pISSN 0513-5796   eISSN 1976-2437
Open Access, Peer-reviewed, Monthly
    Yonsei Med J. 2021 Jan;62(1):75-85. English.
    Published online Dec 23, 2020.
    https://doi.org/10.3349/ymj.2021.62.1.75
    © Copyright: Yonsei University College of Medicine 2021
    Original Article

    Association of Mortality with Antiplatelet Treatment in Patients with Stent Placement or Angioplasty: A Population-Based Nested Case-Control Study

    Ho Geol Woo,1,2,* Hye Ah Lee,3,* Dong-Ryeol Ryu,4 and Tae-Jin Song1
      • 1Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Korea.
      • 2Department of Neurology, Kyung Hee University College of Medicine, Seoul, Korea.
      • 3Clinical Trial Center, Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Korea.
      • 4Department of Nephrology, Seoul Hospital, Ewha Womans University College of Medicine, Seoul, Korea.
    • Corresponding author: Tae-Jin Song, MD, PhD, Department of Neurology, Seoul Hospital, Ewha Womans University College of Medicine, 260 Gonghang-daero, Gangseo-gu, Seoul 07804, Korea. Tel: 82-2-6986-6013, Fax: 82-2-6986-6014, Email: knstar@ewha.ac.kr

      *Ho Geol Woo and Hye Ah Lee contributed equally to this work.
    Received July 16, 2020; Revised September 22, 2020; Accepted October 19, 2020.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Purpose

    Antiplatelet drugs are essential in patients with cardiovascular disease who undergo stent placement. We hypothesized that risks of mortality would differ according to adherence to antiplatelet agents, number of antiplatelet agents, and antiplatelet regimens in patients undergoing stent placement or angioplasty.

    Materials and Methods

    Between 2002 and 2013, we initially enrolled 8671 subjects who underwent stent placement or angioplasty in the National Health Insurance Service-National Sample Cohort in Korea. Using the International Classification of Diseases, 10th revision, the incidence of all-cause death, including cardiovascular disease, cerebrovascular disease, and cancer, was defined. Using a nested case-control study design, controls were matched to cases at a ratio of 4:1, and a total of 5415 subjects were eligible for this study.

    Results

    During a median follow-up period of 3.51 years, the incidence rate of all-cause death was 40 per 1000 person-years. We found that adherence to antiplatelet monotherapy significantly decreased risk of death by cerebro-cardiovascular disease, compared with discontinuation of antiplatelets [adjusted odds ratio (OR) 0.62, 95% confidence interval (CI) (0.41–0.96)]. Compared with dual antiplatelet therapy (DAPT), aspirin and clopidogrel monotherapy significantly reduced death by cerebro-cardiovascular disease [adjusted OR 0.65, 95% CI (0.44–0.95) and adjusted OR 0.58, 95% CI (0.35–0.96), respectively]. There was no significant difference of mortality between aspirin monotherapy and clopidogrel monotherapy.

    Conclusion

    Our study demonstrated that adherence to antiplatelet therapy and antiplatelet monotherapy, compared with DAPT, in patients with stent placement or angioplasty may have a beneficial effect on mortality in cerebro-cardiovascular disease.

    Keywords
    Antiplatelet; stent; mortality

    INTRODUCTION

    Although mortality due to cardiovascular disease is generally decreasing in both Asian and Western countries as a result of progress in medical and surgical treatments and prevention methods, including stent placement or angioplasty, cardiovascular disease remains a major cause of mortality worldwide.1, 2 Moreover, in individuals with coronary artery disease, stroke, and peripheral artery disease (PAD), mortality from non-cardiovascular etiologies can be as high as that from cardiovascular causes.2, 3, 4 While recent clinical trials have sought to focus on morbidity and quality of life, such as recurrence of vascular disease, rather than mortality, mortality is an important outcome for both the physician and patient.2, 3, 4

