Aspirin Versus Clopidogrel for Long-Term Maintenance Monotherapy After Percutaneous Coronary Intervention: The HOST-EXAM Extended Study
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Abstract
Background:
Long-term outcomes of antiplatelet monotherapy in patients who receive percutaneous coronary intervention are unknown. The HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy) Extended study reports the posttrial follow-up results of the original HOST-EXAM trial.
Methods:
From March 2014 through May 2018, 5438 patients who maintained dual antiplatelet therapy without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents were randomly assigned in a 1:1 ratio to receive clopidogrel (75 mg once daily) or aspirin (100 mg once daily). The primary end point (a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission attributable to acute coronary syndrome, and Bleeding Academic Research Consortium type 3 or greater bleeding), secondary thrombotic end point (cardiac death, nonfatal myocardial infarction, ischemic stroke, readmission attributable to acute coronary syndrome, and definite or probable stent thrombosis), and bleeding end point (Bleeding Academic Research Consortium type 2 or greater bleeding) were analyzed during the extended follow-up period. Analysis was performed on the per-protocol population (2431 patients in the clopidogrel group and 2286 patients in the aspirin group).
Results:
During a median follow-up of 5.8 years (interquartile range, 4.8–6.2 years), the primary end point occurred in 12.8% and 16.9% in the clopidogrel and aspirin groups, respectively (hazard ratio, 0.74 [95% CI, 0.63–0.86]; P<0.001). The clopidogrel group had a lower risk for the secondary thrombotic end point (7.9% versus 11.9%; hazard ratio, 0.66 [95% CI, 0.55–0.79]; P<0.001) and secondary bleeding end point (4.5% versus 6.1%; hazard ratio, 0.74 [95% CI, 0.57–0.94]; P=0.016). There was no significant difference in the incidence of all-cause death between the 2 groups (6.2% versus 6.0%; hazard ratio, 1.04 [95% CI, 0.82–1.31]; P=0.742). Landmark analysis at 2 years showed that the beneficial effect of clopidogrel was consistent throughout the follow-up period.
Conclusions:
During an extended follow-up of >5 years after randomization, clopidogrel monotherapy compared with aspirin monotherapy was associated with lower rates of the composite net clinical outcome in patients without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02044250.
Clinical Perspective
What Is New?
In the HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy) Extended study, clopidogrel monotherapy compared with aspirin monotherapy significantly reduced the risk of the composite of all-cause death, nonfatal myocardial infarction, stroke, readmission attributable to acute coronary syndrome, and Bleeding Academic Research Consortium type 3 or greater bleeding in patients without clinical events for 12±6 months after coronary stenting.
Clopidogrel monotherapy was associated with a lower risk in both thrombotic end points and bleeding end points with no significant difference in the risk of all-cause death compared with aspirin monotherapy.
During the extended follow-up duration, the discontinuation rate was higher for aspirin monotherapy, implying a higher compliance with clopidogrel monotherapy.
What Are the Clinical Implications?
Long-term treatment with clopidogrel monotherapy leads to a consistent reduction in cardiovascular events compared with aspirin monotherapy.
The HOST-EXAM Extended study supports clopidogrel as the preferable antiplatelet agent prescribed for secondary prevention of coronary artery disease.
Editorial, see p 118
Antiplatelet therapy is an integral component of pharmacotherapy for the secondary prevention of atherothrombotic cardiovascular events, especially after percutaneous coronary intervention (PCI).1 The HOST-EXAM trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy) showed the superiority of clopidogrel monotherapy over aspirin monotherapy in the prevention of the composite of all-cause death, nonfatal myocardial infarction (MI), stroke, readmission attributable to acute coronary syndrome (ACS), and major bleeding during 24 months of follow-up for patients who received PCI with drug-eluting stents and had successfully completed 6 to 18 months of dual antiplatelet therapy without events.2 The results of this study challenged the notion that aspirin is the antiplatelet agent of choice in the long-term maintenance period after PCI. Clopidogrel monotherapy was also associated with a lower risk of both thrombotic and bleeding end points. However, there was a numerical increase, which did not yield statistical significance, in all-cause death in the clopidogrel arm, adding confusion to the interpretation of the results.
