Fifteen-Year Clinical Outcomes After Sirolimus-Eluting Stent Implantation

Abstract

Background: Clinical outcomes after percutaneous coronary intervention have improved with the use of drug-eluting stents, but data beyond 10 years are limited. The purpose of this study was to evaluate the clinical outcomes of patients undergoing sirolimus-eluting stent implantation with follow-up beyond 10 years and to determine the impact of clinical and angiographic characteristics on long-term prognosis.

Methods and Results: The clinical outcomes of 885 patients who had undergone sirolimus-eluting stent implantation at a single institution were retrospectively reviewed. Primary endpoints included in the analysis were clinically driven target lesion revascularization (cTLR) and target lesion revascularization (TLR). Univariate and multivariate nominal logistic regression was used for data analysis. The incidence rates of cTLR and TLR beyond 10 years after sirolimus-eluting stent implantation were 16.4% and 36.8%, respectively, with cTLR tending to decrease beyond 10 years. Acute coronary syndrome was a predominant trigger for cTLR. Age, statin use, and stent restenosis emerged as predictors of cTLR within 10 years, but no significant predictors other than age were identified beyond 10 years.

Conclusions: Events continue to occur beyond 10 years after sirolimus-eluting stent implantation, with a trend toward an increase in acute coronary syndromes. It is important to be vigilant about the occurrence of acute coronary syndromes during long-term follow-up.

Coronary artery disease remains a major cause of morbidity and mortality worldwide. The clinical use of coronary stents has greatly improved the results of percutaneous coronary intervention.^1,2 The high restenosis rates that have been a problem with bare metal stents have been improved with the use of drug-eluting stents,^1,2 of which sirolimus-eluting stents (SESs) have shown excellent efficacy in reducing restenosis and target lesion revascularization (TLR).^3,4 However, SES-related late restenosis (“late catch-up” phenomenon) and very late stent thrombosis beyond 1 year, although rare, have emerged as problems after SES implantation.^5,6 Although numerous studies have evaluated short- and mid-term outcomes after SES implantation, there are limited data on prognosis beyond 10 years.⁷ The purpose of this study was to evaluate the clinical outcomes of patients undergoing SES implantation with follow-up beyond 10 years and to determine the impact of clinical and angiographic characteristics on long-term prognosis.

Methods

Study Design and Setting

This study was designed as a single-center, single-arm, retrospective study to evaluate clinical outcomes after SES (Cypher; Cordis, Johnson & Johnson, Miami, FL, USA) implantation. A total of 1,218 consecutive patients who had undergone SES implantation between January 2002 and October 2005 were enrolled. Of these, 333 patients who had been treated with SES and another type of stent or who had previously received a SES were excluded. Finally, 885 patients who had been treated for the first time with SES alone were analyzed.

Patient information was collected, including medical history (hypertension, diabetes, insulin use, dyslipidemia, smoking history, previous percutaneous coronary intervention, chronic kidney disease.), medications taken at the time of treatment (antiplatelet agents, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, β-blockers, and statins), lesion characteristics, number of stents implanted, total length of stents, and minimum stent diameter. Clinical follow-up information was obtained during office visits or by telephone contact with primary care physicians or patients. Informed consent was obtained from all patients for both the procedure and subsequent data collection and analysis for research purposes, and the study was also approved by the Institutional Review Board of Kurashiki Central Hospital. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Interventional Procedure

All patients were pretreated with aspirin (100 mg daily) and ticlopidine (200 mg daily)/clopidogrel (75 mg daily). Dual antiplatelet therapy was recommended for at least 8 months. Procedures were performed according to standard clinical guidelines. Decisions regarding therapeutic strategies such as adjunctive devices, pharmacotherapy, and stent expansion pressure were left to the discretion of each operator.