    In cardiovascular disease patients, especially patients with stent placement or angioplasty, antiplatelets are essential drugs.5, 6 Antiplatelet administration has been shown to reduce the risk of stent thrombosis and to reduce the risk of composite cardiovascular outcomes in patients with a coronary stent placement.7, 8, 9 In patients with PAD, treatment with high dose aspirin plus dipyridamole significantly reduced re-occlusion.10, 11 Meanwhile, dual antiplatelet therapy (DAPT) is recommended in intracranial cerebral artery atherosclerosis, regardless of best medical therapy or intracranial artery stent placement.12 However, although previous randomized controlled trials provided high levels of evidence, the results do not necessarily reflect real-world outcomes, especially mortality, because only socalled stable or healthy patients are usually enrolled in randomized controlled studies. In a previous study of patients who underwent coronary stent placement, the rate of all-cause mortality was higher in patients on DAPT than those on mono-antiplatelet therapy (2.0% vs. 1.5%, respectively).13 In contrast, a meta-analysis reported that extended duration DAPT was not associated with a difference in the risk of all-cause, cardiovascular, or non-cardiovascular death, compared with aspirin alone or short duration DAPT. Thus, the association between the number of antiplatelet agents or antiplatelet regimen and mortality is still unclear.

    We hypothesized that risk of mortality would differ according to adherence to antiplatelet therapy, antiplatelet agent regimen, and number of antiplatelet agents in patients with stent placement or angioplasty. We, therefore, assessed the association between antiplatelet treatment strategy and mortality in cardiovascular disease patients with stent placement or angioplasty according to adherence, number of antiplatelet agents, and regimen of antiplatelet agents in the general population of South Korea using a nested case-control study design.

    MATERIALS AND METHODS

    Data source and study subjects

    This study was conducted using data from the National Health Insurance Service (NHIS)-National Sample Cohort (NSC) version 2.0 for the Republic of Korea. A detailed description of data source of this study can be found in previous publications (Supplementary Material, only online).

    For this study, we initially included subjects who underwent stent placement or angioplasty from 2002 to 2013 (n=8671) and were followed up to 2015 for enough follow up after stent placement or angioplasty. We excluded subjects aged <20 years; those who had only one-time prescription history for antiplatelet drugs after stent placement or angioplasty; those who were treated with warfarin and non-vitamin K antagonist oral anticoagulants; those with a history of atrial fibrillation [International Classification of Disease, 10th revision (ICD-10), I48]; and those who had an acute or subacute thrombus within 30 days of stent placement or angioplasty.14 On the basis of the above criteria, a total of 5415 subjects were eligible for this study (Fig. 1). This study was approved by the Institutional Review Board of the College of Medicine, Ewha Womans University (approval number: EUMC 2018-01-056). Informed consent was waived because retrospective anonymized data were used.

    Fig. 1
    Flowchart of the study participants. NHIS, National Health Insurance Service; NOAC, non-vitamin K antagonist oral anticoagulants.

    Case-control selection for the nested case-control study design

    In pharmacoepidemiologic studies, the nested case-control design makes it possible to quantify time-dependent drug exposure and to easily assess associations.15 Considering the time-varying nature of antiplatelet drug use in a real setting, we selected subjects for a nested case-control study. Cases were defined as subjects who died between 2002 and 2015 after stent placement or angioplasty. Date and cause of death in the NHIS-NSC version 2.0 dataset are linked to National Statistical Office/National Administrator's Data using identification numbers, such as social security numbers. This allows for accurate identification of date and cause of death. The date of death was defined as the index date of case. Controls were selected using the incidence density sampling with replacement; it chose controls among a risk set defined as non-cases who are still at risk when the case occurs. Due to the nature of this method, the index dates of controls was decided as that which provided the same follow-up period as those of the matched index cases. Moreover, studies have recommended that incidence density sampling with replacement for the nested case-control design is suitable for unbiased estimation.16, 17 For each case, we randomly selected four controls matched by sex, age at stent placement or angioplasty, and follow-up period (Fig. 1).

