Abstract
Background:
Stent thrombosis (ST) is a serious complication after drug-eluting stents (DES) implantation. To identify the risk factors of mortality following ST, we evaluated adverse event reports used for safety measures after approval.
Methods and Results:
Between July 2004 and August 2019, 2,887 ST case reports were submitted to the Pharmaceutical and Medical Device Agency. Reports of probable or possible ST (n=604), with insufficient data regarding in-hospital outcome or duration between procedure and ST occurrence (n=37) or duplicate reports (n=191) were excluded. Accordingly, 2,045 reports with definite ST were analyzed. Among the subjects, there were 286 in-hospital deaths (14.0%). Multivariate logistic regression analysis revealed that left main trunk (LMT) (odds ratio [OR]: 4.76, 95% confidence interval [CI]: 3.26–6.96), chronic heart failure (CHF) (OR: 2.88, 95% CI: 1.61–5.14), hemodialysis (OR: 2.69, 95% CI: 1.66–4.36), prior stroke (OR: 2.28, 95% CI: 1.15–4.51), over 70 years old (OR: 1.62, 95% CI: 1.22–2.16), and right coronary artery (OR: 0.41, 95% CI: 0.27–0.63) were independent factors for in-hospital death after DES-ST.
Conclusions:
LMT, CHF, hemodialysis, prior stroke, and older age were independently associated with higher risk of in-hospital death following DES-ST. If target patients have these factors, maximum preventive strategies against ST occurrence, including adequate dual-antiplatelet therapy duration and optimal DES deployment procedures, are required.
Stent thrombosis (ST) is a very rare but serious complication following drug-eluting stent (DES) implantation,1
Despite reports showing that ST is associated with unfavorable mortality rates,2–8
there is some limited information on the risk factors for death with DES-ST.2
Clinical outcomes following ST differ for each patient, so it is important to identify the key variables that determine death following ST to enable physicians to provide appropriate healthcare services.
Editorial p 1464
In Japan, since the first approval of DES in 2004, the manufacturers have been required to conduct a comprehensive survey of ST to satisfy the conditions for approval under the Pharmaceuticals and Medical Devices Act. The survey is used as a safety monitoring tool after the approval of each DES product. In this respect, ST case reports have been submitted regularly to the Pharmaceuticals and Medical Devices Agency (PMDA), which is the Japanese regulatory agency.
In the present study, we surveyed the characteristics of ST cases and evaluated independent factors for in-hospital death subsequent to DES-ST using data from the Japanese adverse event reporting system.
Methods
Study Design
Between July 2004 and August 2019, a total of 2,877 ST case reports were submitted to the PMDA ST reporting system by DES manufacturers. Of these, those reporting probable or possible ST (n=604), those with insufficient data regarding the date of procedure, ST occurrence date and in-hospital outcome (n=37), and those with a duplicate report for the same patient (n=191) were excluded, as judged by an independent PMDA reviewer. Finally, 2,045 subjects were identified as having angiographic definite ST and were included in the analysis (Figure 1). ST was defined according to the Academic Research Consortium definition.9
Definite ST was categorized according to the time of occurrence: early ST (EST) was defined as within 30 days after stent implantation, late ST (LST) as 31–365 days after stent deployment, and very late ST (VLST) as >365 days after stent implantation. The analysis included the following types of DES subjected to conditional approval: sirolimus-eluting Cypher stent series (Cordis Corp, Johnson & Johnson, Warren, NJ, USA), paclitaxel-eluting TAXUS stent series (Boston Scientific, Natick, MA, USA), everolimus-eluting XIENCE stent series (Abbott Vascular, Santa Clara, CA, USA), everolimus-eluting PROMUS stent series (Boston Scientific), everolimus-eluting SYNERGY stent (Boston Scientific), zotarolimus-eluting Endeavor stent series (Medtronic, Santa Rosa, CA, USA), zotarolimus-eluting Resolute stent series (Medtronic), and biolimus A9-eluting NOBORI stent (Terumo, Tokyo, Japan).
