Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention: 10-year follow-up of the HOST-EXAM trial.

# Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention: 10-year follow-up of the HOST-EXAM trial *The Lancet 2026* Articles Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention: 10-year follow-up of the HOST-EXAM trial Jeehoon Kang*, Sungjoon Park*, Han-Mo Yang*, Eun-Seok Shin, Seung-Woon Rha, Jang-Whan Bae, Nam Ho Lee, Hyuck-Jun Yoon, Yoon Haeng Cho, Ung Kim, Song-Yi Kim, Sang-Hyun Kim, Jung-Kyu Han, Kyung Woo Park, Hyo-Soo Kim, on behalf of the HOST-EXAM investigators† Summary Background The long-term clinical outcomes of clopidogrel monotherapy versus aspirin monotherapy after Lancet 2026; 407: 1439–47 percutaneous coronary intervention (PCI) remain uncertain. We conducted a 10-year follow-up of the HOST-EXAM Published Online trial to assess the very long-term eects of clopidogrel versus aspirin monotherapy in this setting. March 29, 2026 https://doi.org/10.1016/ S0140-6736(26)00422-8 Methods In HOST-EXAM, patients who had completed dual antiplatelet therapy without clinical events for See Comment page 1400 6–18 months after PCI were randomly assigned to receive clopidogrel 75 mg once daily or aspirin 100 mg once daily. *Contributed equally This study is an investigator-initiated 10-year extended follow-up of the HOST-EXAM trial. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, †Investigators listed in the appendix (pp 5–8) and Bleeding Academic Research Consortium type ≥3 bleeding. The primary analysis was done in the intention-to- Department of Internal treat population. The study is registered with ClinicalTrials.gov (NCT02044250) and is complete. Medicine, Seoul National University Hospital, Seoul, Findings From March 26, 2014, to May 29, 2018, 5530 patients were enrolled and 5438 were randomly assigned to the South Korea (J Kang MD PhD, aspirin group (n=2728) or the clopidogrel group (n=2710). Clinical follow-up status was ascertained on May 1, 2025, J-K Han MD PhD); Department of Cardiovascular Medicine, resulting in a median follow-up duration of 10·5 years (IQR 9·4–11·4) after PCI and a completion rate of 92·8%. Boramae Medical Center, Seoul, Clopidogrel was associated with a lower rate of the primary composite endpoint than aspirin (Kaplan–Meier South Korea (S Park MD, estimate 25·4% for the clopidogrel group vs 28·5% for the aspirin group; hazard ratio 0·86 [95% CI 0·77–0·96]; log-rank S-H Kim MD PhD); Department p=0·0050). Clopidogrel was also associated with a lower rate of the thrombotic endpoint (17·3% vs 20·0%; log-rank of Internal Medicine, Seoul National University College of p=0·0024) and bleeding endpoint (9·1% vs 10·8%; log-rank p=0·020). All-cause mortality was similar between groups. Medicine, Seoul, South Korea (H-M Yang MD PhD, Interpretation During 10 years of follow-up, clopidogrel monotherapy, compared with aspirin monotherapy, was Prof K W Park MD PhD); associated with lower rates of the primary composite, ischaemic, and bleeding outcomes, but not all-cause mortality Department of Cardiovascular Medicine, Ulsan University after PCI. These findings support consideration of clopidogrel as an alternative to aspirin for long-term antiplatelet Hospital, Ulsan, South Korea monotherapy during the chronic maintenance phase after PCI. (E-S Shin MD PhD); Department of Cardiovascular Medicine, Korea University Guro Hospital, Funding Ministry of Health & Welfare, South Korea. Seoul, South Korea (S-W Rha MD PhD); Department Copyright © 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar of Cardiovascular Medicine, technologies. Good SamSun Hospital, Busan, South Korea (J-W Bae MD PhD); Department of Cardiovascular Introduction Methods Medicine, Kangnam Sacred After completion of dual antiplatelet therapy (DAPT), Study design and participants Heart Hospital, Hallym antiplatelet monotherapy is recommended for long-term Details regarding the design of the HOST-EXAM trial University, Seoul, South Korea (N H Lee MD PhD); Department secondary prevention of major adverse cardiovascular have been described previously.7 Briefly, HOST-EXAM of Cardiovascular Medicine, events after percutaneous coronary intervention (PCI). was an investigator-initiated, prospective, randomised, Keimyung University Dongsan Although aspirin has traditionally been the agent of open-label, multicentre trial done at 37 study sites in Hospital, Daegu, South Korea choice,1,2 recent trials and meta-analyses have reported South Korea. Details of the participating centres and (H-J Yoon MD PhD); Department of Cardiovascular Medicine, superiority of clopidogrel monotherapy over aspirin investigators are provided in the appendix (pp 5–8). The Soonchunhyang University monotherapy for secondary prevention in this setting.3–6 randomised antiplatelet treatment strategy was Bucheon Hospital, Bucheon, However, because secondary prevention after PCI is mandated during the initial 24-month follow-up after South Korea (Y H Cho MD PhD); typically continued lifelong, follow-up beyond 5 years is enrolment, whereas antiplatelet therapy during the Department of Cardiovascular Medicine, Yeungnam needed to better understand the eects of antiplatelet post-trial follow-up was at the discretion of the treating University Medical Center, monotherapy. Therefore, we report the prespecified physician. Patients aged 20 years or older who Daegu, South Korea long-term follow-up of the HOST-EXAM trial, with underwent PCI with drug-eluting stents and maintained (U Kim MD PhD); Department outcomes assessed at 10 years to evaluate the comparative DAPT without any clinical events for 6–18 months after of Cardiovascular Medicine, Jeju National University long-term eects of clopidogrel monotherapy versus PCI were eligible for enrolment in the HOST-EXAM Hospital, Jeju, South Korea aspirin monotherapy. trial.3,7 Articles (S-Y Kim MD PhD); Biomedical