or very late ScT. Further, based on anecdotal evidence of scaffold malapposition in patients with late or very late ScT (12), the mechanistic hypothesis was that late or very late ScT would be associated with QCA evidence compatible with device undersizing (see subsequent definitions).
A CONSORT flow diagram is presented in Figure 1. The study belongs to the MiCAT (Mainz intracoronary database) program, which is approved by the ethics committee of the Landesärztekammer Mainz (NCT02180178).
ScT was classified as definite, probable, and possible based on the Academic Research Consortium criteria (13). Timing of ScT was categorized as early when occurring during the first 30 days (divided into acute [within the first 24 h] and subacute), late between 1 month and 1 year, and very late beyond 1 year after BRS implantation. The adjudication of events was based on review of original clinical data by 2 investigators not involved in other analyses.
A list of the methods, definitions, measurements performed, and local reproducibility is provided in the Online Appendix. Briefly, the key QCA parameters (all collected at index) included:
• Minimal lumen diameter (MLD): (pre- or post-procedural) in-BRS MLD;
• Reference vessel diameter (RVD): (pre- or post-procedural) interpolated RVD (vessel size);
• Nominal BRS diameter divided by RVD (BRS sizing);
• Additional parameters included post-procedural residual stenosis and MLD to RVD ratio (which express vessel expansion); the ratio of MLD to nominal BRS diameter, footprint and scaled residual stenosis (markers of device expansion). These parameters are described in detail in the Online Appendix.
The QCA analysis was performed by staff blinded to the clinical characteristics and outcome of the patients.
Impact of an optimal implantation strategy
The outcome of patients treated using an implantation protocol designed to address the issue of incomplete BRS expansion (“optimal implantation technique”) was compared with that of patients treated with a standard implantation technique. While in our previous paper (14) patients were categorized based on the timing of implantation (before or after the introduction of local implantation recommendations on January 1, 2014), a patient-level analysis was used in the present research.
Independently of the timing of implantation, patients who had BRS implanted according to the following rules were grouped to the optimal implantation technique group: 1) Pre-dilatation with a balloon of the same nominal size as the RVD and the BRS; 2) implantation of a BRS of the same size as the reference vessel diameter (ratio of nominal diameter to RVD comprised between 0.9 and 1.1) in a vessel with RVD comprised between 2.5 to 3.5 mm; 3) post-dilatation at 14 to 16 atm with noncompliant balloons of the same size or 0.5 mm larger than the BRS; 4) independent of post-dilatation, achievement of a final residual stenosis <20% and a residual stenosis <20% of the nominal BRS size; 5) no BRS implantation in ostial or true bifurcation lesions; and 6) implantation of adjacent BRS using a scaffold-to-scaffold technique instead of overlap.
To assess the role of QCA parameters, a separate analysis was performed excluding criteria 2 and 4 (implantation technique without QCA parameters).
Continuous variables are presented as mean ± SD or median (interquartile range) based on the inspection of the Q-Q plots. Accordingly, they were compared using a Student unpaired t test, Mann-Whitney U test, Kruskal-Wallis analysis of variance, or analysis of variance. Categorical variables are presented as counts and percentages, and were compared using the Fisher exact test. Kaplan-Meier curves were built to derive the event rates and plot time-to-event curves.
Cox proportional hazards analysis was performed to identify the clinical and procedural parameters relevant for the early and for late or very late ScT separately. To minimize overmodeling (15), the a priori endpoint of this analysis was the role of the implantation strategy in reducing late or very late ScT. This endpoint was also investigated using a propensity score analysis to remove potential treatment assignment bias (Online Appendix).
For the mechanistic (QCA) analysis, the primary hypothesis was that inappropriate BRS sizing would be associated with both early and late or very late ScT. For the purpose of the analysis, inappropriate sizing was prospectively defined as ratio of BRS nominal diameter to RVD <0.85 (undersizing) and >1.15 (oversizing). The relationship between vessel size (RVD) and BRS sizing (ratio of BRS nominal diameter to RVD) with the incidence of ScT was also investigated for possible dichotomization by inspection at 0.1-percentile intervals.
For exploratory purposes, an additional Cox regression analysis was also performed in a total of 45 parameters (see the Online Appendix for a complete list), including the different components of the optimal implantation technique. Finally, receiver-operating characteristic curve analysis was performed to test for the role of RVD, footprint, and ratio of nominal BRS diameter to RVD in predicting ScT. The threshold for statistical significance was set as p < 0.05. Statistical tests and analyses were performed with MedCalc statistical software version 9 (MedCalc Software, Mariakerke, Belgium).