Case data were collected from institutions across Japan by each DES manufacturer under the “Good Post-marketing Study Practice Ordinance” of the Japanese Ministry of Health, Labor, and Welfare, which is the Japanese system to ensure the quality and reliability of the survey. Each case report was made based on information provided by the physician in charge. After submission of a case report, multiple reviewers in the safety department of the PMDA discuss and confirm the diagnosis. If necessary, queries are sent to the manufacturer to collect additional information. Informed consent from individual patients was waived, because post-marketing surveillance to collect adverse event reports for medical device is legally obligated to the marketing authorization holder under the provision of the Pharmaceuticals and Medical Devices Act in Japan. The protocol of the study was approved by the PMDA IRB, which consists of external experts (certification no. H30-A-2), and followed the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation.
Statistical Analysis
Continuous variables are presented as the mean with standard deviation. Differences in continuous parameters were evaluated using an unpaired t-test. Categorical variables are presented as frequency counts and intergroup comparisons were made using Fisher’s exact test or the Chi-square test. To identify independent factors for in-hospital death with ST, a multivariable logistic regression model was constructed using independent variables that were chosen as potentially significant independent factors with a P-value <0.20 by univariate analysis. The final model was obtained using a forward stepwise method with a threshold for exit set at a P-value >0.10. We also added the interaction terms between ST timing and variables into the final model. Factors in each comparison are expressed as odds ratios (ORs) and their 95% confidence intervals (CIs). Statistical analysis was performed using SPSS Statistics software (version 22.0, SPSS Inc., Chicago, IL, USA). A P-value <0.05 was considered statistically significant.
Results
Study Population
A total of 2,045 patients were identified as having angiographic definite ST. The distribution of ST occurrence is shown in
Figure 2. There were 1,288 patients with EST (63.0%), 307 with LST (15.0%), and 450 with VLST (22.0%). The time to ST after stent implantation was minimum, 0.5 h; 25th percentile, 3.0 days; median, 10.0 days; 75th percentile, 223.8 days; and maximum, 2,679 days after PCI.
Baseline Characteristics
Patient, lesion, and procedural characteristics at baseline, which is the time of deployment of the DES related to ST, are shown in
Table 1. A comparison of patient characteristics between those with definite ST and those with probable/possible ST is provided in
Supplementary Table 1A
and a comparison of baseline characteristics among the different timing of ST is shown in
Supplementary Table 1B. The mean patient age was 66.9 years and the proportion of patients over 70 years of age was 45.5%. Most patients (82.7%) were male and approximately 60% presented with stable angina.
Table 1.
Baseline Characteristics
| |
Total patients
(n=2,045) |
Hospital non-survivors
(n=286) |
Hospital survivors
(n=1,759) |
P value |
| Patient-related |
| Age, years |
66.9±11.4 |
70.0±11.8 |
66.4±11.2 |
<0.001 |
| >70 years, % |
45.5 (863/1,897) |
57.4 (159/277) |
43.5 (704/1,620) |
<0.001 |
| Male sex, % |
82.7 (1,634/1,976) |
78.9 (220/279) |
83.3 (1,414/1,697) |
0.07 |
| Prior PCI, % |
37.9 (765/2,017) |
42.0 (119/283) |
37.3 (646/1,734) |
0.13 |
| Prior MI, % |
21.4 (450/2,017) |
27.2 (77/283) |
21.5 (373/1,734) |
0.037 |
| Prior CABG, % |
4.4 (89/2,017) |
5.3 (15/283) |
4.3 (74/1,734) |
0.44 |
| Chronic heart failure, % |
4.1 (81/1,997) |
7.9 (22/279) |
3.4 (59/1,718) |
0.001 |
| Diabetes mellitus, % |
42.1 (842/1,998) |
48.4 (135/279) |
41.1 (707/1,719) |