Research Institute, Seoul Research in context National University Hospital, Evidence before this study drug-eluting stents. Clopidogrel monotherapy was associated Seoul, South Korea (Prof H-S Kim MD PhD) We searched PubMed, MEDLINE, and the Cochrane Library for with sustained reductions in the primary composite endpoint Correspondence to: randomised controlled trials and meta-analyses comparing compared with aspirin monotherapy over 10 years, extending Prof Hyo-Soo Kim, Biomedical P2Y12 inhibitor monotherapy with aspirin monotherapy for the longest previous randomised follow-up of 5 years. The Research Institute, Seoul long-term secondary prevention after percutaneous coronary cumulative long-term benefit was reflected in a lower number National University Hospital, intervention (PCI), published from database inception to needed to treat at 10 years compared with that at 2 years. Seoul 03080, South Korea hyosoo@snu.ac.kr Dec 31, 2025, using the keywords “clopidogrel”, “aspirin”, Treatment adherence was higher in the clopidogrel group than or “antiplatelet monotherapy”, “percutaneous coronary in the aspirin group, in which gastrointestinal discomfort was a intervention”, “drug-eluting stent”, and “secondary common cause of treatment discontinuation, highlighting the Prof Kyung Woo Park, Department of Internal prevention”, with no language restrictions. Evidence from role of tolerability in long-term therapy. Medicine, Seoul National randomised trials before this study was limited to studies with University College of Medicine, Implications of all the available evidence short or intermediate duration of follow-up. The STOPDAPT-2 Seoul 03080, South Korea Combined with data from previous randomised trials and kwparkmd@snu.ac.kr and SMART-CHOICE 3 trials reported lower rates of clinical meta-analyses, our results strengthen the evidence supporting events with clopidogrel than with aspirin, and a 2025 individual See Online for appendix the superiority of clopidogrel monotherapy over aspirin patient data meta-analysis reported that clopidogrel monotherapy for long-term secondary prevention after PCI. monotherapy was superior to aspirin monotherapy for The continued divergence of the event curves and the prevention of major adverse cardiovascular or cerebrovascular decreasing number needed to treat over time suggests that the events. Nevertheless, no randomised trial had previously clinical benefit of clopidogrel is cumulative. The totality of assessed antiplatelet monotherapy beyond 5 years after PCI. contemporary evidence suggests that the role of aspirin as the Added value of this study first-line lifelong antiplatelet therapy after PCI warrants This study reports the 10-year follow-up of the HOST-EXAM reconsideration, especially in health-care systems where randomised trial, providing the longest randomised clopidogrel is accessible and inexpensive. comparison of antiplatelet monotherapy after PCI with The Seoul National University Hospital Clinical Trial Procedures Center and the Medical Research Collaborating Center According to the randomisation assignment, patients were responsible for the scientific conduct of the trial. All received either clopidogrel (75 mg once daily) or aspirin events were adjudicated by an independent clinical (100 mg once daily). Clinical follow-up was scheduled events committee whose members were unaware of the annually for up to 10 years after randomisation. During treatment assignments. Members of the independent the follow-up period, active surveillance was done for any clinical events committee received medical records of prespecified adverse clinical events, along with adverse events after removal of any reference to the assessment of adherence to the study drug. For patients treatment groups. This study was conducted in who did not visit the outpatient clinic, telephone accordance with the standards specified in the follow-up was permitted. Additionally, vital status was International Council for Harmonization Guidelines for cross-checked through the National Health Insurance Good Clinical Practice and the principles of the Service system of South Korea and the South Korea Declaration of Helsinki. National Statistics System. Randomisation and masking Outcomes Randomisation was done by a web-based application The trial endpoints and definitions were identical to (Medical Research Collaborating Center Interactive Web those of the HOST-EXAM trial.3 The primary endpoint Response System) developed by the Medical Research was a composite of all-cause death, non-fatal myocardial Collaborating Center (Seoul, South Korea), without infarction, stroke, readmission due to acute coronary blocking or stratification. Enrolled patients were syndrome, and major bleeding events. Major bleeding randomly assigned in a 1:1 ratio to either the clopidogrel was defined as type ≥3 bleeding according to the Bleeding group or the aspirin group. Randomisation was Academic Research Consortium (BARC). Secondary performed by an independent research coordinator to composite endpoints included the thrombotic composite ensure allocation concealment. Detailed inclusion and endpoint (defined as cardiovascular death, non-fatal exclusion criteria are described in the appendix (p 12). myocardial infarction, ischaemic stroke, readmission Patients and study investigators were not masked to due to acute coronary syndrome, and definite or probable treatment assignment. Clinical data were recorded in stent thrombosis) and any bleeding (defined as BARC web-based electronic case report forms developed by the type ≥2 bleeding). The individual components of the Medical Research Collaborating Center. primary composite endpoint and of the secondary 1440 Articles composite endpoints were also analysed as secondary were also assessed in the per-protocol population, which endpoints. For mortality cases, the cause of death was included