Definitions and Study Endpoints

The primary endpoints were defined as clinically driven TLR (cTLR) and TLR, which are events of particular relevance to SES implantation. Secondary endpoints were defined as myocardial infarction, all-cause death, cardiac death, and stent thrombosis. TLR was defined as any repeat percutaneous coronary intervention or aortocoronary bypass surgery due to restenosis (diameter stenosis >50%) or thrombosis of the target lesion. Clinically driven TLR was defined as TLR performed because of symptoms or objective signs of ischemia. Myocardial infarction was defined as ischemic symptoms or ischemic changes on electrocardiogram plus elevated myocardial troponin or elevated creatine kinase levels to twice the upper limit of normal and creatine kinase-MB fraction.⁸ In-stent restenosis is defined as the re-narrowing of a coronary artery within, proximal to, or distal to the stent after initial percutaneous coronary intervention.⁹ B2/C lesions were defined as those classified as B2 or C in the American Heart Association/American College of Cardiology (AHA/ACC) classification.¹⁰

Statistical Analysis

The Kaplan-Meier method was used to estimate the cumulative incidence of events. Univariate and multivariate nominal logistic regression was performed to assess the significance of each factor in relation to the occurrence of cTLR within 10 years and beyond 10 years. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated for each factor. The final multivariate model provided adjusted ORs and 95% CIs for each significant factor. For the analysis of events beyond 10 years, patients who had not experienced cTLR within 10 years and were still being followed were included. A Cochran-Armitage trend test was performed to examine the trend in acute coronary syndromes over different time periods (≤5 years, >5 to ≤10 years, and >10 to ≤15 years) for the occurrence of cTLR. Data analysis was performed using JMP version 9.0 (SAS Institute Inc., Cary, NC, USA) and R version 3.4.4 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Baseline Characteristics

Baseline characteristics of the 885 patients are shown in Table 1. Mean age was 69±11 years. The proportion of patients undergoing percutaneous coronary intervention was 55.3%, 611 patients (69.1%) had hypertension, 381 patients (43.1%) had diabetes mellitus, 120 patients (13.6%) were on insulin therapy, and 35 patients (4%) were on hemodialysis. The proportion of in-stent restenosis was 26.7% and that of the B2/C lesion was 90.2%.

Table 1.

Baseline Characteristics of the 885 Patients

		Missing value*
Clinical data
Age, years	68.8±10.7	0
Male	646 (73.0)	0
Hypertension	611 (69.1)	1
Diabetes mellitus	381 (43.1)	0
Insulin therapy	120 (13.6)	0
Dyslipidemia	442 (50.5)	9
Current smoking	525 (60.2)	14
Chronic kidney disease	470 (53.1)	0
eGFR (mL/min/1.73 m2)	57.1±21.2	0
Hemodialysis	35 (4.0)	0
Old myocardial infarction	392 (44.3)	0
Previous PCI	489 (55.3)	0
Stable angina	708 (80.0)	0
Acute coronary syndrome	177 (20.0)	0
NSTEMI/unstable angina	122 (13.8)	0
STEMI	33 (3.7)	0
RMI	22 (2.5)	0
Aspirin	877 (99.2)	1
Ticlopidine	862 (97.5)	1
Clopidogrel	14 (1.6)	1
Cilostazol	18 (2.1)	10
Statin	316 (36.3)	14
β-blocker	138 (15.9)	14
ACEi/ARB	391 (44.9)	14
Angiographic data
LMT lesion	74 (8.4)	0
LAD lesion	437 (49.4)	0
LCX lesion	262 (29.6)	0
RCA lesion	387 (43.7)	0
Graft	12 (1.4)	0
Ostial lesion	153 (17.3)	0
Bifurcation lesion	328 (37.1)	0
AHA/ACC class B2/C lesion	798 (90.2)	0
In-stent restenosis	236 (26.7)	0
Chronic total occlusion	152 (17.2)	0
Total number of stents implanted	2.4±1.4	0
Total length of stents, mm	52.2±33.6	0

Data are presented as n (%) or mean±standard deviation, unless otherwise indicated. *Value with no information. AHA/ACC, American Heart Association/American College of Cardiology; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; eGFR, estimated glomerular filtration rate; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; LMT, left main coronary artery; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; RMI, recent myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

Outcomes

Median follow-up duration was 4,162 days (interquartile range [Q1 to Q3], 2,401 to 5,595 days) (Table 2). Figure 1 shows that cTLR and TLR occurred in 16.4% and 36.8% of patients, respectively, over the 15-year follow-up period. The cumulative incidence rate of cTLR was also analyzed at ≤5 years, >5 to ≤10 years, and >10 to ≤15 years using the landmark method. The incidence rate of cTLR tended to decrease over time to 6.7%, 6.6%, and 5.8%, respectively (Figure 2), with acute coronary syndromes accounting for an increasing proportion of cTLR (Figure 3, Supplementary Table). All-cause and cardiac death rates also tended to increase over the 15-year follow-up period. The last stent thrombosis was observed in the 7th year (Figure 4). There was no occurrence of cTLR in non-B2/C lesions beyond 10 years. In addition, there was no occurrence of cTLR in non-dialysis patients beyond 10 years.