0.026 |
| Hyperlipidemia, % |
50.2 (1,002/1,997) |
49.8 (139/279) |
50.2 (863/1,718) |
0.95 |
| Hypertension, % |
63.0 (1,259/1,997) |
66.7 (186/279) |
62.5 (1,073/1,718) |
0.18 |
| Prior stroke, % |
3.1 (62/1,997) |
5.7 (16/279) |
2.7 (46/1,718) |
0.014 |
| Peripheral artery disease, % |
3.1 (61/1,997) |
4.3 (12/279) |
2.9 (49/1,718) |
0.19 |
| Current smoker, % |
34.7 (693/1,996) |
29.7 (83/279) |
35.5 (610/1,717) |
0.07 |
| Chronic kidney disease, % |
12.4 (247/1,998) |
16.5 (46/279) |
11.7 (201/1,719) |
0.031 |
| Hemodialysis, % |
5.7 (114/1,998) |
9.3 (26/279) |
5.1 (88/1,719) |
0.008 |
| Clinical presentation |
|
|
|
0.47 |
| Stable angina, % |
60.6 (1,220/2,013) |
57.4 (163/284) |
61.1 (1,057/1,729) |
|
| Unstable angina, % |
13.4 (270/2,013) |
14.1 (40/284) |
13.3 (230/1,729) |
|
| AMI, % |
26.0 (523/2,013) |
28.5 (81/284) |
25.6 (442/1,729) |
|
| Lesion-related |
| ST vessel, % |
|
|
|
<0.001 |
| LMT |
8.5 (174/2,036) |
26.7 (76/285) |
5.6 (98/1,751) |
|
| LAD |
53.7 (1,093/2,036) |
49.8 (142/285) |
54.3 (951/1,751) |
|
| LCX |
12.4 (252/2,036) |
9.8 (28/285) |
12.8 (224/1,751) |
|
| RCA |
25.4 (517/2,036) |
13.7 (39/285) |
27.3 (478/1,751) |
|
| Lesion type |
| ACC-AHA class (B2/C), % |
83.5 (1,666/1,996) |
86.9 (239/275) |
82.9 (1,427/1,721) |
0.12 |
| ISR lesion, % |
14.9 (294/1,976) |
11.9 (33/278) |
15.4 (261/1,698) |
0.15 |
| Small vessel lesion (≤2.5 mm), % |
27.8 (543/1,950) |
23.1 (60/260) |
28.6 (483/1,690) |
0.07 |
| Moderate/severe calcified lesion, % |
36.8 (737/2,003) |
44.0 (122/277) |
35.6 (615/1,726) |
0.009 |
| CTO, % |
9.0 (181/2,006) |
5.1 (14/277) |
9.7 (167/1,729) |
0.012 |
| Diffuse lesion (>20 mm), % |
55.4 (1,113/2,009) |
58.3 (162/278) |
54.9 (951/1,731) |
0.33 |
| Bifurcation lesion, % |
30.5 (613/2,007) |
44.6 (124/278) |
28.3 (489/1,729) |
<0.001 |
| Procedure-related |
| Stents/lesion, n |
1.54±0.73 |
1.70±0.74 |
1.52±0.73 |
<0.001 |
| Predilatation, % |
77.9 (1,544/1,982) |
81.3 (221/272) |
77.4 (1,323/1,710) |
0.16 |
| Post-dilatation, % |
59.1 (1,170/1,980) |
65.1 (177/272) |
58.1 (993/1,708) |
0.034 |
| Overlap stenting, % |
40.8 (829/2,031) |
50.9 (145/285) |
39.2 (684/1,746) |
<0.001 |
| Use of rotablation, % |
3.7 (74/2,003) |
5.0 (14/279) |
3.5 (60/1,724) |
0.23 |
| Intravascular imaging modality, % |
62.4 (1,235/1,979) |
62.2 (171/275) |
62.4 (1,064/1,704) |
0.95 |
| 1 st-generation DES, % |
67.3 (1,376/2,045) |
59.4 (170/286) |
68.6 (1,206/1,759) |
0.003 |
All values are % (n) or mean±standard deviation. ACC, American College of Cardiology; AHA, American Heart Association; AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CTO, chronic total occlusion; DES, drug-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; LMT, left main trunk; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; ST, stent thrombosis.
There were 286 in-hospital deaths after ST occurrence (14.0%). When compared with the timing of ST, mortality was 15.1% for EST, 16.9% for LST and 8.9% for VLST. According to clinical outcome following ST, all subjects were divided either the hospital non-survivors group (n=286) or the hospital survivors group (outcome defined as discharge, recovered or resolved) (n=1,759). The duration between baseline DES implantation and ST occurrence was minimum: 0 day, 25th percentile: 3.0 days, median: 10.0 days, 75th percentile: 61.25 days, and maximum: 1,703 days in the hospital non-survivors, and minimum: 0 day, 25th percentile: 3.0 days, median: 11.0 days, 75th percentile: 267.5 days, and maximum: 2,679 days in the hospital survivors. The duration between ST occurrence and outcome confirmation date was minimum: 0 day, 25th percentile: 0 day, median: 1.0 days, 75th percentile: 5.0 days, and maximum: 221 days in the hospital non-survivors and minimum: 1 days, 25th percentile: 5.0 days, median: 11.5 days, 75th percentile: 19.0 days, and maximum: 82 days in the hospital survivors.
