Few researchers have investigated the optimal long-term antithrombotic therapy regimen, especially after first-generation drug-eluting stent (DES) use. This study aimed to evaluate the impact of mid-term antithrombotic therapy on long-term outcomes in patients treated with the first sirolimus-eluting coronary stent (Cypher™).
Methods
Between 2004 and 2009, 1021 patients underwent Cypher™ implantation at our institute; among them, 567 patients had available data on antithrombotic therapy at year 5. We assessed patients’ antithrombotic therapy at year 5 post Cypher™ implantation and examined their association with adverse events from year 5 to year 10 post Cypher™ implantation.
Results
Patients with dual-antiplatelet therapy (DAPT) at year 5 had significantly lower risk of stent thrombosis (ST) than those with single-antiplatelet therapy (SAPT) (hazard ratio [HR] 0.24, p = 0.034). The HR of major bleeding in DAPT, compared to SAPT, was high, but the difference was not significant (HR 1.72, p = 0.26). Risk of major bleeding was significantly higher in patients on oral anticoagulants (OAC) than in those in other groups (OAC/SAPT; HR 5.31, p = 0.0048, OAC/DAPT; HR 3.08, p = 0.022), without significant reduction in the risk of cardiovascular events.
Conclusions
The incidence of ST after Cypher™ implantation in patients with DAPT at year 5 was significantly lower than that in SAPT. However, the risk of bleeding was higher with DAPT than with SAPT. Moreover, the risk of major bleeding was significantly higher in patients on anticoagulant therapy than in other patients. New options for the use of antithrombotic drugs after percutaneous coronary intervention warrant further studies on the optimal antithrombotic therapy for first-generation DES.
Key Summary Points
Why carry out this study?
It is unclear whether dual antiplatelet agent therapy (DAPT) should be continued for patients after first-generation coronary drug-eluting stent (DES) implantation.
This study roughly approximates the effect of continued DAPT after first-generation DES implantation.
What was learned from the study?
Long-term DAPT use significantly reduced the risk of stent thrombosis but increased the risk of major bleeding.
The decision to continue DAPT should be made on a patient-by-patient basis.
There was no marked difference between the number of benefits from reduced stent thrombosis and the number of risks from major bleeding.
Introduction
Coronary artery drug-eluting stents (DES) were introduced into clinical use more than 15 years ago. Several patients have benefited from this cornerstone therapy for ischemic heart disease (IHD). However, after stent implantation, dual antiplatelet agent therapy (DAPT) is required, in principle, to prevent stent thrombosis (ST), [1] but the resulting increase in bleeding events is a crucial problem. Therefore, the new-generation DES attempt to shorten the DAPT period, and the optimal DAPT period has been set to be shorter than before, depending on the balance between ST and bleeding events [2, 3]. However, while there have been many studies on the DAPT duration of new-generation DES, there are few studies on first-generation DES. The risk of ST is considered to be higher with first-generation DES than with second-generation stents [4]. In addition, the mechanism of stent failure is considered to change with time post-implantation because of the long-term effects of stents on local vessels [5‐9]. Therefore, the optimal antithrombotic therapy for the first-generation DES may be different from that of the new-generation DES due to two factors: differences in stents and differences in time post-implantation. Cypher™ is a benchmark first-generation DES. A good understanding of the impact of the mid-term management of patients with these stents on long-term prognoses would be of high clinical value. In this study, we aimed to examine the mid-term status of antithrombotic agents after Cypher™ placement to assess their effects on long-term prognoses.
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Methods
Study Design and Patients
This study is a retrospective, single-center, observational cohort study in Japan. We collected data from patients who received initial Cypher™ stents for IHD at Ome Municipal General Hospital between April 2004 and December 2009. Patients who died or those who could not be followed up for at least 5 years after the procedure were excluded. We assessed antithrombotic use at year 5 post percutaneous coronary intervention (PCI), and patients were divided into three groups, based on antithrombotic therapy type, as follows: single antiplatelet therapy (SAPT) group, DAPT group, and a group of patients using oral anticoagulants regardless of antiplatelet drug status (OAC). Patients who were not using any antithrombotic drugs were excluded. The association between groups divided by antithrombotic therapy and adverse events between year 5 and year 10 post-PCI were statistically examined.