Incidence and clinical presentation of ScT
The registry included a total of 657 patients (Figure 1) with a mean age of 63 ± 12 years (79% men, 21% diabetic, 67% acute coronary syndrome) who received a total of 925 BRS (1.41 ± 0.83 per patient). The clinical and procedural characteristics of the patients are presented in Table 1. In patients who subsequently developed early ScT, index clinical presentation included stable angina (n = 6), unstable angina (n = 3), non–ST-segment elevation myocardial infarction (NSTEMI) (n = 4), or ST-segment elevation myocardial infarction (STEMI) (n = 1). In patients with late or very late ScT, index clinical presentation included stable angina (n = 4), NSTEMI (n = 5), or STEMI (n = 5).
The database was closed at the beginning of 2017. A 3-year follow-up was therefore possible in the patients who received a BRS until January 2015 (n = 416). Follow-up data were available in 386 (93%) patients. The 2-year mark had been reached by all patients (n = 657), and 2-year follow-up data were available in 586 (89%) patients. Finally, 1-year follow-up data were available in 606 (92%) patients. The median follow-up was 1,076 (IQR: 762 to 1,206) days. Features of lesion complexity (chronic total occlusion, number of vessels treated, total implanted BRS length) were more common in patients with late or very late ScT, whereas no characteristic was identified for early ScT. An optimal implantation technique was used less frequently in patients who later developed ScT independently of the timing.
Figure 2 depicts the Kaplan-Meier curve for the incidence of ScT and the clinical presentation at the time of ScT. There were 25 definite ScTs, 2 probable ScTs, and 1 possible ScT. Fourteen ScTs occurred early (8 “acute” or within 1 day, 6 “subacute” or within 1 month), 5 late (within 1 year), and 9 very late. Overall, the Kaplan-Meier incidence was 2.2% at 30 days, 3.0% at 12 months, and 4.7% at 3 years. The most frequent presentation was STEMI in both early (n = 10) and late or very late (n = 6) ScT. Two patients died within 1 month (7 and 24 days after implant, probable ScT), 1 died of sudden death on day 247 (possible ScT), and 1 died after resuscitation attempts in the catheterization laboratory (definite ScT) on day 452. Four patients with late ScT presented with NSTEMI.
Early ScT patients developed ScT while on dual antiplatelet therapy except for 1 patient who had a pharmacological history that was considered unreliable. Of the late or very late ScT patients, only 4 were on dual antiplatelet therapy (p = 0.0001 vs. early ScT; ScT on days 109, 247, 450, and 996 after index). One patient (ScT on day 138) had prematurely interrupted both aspirin and clopidogrel following gastrointestinal bleeding during triple therapy. One patient (ScT on day 502) was on anticoagulant therapy with vitamin K antagonists only. The other patients developed ScT 2 to 631 (median 112 [IQR: 32 to 258]) days after P2Y12 interruption. Six of the early ScT lesions were treated with percutaneous transluminal coronary angioplasty only, 4 with drug-eluting stent implantation, and 11 late or very late ScT patients were treated with drug-eluting stent implantation. Early ScT had no impact on cardiac function as assessed by echocardiography during subsequent follow-up, whereas ScT resulted in death or impaired contractility in all but 1 of the late or very late ScT patients.
Clinical predictors of ScT and the role of the implantation technique
The results of the Cox analysis are presented in Online Tables 1S and 2S. At index, an optimal implantation technique was used in 311 patients. The role of this implantation strategy is presented in Figure 3 for both early and late or very late ScT. The incidence of both early and late ScT was lower (early: from 3.7% to 0.7%, 81% decrease; late: from 4.4% to 0.6%, 86% decrease) in cases in which the optimal implantation technique was used. For early ScT (Online Table 1S), the optimal implantation technique was the only predictor of ScT (hazard ratio [HR]: 0.19; 95% confidence interval [CI]: 0.04 to 0.82; p = 0.028). For late or very late ScT (Online Table 2S), the implantation technique was associated with an HR of 0.11 (95% CI: 0.01 to 0.83; p = 0.033).
Exploratory analysis evidenced that the implantation technique was the only predictor of early ScT, whereas estimated glomerular filtration rate (HR:1.02; 95% CI: 1.01 to 1.04; p = 0.011), treatment of stenoses in the right coronary (HR: 3.24; 95% CI: 1.10 to 9.52; p = 0.033), prior coronary intervention (HR: 1.02; 95% CI: 1.00 to 1.04; p = 0.024), and total implanted BRS length (HR: 3.22; 95% CI: 1.10 to 9.39; p = 0.034) were predictors of late or very late ScT in multivariable analysis. The role of implantation technique remained significant after propensity score adjustment (HR: 0.10; 95% CI: 0.01 to 7.81; p = 0.03).