    If a patient had more than two instances of stent placement or angioplasty between 2002 and 2013, the last procedure was used in the analysis. We used procedure codes (M6551-2 and M6561-4 for stent placement in the coronary artery, M6601-2 for stent placement in the intracranial and extracranial cerebral arteries, M6611-3 and M6603-5 for stent placement in other peripheral arteries, and M6593-7 for balloon angioplasty) and material codes (J5083 for drug eluting stent and J5231-2 for bare metal stent) to identify patients according to site of stent placement or angioplasty and type of procedure during 2002 to 2013. The ICD-10 codes used to define risk factors and concomitant diseases have been described previously.18, 19 Timing of stent placement or angioplasty was defined as the period of visit to an outpatient clinic or hospital admission shortly before stent placement or angioplasty until the time of stent placement or angioplasty. Also, intensive care unit (ICU) admission was defined as the presence of the physicians' procedure codes for intensive care (AJ001–3).20 The primary outcome of interest was all-cause death (n=1083), whereas secondary outcomes were composite all-cause death, including death by cerebrocardiovascular disease (n=555) and cancer (n=405). Death from cerebro-cardiovascular diseases included death due to cardiovascular disease (ICD-10, I00-I09, I11, I13, and I20–I51; n=434) and cerebrovascular disease (ICD-10, I60–I69; n=161). Cancer deaths were identified by ICD–10 underlying cause-of-death codes C00–C97. Diagnosis of cancer using the ICD-10 code had been validated by comparison with the Korean National Cancer Incidence Database.

    Exposure assessments

    For a total of 5415 subjects, we evaluated antiplatelet drug patterns for 2 years after stent placement or angioplasty. In the first year, the pattern was confirmed every 3 months. The pattern of antiplatelet use was defined based on the number of antiplatelet prescriptions (1 antiplatelet drug, 2 antiplatelet drugs, and ≥3 antiplatelet drugs) and drug regimen. All antiplatelet prescriptions (aspirin, cilostazol, clopidogrel, ticlopidine, triflusal, ticagrelor, and prasugrel) for each subject were identified. To analyze the antiplatelet regimen taking into account the frequency of prescription of antiplatelets (except when the frequency of drug use was <1%), subjects were categorized according to the use of aspirin, clopidogrel, and cilostazol alone or in combination with each other. In terms of drug persistence, the “proportion of days covered” concept was applied. Thus, when the claimed prescription accounted for more than 80% of the antiplatelet drugs prescribed within the measurement period, it was defined as “continuous use” for the same drug or otherwise as “discontinuation.”21 When the claimed prescription accounted for less than 80% of the prescribed antiplatelet drugs within the measurement period, it was defined as “others or non-use.” In the present study, measurement period was alternatively defined and evaluated according to the following criteria: Fig. 2A) medication pattern for 6 months from 6 months before the index date; Fig. 2B) medication pattern for 9 months starting 3 months before the index date (Fig. 2).

    Fig. 2
    Nested case-control study design. (A) Medication patterns for 6 months from 6 months before index data. (B) Medication patterns for 9 months from 3 months before index date.

    Statistical analysis

    Basic characteristics of the study subjects are summarized as means with standard deviations for numerical variables and number of subjects with percentages for categorical variables. The significance of differences in basic characteristics between case and control groups was evaluated using independent Student's t-test and the chi-square test. To assess the effect of antiplatelet drug patterns (number and regimen) on adverse outcomes, we used logistic regression analysis and expressed the results as odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable logistic regression was carried out by adjusting for covariates, including sex, age, income level, procedure type, timing of stent replacement or angioplasty, ICU admission, baseline comorbidities (hypertension, diabetes mellitus, dyslipidemia, myocardial infarction, heart failure, stroke, chronic kidney disease, PAD, and cancer), and concomitant statin use. Moreover, adverse outcomes were compared between study patients according to number (mono, dual, and triple) and regimen (aspirin, clopidogrel, and DAPT) of medications for the periods 6 months from 6 months before the index data and 9 months from 3 months before the index date. Multicollinearity was assessed based on the variance inflation factor and had a value <6.0.