Given that antiplatelet monotherapy is often prescribed lifelong for secondary prevention,3,4 the potentially conflicting results at 2 years of significantly lower rates of composite net clinical events and a numerically higher rate of mortality need clarification and warrant longer-term follow-up. Therefore, the HOST-EXAM Extended study was designed to perform a posttrial extended follow-up of the patients enrolled in the HOST-EXAM trial to compare the longer-term outcomes between clopidogrel and aspirin monotherapy.
Methods
The data that support the findings of this study are available from the corresponding author on reasonable request.
Trial Design and Oversight
Details on the design of the HOST-EXAM trial have been described previously.5 Briefly, the HOST-EXAM trial was an investigator-initiated, prospective, randomized, open-labeled, multicenter trial done at 37 study sites in Korea. In March 2020, an extended follow-up was planned, and the study protocol was submitted to the National Evidence-Based Healthcare Collaborating Agency of Korea. All investigators were invited to participate in the posttrial extended follow-up analysis. The extended follow-up study was called the HOST-EXAM Extended study, which was composed of the HOST-EXAM in-trial period and posttrial follow-up period (Figure S1). Because the original study was terminated before initiation of the extended study, and some patients had experienced additional clinical events (including mortality events) or were being followed up in a different medical center when the extended study was initiated, we could not obtain informed consent prospectively for all patients. Obtaining data from all of the patients who were enrolled in the original HOST-EXAM trial would be of paramount importance to understand the full impact of antiplatelet therapy during the extended follow-up of these patients. Therefore, the patients who performed clinical follow-up in the original center were enrolled in the prospective cohort after providing informed consent, and those who could not provide informed consent (eg, they already had events before study initiation or were being followed up at centers other than the original participating hospitals) were enrolled in the retrospective cohort. Because the original HOST-EXAM trial mandated the allocated antiplatelet therapy up to 24 months after enrollment, the posttrial follow-up antiplatelet prescription was at the discretion of the treating physician.
The Seoul National University Hospital Clinical Trial Center and Medical Research Collaborating Center were responsible for the scientific conduct of the trial. All events were adjudicated by an independent clinical event committee, and committee members were unaware of the trial-group assignments. Members of the independent clinical event committee received medical records of adverse events after removal of any reference to the treatment groups.
The trial protocol of the HOST-EXAM Extended study was approved by the institutional review board at each participating site. This study was conducted in accordance with the standards specified in the International Council for Harmonization Guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki.
Study Population, Randomization, and Follow-Up
Patients ≥20 years of age who underwent PCI with drug-eluting stents and maintained dual antiplatelet therapy without any clinical events during 12±6 months after PCI were eligible for the HOST-EXAM study.2,5 There was no restriction on the clinical diagnosis at the index PCI period, stenosis location, length, or number of lesions/vessels at the time of PCI. Patients who met all the inclusion criteria and none of the exclusion criteria were randomly assigned in consecutive order to either the clopidogrel group (75 mg once daily) or the aspirin group (100 mg once daily) in a ratio of 1:1. Detailed inclusion and exclusion criteria of the HOST-EXAM study are described in the Supplemental Appendix. After the initial 2-year follow-up of this trial, the single antiplatelet agent was determined by the treating physician with no mandatory designation. Clinical follow-up was performed according to standard therapy. For those patients who did not visit the outpatient clinic, a telephone interview was permitted. The final clinical status was ascertained in March 2022. In addition, the vital status of all patients was cross-checked through the National Health Insurance Service system of Korea and the Korea National Statistics System. For mortality cases, the definite cause of death was confirmed by the recorded data classified by the International Classification of Disease, 10th revision, Clinical Modification codes.
