Current Outcomes after Revascularization for Coronary Very Late Stent Thrombosis

Abstract

Objective: Limited data are available regarding current outcomes after revascularization for angiographically confirmed very late stent thrombosis (VLST). Therefore, this study investigated the current outcomes of patients with VLST and the risk factors for major adverse cardiovascular events (MACE).

Methods: Consecutive patients who underwent revascularization for angiographically confirmed VLST between January 2014 and January 2016 were enrolled in this study. The patients were divided into two groups according to the occurrence of MACE during follow-up. The clinical and interventional parameters between groups were compared.

Results: A total of 564 patients with an average age of 61.61 ± 10.71 years were enrolled. Eight patients died during hospitalization. MACE occurred in 100 patients after a mean follow-up of 620 days. The total MACE rate was 35.46%, and Kaplan-Meier survival analysis indicated an estimated MACE-free survival rate of 22%. Multivariable Cox regression analysis revealed that left ventricular ejection fraction and peak troponin I at VLST onset were independent predictors of MACE.

Conclusions: Long-term outcomes after revascularization for VLST remained unfavorable. Left ventricular ejection fraction and peak troponin I at the onset of VLST were independent risk factors for poor prognosis.

Main article text

Introduction

Percutaneous coronary intervention (PCI) is currently the primary treatment for acute coronary syndrome (ACS), one of the most serious threats to human health worldwide [1]. Very late stent thrombosis (VLST), defined as thrombosis occurring more than 1 year after stent implantation, is a rare but catastrophic complication of PCI that presents primarily as acute myocardial infarction (MI) or even sudden cardiac death [2]. The mechanism underlying VLST is complicated. VLST risk factors include patient- and lesion-related factors, procedural and stent-related factors, and pharmacotherapy-related factors [3]. Recent studies have suggested that: hypersensitivity and inflammation reactions, changes in shear stress, plaque rupture, and neointimal erosion may be involved in the development of VLST [3].

Emergent revascularization combined with optimized drug therapies have become the standard strategy for patients with VLST [4]. However, studies have provided limited information regarding the outcomes of patients with angiographically confirmed VLST as therapies have improved [5]. Therefore, we conducted a two-center registry study enrolling consecutive patients presenting with definite VLST, to identify the current incidence of major adverse cardiac events (MACE) after revascularization for VLST and the determinants of these events.

Methods

Patient Population

All consecutive patients with angiographically confirmed very late stent thrombosis (according to the Academic Research Consortium (ARC) stent thrombosis definitions [6]) at the First Hospital of Jilin University and First affiliated Hospital of Shantou University between January 1, 2014, and January 1, 2016, were enrolled (ClinicalTrials.gov: NCT03491891). This study was approved by the Institutional Review Board of the First Hospital of Jilin University (No. 2013256). All participants provided informed consent.

VLST was defined according to the ARC definition [6]. Coronary angiograms of both procedures (index PCI and PCI for VLST) were reviewed by two experienced interventional cardiologists independently. A consensus was established between reviewers or, in the event of divergent results, by a third reviewer.

Data Collection

Clinical follow-up information was obtained from hospital records or telephone interviews with the patients and their relatives every 3 months until 3 years after discharge. MACE were defined as nonfatal MI, recurrent of stent thrombosis, target vessel revascularization (TVR), heart failure requiring hospitalization, and all-cause death. Recurrent stent thrombosis was defined according to the ARC stent thrombosis definitions [6]. The diagnosis of myocardial infarction (MI) conformed to the 2012 ESC global definition of acute MI. TVR was defined as ischemia-driven PCI or coronary artery bypass grafting (CABG) performed in the same vessel as the index PCI.