    Because the majority of the included patients underwent coronary artery stent placement, subgroup analysis was performed on patients who underwent coronary artery stent placement. In addition, to reduce the possibility of grouping subjects into “others or non-use” by reducing the measurement period, the measurement period was redefined and analyzed as follows: medication pattern for 3 months from 1 month before the index date. All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA), and statistical significance was set at p>0.05 in two-sided tests.

    RESULTS

    Comparison of baseline characteristics

    Baseline characteristics of selected cases and controls are shown in Table 1. There were no significant differences in sex or age at stent placement or angioplasty between cases and controls. Histories of hypertension, diabetes mellitus, chronic kidney disease, PAD, stroke, cancer, and heart failure were more prevalent in the all-cause death group than in the control group (all p<0.001). History of dyslipidemia and concomitant statin use was more prevalent in the control group than the all-cause death group (p=0.019 and p<0.001). According to site of stent placement among all included patients, 3.6% had undergone stent placement in an intracranial or extracranial artery, 88.4% had undergone coronary artery stent placement, and 7.9% had undergone stent placement in other peripheral arteries. Using drug eluting stent and ICU admission were more prevalent in the all-cause death group than in the control group (all p<0.001). Timing of stent placement or angioplasty was longer in the all-cause death group than in the control group (p<0.001).

    Table 1
    Baseline Characteristics of All-Cause Mortality Cases and Their Matched Controls

    Mortality and pattern of antiplatelet use

    The incidence rate of all-cause death in this study was 40 per 1000 person-years (median follow-up: 3.51 years, interquartile range 1.64–6.00 years). Among patients with an all-cause death, 5.8% had undergone stent placement in an intracranial or extracranial artery, 80.3% had undergone coronary artery stent placement, and 13.9% had undergone stent placement in other peripheral arteries. Fig. 3 shows the pattern of antiplatelet treatment for the 2-year follow-up period after stent placement. Although 74.1% of patients at the 1-month follow-up after stent placement were receiving DAPT, only 48.7% and 27.9% of patients at the 1-and 2-year follow-ups after stent placement were receiving DAPT. Although 3.8% of patients were on antiplatelet monotherapy and 15.6% of patients had discontinued antiplatelets at the 1-month follow-up after stent placement, these values increased to 8.9% and 38.3% of patients at 1-year follow-up and 20.3% and 49.8% of patients at 2-year follow-up after stent placement, respectively.

    Fig. 3
    Patterns of antiplatelet treatment for the 2-year follow-up period after stent placement.

    Mortality according to number of antiplatelet medications and treatment regimen

    When analyzing adherence to medication, we found that adherence to antiplatelet monotherapy was negatively associated with risk of death by cerebro-cardiovascular disease, compared with discontinuation of antiplatelets, for 6 months from 6 months before the index date [crude OR 0.57, 95% CI (0.38–0.86), adjusted OR 0.60, 95% CI (0.38–0.96)]. This association was still evident for the 9-month time period from 3 months before the index date [crude OR 0.65, 95% CI (0.44–0.95), adjusted OR 0.62, 95% CI (0.41–0.96)] (Table 2). Moreover, we found that antiplatelet monotherapy was negatively associated with risk of all-cause death, compared with discontinuation of antiplatelets, for 9 months from 3 months before the index date [crude OR 0.75, 95% CI (0.58–0.98), adjusted OR 0.70, 95% CI (0.52–0.96)] (Supplementary Table 1, only online).