all patients who received the allocated single confirmed by the recorded data classified by the codes antiplatelet therapy throughout follow-up unless an from the ICD-10 Clinical Modification guideline. Detailed adverse clinical event occurred. definitions of each clinical event are described in the Continuous variables were reported as mean (SD), and appendix (pp 13–19). categorical variables were presented as counts and proportions. Dierences between continuous variables Statistical analysis were compared by Student’s t test for independent data. The working hypothesis of the HOST-EXAM trial was The primary composite endpoint was analysed by a Cox that clopidogrel would be superior to aspirin as a chronic proportional hazards model and Kaplan–Meier curves to maintenance monotherapy agent, which required estimate the risk of clinical events according to the type of 5530 patients to ensure at least 80% power with a antiplatelet agent. No variables other than the trial group two-sided α of 0·05 based on the assumed event rates. were used for stratification. Event-free survival with The current study was an extended follow-up of this incomplete follow-up was counted as censored data for all population; therefore, no additional sample size time-to-event analyses. A Cox proportional hazards model calculation was done. The primary analysis was done on was used for analysis of subgroups, defined according to an intention-to-treat basis and included all randomly age (<65 years or ≥65 years), sex (male or female), BMI assigned patients. As a sensitivity analysis, outcomes (≥25 kg/m² or <25 kg/m²), renal function, diabetes, 5530 patients enrolled 92 excluded 50 did not meet eligibility criteria 28 declined to participate 14 randomisation error 5438 randomly assigned 2710 assigned to clopidogrel monotherapy 2728 assigned to aspirin monotherapy 62 excluded during the trial period 73 excluded during the trial period 8 withdrew consent 1 withdrew consent 41 lost to follow-up 50 lost to follow-up 13 used a different antiplatelet regimen 22 used a different antiplatelet regimen 1 aspirin 9 other antiplatelet agent 11 other antiplatelet agent 13 no antithrombotic agent 1 no antithrombotic agent 2648 entered the post-trial period 2655 entered the post-trial period 510 excluded after trial period 614 excluded after trial period 173 lost to follow-up 126 lost to follow-up 337 used a different antiplatelet regimen 488 used a different antiplatelet regimen 113 aspirin 276 clopidogrel 87 other antiplatelet agent 105 other antiplatelet agent 83 oral anticoagulants 76 oral anticoagulants 54 no antithrombotic agent 31 no antithrombotic agent 2138 adhered to the protocol during the 2041 adhered to the protocol during the 10-year follow-up 10-year follow-up 2710 included in intention-to-treat analysis 2728 included in intention-to-treat analysis Figure 1: Trial profile Patients who underwent PCI with a drug-eluting stent and maintained dual antiplatelet therapy without any clinical events within 6–18 months after the index PCI were eligible for enrolment in the HOST-EXAM trial. Patients were followed up for up to 10 years. The primary endpoint was analysed in the intention-to-treat population. PCI=percutaneous coronary intervention. Articles clinical presentation (acute myocardial infarction or not, acute coronary syndrome or not), complex PCI, and high bleeding risk. The specific definitions of complex PCI and high bleeding risk are shown in the appendix (pp 13–14). Statistical tests were done using SPSS version 24 and R version 4.3.3. All p values were two-sided, and p<0·05 was considered statistically significant. This study is registered with ClinicalTrials.gov (NCT02044250), and is complete. Role of the funding source The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Results Between March 26, 2014, and May 29, 2018, 5530 patients were enrolled, of whom 5438 remained event-free for 6–18 months after PCI, successfully received the intended duration of DAPT, and were randomly assigned to either clopidogrel monotherapy (n=2710) or aspirin mono- therapy (n=2728; figure 1). Clinical and angiog raphic characteristics were well matched between groups (appendix pp 20–22). Clinical events during the 10-year follow-up period were collected up to May 1, 2025. The median duration of follow-up was 10·5 years (IQR 9·4–11·4) after PCI and 10·7 years (IQR 9·8–11·5) in survivors. Among the total population, nine patients withdrew informed consent, 390 patients were lost to C follow-up (including 91 patients who were lost to follow-up in the in-trial period), and 860 patients used a dierent antithrombotic strategy during the follow-up period, leaving 4179 (76·8%) of 5438 patients in the per- protocol population. Information on adverse clinical outcomes, including vital status, was complete in 2496 (92·1%) of 2710 patients in the clopidogrel group and 2552 (93·5%) of 2728 patients in the aspirin group, 0 1 2 3 4 5 6 7 8 9 10 corresponding to outcome ascertainment in 5048 Number at risk (92·8%) of 5438 patients overall. (censored) During the follow-up period, the primary composite Aspirin 2728 2663 2609 2555 2510 2442 2392 2328 2022 1529 888 (0) (17) (32) (65) (89) (126) (156) (196) (466) (939) (2458) endpoint occurred in 646 patients (Kaplan–Meier Clopidogrel 2710 2649 2600 2543 2483 2422 2368 2307 2022 1533 902 estimate 25·4%) who received clopidogrel monotherapy, (0) (27) (51) (89) (125) (160) (202) (245) (507) (972) (2493) and in 739 patients (Kaplan–Meier estimate 28·5%) who D 30 25 Figure 2: Cumulative incidence of the primary composite endpoint, secondary composite endpoints, and all-cause death in the intention-to- 20 treat population 15 (A) Cumulative incidence of the primary composite endpoint, consisting of all- 10 cause death, non-fatal myocardial infarction, stroke, readmission due to acute 5 coronary syndrome, and major bleeding (Bleeding Academic Research 0 Consortium type ≥3 bleeding). (B) Cumulative incidence of the secondary 0 1 2 3 4 5 6 7 8 9 10 composite thrombotic endpoint, consisting of cardiac death, non-fatal Time since randomisation (years) Number at risk myocardial infarction, ischaemic stroke, readmission due to acute coronary (censored) syndrome, or definite or probable stent thrombosis. (C) Cumulative incidence of Aspirin 2728 2707 2687 2645 2614 2562 2521 2473 2185 1670 977 any bleeding. (D) Cumulative incidence of all-cause death. HRs are for (0) (3) (5) (12) (12) (18) (19) (19) (265) (748) (2406) clopidogrel monotherapy versus aspirin monotherapy. NNTs are shown only Clopidogrel 2710 2681 2653 2609 2563 2517 2473 2427 2138 1642 976 when the absolute risk difference excludes zero. HR=hazard ratio. NNT=number (0) (5) (8) (15) (20) (31) (36) (36) (282) (750) (2372) needed to treat. 