Our study was approved by the Ethics Committee of Ome Municipal General Hospital (April 30, 2019, reference number 3) and performed in accordance with the Helsinki Declaration of 1964 and its later amendments, and details and other matters related to the study were published based on the recommendations of the Ministry of Health, Labor and Welfare. Informed consent was written and provided by all patients. The primary endpoints of the study were ST and major bleeding incidence from year 5 to year 10 post-PCI. Secondary endpoints examined were all-cause death, cardiac death, non-fatal acute myocardial infarction (AMI), and target lesion revascularization (TLR).
Definitions
The data on baseline clinical characteristics were obtained from hospital charts. The combination of aspirin and P2Y-12 inhibitors was defined as DAPT, and single use of aspirin or P2Y-12 inhibitors was defined as SAPT. ST was defined according to the Academic Research Consortium definition [10]. Since unexplained deaths are more common long term, this study only analyzed definite and probable ST and excluded possible ST. Major bleeding was defined as Bleeding Academic Research Consortium type 3a or higher [11]. All-cause death was regarded as cardiac-related death unless unequivocal non-cardiac causes could be identified. AMI was defined as the presence of ischemic symptoms, followed by a typical increase in troponin concentration above the 99th percentile upper reference limit, or creatine kinase or creatine kinase-MB concentrations to more than twice the normal values. TLR was defined as either PCI or coronary artery bypass grafting for stenosis or thrombosis, within a stent or within the 5-mm border adjacent to the stent.
Statistical Analysis
Categorical variables were compared using the chi-squared test or Fisher’s exact test. Continuous variables were compared using Student’s t test. All reported p values were two-sided. Normally distributed, continuous variables are expressed as mean ± standard deviation. Variables with non-normal distribution are expressed as median (interquartile range [IQR]). The cumulative incidence of clinical events was estimated using the Kaplan–Meier method, and clinical endpoints were tested using the log-rank test. Multivariable hazard ratios (HR) were evaluated with Cox proportional hazards models. A p value < 0.05 was considered statistically significant. Time in therapeutic range (TTR) was calculated using the fraction of international normalized ratios per the range method with the target prothrombin time-international normalized ratio (PT-INR) set as 1.60–2.59, a commonly used value in Japan. Follow-up was censored at the last known date. When Cypher™ implantation was performed more than twice in the same patient, the first record was used. The incidence of ST, major bleeding, all-cause death, cardiac-related death, non-fatal AMI, and TLR were analyzed. When ST, major bleeding, non-fatal AMI, or TLR occurred within the first 5 years, they were excluded from each parameter. All analyses were conducted by a physician (Ken Kurihara) using JMP®12 software (SAS Institute Inc., Cary, NC, USA).
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Results
Figure 1 demonstrates the flow chart of the study. A total of 1021 patients received their first Cypher™ stents at our hospital between April 2004 and December 2009. Of these, 686 patients were confirmed to be alive at year 5. Further, 584 patients had available data on antithrombotic therapy at year 5. After excluding patients who were not using any antithrombotic drugs, 567 patients were divided into SAPT, DAPT, and OAC groups. Table 1 shows a detailed breakdown of each group of antithrombotic drugs. TTR was also calculated to determine whether warfarin control was adequate. The mean TTR across all patients was 61.6%, which is considered relatively good, and 61.2% of patients had a TTR greater than 60%. Table 2 describes the clinical backgrounds of the entire cohort and of patients divided by their antithrombotic therapy group. Significant differences in age were observed between the patients of each group, without significant differences in other factors. Figure 2 shows the result of Kaplan–Meier analysis of the incidence of ST divided by the antithrombotic therapy groups, which demonstrates a significant difference in the results among the three groups. Figure 3 shows the Kaplan–Meier assessment of major bleeding, showing a significant difference among the three groups as well. Figures 4, 5, 6, and 7 show the Kaplan–Meier analysis of secondary endpoints. Among the events of all-cause death, cardiac death, non-fatal MI, and TLR, there was no significant difference among the three groups. Table 3 shows the incidence of cardiac events by antithrombotic therapy. Table 4 shows the results of Cox proportional hazards analysis for probable and definite ST and major bleeding events. The HR of ST in DAPT to SAPT was 0.24, which was statistically significant (p = 0.034). On the other hand, the HR of major bleeding in DAPT to SAPT was also high, but the difference was not significant (HR 1.72, p = 0.26). The HR of major bleeding in OAC was significantly higher than that in other groups (OAC/SAPT: HR 5.31, p = 0.0048, OAC/DAPT: HR 3.08, p = 0.022).