The comparison of patient, lesion, and procedural background of patients with in-hospital death or in-hospital survival is shown in
Table 1. At baseline, non-survivors were significantly older than survivors. More non-survivors had prior myocardial infarction (MI), chronic heart failure (CHF), diabetes mellitus, chronic kidney disease (CKD), and received hemodialysis. With regard to lesion background, the proportion of ST-related coronary vessels, especially the prevalence of left main trunk (LMT) disease, moderate to severely calcified lesion, and bifurcation lesion was significantly higher in non-survivors than in survivors. The proportion of 1st-generation DES devices such as Cypher and TAXUS was significantly different between non-survivors and survivors.
ST Characteristics
Information regarding ST is given in
Table 2. The rate of dual-antiplatelet therapy (DAPT) at the time of ST did not differ between the 2 groups. On comparison of the timing of ST, DAPT was administered in 87.8% of EST, 71.3% of LST, and 33.9% of VLST cases. The proportion of VLST was significantly lower in non-survivors than in survivors. PCI was performed for >90% of patients as treatment for ST in both groups. Most patients underwent thrombus aspiration and balloon angioplasty. The rate of intra-aortic balloon pumping (IABP) and percutaneous cardiopulmonary support (PCPS) was significantly different between groups.
Table 2.
Status of Antiplatelet Therapy, and Timing and Treatment of ST
| |
Total patients
(n=2,045) |
Hospital non-survivors
(n=286) |
Hospital survivors
(n=1,759) |
P value |
| DAPT at the time of ST occurrence, % |
73.5 (1,489/2,027) |
78.0 (220/282) |
72.7 (1,269/1,745) |
0.07 |
| Aspirin |
87.0 (1,763/2,027) |
86.9 (245/282) |
87.0 (1,518/1,745) |
1.00 |
| Clopidogrel |
38.2 (775/2,027) |
47.2 (133/282) |
36.8 (642/1,745) |
0.001 |
| Prasugrel |
2.6 (53/2,027) |
1.4 (4/282) |
2.8 (49/1,745) |
0.25 |
| Ticlopidine |
33.4 (678/2,027) |
31.6 (89/282) |
33.8 (589/1,745) |
0.51 |
| Other antiplatelet agent* |
9.4 (191/2,027) |
5.3 (15/282) |
10.0 (176/1,745) |
0.02 |
| Time of ST |
|
|
|
0.014 |
| Early |
63.0 (1,288/2,045) |
67.8 (194/286) |
62.2 (1,094/1,759) |
|
| Late |
15.0 (307/2,045) |
18.2 (52/286) |
14.5 (255/1,759) |
|
| Very late |
22.0 (450/2,045) |
14.0 (40/286) |
23.3 (410/1,759) |
|
| Treatment for ST |
| PCI for ST, % |
95.7 (1,950/2,038) |
93.7 (268/286) |
96.0 (1,682/1,752) |
0.08 |
| Thrombectomy, % |
70.0 (1,406/2,008) |
71.7 (203/283) |
69.7 (1,203/1,725) |
0.53 |
| Balloon angioplasty, % |
84.1 (1,714/2,008) |
82.5 (232/283) |
85.9 (1,482/1,725) |
0.09 |
| BMS implantation, % |
12.1 (243/2,009) |
11.7 (33/283) |
12.2 (210/1,726) |
0.92 |
| DES implantation, % |
14.8 (297/2,009) |
10.6 (30/283) |
15.5 (267/1,726) |
0.037 |
| IABP, % |
24.0 (483/2,015) |
46.8 (131/280) |
20.3 (352/1,735) |
<0.001 |
| PCPS, % |
7.5 (152/2,018) |
35.3 (100/283) |
3.0 (52/1,735) |
<0.001 |
| CABG for ST, % |
2.7 (54/2,033) |
1.1 (3/285) |
2.9 (51/1,748) |
0.07 |
All values are % (n). *Other platelet agent includes cilostazol and sarpogrelate. BMS, bare metal stent; DAPT, dual-antiplatelet therapy; IABP, intra-aortic balloon pumping; PCPS, percutaneous cardiopulmonary support. Other abbreviations as in Table 1.