1442 ecnedicni evitalumuC )%( stneve fo 30 20 10 0 ecnedicni evitalumuC )%( stneve fo B 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Number at risk (censored) Aspirin 2728 2644 2554 2489 2431 2349 2286 2215 1920 1428 828 (0) (12) (29) (49) (63) (86) (106) (119) (360) (811) (2222) Clopidogrel 2710 2641 2575 2516 2452 2393 2324 2252 1939 1458 843 (0) (17) (37) (66) (88) (113) (134) (155) (411) (856) (2292) ecnedicni evitalumuC )%( stneve fo A 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 Number at risk (censored) Aspirin 2728 2621 2516 2442 2383 2290 2217 2138 1834 1352 779 (0) (3) (6) (14) (15) (19) (20) (20) (239) (661) (1989) Clopidogrel 2710 2625 2552 2481 2412 2345 2267 2187 1880 1410 820 (0) (4) (8) (20) (24) (35) (35) (35) (263) (683) (2064) ecnedicni evitalumuC )%( stneve fo Aspirin Clopidogrel HR 0·86 (95% CI 0·77–0·96); p=0·0050 Log-rank p=0·0050 NNT 32·7 (95% CI 18·0–173·8) HR 0·82 (95% CI 0·72–0·93); p=0·0024 Log-rank p=0·0024 NNT 35·9 (95% CI 19·9–178·7) HR 0·81 (95% CI 0·68–0·97); p=0·020 Log-rank p=0·020 NNT 53·6 (95% CI 31·0–197·9) HR 1·07 (95% CI 0·92–1·24); p=0·40 Log-rank p=0·40 Articles Clopidogrel Aspirin Hazard ratio p value Absolute risk Number needed to (n=2710) (n=2728) (95% CI) reduction (95% CI) treat (95% CI) Primary composite endpoint* 646 (25·4%) 739 (28·5%) 0·86 (0·77–0·96) 0·0050 3·1 (0·6 to 5·6) 32·7 (18·0–173·8) Thrombotic composite endpoint† 418 (17·3%) 506 (20·0%) 0·82 (0·72–0·93) 0·0024 2·8 (0·6 to 5·0) 35·9 (19·9–178·7) Any bleeding (BARC type ≥2)‡ 217 (9·1%) 270 (10·8%) 0·81 (0·68–0·97) 0·020 1·7 (0·0 to 3·4) ·· All-cause death§ 338 (13·4%) 322 (12·5%) 1·07 (0·92–1·24) 0·40 –0·9 (–2·8 to 0·9) ·· Cardiovascular death 167 (7·1%) 171 (6·9%) 0·99 (0·80–1·23) 0·95 –0·1 (–1·6 to 1·4) ·· Non-cardiovascular death 171 (6·9%) 151 (6·0%) 1·15 (0·93–1·43) 0·21 –0·9 (–2·3 to 0·5) ·· Non-fatal myocardial infarction 85 (3·6%) 105 (4·2%) 0·82 (0·62–1·09) 0·17 0·6 (–0·5 to 1·7) ·· Stroke 110 (4·6%) 154 (6·4%) 0·72 (0·56–0·92) 0·0081 1·8 (0·4 to 3·1) 57·2 (32·7–228·5) Ischaemic stroke 85 (3·6%) 104 (4·3%) 0·81 (0·61–1·08) 0·16 0·8 (–0·4 to 1·9) ·· Haemorrhagic stroke 25 (1·0%) 50 (2·1%) 0·50 (0·31–0·81) 0·0050 1·1 (0·4 to 1·8) 92·5 (55·5–279·1) Readmission due to acute coronary 208 (8·7%) 277 (11·0%) 0·75 (0·63–0·90) 0·0017 2·3 (0·6 to 4·0) 42·9 (24·8–158·5) syndrome Percutaneous coronary intervention 157 (6·8%) 207 (8·5%) 0·76 (0·62–0·93) 0·0084 1·7 (0·1 to 3·2) 59·1 (30·9–690·3) Coronary artery bypass surgery 5 (0·2%) 8 (0·3%) 0·62 (0·20–1·90) 0·41 0·1 (–0·2 to 0·4) ·· Medical treatment 46 (1·8%) 62 (2·4%) 0·74 (0·51–1·09) 0·13 0·6 (–0·2 to 1·4) ·· Major bleeding (BARC type ≥3) 133 (5·6%) 190 (7·7%) 0·71 (0·57–0·88) 0·0019 2·1 (0·7 to 3·5) 47·5 (28·3–148·4) Data are n (%), unless otherwise specified. Number needed to treat is shown only when the 95% CI for the absolute risk reduction excludes 0. BARC=Bleeding Academic Research Consortium. *Primary composite endpoint is defined as a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and major bleeding (BARC type ≥3). †Thrombotic composite endpoint is defined as cardiac death, non-fatal myocardial infarction, ischaemic stroke, readmission due to acute coronary syndrome, and definite or probable stent thrombosis. ‡Any bleeding defined as any BARC type ≥2 bleeding events. § The specific causes of mortality events are described in the appendix (pp 23–24). Table: Clinical outcomes during the 10-year follow-up in the intention-to-treat population received aspirin monotherapy (hazard ratio [HR] 0·86 The eect of clopidogrel versus aspirin monotherapy on [95% CI 0·77–0·96]; log-rank p=0·0050). The number the primary composite endpoint was generally consistent needed to treat to prevent one primary endpoint event across prespecified subgroups (figure 3). A significant was 33. The secondary thrombotic endpoint occurred in interaction was observed in the subgroup analysis 418 (17·3%) patients in the clopidogrel group and 506 according to chronic kidney disease, showing a larger (20·0%) patients in the aspirin group (HR 0·82 [95% CI reduction in risk among patients with chronic kidney 0·72–0·93]; log-rank p=0·0024). The benefit in disease. Subgroup analyses of the secondary composite thrombotic events was primarily driven by lower rates of endpoints are shown in the appendix (pp 41–43). non-fatal stroke and readmission due to acute coronary A per-protocol analysis was done including patients syndrome in the clopidogrel group. Any bleeding (BARC who completed the follow-up and adhered to the assigned type ≥2) occurred in 217 (9·1%) patients in the clopidogrel medication, excluding those who discontinued the group and 270 (10·8%) patients in the aspirin group allocated medication before a clinical event or during (HR 0·81 [95% CI 0·68–0·97]; log-rank p=0·020). The follow-up. A total of 4179 patients (2138 [78·9%] in the dierence in bleeding outcomes was primarily driven by clopidogrel group and 2041 [74·8%] in the aspirin group) BARC type 3 bleeding rather than type 2 bleeding. There