Fig. 1
Flow chart showing patient selection
Table 1
Breakdown of antithrombotic drugs groups
All patients
567
DAPT
344
OAC
52
clopidogrel
131
OAC + DAPT
13
ticlopidine
213
OAC + SAPT
34
SAPT
171
OAC only
5
aspirine
148
Warfarin
47
clopidogrel
17
DOAC
5
Mean TTR of warfarin use (PT-INR 1.60–2.59)
61.6%
Patients with TTR ≧ 60%
61.2%
DAPT dual antiplatelet therapy, SAPT single antiplatelet therapy, OAC oral anticoagulant therapy, DOAC direct oral anticoagulants, TTR time in therapeutic range
Table 2
Antithrombotic therapy at 5 years and baseline characteristics
Baseline characteristics
SAPT (n = 130)
DAPT (n = 255)
OAC (n = 46)
p
Age (years)
67.7 ± 9.4
65.6 ± 10.1
70.8 ± 9.2
0.0004
Male
128 (74.9)
269 (78.2)
35 (67.3)
0.22
Diabetes mellitus
57(33.3)
123 (35.8)
19 (36.5)
0.84
Dyslipidemia
77 (45.0)
152 (44.2)
22 (42.3)
0.94
Hypertension
86 (50.3)
157 (45.6)
29 (55.8)
0.3
Current smoker
28 (16.4)
71 (20.6)
6 (11.5)
0.18
Hemodialysis
4 (2.3)
8 (2.3)
3 (5.8)
0.43
History of MI
34 (19.9)
80 (23.3)
14 (26.9)
0.51
Previous PCI
34 (19.9)
72 (20.9)
17 (32.7)
0.15
Post CABG
10 (5.8)
17 (4.9)
5 (9.6)
0.44
Restenosis lesion
10 (5.8)
23 (6.7)
6 (11.5)
0.41
Chronic total occlusion
8 (4.7)
15 (4.4)
5 (9.6)
0.33
Acute coronary syndrome
61 (35.7)
154 (44.8)
19 (36.5)
0.11
Bifurcation lesion
24 (14.0)
58 (16.9)
7 (13.5)
0.63
LMCA
6 (3.5)
15 (4.4)
1 (1.9)
0.63
RCA
40 (23.4)
83 (24.1)
10 (19.2)
0.73
LAD
101 (59.1)
209 (60.8)
33 (63.5)
0.84
LCx
29 (17.0)
56 (16.3)
8 (15.4)
0.96
Bypass
1 (0.6)
3 (0.9)
1 (1.9)
0.71
Multivessel
25 (14.6)
62 (18.0)
8 (15.4)
0.59
Number of stents used
1.42 ± 0.58
1.44 ± 0.64
1.40 ± 0.57
0.88
Stent size (mm)
2.96 ± 0.37
2.98 ± 0.36
2.96 ± 0.38
0.84
Length of stents used (mm)
32.7 ± 15.2
33.0 ± 17.1
30.5 ± 15.7
0.58
Continuous variables are expressed as mean ± SD, SAPT single antiplatelet therapy, DAPT dual antiplatelet therapy, OAC oral anticoagulant therapy, MI myocardial infarction, PCI percutaneous coronary intervention, CABG coronary artery bypass grafting, LMCA left main coronary artery, RCA right coronary artery, LAD left anterior descending coronary artery, LCx left circumflex coronary artery
Fig. 2
Kaplan–Meier analysis of the incidence of definite and probable stent thrombosis according to antithrombotic groups
Fig. 3
Kaplan–Meier analysis of the incidence of major bleeding according to antithrombotic groups
Fig. 4
Kaplan–Meier analysis of the incidence of all-cause death according to antithrombotic groups
Fig. 5
Kaplan–Meier analysis of the incidence of cardiac death according to antithrombotic groups
Fig. 6
Kaplan–Meier analysis of the incidence of non-fatal acute myocardial infarction according to antithrombotic groups
Fig. 7
Kaplan–Meier analysis of the incidence of target lesion revascularization according to antithrombotic groups