Statistical Analysis

Data are summarized as numbers (and percentages) for categorical variables. Continuous variables are expressed as mean ± SD. Qualitative data were compared with chi-square or Fisher’s exact tests, whereas quantitative data were compared with the Mann-Whitney U test. All tests were two-sided and had a significance level of 0.05. Predictors of MACE were assessed with Cox regression, with univariate and multivariate analyses. Kaplan-Meier survival analyses were used to demonstrate the cumulative incidence of MACE and estimate MACE-free survival. Various correction methods were applied according to specific situations. Statistical analysis was performed in Statistical Package for Social Sciences version 23 (SPSS, Chicago, IL, USA).

Results

Patient Characteristics

In this follow-up study, 564 patients with an angiographically confirmed VLST were enrolled. The clinical characteristics of the patients are shown in Table 1. Angiographic and interventional parameters for both procedures are shown in Table 2. A total of 428 men (75.89%) were included in this study, and the average age was 61.61 ± 10.71 (29–91) years. The mean time from the index PCI to the occurrence of VLST was 1678.91 ± 1167.22 (365–5247) days. The clinical diagnosis for the index PCI was acute MI in 394 (69.86%) patients. Most patients (n = 546, 96.81%) had acute MI and underwent emergent PCI. Of these, 12 (2.12%) patients presented with cardiac arrest, and 18 (3.19%) patients had complications of cardiogenic shock. VLST occurred most frequently in the left anterior descending artery (LAD) (LAD, 51.06%; right coronary artery, 32.62%; circumflex, 16.31%). VLST was associated with a first-generation drug-eluting stent (DES) in 442 patients (78.37%) and a second-generation DES in 122 (21.63%) patients. Additionally, 222 (39.36%) patients were taking clopidogrel at the time of VLST, 302 (53.55%) patients were taking aspirin, and 218 (38.65%) patients were undergoing dual antiplatelet therapy (DAPT).

Table 1

Patient Characteristics.