Table 2.

Clinical Outcome of the 885 Patients

Outcome
Median follow-up duration, days [interquartile range]	4,162 [2,400 to 5,595]
Clinically driven TLR	109 (12.3)
TLR	253 (28.6)
All-cause death	496 (56.0)
Cardiac death	157 (17.7)
Myocardial infarction	101 (11.4)
Stent thrombosis	18 (2.0)

Data are presented as n (%) unless otherwise indicated. TLR, target lesion revascularization.

Figure 1.

Kaplan-Meier curves for target lesion revascularization (TLR) and clinically driven target lesion revascularization during 15-year follow-up.

Figure 2.

Kaplan-Meier curves with 5-year landmark analysis for clinically driven target lesion revascularization.

Figure 3.

Classification of triggers for clinically driven target lesion revascularization: acute coronary syndrome (ACS) or chronic coronary syndrome (CCS).

Figure 4.

Kaplan-Meier curves for all-cause death, cardiac death, myocardial infarction (MI), and definite stent thrombosis (ST) during 15-year follow-up.

Predictors of cTLR

Tables 3 and 4 show the univariate and multivariate analyses of predictors of cTLR within 10 years and beyond 10 years. In multivariate analysis, age (OR 0.54, 95% CI 0.33 to 0.85, P=0.008), statin (OR 0.55, 95% CI 0.32 to 0.89, P=0.015) and stent restenosis (OR 1.68, 95% CI 1.05 to 2.67, P=0.032) were significant predictors within 10 years (Table 3). In univariate analysis, older age was the only negative significant predictor beyond 10 years (OR 0.25, 95% CI 0.04–0.92, P=0.035) (Table 4).

Table 3.

Univariate and Multivariate Analyses of Predictors of Clinically Driven Target Lesion Revascularization Within 10 Years

	Univariate analysis			Multivariate analysis
	OR	95% CI	P value	Adjusted OR	95% CI	P value
Age >70 years	0.59	0.37 to 0.92	0.021	0.54	0.33 to 0.85	0.008
Male	1.09	0.67 to 1.82	0.743
Diabetes mellitus	1.23	0.80 to 1.91	0.341
Chronic kidney disease	0.75	0.48 to 1.16	0.197
Statin	0.59	0.35 to 0.96	0.033	0.55	0.32 to 0.89	0.015
Bifurcation lesion	1.34	0.85 to 2.07	0.198
CTO	1.14	0.63 to 1.95	0.653
Diffuse lesion >20 mm	0.96	0.61 to 1.50	0.841
In-stent restenosis lesion	1.69	1.06 to 2.65	0.028	1.68	1.05 to 2.67	0.032
Total stent length >44 mm	1.06	0.68 to 1.64	0.797
Minimal stent diameter <2.5 mm	0.26	0.01 to 1.23	0.1

CI, confidence interval; CTO, chronic total occlusion; OR, odds ratio.

Table 4.

Univariate Analysis of Predictors of Clinically Driven Target Lesion Revascularization Beyond 10 Years

	Univariate analysis
	OR	95% CI	P value
Age >70 years	0.25	0.04 to 0.92	0.035
Male	1.54	0.49 to 6.81	0.485
Diabetes mellitus	0.65	0.20 to 1.80	0.42
Chronic kidney disease	0.94	0.33 to 2.51	0.904
Statin	0.79	0.26 to 2.18	0.656
Bifurcation lesion	0.73	0.23 to 2.01	0.55
Chronic total occlusion	1.3	0.29 to 4.17	0.694
Diffuse lesion >20 mm	2.27	0.83 to 6.49	0.111
In-stent restenosis lesion	1.21	0.33 to 3.52	0.754
Total stent length >44 mm	2.3	0.86 to 6.80	0.099
Minimal stent diameter <2.5 mm	1.64	0.09 to 9.06	0.664

CI, confidence interval; OR, odds ratio.