Table 3
Antithrombotic therapy and clinical event rate between 5 and 10 years
Antithrombotic therapy at 5 years
p
SAPT (n = 171)
DAPT (n = 344)
OAC (n = 52)
Definite/probable ST
4.5%
1.1%
0.0%
0.044
Major bleeding
3.7%
6.0%
18.6%
0.0043
All-cause death
12.8%
10.3%
19.2%
0.29
Cardiac death
4.7%
5.5%
3.1%
0.98
Non-fatal AMI
7.4%
7.6%
3.7%
0.91
TLR
9.4%
7.9%
4.9%
0.84
SAPT single antiplatelet therapy, DAPT dual antiplatelet therapy, OAC oral anticoagulant therapy, ST stent thrombosis, AMI acute myocardial infarction, TLR target lesion revascularization
Table 4
Antithrombotic therapy and hazard ratio of clinical event
ST
Major bleeding
HR
CI
p
HR
CI
p
DAPT/SAPT
0.24
0.05–0.89
0.034
1.72
0.69–5.21
0.26
OAC/SAPT
-
0–1.31
0.081
5.31
1.69–17.95
0.0048
OAC/DAPT
-
0–6.58
0.38
3.08
1.20–7.09
0.022
CI confidence interval, HR hazard ratio, ST stent thrombosis, SAPT single antiplatelet therapy, DAPT dual antiplatelet therapy, OAC oral anticoagulant therapy
×
×
×
×
×
×
×
Table 5 outlines ST and bleeding risk based on antithrombotic status corrected for age, which was the patient characteristic that differed significantly. Consistently, the risk of ST in DAPT was significantly lower than that in SAPT (HR 0.21, p = 0.024). The major bleeding risk of OAC was also significantly higher for SAPT and tended to be higher for DAPT after adjustment (OAC/SAPT: HR 4.24, p = 0.014, OAC/DAPT: HR 2.29, p = 0.084). Because the OAC group comprises subgroups of OAC only, OAC + SAPT, and OAC + DAPT, we further investigated whether there were differences in bleeding events between these three subgroups. However, no significant differences were found (Fig. 8).
Table 5
Antithrombotic therapy and adjusted hazard ratio of clinical event
Adjusted by age
ST
Major bleeding
HR
CI
p
HR
CI
p
DAPT/SAPT
0.21
0.04–0.81
0.024
1.85
0.74–5.60
0.20
OAC/SAPT
–
0–1.51
0.10
4.24
1.35–14.38
0.014
OAC/DAPT
–
0–8.77
0.44
2.29
0.88–5.31
0.084
CI confidence interval, HR hazard ratio, ST = stent thrombosis, SAPT single antiplatelet therapy, DAPT dual antiplatelet therapy, OAC oral anticoagulant therapy
Fig. 8
Kaplan–Meier analysis of the incidence of major bleeding according to anticoagulation subgroups
×
For patients with ST and bleeding events, the antithrombotic medications administered immediately prior to the event were also examined (Table 6). Two of the three patients with ST in the DAPT group had been switched to SAPT and OAC + SAPT immediately before the event. In terms of antithrombotic medications administered immediately before the event in patients with major bleeding, although there was a trend toward DAPT being switched to SAPT over time, the percentage of patients who were continued on DAPT remained high than that of patients who had ST events.