Variables	Overall (n = 564)	Event free (n = 364)	With event (n = 200)	P value
Baseline characteristics
Age (years)	61.61 ± 10.71	60.18 ± 10.42	64.23 ± 10.00	.001
Male, n (%)	428 (75.89%)	282 (77.47%)	146 (73%)	.401
BMI (kg/m2)	24.74 ± 2.73	24.96 ± 2.81	24.33 ± 2.54	.070
History of HT, n (%)	308 (54.61%)	192 (34.04%)	116 (58%)	.072
History of DM, n (%)	210 (37.23%)	122 (33.52%)	88 (44%)	.397
History of HL, n (%)	74 (13.12%)	44 (12.09%)	30 (15%)	.081
Current drinking, n (%)	82 (14.54%)	48 (13.19%)	34 (17%)	.488
Current smoking, n (%)	336 (59.57%)	206 (56.596%)	130 (65%)	.379
History of MI, n (%)	384 (68.09%)	250 (68.68%)	134 (67%)	.379
History of HF, n (%)	62 (10.99%)	14 (3.85%)	48 (24%)	.772
AMI as initial diagnosis, n (%)	394 (69.86%)	256 (70.33%)	138 (69%)	.401
STEMI as initial diagnosis, n (%)	268 (47.52%)	158 (43.41%)	110 (55%)	.062
Duration to occurrence of VLST (days)	1678.91 ± 1165.14	1515.21 ± 1105.50	1976.84 ± 1222.16	.001
Cardiac arrest, n (%)	12 (2.13%)	6 (1.65%)	6 (3%)	.484
Cardiac shock, n (%)	18 (3.19%)	6 (1.65%)	12 (6%)	.669
Systolic pressure (mmHg)	132.74 ± 20.85	133.46 ± 19.57	131.43 ± 23.04	.623
Diastolic pressure (mmHg)	78.35 ± 11.36	78.86 ± 11.44	77.41 ± 11.22	.572
Heart rate (bpm)	76.27 ± 14.22	75.13 ± 14.44	78.35 ± 13.63	.019
Killip ≥2, n (%)	80 (14.18%)	22 (6.04%)	58 (29%)	<0.001
Laboratory tests
Peak troponin I (ng/mL)	42.57 ± 83.98	33.04 ± 71.09	59.91 ± 101.54	.023
WBC (×109/L)	9.54 ± 3.45	9.14 ± 3.02	10.28 ± 4.03	.026
RBC (×1012/L)	4.62 ± 0.58	4.65 ± 0.59	4.57 ± 0.55	.143
HGB (g/L)	140.48 ± 17.49	141.63 ± 17.58	138.39 ± 17.23	.090
Platelets (×109/L)	213.73 ± 64.56	213.32 ± 64.86	214.47 ± 64.34	.685
TC (mmol/L)	4.38 ± 1.33	4.38 ± 1.26	4.37 ± 1.45	.716
LDL (mmol/L)	2.71 ± 1.05	2.71 ± 1.07	2.73 ± 1.01	.787
HDL (mmol/L)	1.12 ± 0.26	1.12 ± 0.27	1.12 ± 0.25	.843
TG (mmol/L)	2.04 ± 1.29	2.08 ± 1.38	1.96 ± 1.11	.977
Fasting blood glucose (mmol/L)	7.17 ± 3.12	7.00 ± 3.18	7.49 ± 2.99	.051
HbA1c (%)	6.54 ± 1.83	6.50 ± 1.92	6.61 ± 1.64	.269
Fibrinogen (g/L)	3.37 ± 0.96	3.33 ± 0.93	3.45 ± 1.00	.193
eGFR (mL/min/1.73 m2)	94.22 ± 21.43	97.34 ± 18.30	88.54 ± 25.32	.001
LVEF (%)	51.21 ± 8.95	53.44 ± 7.25	47.14 ± 10.27	<0.001
Medications before VLST
Aspirin, n (%)	302 (53.55%)	200 (54.95%)	102 (51%)	.834
Clopidogrel, n (%)	222 (39.36%)	154 (42.31%)	68 (34%)	.525
Statins, n (%)	258 (45.74%)	178 (48.9%)	80 (40%)	.214
Discharge medications (n = 548, 364, 184 per group)
Aspirin, n (%)	498 (90.88%)	340 (93.41%)	158 (85.87%)	.001
Clopidogrel, n (%)	268 (47.52%)	182 (50%)	86 (46.74%)	.041
Ticagrelor, n (%)	126 (22.34%)	80 (21.98%)	46 (25%)	.610
DAPT, n (%)	374 (66.31%)	248 (68.13%)	126 (68.48%)	.954
Statins, n (%)	460 (81.56%)	306 (84.07%)	154 (83.70%)	.937
ACEI/ARB, n (%)	292 (51.77%)	202 (55.49%)	90 (48.91%)	.366
β blockers, n (%)	336 (59.57%)	242 (66.48%)	94 (51.09%)	.302

ACEI, angiotensin converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin receptor inhibitor; CABG, coronary artery bypass graft; DAPT, dual antiplatelet therapy; EES, everolimus eluting stent; eGFR, estimated glomerular filtration rate; HDL, high density lipoprotein; HGB, hemoglobin; LAD, left anterior descending artery; LCX, left circumflex artery; LDL, low density lipoprotein; LM, left main; LVEF, left ventricular eject fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; RCA, right coronary artery; SES, sirolimus eluting stent; TCL, total cholesterol; TG, triglyceride; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction; WBC, white blood cell; VLST, very late stent thrombosis; ZES, zotarolimus eluting stent.

Table 2

Angiographic and Interventional Characteristics of both Procedures.