The multivariable analysis identified significant independent factors for in-hospital death, including LMT disease (OR: 4.76, 95% CI: 3.26–6.96), CHF (OR: 2.88, 95% CI: 1.61–5.14), hemodialysis (OR: 2.69, 95% CI: 1.66–4.36), prior stroke (OR: 2.28, 95% CI: 1.15–4.51), age >70 years (OR: 1.62, 95% CI: 1.22–2.16), and right coronary artery (RCA) disease (OR: 0.41, 95% CI: 0.27–0.63) (Table 3). In the multivariable analysis, the timing of ST and the generation of DES were not significantly associated with in-hospital death. None of the interactions we tested were significant.
Supplementary Table 2
shows the multivariable logistic regression model using independent variables chosen as potential independent factors with a P-value <0.10 by univariate analysis. In this additional analysis, significant independent factors for in-hospital death were consistent with the original analysis.
Table 3.
Univariate and Multivariate Analyses Investigating the Relationship Between Lesion-Related Variables and In-Hospital Mortality Due to ST
| Independent variables |
Hospital mortality |
| Univariate analysis |
Multivariable analysis |
| OR (95% CI) |
P value |
OR (95% CI) |
P value |
| LMT |
5.73 (4.00–8.21) |
<0.001 |
4.76 (3.26–6.96) |
<0.001 |
| Chronic heart failure |
2.41 (1.45–4.00) |
<0.001 |
2.88 (1.61–5.14) |
<0.001 |
| Hemodialysis |
2.17 (1.46–3.22) |
<0.001 |
2.69 (1.66–4.36) |
<0.001 |
| Prior stroke |
2.21 (1.23–3.96) |
<0.001 |
2.28 (1.15–4.51) |
0.018 |
| Age >70 years |
1.71 (1.30–2.25) |
<0.001 |
1.62 (1.22–2.16) |
0.001 |
| RCA |
0.38 (0.26–0.57) |
<0.001 |
0.41 (0.27–0.63) |
<0.001 |
| Male |
0.75 (0.55–1.02) |
0.068 |
|
|
| Smoking |
0.77 (0.58–1.01) |
0.060 |
|
|
| Diabetes mellitus |
1.19 (0.92–1.54) |
0.178 |
|
|
| Peripheral artery disease |
1.53 (0.80–2.92) |
0.195 |
|
|
| Prior PCI |
1.23 (0.95–1.58) |
0.119 |
|
|
| Prior CABG |
1.90 (1.17–3.09) |
0.009 |
|
|
| Type B2/C |
1.37 (0.94–1.99) |
0.099 |
|
|
| Moderate/severe calcified lesion |
1.42 (1.10–1.84) |
0.007 |
|
|
| Bifurcation lesion |
2.81 (2.07–3.82) |
<0.001 |
|
|
| Small vessel disease |
0.75 (0.55–1.02) |
0.066 |
|
|
| CTO |
0.57 (0.33–1.01) |
0.053 |
|
|
| Restenosis lesion |
0.74 (0.50–1.09) |
0.130 |
|
|
| 1 st-generation DES |
0.62 (0.47–0.81) |
<0.001 |
|
|
| EST |
1.28 (0.98–1.67) |
0.068 |
|
|
| LST |
1.31 (0.94–1.82) |
0.106 |
|
|
| VLST |
0.54 (0.38–0.76) |
<0.001 |
|
|
| DAPT at the time of ST occurrence |
1.33 (0.99–1.80) |
0.063 |
|
|
| Clopidogrel use at the time of ST occurrence |
1.44 (1.11–1.85) |
0.005 |
|
|
CI, confidence interval; EST, early stent thrombosis; LST, late stent thrombosis; OR, odds ratio; VLST, very late stent thrombosis. Other abbreviations as in Tables 1,2.
In the current survey, the rate of in-hospital death following ST in the LMT was 43.7%. Comparison of variables between hospital non-survivors and survivors in the LMT subgroup is provided in
Supplementary Table 3. The rates of prior MI, CKD, hemodialysis, type B2/C, DAPT usage at the time of ST, IABP for ST, and PCPS for ST were significantly higher in the LMT hospital non-survivors than that in hospital survivors.