Table 6
Antithrombotic medications at 5 years and at the time of the clinical event
There have been several reports on the short-term effects of patient characteristics and medical therapy during Cypher™ placement on clinical outcomes [12‐14]. Nonetheless, the optimal use of antithrombotic agents at mid-term has not been well investigated. The effects of mid-term medical therapy on clinical outcomes may differ from early term effects. This is important, since more than 15 years have passed since Cypher™ placement treatment strategies were initiated. We examined the status of antithrombotic therapy at 5 years in determining the association between antithrombotic therapy and events at 10 years, based on the fact that 5 years is half of the 10-year observation period and patients who have been on DAPT for 5 years are more likely to remain on DAPT thereafter. This is the first study to assess clinical outcomes based on mid-term antithrombotic therapy.
Clinical Characteristics and ST Incidence
The characteristics of the subjects, their lesions, and the procedures were similar to those reported in large studies conducted in Japan, indicating that the study population closely resembled patients who were treated in daily practice. Furthermore, in other studies investigating the long-term prognosis of Cypher™, the incidence of ST was 3.7–8.3% [15, 16], which was similar to our results (Fig. 9). Therefore, the results of this study may be applicable in clinical practice.
Fig. 9
Ten-year cumulative incidence of definite and probable stent thrombosis
×
DAPT vs. SAPT
It is well known that discontinuation of antithrombotic drugs increases the risk of ST in Cypher™ stents [17, 18]. Although there are many studies comparing antithrombotic therapy and cardiac events in the early stage of Cypher™ implantation, there are not many long-term studies. Yano et al. [12] investigated the relationship between antiplatelet drugs and ST up to 5 years after Cypher™ implantation and found that complete discontinuation of antiplatelet drugs increased the risk of ST, but there was no significant difference between DAPT and SAPT. On the other hand, we examined the effect of antithrombotic drugs at 5 years on cardiac events up to 10 years. To our knowledge, this is the longest study to evaluate differences between DAPT and SAPT after Cypher™ implantation. Our research has shown that the incidence of ST was significantly reduced in the DAPT group, and the result was similar after adjusting for confounding factors. Despite the low rate of ST with the DAPT group compared to SAPT, there was a tendency for more bleeding. As antithrombotic therapy was administered based on the opinion of the attending physician, DAPT was likely continued in patients at high risk of ST. The fact that the incidence of ST was lower even though the patients were high risk supports the result that DAPT is more potent than SAPT in reducing ST, even after 5 years of treatment. This may also apply to bleeding events, and therefore, it seems reasonable to select DAPT or SAPT based on risk stratification.
Because antithrombotic medications used at 5 years post-PCI do not necessarily reflect those administered immediately prior to the event, we also examined the occurrence of ST and major bleeding with respect to antithrombotic status immediately prior to the event. For ST, two of the three patients originally in the DAPT group had been shifted to other antithrombotic therapy. Given these results, the significance of DAPT for preventing ST does not appear to change, at least not significantly. Although it is expected that the antithrombotic medications of patients who did not have an event would have been changed between the 5th and 10th years, statistical analysis is difficult to perform because of the paucity of information, as many patients were receiving their medications at other hospitals and the timing of changes in antithrombotic medications varied across patients. This may be a limitation of our retrospective study.
In addition, aspirin was used in most of the patients on SAPT during this period. There is a possibility that SAPT with P2Y12 inhibitor monotherapy may be advantageous over aspirin, and this needs to be investigated further.