Among the individual components of the implantation technique (QCA parameters, pre- or post-dilatation, lesion characteristics), stenting in overlap, percent residual stenosis, and small RVD were univariate predictors of early events and ostial lesions, and percent residual stenosis and large RVD were univariate predictors of late or very late events (Online Tables 1S and 2S). In a separate analysis in which vessel size and BRS sizing parameters were excluded from the definition, the other components of the implantation technique (pre- or post-dilatation, lesion characteristics) were not associated with either early ScT (HR: 0.44; 95% CI: 0.10 to 1.95; p = 0.28) or late or very late ScT (HR: 0.22; 95% CI: 0.29 to 1.66; p = 0.143). The implantation pressure was not a predictor of early (HR: 1.00; 95% CI: 0.78 to 1.29; p = 0.970) or late or very late ScT (HR: 1.10; 95% CI: 0.85 to 1.43; p = 0.479).
QCA: Mechanistic role of vessel size and BRS sizing
QCA data were available in 664 lesions (n = 635), and the remaining films were either of insufficient quality for analysis or not archived by technical error. At index (Online Table 3S), patients who later developed early ScT had evidence of incomplete BRS expansion (lower post-procedural MLD, lower MLD and nominal diameter, higher scaled stenosis and maximum footprint; all p = 0.027 or lower), whereas patients with late or very late ScT had evidence of BRS undersizing (lower nominal diameter and RVD; p < 0.001), with no difference between late and very late events.
Figure 4 describes the U-shaped incidence of ScT as a function of RVD. The 3-year incidence of ScT was lower (p = 0.0002) for RVD comprised between 2.5 and 3.5 mm (2.7%) as compared with vessels with RVD <2.5 mm (8.2%) and with vessels with RVD >3.5 mm (14.7%). Importantly, except for 2 cases, ScTs in vessels ≤3 mm occurred early, those in vessels ≥3.25 mm occurred late. A similar relationship was observed with regard to BRS sizing (ratio of nominal BRS diameter to RVD). The 3-year incidence of ScT was low (Kaplan-Meier estimate: 2.5%) for correctly sized BRS, whereas it was higher in both undersized (ratio of nominal diameter to RVD <0.85, Kaplan-Meier estimate: 14.6%) and oversized BRS (ratio of nominal diameter to RVD >1.15, Kaplan-Meier estimate: 8.7%; p = 0.0001).
Online Table 4S and Online Figure 1S present the data of the receiver-operating characteristic curve analysis. The maximum footprint (which we previously identified as best predictor of early ScT) (8) was associated with early events (area under the curve: 0.825; 95% CI: 0.793 to 0.854; p < 0.0001) but not with late events (area under the curve: 0.509; 95% CI: 0.469 to 0.548; p = 0.911). In contrast, RVD and the ratio of nominal diameter to RVD expressing vessel size and BRS sizing were strongly associated with both early and late events (area under the curve between 0.725 and 0.782, respectively; p < 0.01 for all).
Cox regression analysis (Table 2) revealed the direction of these associations. Features of incomplete vessel or BRS expansion (low post-procedural RVD and MLD, high nominal and RVD ratio, high percent residual stenosis and high scaled stenosis) (see the Online Appendix for definitions) were strongly associated with early ScT (all p < 0.002) but not late or very late ScT (all p > 0.10). In contrast, features of large vessel size (large RVD) and BRS undersizing (low nominal diameter to RVD ratio) were associated with late or very late ScT (all p < 0.001).
Figure 4 depicts the role of vessel size (RVD, left panel) and BRS sizing (middle panel) on the risk of ScT. Small RVD and oversizing were predictors of early ScT, whereas large RVD and undersizing were predictors of late ScT. Figure 5 and Online Figure S2 depict the relationship between QCA parameters and timing or incidence of ScT.
The key findings of this all-comer registry are: 1) early and late or very late ScT were almost equally frequent and both associated with adverse presentation (∼80% and ∼50% STEMI, respectively), and late events were more consistently associated with permanent impairment in contractile function; 2) vessel or BRS underexpansion is the major feature of early ScT; 3) in contrast, BRS implantation in larger (>3.5 mm) vessels as well as BRS undersizing emerged as predictors of late or very late ScT; and 4) the technique used at the time of implantation is a major predictor of both early and late or very late ScT.