    Table 2
    Risk of Death by Cerebro-Cardiovascular Disease according to Number of Antiplatelet Medications and Regimen of Medications for 6 Months from 6 Months before the Index Date and for 9 Months from 3 Months before the Index Date

    Aspirin monotherapy was negatively associated with risk of death by cerebro-cardiovascular disease, compared with discontinuation of antiplatelets, for 6 months from 6 months before the index date [adjusted OR 0.61, 95% CI (0.38–0.97)] and for 9 months from 3 months before the index date [adjusted OR 0.62, 95% CI (0.40–0.96)]. Moreover, we found that aspirin monotherapy was negatively associated with risk of all-cause death and death by cancer, compared with discontinuation of antiplatelets, for 9 months from 3 months before the index date [adjusted OR 0.71, 95% CI (0.52–0.98) and adjusted OR 0.55, 95% CI (0.33–0.91), respectively]. Clopidogrel monotherapy was negatively associated with risk of death by cerebro-cardiovascular disease, compared with discontinuation of antiplatelets, for 9 months from 3 months before the index date [adjusted OR 0.55, 95% CI (0.32–0.96)] (Table 2 and Supplementary Table 1 and 2, only online). There was no significant association between risk of death by cardiovascular disease and cerebrovascular disease and number and regimen of medication (Supplementary Table 3 and 4, only online).

    In comparisons of mortality according to number of antiplatelet agents (mono, dual, and triple) and regimen (aspirin, clopidogrel, and DAPT), we found that antiplatelet monotherapy was negatively related to risk of death by cerebro-cardiovascular disease compared with DAPT, for 9 months from 3 months before the index date [adjusted OR 0.72, 95% CI (0.52–0.99)]. Moreover, we found that aspirin monotherapy was negatively related to risk of all-cause death for 6 months from 6 months before the index date and for 9 months from 3 months before the index date [adjusted OR 0.74, 95% CI (0.57–0.97) and adjusted OR 0.72, 95% CI (0.55–0.95), respectively], death by cerebro-cardiovascular disease for 6 months from 6 months before the index date and for 9 months from 3 months before the index date [adjusted OR 0.66, 95% CI (0.45–0.96) and adjusted OR 0.65, 95% CI (0.44–0.95), respectively], compared with DAPT. Clopidogrel monotherapy was negatively related to risk of death by cerebro-cardiovascular disease for 9 months from 3 months before the index date [adjusted OR 0.58, 95% CI (0.35–0.96)], compared with DAPT. There was no significant difference in mortality between aspirin monotherapy and clopidogrel monotherapy (Table 3 and 4).

    Table 3
    Comparisons of Mortality between Study Patients according to Number (Mono, Dual, and Triple) of Medications for 6 Months from 6 Months Before the Index Data and for 9 Months from 3 Months before the Index Date

    Table 4
    Comparisons of Mortality between Study Patients according to Regimen (Aspirin, Clopidogrel, and Dual Antiplatelet) of Medication for 6 Months from 6 Months before the Index Date and 9 Months from 3 Months before the Index Date

    Subgroup analysis of patients who received stent placement in the coronary artery

    We found that antiplatelet monotherapy was negatively related to risk of death by cerebro-cardiovascular disease in patients with coronary artery stent placement, compared with DAPT, for 6 months from 6 months before the index date [adjusted OR 0.69, 95% CI (0.48–0.99)]. Comparisons of mortality according to medication regimen (aspirin, clopidogrel, DAPT) in these patients revealed that aspirin was negatively related to risk of all-cause death for 6 months from 6 months before the index date and for 9 months from 3 months before the index date [adjusted OR 0.73, 95% CI (0.54–0.98) and adjusted OR 0.72, 95% CI (0.53–0.98), respectively], death by cerebro-cardiovascular disease for 6 months from 6 months before the index date and for 9 months from 3 months before the index date [adjusted OR 0.58, 95% CI (0.38–0.88) and adjusted OR 0.58, 95% CI (0.38–0.90), respectively], compared with DAPT (Supplementary Table 5 and 6, only online).