were included in the analysis, and adherence to the was no significant dierence in the risk of all-cause death allocated medication was higher in the clopidogrel group between the two groups (13·4% vs 12·5%; HR 1·07 (p<0·0004). The reasons for discontinuation of the study [95% CI 0·92–1·24]; log-rank p=0·399). The Kaplan– drug are presented in the appendix (p 27), showing that Meier curves for the endpoints are shown in figure 2. gastrointestinal discomfort and minor bleeding were Among other secondary endpoints, the risks of stroke, more common in the aspirin group. Baseline readmission due to acute coronary syndrome, and major characteristics and clinical outcomes of patients included bleeding were lower in the clopidogrel group (table). in and excluded from the per-protocol population are Cause of mortality and type of bleeding according to the shown in the appendix (pp 28–36). Clopidogrel BARC definition are presented in the appendix monotherapy yielded results similar to those in the (pp 23–25). intention-to-treat analysis; however, the eect estimate In a landmark analysis conducted 2 years after was larger in the per-protocol analysis for the primary randomisation, the event rates for the primary and composite endpoint (24·0% vs 29·8%; HR 0·76 [95% CI secondary composite endpoints were numerically lower 0·67–0·86]; log-rank p<0·0001), and secondary in the clopidogrel group but the dierence was not composite endpoints (thrombotic composite endpoint: statistically significant. All-cause death was similar 15·5% vs 21·0%; 0·69 [0·60–0·81]; log-rank p<0·0001; between groups (appendix pp 26, 37–40). bleeding endpoint: 8·6% vs 11·3%; 0·73 [0·59–0·89]; Articles log-rank p=0·0024). The number needed to treat was 17, analyses according to prespecified subgroups are shown which was lower than in the intention-to-treat analysis. in the appendix (pp 52–61). The clinical benefit of clopidogrel in the per-protocol analysis was driven by a lower rate of non-fatal myocardial Discussion infarction, stroke, readmission due to acute coronary Patients after PCI require lifelong antiplatelet syndrome, and major bleeding. The Kaplan–Meier monotherapy after completion of DAPT. Aspirin has curves for the endpoints are shown in the appendix traditionally been the treatment of choice in this clinical (pp 44–47). A landmark analysis 2 years after setting. However, recent randomised trials and meta- randomisation in the per-protocol analysis also showed analyses have reported that clopidogrel monotherapy is similar results to those in the intention-to-treat superior to aspirin monotherapy in the chronic population; however, the relative risk reduction was maintenance phase of secondary prevention.3,5,6,8 larger than in the intention-to-treat analysis (appendix Although, the longest follow-up reported in these studies pp 48–51). Additional sensitivity analyses and subgroup is up to 5 years.8 The current report presents the final Number of events/number of patients Hazard ratio (95% CI) p value pinteraction Clopidogrel group Aspirin group Age (years) ≥65 410/1177 459/1186 0·88 (0·77–1·00) 0·056 0·60 <65 236/1534 280/1541 0·83 (0·70–0·98) 0·034 Sex Male 471/2015 523/2039 0·89 (0·79–1·01) 0·068 0·30 Female 175/695 216/689 0·78 (0·64–0·96) 0·017 BMI ≥25 kg/m² Yes 245/1221 288/1178 0·80 (0·68–0·95) 0·011 0·21 No 376/1390 415/1445 0·92 (0·80–1·06) 0·26 Acute myocardial infarction Yes 236/989 260/998 0·90 (0·76–1·08) 0·26 0·49 No 410/1721 479/1730 0·84 (0·73–0·95) 0·0079 Acute coronary syndrome Yes 471/1964 511/1957 0·90 (0·80–1·02) 0·11 0·17 No 228/746 175/771 0·77 (0·63–0·93) 0·0080 Multivessel disease Yes 369/1343 412/1352 0·88 (0·76–1·01) 0·068 0·68 No 277/1367 326/1376 0·84 (0·71–0·98) 0·031 Diabetes Yes 265/935 305/925 0·85 (0·72–1·00) 0·054 0·87 No 382/1785 434/1793 0·87 (0·75–0·99) 0·040 Chronic kidney disease Yes 136/356 174/337 0·69 (0·55–0·87) 0·0013 0·041 No 510/2354 565/2391 0·90 (0·80–1·01) 0·083 Proton pump inhibitor Yes 80/290 110/331 0·80 (0·60–1·07) 0·13 0·57 No 566/2420 629/2397 0·87 (0·78–0·98) 0·019 Complex PCI* Yes 145/598 184/595 0·74 (0·60–0·92) 0·0068 0·13 No 498/2091 551/2114 0·90 (0·80–1·02) 0·090 High bleeding risk† Yes 219/521 231/467 0·79 (0·66–0·95) 0·013 0·19 No 355/1800 385/1832 0·93 (0·80–1·07) 0·31 0·5 1·0 1·5 Favours clopidogrel monotherapy Favours aspirin monotherapy Figure 3: Subgroup analysis of the primary composite endpoint in the intention-to-treat population Hazard ratios for the primary composite endpoint (all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and major bleeding [Bleeding Academic Research Consortium type ≥3]) in the two groups are shown according to prespecified subgroups. *Complex PCI was defined as having at least one of the following features: three vessels treated, three or more stents implanted, three or more lesions treated, bifurcation with two stents implanted, total stent length greater than 60 mm, or chronic total occlusion. †High bleeding risk was defined according to the Academic Research Consortium for High Bleeding Risk definition. PCI=percutaneous coronary intervention. 