Vessel and BRS choice
The current data confirm the importance of sizing as a possible determinant of ScT. In line with previous results (7,8) and with findings of the ABSORB III (A Clinical Evaluation of Absorb™ BVS, the Everolimus Eluting Bioresorbable Vascular Scaffold in the Treatment of Subjects With de Novo Native Coronary Artery Lesions) trial (16), an increased risk of early ScT was demonstrated in vessels <2.5 mm and in cases in which a >15% oversized BRS was chosen and incompletely expanded.
In contrast, compatible with anecdotal evidence of malapposition in patients with late or very late ScT (12,17), a >15% undersizing and implantation in vessels larger than 3.5 mm were strong predictors of late events. Even in the RVD range comprised between 2.5 and 3.5 mm, BRS sizing remained a predictor of events. These data appear to suggest that an interaction between 2 parameters (vessel size and choice of an appropriate BRS), both strongly associated with ScT, underlie the differences in the mechanisms of early versus late events.
In line with the importance of the previous 2 parameters, an optimal implantation technique was associated with a lower incidence of both early and late events (81% and 86%, respectively). Of note, when QCA parameters were excluded from the definition of “optimal implantation,” pre- or post-dilatation and lesion selection criteria (no implantation in ostial stenoses, bifurcation lesions, no overlap) taken alone were not associated with a reduction in ScT rates. These data confirm the concept that, of all procedural parameters, sizing may have the largest impact in preventing both early and late complications.
The registry nature of this study has clear inherent limitations (including the 3-year dropout rate of 7%), which we previously discussed in detail (14), and the evidence provided here should be seen as hypothesis generating and exploratory. However, the real-life design and the complexity of the patients or lesions treated here provides directly applicable information that complements that of randomized studies, and confirmation in randomized trials is to some extent unfeasible (e.g., with regard to the role of the implantation technique or to under- or oversizing). Further, ScT is a complex phenomenon in which vessel or stent architecture, structure, resorption timing, and a number of patient characteristics play a role. It is likely that larger cohorts would have allowed identifying other clinical or procedural parameters and possible causes and mechanisms. However, we designed a study with a clear primary endpoint, which fits with the number of events available, and the strength of the association between QCA parameters and ScT emphasize the importance of the mechanisms identified here. For the analysis, late and very late ScT were pooled. However, all late ScT occurred at a time in which resorption has already started, and the 2 patient groups did not differ in any of the key features. Reflecting current clinical practice, a large proportion of patients had an acute coronary syndrome at index, which exposes to the risk of wrong sizing. Whether the present data apply to different cohorts will need to be studied. Finally, our data do not allow the investigation of other possible implantation strategies. For instance, it is possible that the use of fractional flow reserve or imaging after BRS implantation would have modified the incidence of events.
In a recent editorial, Yamaji et al. (18) discussed the current evidence on the role of device, operator technique, or lesion, vessel, patient factors in contributing to BRS complications. The present data show that the technique used at the time of the implantation as well as, in particular, a meticulous attention to vessel size, BRS sizing, and device or vessel expansion were strong predictors of risk. Whether the same predictors apply for other device types in this class and whether newer generations of BRS will reduce complications rates will need to be tested.
WHAT IS KNOWN? A higher rate of device thrombosis has been shown in patients treated with BRS, and the mechanism of late events remains elusive.
WHAT IS NEW? We report on the incidence, clinical presentation, and predictors of early versus late or very late ScT in a single-center registry. We found that although early thrombosis is mostly associated with incomplete BRS deployment, late events are associated with large reference vessel size and scaffold undersizing. Importantly, the incidence of both early and late events was lower with an optimized implantation technique.
WHAT IS NEXT? Larger-scale trials are required to better define the outcomes after scaffold implantation.
Abbott Vascular had no role in any phase of this research. Drs. Gori and Münzel have received speaker fees from Abbott Vascular. Dr. Gori is a professor at and received research grant support from the German Center for Cardiac and Vascular Research (DZHK). Dr. Ellis has received research grant support from and served as a consultant for Abbott Vascular. Dr. Polimeni has received grant support from the European Association of Percutaneous Coronary Interventions. Dr. Münzel has received research grant support from the Center for Translational Vascular Biology (Mainz, Germany). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bioresorbable scaffolds
- minimal lumen diameter
- non–ST-segment elevation myocardial infarction
- quantitative coronary angiography
- reference vessel diameter
- scaffold thrombosis
- ST-segment elevation myocardial infarction
- Received June 27, 2017.
- Revision received August 11, 2017.
- Accepted August 14, 2017.
- 2017 American College of Cardiology Foundation
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