    Sensitivity analysis of medication patterns for 3 months from 1 month before the index date

    To reduce the possibility of grouping subjects into “others or non-use,” we analyzed medication patterns for 3 months from 1 month before the index date and found that antiplatelet monotherapy was negatively related to risk of death by cerebrovascular disease, compared with DAPT, for this time period [adjusted OR 0.41, 95% CI (0.21–0.82)]. Moreover, we found that aspirin monotherapy was negatively related to risk of all-cause death and death by cerebrovascular disease for 3 months from 1 month before the index date [adjusted OR 0.75, 95% CI (0.57–0.99) and adjusted OR 0.44, 95% CI (0.20–0.96), respectively]. Clopidogrel monotherapy was negatively related to risk of death by cerebrovascular disease for 3 months from 1 month before the index date [adjusted OR 0.33, 95% CI (0.11–0.93)] (Supplementary Table 7 and 8, only online).

    DISCUSSION

    In the present study of patients who underwent stent placement or angioplasty, we found that antiplatelet monotherapy, including aspirin or clopidogrel, was negatively associated with risk of death by cerebro-cardiovascular disease, compared with discontinuation of antiplatelets and DAPT. Furthermore, aspirin monotherapy was negatively related to risk of all-cause death and death by cancer, compared with discontinuation of antiplatelets. In addition, aspirin monotherapy was negatively related to risk of all-cause death, compared with DAPT. However, there was no significant difference in mortality between aspirin monotherapy and clopidogrel monotherapy.

    A previous study proposed that antiplatelet monotherapy among patients with high risk occlusive vascular events decreased vascular mortality.22 Furthermore, aspirin treatment decreased risk of myocardial infarction and stroke, death by cardiovascular disease, and all-cause death.23, 24 Additionally, clopidogrel treatment for secondary prevention with stroke resulted in greater relative-risk reduction than aspirin treatment.25 With respect to cancer, a previous clinical trial demonstrated that aspirin monotherapy was associated with a reduction in overall cancer incidence between 3 and 5 years after treatment.26 Because aspirin interrupts neoplastic transformation of normal colorectal epithelium to sporadic adenomas, aspirin monotherapy is associated with decreased mortality from colorectal cancer.27 It has been shown to reduce cancer incidence by 10% during the first 10 years of treatment.27 Recent study using registry data of the National Institute of Health showed that there were no differences in death occurrence from any cause, myocardial infarction, repeat percutaneous coronary intervention, stent thrombosis, and ischemic stroke between aspirin and clopidogrel monotherapy. Although previous observational study of patients who underwent drug-eluting stent showed that clopidogrel was associated with a reduced risk for cardiac death, myocardial infarction, or stroke, less than half of the patients enrolled in these studies were diagnosed with acute coronary syndrome.28, 29 These results are similar to our findings in patients on prolonged antiplatelet treatment due to stent placement or angioplasty.

    In real-world patients, long-term adherence to DAPT after stent placement might raise compliance issues. In one systemic review, adherence to DAPT after stent placement in the coronary artery was high at 1 month (about 90%), began to decline by 6 months, and was lower still at 12 months.30 One clinical trial reported a rate of early discontinuation of antiplatelet medications as high as 30% after 12 months.31 Furthermore, real-world practice is characterized by frequent, transient interruptions, alternative prescriptions, or complete cessation of DAPT, regardless of guidelines. Of note, the rate and clinical consequences of DAPT beyond 12 months after stent placement in real-world patients still need to be determined. Despite the benefits of DAPT or antiplatelet monotherapy, antiplatelet therapy is sometimes prematurely discontinued after stent placement by the patient or healthcare provider. In previous reports, discontinuation of aspirin for secondary prevention increased the risk of all-cause mortality.32, 33 Furthermore, discontinuation of DAPT within 6 months and 1 year after stent placement increased the risks of all-cause mortality, cardiovascular death, myocardial infarction, and all-cause mortality.34, 35 These results are similar to our findings showing that adherence to antiplatelet therapy with aspirin reduced all-cause deaths and death by cerebro-cardiovascular disease, and cancer and to that with clopidogrel reduced deaths by cerebro-cardiovascular disease.