Discussion
In this analysis assessing the independent factors for in-hospital death of patients with DES-ST, we determined that 14.0% of patients died in hospital. LMT disease, CHF, hemodialysis, prior stroke, and age >70 years were independently associated with higher risk of death in hospital, whereas RCA disease was associated with lower risk of in-hospital death.
Some reports have revealed high mortality risk in patients with ST, ranging from 5% to 45%.2–8
The RESTART study reported 30-day mortality rates of 14.8% with EST, 15.9% with LST, and 6.3% with VLST.3
Similarly, Kerkmeijer et al reported a high all-cause mortality of 18.1% following ST occurrence.2
These results are similar to those in our analysis. Conversely, Armstrong et al reported that in-hospital mortality was 7.9% with EST, 3.8% with LST, and 3.6% with VLST in the CathPCI Registry,4
and the 30-day mortality was 13% with EST, 6% with LST, and 3% with VLST in the Veterans Affairs Clinical Assessment Reporting and Tracking (VA CART) program.5
Despite this wide variation in reported mortality, the unfavorable short-term outcomes observed in patients with EST compared with LST/VLST in the present study are consistent with those of previous studies. Approximately 60% of all ST cases were EST in both the present analysis and in the RESTART study. Likewise, nearly half of the ST cases (48%) were EST in Kerkmeijer’s report. In contrast, the proportion of EST was approximately 20% in both the CathPCI Registry and the VA CART program. Although the timing of ST was not an independent factor for in-hospital death in the current analysis, the proportion of EST might affect the mortality rate in the different studies. Another explanation for the variation in mortality could be the proportion of ST in the LMT in each study. As described next, ST in the LMT would be associated with higher risk of in-hospital death. The proportion of LMT-ST was approximately 1% in both the CathPCI Registry and VA CART program, approximately 3% in the RESTART, and 8.5% in the current analysis. Therefore, the variation in mortality rate might be attributed to the sample size, and the proportions of EST and LMT-ST in each study.
The major finding in this analysis was that LMT disease, CHF, hemodialysis, prior stroke, and age >70 years were independently associated with the risk of in-hospital death. Of these, LMT disease was the strongest factor. Despite improvements in both devices and techniques, PCI for LMT disease remains challenging. Recently, several studies have demonstrated that PCI with DES is an acceptable treatment in selected patients with LMT disease of low or intermediate anatomical complexity.10–12
Those studies reported the incidence of ST was 5.1% at 5 years in the SYNTAX LMT subgroup analysis,10
approximately 1% at 5 years in the EXCEL study,11
and 2% at 5 years in the NOBLE study.12
However, once ST occurs inside the DES implanted in the LMT, the mortality rate with LMT-ST will be higher than that with ST in the other vessels because of the large amount of myocardium at risk of ischemia. Thus, when PCI is chosen as the treatment for LMT disease, physicians should take the maximum preventive strategies against ST occurrence, including adequate DAPT duration and optimal DES deployment procedures (including stent expansion and intravascular imaging-guided PCI).