Variables	Overall (n = 564)	Event free (n = 364)	With event (n = 200)	P value
Parameters during index PCI
No. of diseased vessels, n (%)	2.20 ± 0.80	2.12 ± 0.81	2.34 ± 0.78	.025
PCI related vessel
LAD, n (%)	288 (51.06%)	186 (51.10%)	102 (51%)	.987
LCX, n (%)	92 (16.31%)	62 (17.03%)	30 (15%)	.658
RCA, n (%)	184 (32.62%)	116 (31.87%)	68 (34%)	.631
Chronic total occlusion, n (%)	32 (5.67%)	22 (6.04%)	10 (5%)	.005
Severe calcification, n (%)	14 (2.48%)	8 (2.20%)	6 (3%)	.989
Severe tortuosity, n (%)	12 (2.13%)	6 (1.65%)	6 (3%)	.666
Ostial lesion, n (%)	30 (5.32%)	24 (6.59%)	6 (3%)	.761
Proximal lesion, n (%)	406 (71.99%)	260 (71.43%)	146 (73%)	.198
Bifurcation lesion, n (%)	128 (22.70%)	84 (23.08%)	44 (22%)	.836
Visual thrombosis, n (%)	30 (5.32%)	22 (6.04%)	8 (4%)	.464
Vessel dilation, n (%)	8 (1.42%)	4 (1.10%)	4 (2%)	.349
Two stent technique during index PCI, n (%)	12 (2.13%)	8 (2.20%)	4 (2%)	.912
Aspiration during procedure, n (%)	36 (6.38%)	28 (4.96%)	8 (4%)	.912
Stent type during index PCI
SES, n (%)	442 (78.37%)	274 (75.27%)	168 (84%)	.134
ZES, n (%)	62 (11.00%)	46 (12.64%)	16 (8%)	.234
EVS, n (%)	62 (11.00%)	44 (12.09%)	18 (9%)	.428
Stent overlap, n (%)	178 (31.56%)	108 (29.67%)	70 (35%)	.357
Post-dilation, n (%)	126 (22.34%)	86 (23.63%)	40 (20%)	.357
Minimum stent diameter (mm)	2.89 ± 0.37	2.91 ± 0.38	2.84 ± 0.33	.130
Maximum stent diameter (mm)	2.99 ± 0.37	3.03 ± 0.38	2.93 ± 0.33	.042
Total stent length (mm)	39.63 ± 19.47	38.62 ± 20.04	41.47 ± 18.34	.026
Release pressure (atm)	13.46 ± 2.73	13.62 ± 2.88	13.16 ± 2.42	.171
No. of stents per artery	1.42 ± 0.64	1.40 ± 0.64	1.44 ± 0.66	.579
Parameters during PCI for VLST
Spontaneous recanalization after AMI, n (%)	228 (40.43%)	146 (40.11%)	82 (41%)	<0.001
Aspiration during procedure, n (%)	102 (18.09%)	60 (16.48%)	42 (21%)	.884
Revascularization therapy
Angioplasty only, n (%)	212 (37.59%)	126 (34.62%)	86 (43%)	.346
Re-stenting, n (%)	336 (59.57%)	224 (61.54%)	118 (54%)	.218
CABG, n (%)	20 (3.55%)	14 (3.85%)	6 (3%)	.975
Stent type during re-stenting
SES (n = 334, 226, 108 in each group)	208 (62.28%)	134 (59.29%)	74 (68.52%)	.713
ZES (n = 334, 226, 108 in each group)	80 (23.95%)	60 (26.55%)	20 (18.52%)	.250
EVS (n = 334, 226, 108 in each group)	46 (13.77%)	32 (14.16%)	14 (12.96%)	.255

AMI, acute myocardial infarction; CABG, coronary artery bypass graft; CABG, coronary artery bypass graft; EES, everolimus eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery; PCI, percutaneous coronary intervention; SES, sirolimus eluting stent; ZES, zotarolimus eluting stent.

Parameters of Emergent PCI for VLST

The parameters for emergent PCI for VLST are listed in Table 2. Spontaneous reperfusion occurred in 228 patients (40.43%), and thrombus aspiration was performed in 102 (18.09%) patients. Of these, 184 patients (32.62%) were treated with balloon angioplasty only, 24 patients (4.26%) were treated with drug coated balloons after balloon angioplasty, 332 patients (58.87%) underwent balloon angioplasty followed by implantation of an additional stent, and 20 patients (3.55%) underwent CABG after urgent coronary angiography.