    Antiplatelet monotherapy, including aspirin or clopidogrel, significantly decreased the risk of death by cerebro-cardiovascular disease, compared with DAPT, in our study. In addition, aspirin monotherapy was significantly associated with reduced risk of all-cause death, compared with DAPT. Although one clinical trial reported that prolonged DAPT (30 months) after stent placement in the coronary artery reduced the risk of major adverse cerebro-cardiovascular and cerebrovascular events, myocardial infarction, and stent thrombosis, it was associated with an unexpected increase in all-cause death.36 In addition, another trial demonstrated that there was no difference in cardiovascular or non-cardiovascular mortality, all-cause death, or stent thrombosis between prolonged DAPT (median period 33.4 months) and antiplatelet monotherapy.37 Furthermore, in a systemic review and meta-analysis, prolonged DAPT, compared with antiplatelet monotherapy or short duration DAPT, was not associated with cardiovascular or non-cardiovascular death or all-cause mortality. Our results are not sensitive to the exclusion of any trial, and although the enrolled subjects varied, we found that antiplatelet monotherapy (median follow-up: 3.51 years) was negatively associated with risk of death by cerebro-cardiovascular disease and all-cause death, compared with prolonged DAPT, in a real-world setting.

    Unlike stent placement in the coronary artery, data regarding the effects of antiplatelet strategies after stent placement in patients with PAD or cerebral artery disease are limited.12, 38 In patients with PAD, DAPT significantly reduced re-occlusion and resulted in maintenance of target artery at 6 months after the procedure, compared to aspirin monotherapy.10, 11 It is recommended that patients who undergo procedures in the carotid artery receive DAPT (currently aspirin and clopidogrel) throughout the periprocedural period to decrease the risk of stent thrombosis/embolization; however, there is no evidencebased consensus as to how long DAPT should be continued or what kinds of antiplatelet drugs should be given.39 Data regarding antiplatelet management in patients treated with stent placement in the intracranial cerebral artery are even more limited. Although our dataset included patients from the general population who underwent stent placement or angioplasty in a peripheral artery or intracranial or extracranial cerebral arteries, it was not possible to perform subgroup analysis due to the small number of patients who received stent placement or angioplasty in these vessels. Therefore, further study of these specific populations is needed.

    Our current study has several limitations. First, case-control studies have several inherent limitations, particularly selection bias due to the retrospective nature of the study. Second, we used ICD coding to select study subjects. Although the accuracy of diagnosis of vascular risk factors using ICD-10 codes was 85.0–94.1% in previous studies using the NHIS-HEALS dataset and the overall sensitivity of cancer diagnosis using ICD-10 codes was previously found to be 92.8%, because we relied on ICD coding of the principal diagnosis, we were not able to validate individual ICD codes.40, 41, 42 Third, because of the exclusion of patients who had an acute or subacute thrombus within 30 days after stent placement or angioplasty, we may have underestimated adverse outcomes. Fourth, due to the lack of detailed clinical information in health claims data, we were not able to collect data on the severity of stenosis of the artery into which the stent was implanted, radiological findings, blood pressure, glucose level, low-density lipoprotein level, or length of ICU stay, which are strong prognostic factors in patients with stent placement or angioplasty. Fifth, currently, because there is no standard for exposure period and washout period after stent placement or angioplasty, we cannot confirm that a proper washout period and exposure period were followed. Therefore, we used a nested case-control study design to analyze dynamic variations in patterns of antiplatelet treatment and evaluated whether relationships between the patterns of antiplatelet treatment and clinical outcomes were consistent considering variable exposure periods and washout periods or not. Finally, because of the nested case-control study design and the time-varying nature of antiplatelet drug use after stent placement or angioplasty among the patients in our study, we cannot provide recommendations on when prescriptions should be changed from antiplatelet monotherapy to DAPT. Despite these limitations, a major strength of this study is that we evaluated real-world prognoses of patients with stent placement or angioplasty according to treatment with antiplatelets using nationwide health insurance claims data. Because the NHIS in Korea is a single payer insurer, we were able to access detailed prescription data for antiplatelets for an extended period after stent placement or angioplasty.