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Anticoagulant Therapy
Of the patients who received anticoagulants at year 5, none experienced ST between years 5 and 10. In terms of antithrombotic medication administered immediately before the ST event, one patient was on warfarin + SAPT, but the PT-INR of this patient was 1.16, which is inadequate for anticoagulation. It has been reported that anticoagulation in post-acute coronary syndrome patients suppresses subsequent cardiac events, but the benefits do not outweigh the risks because of the increased risk of bleeding [19, 20]. The results of our study are similar, with the advantage of lower ST in patients on anticoagulation being outweighed by the disadvantage of bleeding. In this study, most of the patients on anticoagulation at year 5 were on warfarin. Furthermore, since the majority of patients at 5 years after stenting were receiving antiplatelet therapy before the WOEST trial (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) [2], many patients were using more antiplatelet drug combinations than we currently do. We further analyzed the OAC only, OAC + SAPT, and OAC + DAPT subgroups to examine the breakdown of patients who had bleeding events in the OAC group, but due to the small number of patients who had bleeding events, no statistical differences were evident. The mean PT-INR in patients who had been taking warfarin until immediately before the bleeding event was not particularly high at 2.43 (2.07–3.08). These results indicate that even with a PT-INR relatively close to the therapeutic range, a bleeding event can occur when warfarin is used. By using direct OAC or reducing the dose of antiplatelet agents, bleeding risk could be reduced without increasing the incidence of ST, and this necessitates further study.
Limitations
This single-center, retrospective observational study has several limitations. (A) Some degree of bias was unavoidable because the administration of antithrombotic agents was at the discretion of the attending physician, although there were no significant differences in the characteristics of each group. (B) We used data on antithrombotic agents at year 5 as predictors of clinical outcomes over years 5–10 but did not consider patient status before or after. (C) We did not consider all factors that may affect clinical outcomes, including low-density lipoprotein cholesterol or HbA1c. (D) It is not known if similar trends will be observed with other first-generation DES, since the Cypher™ stent was used in all patients.
Although there are various limitations, it is significant that this study could show that medium-term use of antithrombotic agents affects long-term outcomes.
Conclusions
There are no clear indications for the use of specific antithrombotic agents with first-generation DES, and in many cases, multiple antithrombotic agents are used due to the fear of ST. The results of this study clearly show the superiority of DAPT over SAPT in preventing ST. However, bleeding events are also common, and the combined risk of ST and bleeding events does not warrant the continued use of DAPT. In the absence of a robust prospective study of the prognostic value of first-generation antithrombotics, it seems reasonable to consider the risk of ST and bleeding when choosing antithrombotic therapy. In addition, incidence of major bleeding in the OAC group was significantly higher than that in other groups. As there are new options for the use of antithrombotic drugs after PCI at present, the optimal antithrombotic therapy for first-generation DES needs to be studied in detail.
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Acknowledgements
We thank the participants of this study.
Funding
No funding or sponsorship was received for this study or publication of this article. The journal’s Rapid Service Fee was funded by the authors.
Medical Writing, Editorial, and Other Assistance
We would like to thank Editage [http://www.editage.com] for editing and reviewing this manuscript for English language.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
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Author Contributions
Conception and design, data collection, statistical analysis and writing: KK; data collection and revision: SK, AK, AT, KY, HN, YO, TM, AS, and YO; Revision and final approval: KO, TS.
Disclosures
Ken Kurihara, Akifumi Tanaka, Kento Yabe, Toru Miyazaki, Asami Suzuki, Yuichi Ono, Kenichiro Otomo, and Tetsuo Sasano all have nothing to disclose. Yuki Osaka is currently affiliated to Nitobe Memorial Nakano General Hospital. Hidetsugu Nomoto is currently affiliated to Nomoto Clinic. Ayaka Kimura is currently affiliated to Shuuwa General Hospital. Shiho Kawamoto is currently affiliated to Tokyo Yamate Medical Center.
Compliance with Ethics Guidelines
Our study was approved by the ethics committee of Ome Municipal General Hospital (April 30, 2019, reference number 3) and performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
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