In addition, this analysis revealed that patients with CHF, hemodialysis, history of stroke, and older age were associated with increased risk of in-hospital death. These factors are well known as risk factors for death in ST presenting with ST-elevation MI (STEMI).13–15
Therefore, the current findings are consistent with previous studies, because many patients with ST present with STEMI. In contrast, RCA-ST was associated with a lower risk of in-hospital death compared with ST in other vessels, a finding that is consistent with the results of previous studies.16,17
A possible reason for this is that the damaging effect on left ventricular function is often more severe with occlusion of the left coronary artery than with the RCA.16,17
ST is a very rare complication of DES, with a reported incidence of 0.5% per year.18–20
Therefore, it is impractical to conduct a prospective clinical trial to evaluate DES-ST. Real-world data (RWD) are data related to patient health status and/or the delivery of healthcare routinely derived from a variety of sources such as disease registries, electronic health records, and healthcare claims databases.21,22
The collection of RWD has the potential to complement knowledge obtained from traditional clinical trials limited to specialized research settings, limited sample sizes, specific study populations, and limited follow-up periods. Nonetheless, even using RWD, it would be difficult to collect sufficient data related to low-incidence events. We consider that data collection from real-world adverse event reports may represent a useful and efficient method to evaluate serious but very rare adverse events such as ST.23
Study Limitations
First, there was limited information concerning the results of laboratory investigations, echocardiographic findings, and medications except for antithrombotic agents. Second, although DES manufacturers have an obligation to collect all ST cases and report them to the PMDA, they might not have captured some cases because of miscommunication between manufacturers and medical institutions. Therefore, there is a possibility of underreporting of ST, especially for LST and VLST. In addition, a reporting bias could not be eliminated, such as only the cases with poor prognosis being reported. Third, this analysis did not include patients with probable or possible ST, so the results may have underestimated the true mortality rate for ST in the entire population undergoing PCI using DES. Fourth, although the current analysis included a large number of patients with DES-ST, data relative to patients without ST were unavailable. Therefore, the incidence of ST or the risk factors for ST were not evaluated. Fifth, although each ST case report was made under the “Good Post-marketing Study Practice Ordinance”, data reliability relied on each physician providing the information. Lastly, because long-term follow-up data are unavailable, the long-term outcomes remain to be clarified.
Conclusions
We determined that LMT, CHF, hemodialysis, prior stroke, and age >70 years were independently associated with a higher risk of in-hospital death following DES-ST, but RCA disease was associated with a lower risk. Among these factors, LMT disease was the strongest predictor of in-hospital death. The current analysis suggests that when a target patient and/or lesion following PCI is associated with these factors, extreme caution against the potential occurrence of ST is required.
Acknowledgments
We thank all members of the PMDA review team for their input. The views expressed in this article are those of the authors and do not necessarily reflect the official views of the PMDA. We also thank Editage (https://www.editage.com) for English language editing.
Data Availability
The deidentified participant data that underlie the results will be shared on request basis to the corresponding author to request data sharing, beginning 12 months and ending 36 months following article publication. Because the data include confidential data, all proposed uses will be reviewed by the PMDA review committee.
Funding
This study was carried out with no external sources of funding.
Conflict of Interest Statement
All authors have no conflicts of interest to declare.
Disclosures
All authors have no conflicts of interest to declare. This study was carried out with no external sources of funding.
The protocol of the study was approved by the IRB of PMDA (no. H30-A-2).
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0133
References
- 1.
Holmes DR Jr, Kereiakes DJ, Garg S, Serruys PW, Dehmer GJ, Ellis SG, et al. Stent thrombosis. J Am Coll Cardiol 2010; 56: 1357–1365.
- 2.
Kerkmeijer LS, Claessen BE, Baber U, Sartori S, Chandrasekhar J, Stefanini GG, et al. Incidence, determinants and clinical impact of definite stent thrombosis on mortality in women: From the WIN-DES collaborative patient-level pooled analysis. Int J Cardiol 2018; 263: 24–28.
- 3.
Kimura T, Morimoto T, Kozuma K, Honda Y, Kume T, Aizawa T, et al. Comparisons of baseline demographics, clinical presentation, and long-term outcome among patients with early, late, and very late stent thrombosis of sirolimus-eluting stents: Observations from the Registry of Stent Thrombosis for Review and Reevaluation (RESTART). Circulation 2010; 122: 52–61.
- 4.
Armstrong EJ, Feldman DN, Wang TY, Kaltenbach LA, Yeo KK, Wong SC, et al. Clinical presentation, management, and outcomes of angiographically documented early, late, and very late stent thrombosis. JACC Cardiovasc Interv 2012; 5: 131–140.
- 5.
Armstrong EJ, Maddox TM, Carey EP, Grunwald GK, Shunk KA. Mortality after presentation with stent thrombosis is associated with time from index percutaneous coronary intervention: A report from the VA CART program. Am Heart J 2014; 168: 560–567.
- 6.
Claessen BE, Henriques JP, Jaffer FA, Mehran R, Piek JJ, Dangas GD. Stent thrombosis: A clinical perspective. JACC Cardiovasc Interv 2014; 7: 1081–1092.
- 7.
Kuramitsu S, Ohya M, Shinozaki T, Otake H, Horie K, Kawamoto H, et al. Risk factors and long-term clinical outcomes of second-generation drug-eluting stent thrombosis. Circ Cardiovasc Interv 2019; 12: e007822.