Discussion

There are reports of follow-up up to 10 years after SES implantation, but no reports of longer-term follow-up beyond 10 years. The key findings of this study are as follows: (1) the incidence rate of cTLR remained constant throughout the 15-year follow-up period, but decreased slightly in the very long term beyond 10 years; (2) beyond 10 years, the incidence rate of cTLR decreased, but that of acute coronary syndrome increased; and (3) within 10 years, age and stent restenosis emerged as predictors of cTLR, but no significant predictors were identified beyond 10 years, except for age. The incidence rate of TLR up to 5 years at our institution was 19.9%, higher than that found in previous studies (8% to 16%);^11–14 the incidence rate of TLR up to 10 years at our institution was 27.9%, also higher than that in a previous study (22.5%).¹⁵ This difference may be due to the greater number of complex lesions in this study, such as B2/C and chronic total occlusion lesions, as well as differences in postprocedural follow-up methods. In a study examining complex PCI cases, such as chronic total occlusion lesions and bifurcation lesions, the incidence rate up to 10 years was 29.4%, showing a similar trend to our study.¹⁶ The incidence rates of TLR at 15 years have been reported to be 44.6% after percutaneous old balloon angioplasty and 36% after bare metal stenting.^17,18 The incidence rate of TLR after SES implantation in this study was better than that after percutaneous old balloon angioplasty, but similar to that after bare metal stenting in the long term. Patients implanted with SES may require the same careful monitoring as those implanted with bare metal stents, even during long-term follow-up beyond 10 years.

The incidence rate of cTLR beyond 10 years was slightly lower than that within 10 years, but remained constant. The higher proportion of acute coronary syndromes compared to chronic coronary syndromes may affect prognosis. Long-term follow-up of patients undergoing SES implantation should pay special attention to the occurrence of acute coronary syndromes. In previous studies, TLR or stent thrombosis after SES implantation are associated with neo atherosclerosis and thrombosis with its rupture in earlier phase.¹⁹ The different triggers for acute coronary syndromes and the absence of stent thrombosis in patients beyond 7 years after implantation suggest that the mechanisms leading to cTLR are different in the early and late periods after SES implantation. Predictors of cTLR beyond 10 years have not been shown to be similar to those within 10 years. The mechanism of in-stent restenosis after SES implantation may be different in the very long term. In a previous study, chronic kidney disease without hemodialysis was found to be an independent predictor of stent thrombosis and was not found to be a predictor of TLR.¹³ In our study, perhaps due to the low occurrence of stent thrombosis, chronic kidney disease was not a predictor of cTLR. The fact that chronic kidney disease and older age were negative predictors for cTLR may suggest that clinical decisions are influenced by these factors.

Study Limitations

This study has three major limitations. First, this is a single-center, retrospective study that is not free from bias regarding background disease, lesions, treatment, and indications for additional treatment. Second, this is an observational study with a long follow-up period, but we were not able to assess changes in morbidity or treatment, such as antiplatelet therapy or statin, during the follow-up period. Early events in some patients or loss to follow-up in some patients may have biased the occurrence of events beyond 10 years. For example, there may have been a bias that cTLR does not occur in patients with non-B2/C lesions or on dialysis beyond 10 years. Third, the indications for percutaneous coronary intervention and the practice of follow-up have changed. Follow-up coronary angiography after percutaneous coronary intervention was commonly performed in Japan, but routine follow-up coronary angiography is no longer recommended since around 2018 because it has been suggested that routine follow-up coronary does not improve clinical outcomes.²⁰ The importance of ischemic assessment has also been emphasized. Thus, the trend at the end of the follow-up period may have changed from the previous trend.

Conclusions

Events continue to occur beyond 10 years after SES implantation, with a trend toward an increase in acute coronary syndromes. It is important to be vigilant about the occurrence of acute coronary syndromes during long-term follow-up.

Acknowledgments

We extend our gratitude to Ms. Makiko Kanaike and Ms. Takako Yukiyoshi, the medical department secretaries, for their invaluable assistance in data collection.

Disclosures

The authors declare no conflicts of intrest associated with this manuscript.

Sources of Funding

None.

IRB Information

The present study was approved by the Institutional Review Board of Kurashiki Central Hospital (Reference no. 4205).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0929

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