1444 Articles 10-year follow-up results from the HOST-EXAM cerebrovascular events at 5·5 years, with no significant programme. To the best of our knowledge, this is the first dierences in mortality and major bleeding for secondary study to assess 10-year clinical outcomes of antiplatelet prevention of coronary artery disease.6 Incorporating monotherapy following PCI with drug-eluting stents and these new data, the 2024 European guidelines now give provides the longest follow-up currently available clopidogrel a class I, level A recommendation for comparing clopidogrel monotherapy versus aspirin long-term maintenance in post-PCI secondary monotherapy in the secondary prevention setting. Our prevention.1 data show that clopidogrel continued to be superior to Despite recent changes in clinical guidelines and the aspirin in terms of the primary composite, thrombotic, positive primary results from randomised comparisons and bleeding endpoints up to 10 years. The number and meta-analyses, the longest follow-up available for needed to treat to prevent a net adverse clinical event clopidogrel versus aspirin monotherapy is approximately during follow-up was 33 in the intention-to-treat 5 years. Because secondary prevention is required population and 17 in the per-protocol population. The indefinitely, further evidence on the long-term benefits reduction in clinical events was primarily driven by a of clopidogrel is needed. After the initial HOST-EXAM lower incidence of readmission due to acute coronary trial, we reported the mid-term results of the syndrome within the thrombotic composite endpoint. HOST-EXAM extended study, which showed consistent For bleeding events, the lower rate of BARC type 3 and continuous benefits of clopidogrel up to 5 years.8 bleeding, including haemorrhagic stroke, mainly drove Similar findings were reported in the 5-year results of the the reduction in bleeding. All-cause death was similar STOPDAPT-2 trial, which suggested that clopidogrel between the two groups. A landmark analysis at 2 years might be an alternative to aspirin in the maintenance after randomisation showed continued divergence of the phase after PCI. One major limitation of the clinical event curves beyond 2 years and subgroup STOPDAPT-2 trial 5-year data is that they derive from an analyses showed consistent eects with no significant extension of a study that compared dierent antiplatelet interactions between the treatment and specific strategies immediately after PCI (ie, clopidogrel subgroups. monotherapy following 1 month of DAPT in the Antiplatelet therapy is a cornerstone of secondary clopidogrel group vs aspirin monotherapy following prevention in patients with atherosclerotic cardiovascular 12 months of DAPT in the aspirin group), which disease and is generally indicated indefinitely.1,2 Among introduced selection bias in the comparison of antiplatelet agents, the potential benefit of clopidogrel monotherapies beyond 1–5 years. The results therefore monotherapy over aspirin was first suggested in the did not represent a direct comparison of antiplatelet CAPRIE trial.9 Although, the findings of CAPRIE did not monotherapy after completion of DAPT in patients with substantially change clinical practice, largely owing to stabilised coronary artery disease.4 Also, along with the the modest absolute benefit with borderline statistical HOST-EXAM trial and SMART-CHOICE 3 trial, all trials significance, heterogeneity across subgroups, the were conducted in east Asian cohorts, which limits the inclusion of a non-PCI population, and the high cost of generalisability to non-Asian populations. In the current clopidogrel as a patented agent at that time. However, the study, we compared clopidogrel versus aspirin substantial reduction in the cost of clopidogrel over the monotherapy in patients with stabilised coronary artery past three decades, together with the positive long-term disease over an extended follow-up. Maintaining results from the current study, warrants a reappraisal of long-term follow-up is challenging and has been achieved the benefits of clopidogrel over aspirin. Moreover, in only a few clinical trials. Among these, the SYNTAX considering the current life expectancy and average age trial compared only mortality events between PCI and of patients with coronary artery disease undergoing PCI, coronary artery bypass surgery for coronary artery which is typically around 60 years,3,10,11 we can anticipate disease.12 Compared with SYNTAX, our study evaluated a that these patients will likely require antiplatelet broader spectrum of adverse events, including both monotherapy for at least a decade, if not longer. ischaemic and bleeding outcomes, with robust clinical Therefore, confirming the long-term benefits of follow-up and outcome ascertainment of 92·8% of antiplatelet monotherapy is essential to lifelong post-PCI patients. pharmacotherapy. The short-term to mid-term benefits The per-protocol analysis should be interpreted with of clopidogrel over aspirin monotherapy were confirmed caution because such analyses are prone to bias. In in two large-scale randomised clinical trials, the particular, treatment discontinuation can be influenced HOST-EXAM trial and the SMART-CHOICE 3 trial.3,5 by non-medical factors. Nevertheless, our findings from Both trials reported reductions in clinical events with the per-protocol analysis support the benefit of clopidogrel monotherapy during the chronic clopidogrel over aspirin. Based on the per-protocol maintenance phase after PCI during 2–3 years of analyses of previous results, the event rate of the primary follow-up after randomisation. In a 2025 individual composite endpoint at 2 years from the HOST-EXAM patient data meta-analysis, clopidogrel was associated trial was 5·4% for the clopidogrel group versus 8·7% for with lower rates of major adverse cardiac and the aspirin group. This event rate increased to 12·8% Articles versus 16·9% (clopidogrel vs aspirin) in the 5-year In fact, 18·7% of the aspirin group and 12·9% of the mid-term follow-up results, and in the current 10-year clopidogrel group changed their antiplatelet regimen follow-up to 24·0% versus 29·8% (clopidogrel during follow-up. Although a per-protocol analysis was vs aspirin).3,8 The number needed to treat decreased done to reflect the actual agents used, exclusion of some accordingly from 45 patients in the 2-year follow-up to patients might introduce bias. This limitation could 24 patients in the 5-year follow-up, and to 17 patients in preclude definitive conclusions, as the data do not the current analysis. The continued gradual decrease in represent a randomised comparison over a 10-year period, the number needed