    In conclusion, adherent antiplatelet therapy in patients with stent placement or angioplasty may have a beneficial inhibitory effect on mortality by cerebro-cardiovascular disease. Antiplatelet monotherapy, including aspirin or clopidogrel, appears to be associated with a lower risk of mortality by cerebrocardiovascular disease than DAPT.

    SUPPLEMENTARY MATERIALS

    SUPPLEMENTARY MATERIAL

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    Supplementary Table 1

    Risk of All-Cause Death according Number and Regimen of Medication for 6 Months from 6 Months and 9 Months from 3 Months before Index Date

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    Supplementary Table 2

    Risk of Death by Cancer according Number and Regimen of Medication for 6 Months from 6 Months and 9 Months from 3 Months before Index Date

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    Supplementary Table 3

    Risk of Death by Cardiovascular Disease according Number and Regimen of Medication for 6 Months from 6 Months and 9 Months from 3 Months before Index Date

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    Supplementary Table 4

    Risk of Death by Cerebrovascular Disease according Number and Regimen of Medication for 6 Months from 6 Months and 9 Months from 3 Months before Index Date

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    Supplementary Table 5

    Comparisons of Mortality for Patients Who Received Stent Placement in a Coronary Artery according to Number (Mono, Dual, and Triple) of Medication for 6 Months from 6 Months and 9 Months from 3 Months before Index Date

    Click here to view.(30K, pdf)

    Supplementary Table 6

    Comparisons of Mortality for Patients Who Received Stent Placement in a Coronary Artery According to Regimen (Aspirin, Clopidogrel, and Dual Antiplatelet) of Medication for 6 Months from 6 Months and 9 Months from 3 Months before Index Date

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    Supplementary Table 7

    Comparisons of Mortality between Study Patients according to Number (Mono, Dual, and Triple) of Medication for 3 Months from 1 Months

    Click here to view.(29K, pdf)

    Supplementary Table 8

    Comparisons of Mortality between Study Patients according to Regimen (Aspirin, Clopidogrel, and Dual Antiplatelet) of Medication for 3 Months from 1 Months

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    Notes

    The authors have no potential conflicts of interest to disclose.

    AUTHOR CONTRIBUTIONS:

    • Conceptualization: Ho Geol Woo and Tae-Jin Song.

    • Data curation: all authors.

    • Formal analysis: Ho Geol Woo, Hye Ah Lee, and Tae-Jin Song.

    • Funding acquisition: Tae-Jin Song.

    • Investigation: all authors.

    • Methodology: all authors.

    • Project administration: Tae-Jin Song.

    • Resources: all authors.

    • Software: Ho Geol Woo and Hye Ah Lee.

    • Supervision: Dong-Ryeol Ryu.

    • Validation: all authors.

    • Visualization: Ho Geol Woo, Hye Ah Lee, and Tae-Jin Song.

    • Writing—original draft: Ho Geol Woo and Hye Ah Lee.

    • Writing—review & editing: all authors.

    • Approval of final manuscript: all authors.

    ACKNOWLEDGEMENTS

    This project was supported by a grant (2018R1D1A1B07040959 to T-JS) of the Basic Science Research Program through the National Research Foundation funded by the Ministry of Education, Republic of Korea.

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    MeSH Terms
    Angioplasty*
    Aspirin
    Cardiovascular Diseases
    Case-Control Studies*
    Cerebrovascular Disorders
    Clopidogrel
    Cohort Studies
    Follow-Up Studies
    Humans
    Incidence
    International Classification of Diseases
    Korea
    Mortality*
    National Health Programs
    Odds Ratio
    Platelet Aggregation Inhibitors
    Stents*
    Metrics
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