- 8.
Ohno Y, Yamaji K, Kohsaka S, Inohara T, Amano T, Ishii H, et al; J-PCI Registry Investigators. Incidence and in-hospital outcomes of patients presenting with stent thrombosis (from the Japanese Nationwide Percutaneous Coronary Intervention Registry). Am J Cardiol 2020; 125: 720–726.
- 9.
Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al; Academic Research Consortium. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation 2007; 115: 2344–2351.
- 10.
Morice MC, Serruys PW, Kappetein AP, Feldman TE, Ståhle E, Colombo A, et al. Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial. Circulation 2014; 129: 2388–2394.
- 11.
Stone GW, Kappetein AP, Sabik JF, Pocock SJ, Morice MC, Puskas J, et al; EXCEL Trial Investigators. Five-year outcomes after PCI or CABG for left main coronary disease. N Engl J Med 2019; 381: 1820–1830.
- 12.
Mäkikallio T, Holm NR, Lindsay M, Spence MS, Erglis A, Menown IB, et al; NOBLE study investigators. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): A prospective, randomised, open-label, non-inferiority trial. Lancet 2016; 388: 2743–2752.
- 13.
Eagle KA, Lim MJ, Dabbous OH, Pieper KS, Goldberg RJ, Van de Werf F, et al; GRACE Investigators. A validated prediction model for all forms of acute coronary syndrome: Estimating the risk of 6-month postdischarge death in an international registry. JAMA 2004; 291: 2727–2733.
- 14.
Gale CP, Manda SO, Batin PD, Weston CF, Birkhead JS, Hall AS. Predictors of in-hospital mortality for patients admitted with ST-elevation myocardial infarction: A real-world study using the Myocardial Infarction National Audit Project (MINAP) database. Heart 2008; 94: 1407–1412.
- 15.
Ryu KS, Bae JW, Jeong MH, Cho MC, Ryu KH; Korea Acute Myocardial Infarction Registry Investigators. Risk scoring system for prognosis estimation of multivessel disease among patients with ST-segment elevation myocardial infarction. Int Heart J 2019; 60: 708–714.
- 16.
Backhaus SJ, Kowallick JT, Stiermaier T, Lange T, Koschalka A, Navarra JL, et al. Culprit vessel-related myocardial mechanics and prognostic implications following acute myocardial infarction. Clin Res Cardiol 2020; 109: 339–349.
- 17.
Watanabe Y, Sakakura K, Fujita H, Ohya M, Horie K, Yamanaka F, et al; REAL-ST Registry Investigators. Comparison of clinical characteristics of stent thrombosis between the right coronary artery and the left coronary artery: A subanalysis of the REAL-ST registry. Circ J 2020; 84: 169–177.
- 18.
Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: Data from a large two-institutional cohort study. Lancet 2007; 369: 667–678.
- 19.
Kimura T, Morimoto T, Nakagawa Y, Kawai K, Miyazaki S, Muramatsu T, et al. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: Five-year outcome of the j-Cypher Registry. Circulation 2012; 125: 584–591.
- 20.
Smits PC, Vlachojannis GJ, McFadden EP, Royaards KJ, Wassing J, Joesoef KS, et al. Final 5-year follow-up of a randomized controlled trial of everolimus- and paclitaxel-eluting stents for coronary revascularization in daily practice: The COMPARE Trial (A trial of everolimus-eluting stents and paclitaxel stents for coronary revascularization in daily practice). JACC Cardiovasc Interv 2015; 8: 1157–1165.
- 21.
Sherman RE, Anderson SA, Dal Pan GJ, Gray GW, Gross T, Hunter NL, et al. Real-world evidence: What is it and what can it tell us? N Engl J Med 2016; 375: 2293–2297.
- 22.
Food and Drug Administration. Use of real-world evidence to support regulatory decision-making for medical devices: Draft guidance for industry and Food and Drug Administration staff. July 27, 2016. (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM513027.pdf) (accessed February 18, 2020).
- 23.
Konishi A, Mitsutake Y, Ho M, Handa N, Koike K, Mochizuki S, et al. Patient and lesion characteristics in late/very late stent thrombosis with everolimus-eluting stents from real-world adverse event reporting. J Cardiol 2019; 75: 255–260.