to treat underscores the cumulative but only during the first 2 years. Second, because the benefit of clopidogrel monotherapy over aspirin. HOST-EXAM trial cohort was entirely east Asian, the Several points from our study warrant discussion. First, generalisability of these results to other populations might no significant dierence in all-cause mortality was be limited, particularly given the high prevalence of observed between the two treatment groups. Clopidogrel CYP2C19 loss-of-function alleles and the routine use monotherapy was associated with a lower risk of both of imaging-guided PCI in this region. Regarding the issue thrombotic and bleeding events, yet this benefit did not of clopidogrel resistance, previous studies have shown that translate into a reduction in long-term mortality. Although the prevalence of intermediate or poor metabolisers for clopidogrel monotherapy is superior at preventing clopidogrel is higher in east Asian populations.19 None of non-fatal myocardial infarction and stroke, these events the previous randomised clinical trials investigated might not result in immediate mortality in the modern potential interactions between clopidogrel metabolising era of rapid revascularisation and intensive secondary phenotypes and clinical outcomes.3–5 Although clopidogrel prevention. Unlike the acute phase after a vascular event appears to be superior to aspirin, whether the results are (eg, acute myocardial infarction), during which antiplatelet influenced by metaboliser status remains unknown. therapy can be lifesaving, the marginal benefit of one agent However, clopidogrel resistance has mainly been over another in the chronic maintenance phase might be associated with acute outcomes, whereas its association too small to alter overall survival in patients with multiple with outcomes in the chronic maintenance phase remains comorbidities. Second, protocol adherence was higher in unclear.20,21 Third, the open-label design of the HOST-EXAM the clopidogrel group, and the treatment eect associated trial could potentially introduce bias in the adjudication of with clopidogrel was more pronounced in the per-protocol certain clinical endpoints, such as readmission due to population. During the 10-year follow-up, 350 (12·9%) acute coronary syndrome, which might be more patients in the clopidogrel group used a dierent susceptible to physician discretion than harder endpoints. antithrombotic medication, compared with 510 (18·7%) in However, to minimise this potential bias, all suspected the aspirin group. Non-adherence to aspirin is common clinical events were strictly adjudicated by an independent for various reasons, including nuisance bruising, clinically clinical events committee. In addition, our additional relevant bleeding events, or gastrointestinal discomfort, analysis showed that a substantial majority (70·3%) of which might contribute to adverse clinical outcomes.13–15 these readmissions due to acute coronary syndrome In our study, gastrointestinal discomfort and physician- required urgent revascularisation, suggesting that these initiated switches in the aspirin group led to a higher events represented clinically significant ischaemic incidence of discontinuation. Third, although the open- episodes rather than subjective overdiagnosis. Fourth, we label design might have introduced some subjectivity in did not systematically collect data on the temporary reporting gastrointestinal symptoms, gastrointestinal discontinuation of study medications due to urgent or intolerance is a well established side-eect of aspirin, elective non-study-related invasive procedures. Given that whereas the observed higher adherence in the clopidogrel periprocedural management of antiplatelet agents can group suggests better tolerability with long-term use. aect both ischaemic and bleeding risks, the lack of this These findings challenge the traditional preference for information might represent a confounding factor. routine aspirin use, suggesting that current treatment However, given the consistency of findings from previous strategies might warrant reconsideration.16,17 studies, it is unlikely that these unrecorded interruptions Although not covered in our study, an important issue in would materially alter the primary conclusions of our long-term follow-up is perioperative antiplatelet manage- study. Fifth, adjustment for multiple testing across ment. Existing perioperative guidelines were formulated multiple outcomes was not done. Therefore, the statistical within a DAPT framework or for patients receiving aspirin significance of secondary endpoints should be interpreted monotherapy.18 Therefore, future research is needed on with caution. Sixth, the under-representation of women perioperative antiplatelet management in patients (1348 (25·4%) of 5438) in our study cohort might limit the receiving clopidogrel monotherapy. generalisability of the findings. Seventh, a small proportion This study has several limitations that should be noted. of the total population (104 [1·9%] of 5438 patients) First, this was an extended follow-up of a randomised trial received PCI with a first-generation drug-eluting stent. in which no antiplatelet regimen was mandated after the However, previous studies have shown no dierence 2-year trial period. Physician discretion in antiplatelet between new-generation and first-generation drug-eluting selection could have been influenced by multiple factors. stents, particularly beyond the first year after PCI. 22 1446 Articles In conclusion, among stabilised patients who 6 Valgimigli M, Choi KH, Giacoppo D, et al. Clopidogrel versus underwent PCI with a drug-eluting stent, clopidogrel aspirin for secondary prevention of coronary artery disease: a systematic review and individual patient data meta-analysis. monotherapy was associated with significantly lower Lancet 2025; 406: 1091–102. risk of