Outcomes of Patients with VLST

After a median follow-up of 620 (249–1281) days, MACE occurred in 200 (35.46%) patients. Sixteen patients (2.8%) died of a cardiac cause during hospitalization. At the longest available follow-up, 24 of 40 deaths (60%) were cardiac in nature. The cumulative incidence of all-cause mortality and cardiac mortality was 3.7% and 2.1%, respectively, at 1 year; 7.2% and 5.1%, respectively, at 2 years; and 12.1% and 8.4%, respectively at 3 years. During the follow-up, heart failure requiring hospitalization occurred in 122 (21.63%) patients, 86 of whom (70.5%) had MI twice, and 70 (57.4%) of whom had LAD lesions. The cumulative incidence of heart failure requiring hospitalization at 1, 2, and 3 years was 15.6%, 20.7%, and 27.1%, respectively. A total of 44 (7.8%) cases of angiographically confirmed recurrent stent thrombosis were observed. The timing of definite recurrent stent thrombosis was subacute in two patients, late in 18 patients, and very late in 24 patients. The cumulative incidence of definite recurrent stent thrombosis at 30 days, and 1, 2, and 3 years was 0.4%, 3.8%, 6.8%, and 11.3%, respectively. Of note, recurrent stent thrombosis was the most common cause of MI (84%) during follow up. At the longest follow-up, TVR (including emergent PCI for recurrent stent thrombosis) was performed in 64 (11.35%) patients: 62 (96.88%) with repeated PCI and 2 (3.12%) with CABG. Twenty-four (37.5%) TVRs were associated with angioplasty only, 6 (9.38%) were associated with balloon angioplasty followed by drug coated balloons, and 32 (50%) were associated with additional DES implantation.

At the longest available follow-up, continuous DAPT had been administered to 374 (68.25%) patients. In the remaining patients, aspirin or clopidogrel was taken at least 1 year after the occurrence of VLST, but no significant difference was observed between patients with versus without MACE. Moreover, no significant difference was found among revascularization strategies (angioplasty alone, 37.59%, P = 0.346; re-stent, 58.87%, P = 0.218; CABG, 3.55%, P = 0.975). Kaplan-Meier survival analysis indicated that the estimated MACE free survival during follow-up was only 22% (Figure 1). After adjustment in the Cox proportional hazard model, peak troponin I and left ventricular ejection fraction (LVEF) were found to be independent predictors of MACE (Table 3 and Supplementary Table S1).

Figure 1

Kaplan–Meier Cumulative Major Adverse Cardiac Event (MACE)-Free Survival During Follow-Up.

Table 3

Multivariable Cox Regression Analysis of the Predictors of MACE.

Variables	HR	95%CI	P value
Age	1.012	0.989–1.012	.302
Killip ≥2	1.675	0.999–2.801	.051
Peak troponin I	1.003	1.001–1.005	.015
WBC	1.029	0.967–1.095	.369
LVEF	0.960	0.940–0.981	<0.001
eGFR	0.995	0.985–1.005	.337

eGFR, estimated glomerular filtration rate; LVEF, left ventricular eject fraction; WBC, white blood cell.

Discussion

This observational study in a large cohort of patients with definite VLST demonstrated that the clinical outcomes after revascularization remained unfavorable despite improvements in various revascularization strategies. Peak troponin I and LVEF were independent predictors of MACE in this group of patients.

The rates of in-hospital mortality and long-term mortality observed in patients with VLST were similar to those previously reported (3% and 10%, respectively) [7–10]; hence, our findings suggested that no improvement was achieved in mortality during the past decade. The high incidence of heart failure was remarkable. More than one-fifth of patients had heart failure requiring hospitalization during the follow-up. Prior studies on the prognosis of patients with VLST have rarely paid substantial attention to readmission for heart failure [7, 8], although this complication is not rare among patients with VLST. Possible explanations for the high incidence of heart failure may include the following: first, patients who receive PCI for MI might be likely to develop stent thrombosis [11]; second, most patients with VLST have acute MI [12]; third, stented LADs are likely to develop VLST [13]. Currently, recurrent stent thrombosis and TVR have not been completely eradicated. In this study, the incidence of both events was lower than previously reported [7, 8], possibly because of progress in PCI technology and the application of more effective antiplatelet agents in recent years.

Given the observational nature of the present study, the best available treatment for VLST could not be determined. Previous observational studies have reported varying results regarding the effects of angioplasty alone and re-stenting in patients with stent thrombosis [7, 10, 13, 14]. In this study, no significant difference in long-term outcomes was observed among revascularization strategies. Of note, intravascular ultrasound or optical coherence tomography may provide new insights into the treatment of patients with VLST [9], and randomized controlled trials are urgently needed to determine the optimal revascularization strategy for this group of patients. Moreover, controversy regarding the duration of DAPT after DES implantation persists. Previous studies have shown that prolonged DAPT may decrease ischemic events but increase bleeding events, without changing the overall prognosis [15]. Studies in patients with VLST have indicated that extending the duration of DAPT might improve overall prognosis [7]. However, in this study, all patients received standard antiplatelet therapy for more than 1 year after PCI. More than half the patients received aspirin at the onset of VLST, and nearly one-third of the patients received DAPT, yet VLST nonetheless occurred. Moreover, long-term antiplatelet therapy was not found to decrease the incidence of MACE in this study. The DAPT guidelines released in 2017 recommended shortening the duration of DAPT according to the DAPT risk score [16]. Hence, individualized anti-platelet therapy based on patient characteristics and the results of intravascular imaging might be favorable. Additionally, although univariable Cox regression analysis indicated that age, Killip ≥2, peak troponin I, WBC count, LVEF, and eGFR were possible predictors of MACE after VLST in this study, multivariable Cox regression analysis confirmed that the independent risk factors affecting the prognosis were LVEF and peak troponin I, thus potentially indicating diminished heart function after recurrence of myocardial infarction. Therefore, VLST prevention might be more important than treatment. Identifying potential high-risk patients with VLST and providing active intervention as early as possible might be a valuable strategy to avoid VLST. However, determining the pathogenesis underlying VLST is much more important. We have obtained serum samples from patients before and after the initial PCI, and hope to find additional clues regarding VLST pathogenesis.

This study had several limitations. First, this study was an observational study, and the sample size was insufficient to allow for more specific subgroup analysis; second, because few patients underwent intravascular imaging, the effects of such imaging on prognosis were not determined; third, the observational nature of the present study did not enable the effects of different revascularization strategies on prognosis to be assessed.

Conclusion

Long-term outcomes after revascularization for VLST remained unfavorable. LVEF and peak troponin I at VLST onset were independent risk factors for poor prognosis.

Data Availability Statement

Data will be made available if required.

Ethics Statement

The study was approved by our institute’s ethics committee (No. 2013-256). Written consent for submission and publication of this research was obtained from the patients.

Author Contributions

Yang Zheng, Xinxin Chen, and Xiang Wang conceived and designed the paper. Yunqing Hou, Yan Gu, and Muli Wu coordinated the data acquisition. Xiang Wang and Yang Zheng contributed to critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. Xiang Wang and Xinxin Chen were responsible for the overall content of the article and data analysis.

Conflicts of Interest

The authors of this work have no conflict of interest to declare.

Supplementary Material

Supplementary material for this paper is available at https://cvia-journal.org/wp-content/uploads/2024/03/supplementary_table.pdf

Citation Information

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