the primary composite endpoint (all-cause death, 7 Lee H, Koo BK, Park KW, et al, and the HOST-EXAM investigators. non-fatal myocardial infarction, stroke, readmission due A randomized clinical trial comparing long-term clopidogrel vs aspirin monotherapy beyond dual antiplatelet therapy after drug- to acute coronary syndrome, and BARC type ≥3 bleeding) eluting coronary stent implantation: design and rationale of the than aspirin monotherapy over 10 years of follow-up. harmonizing optimal strategy for treatment of coronary artery This clinical benefit was consistent across both stenosis-extended antiplatelet monotherapy (HOST-EXAM) trial. Am Heart J 2017; 185: 17–25. thrombotic and bleeding endpoints, with no significant 8 Kang J, Park KW, Lee H, et al. Aspirin versus clopidogrel for long- dierence observed in all-cause death. These findings term maintenance monotherapy after percutaneous coronary suggest that clopidogrel might be considered as a intervention: the HOST-EXAM extended study. Circulation 2023; 147: 108–17. preferred agent for long-term antiplatelet monotherapy 9 CAPRIE Steering Committee. A randomised, blinded, trial of during the chronic maintenance phase after PCI. clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–39. Contributors 10 Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without H-SK, KWP, JK, and H-MY conceptualised the study. JK, H-MY, E-SS, aspirin in high-risk patients after PCI. N Engl J Med 2019; S-WR, J-WB, NHL, H-JY, YHC, UK, S-YK, S-HK, J-KH, KWP, and H-SK 381: 2032–42. curated the data. JK, SP, and H-MY did the formal analysis. H-SK, KWP, 11 Movahed MR, Ramaraj R, Jamal MM, Hashemzadeh M. and H-MY acquired the funding. E-SS, S-WR, J-WB, and J-KH did the Nationwide trends in the utilisation of percutaneous coronary investigation and methodology. E-SS, S-WR, J-WB, NHL, H-JY, YHC, intervention (PCI) in the United States of America based on gender UK, S-YK, S-HK, and J-KH were responsible for the project and ethnicities. EuroIntervention 2009; 5: 343–48. administration. NHL, H-JY, YHC, UK, S-YK, and S-HK were responsible 12 Thuijs DJFM, Kappetein AP, Serruys PW, et al, and the SYNTAX for supervision and validation. JK, SP, and H-MY wrote the original Extended Survival Investigators. Percutaneous coronary draft. H-SK and KWP performed the manuscript revisions. JK, SP, intervention versus coronary artery bypass grafting in patients with H-MY, KWP, and H-SK accessed and verified the data. All authors had three-vessel or left main coronary artery disease: 10-year follow-up access to all the included data and were responsible for the decision to of the multicentre randomised controlled SYNTAX trial. Lancet submit for publication. 2019; 394: 1325–34. 13 Ajrouche A, Estellat C, De Rycke Y, Tubach F. Trajectories of Declaration of interests adherence to low-dose aspirin treatment among the French H-SK reports research grants or speaker’s fees from Daiichi Sankyo, population. J Cardiovasc Pharmacol Ther 2020; 25: 37–46. Boston Scientific, Terumo, Biotronik, Dio, Medtronic, Abbott Vascular, 14 Kumbhani DJ, Steg PG, Cannon CP, et al, and the REduction of Edwards Life Science, Amgen, and Boehringer Ingelheim. KWP reports Atherothrombosis for Continued Health Registry Investigators. speaker’s fees from Daiichi Sankyo, Novartis, Amgen, InnoN Adherence to secondary prevention medications and four-year Pharmaceutical, and DaeWoong Pharmaceutical, unrelated to the outcomes in outpatients with atherosclerosis. Am J Med 2013; submitted work. All other authors declare no competing interests. 126: 693–700. 15 Koskinas KC, Räber L, Zanchin T, et al. Clinical impact of Data sharing gastrointestinal bleeding in patients undergoing percutaneous Any relevant inquiry should be emailed to H-SK or KWP. Upon coronary interventions. Circ Cardiovasc Interv 2015; 8: e002053. publication of this trial, de-identified individual participant data and 16 Raber I, McCarthy CP, Vaduganathan M, et al. The rise and fall of additional documents (eg, study protocol, statistical analysis plan, aspirin in the primary prevention of cardiovascular disease. Lancet informed consent forms, and a data dictionary defining each field) will 2019; 393: 2155–67. be available for sharing, subject to approval by the steering committee. 17 Jacobsen AP, Raber I, McCarthy CP, et al. Lifelong aspirin for all in Acknowledgments the secondary prevention of chronic coronary syndrome: still This research was supported by a grant from the Patient-Centered sacrosanct or is reappraisal warranted? Circulation 2020; 142: 1579–90. Clinical Research Coordinating Center funded by the Ministry of Health & Welfare, South Korea (grant number RS-2025–02263992). 18 Thompson A, Fleischmann KE, Smilowitz NR, et al, and the Peer Review Committee Members. 2024 AHA/ACC/ACS/ASNC/HRS/ References SCA/SCCT/SCMR/SVM Guideline for perioperative cardiovascular 1 Vrints C, Andreotti F, Koskinas KC, et al, and the ESC Scientific management for noncardiac surgery: a report of the American Document Group. 2024 ESC guidelines for the management of College of Cardiology/American Heart Association joint committee chronic coronary syndromes. Eur Heart J 2024; 45: 3415–537. on clinical practice guidelines. Circulation 2024; 150: e351–442. 2 Rao SV, O’Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/ 19 Pereira NL, Farkouh ME, So D, et al. 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JACC Cardiovasc Interv monotherapy in patients at high risk of subsequent cardiovascular 2019; 12: 637–47. event after percutaneous coronary intervention (SMART-CHOICE 3): a randomised, open-label, multicentre trial. Lancet 2025; 405: 1252–63. --- [PDF原文](https://sci-net.xyz/storage/7932541/91c5061eda95dfa941438127bfc67276a68bb00202fea2eb30b62be8a24f8d21/Aspirin-versus-clopidogrel-for-chronic-maintenance-monotherapy-after-percutaneous-coronary.pdf) DOI: 10.1016/S0140-6736(26)00422-8