Trial End Points and Definitions
The trial end points and definitions were identical to those of the HOST-EXAM trial.2 The primary end point was a composite of all-cause death, nonfatal MI, stroke, readmission attributable to ACS, and major bleeding complications during the follow-up period. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3 or greater bleeding. Secondary composite end points included the thrombotic composite end point (defined as cardiac death, nonfatal MI, ischemic stroke, readmission attributable to ACS, and definite or probable stent thrombosis) and any bleeding (defined as BARC type 2 or greater bleeding). End points were defined according to the Academic Research Consortium definition.6 The individual components of the primary end point, secondary composite end point, and revascularization were also analyzed as secondary end points. Detailed definitions of each clinical event are given in the Supplemental Appendix.
Statistical Analysis
The working hypothesis of the HOST-EXAM study was that clopidogrel would be superior to aspirin as a long-term maintenance monotherapy agent, which required 5530 patients to ensure a power of at least 80% with a 2-sided α of 5% according to event rate assumptions. The present study was an extended follow-up of the HOST-EXAM population; therefore, no additional sample size calculation was performed. The primary analysis was performed on the basis of per-protocol analysis, including those who received the allocated single antiplatelet therapy for the full duration of follow-up unless they experienced an adverse clinical event. The intention-to-treat analysis was also performed, including all patients randomized to a treatment arm in the former study.
Continuous variables were reported as mean±SD, and categorical variables were presented as absolute values and their proportions. Differences between continuous variables were compared by the Student t test for independent data. The primary end point was analyzed by a Cox proportional hazards model and Kaplan-Meier survival curves to estimate the risk of clinical events according to the type of antiplatelet agent. No factor variables other than the trial group were used for stratification. Event-free survival with incomplete follow-up was counted as censored data for all time-to-event analyses. A Cox proportional hazards model was used for analysis of subgroups, defined according to age (<65 or ≥65 years), sex (male or female), body mass index (≥25 or <25 kg/m2), renal function, diabetes, clinical presentation (acute MI or not, and ACS or not), angiographic severity (single-vessel disease versus multivessel disease), complex PCI,7 high bleeding risk,8 and proton pump inhibitor use. The specific definitions of complex PCI and high bleeding risk are given in the Supplemental Appendix. Statistical tests were performed with SPSS version 24 (SPSS Inc) and R programming language version 4.0.4 (R Foundation for Statistical Computing).
Results
Participants and Follow-Up
From March 2014 through May 2018, a total of 5438 patients who were event-free for 6 to 18 months after PCI and successfully received the intended duration of dual antiplatelet therapy were successfully randomized from 37 centers (Figure 1). Among the total population, 9 patients withdrew informed consent, 618 patients used a different antiplatelet regimen from the allocated arm (including 583 patients who used a different antiplatelet regimen in the posttrial period), and 94 patients were lost to follow-up (including 3 patients who were lost to follow-up in the posttrial period), leaving 4717 patients analyzed in the per-protocol population (2431 patients in the clopidogrel group and 2286 patients in the aspirin group). The vital status was cross-checked in the total population. The clinical follow-up status was ascertained in March 2022, and the median follow-up duration was 5.8 years (interquartile range, 4.7–6.2 years).
Figure 1. Enrollment, randomization, and follow-up. The follow-up duration of patients who were enrolled in the HOST-EXAM trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy; ie, those who underwent percutaneous coronary intervention with a drug-eluting stent and maintained dual antiplatelet therapy without any clinical events during 12±6 months after the index procedure), was extended in the HOST-EXAM Extended study. The follow-up comprised the in-trial follow-up period and the posttrial follow-up period. The study end points were analyzed during the entire follow-up duration in the per-protocol population (patients who continued to receive the original allocated treatment).
Baseline characteristics of each group are shown in Table 1, and the concomitant medications are shown in Table S1. The mean age was 63.3±10.7 years, and the mean body mass index was 24.8±3.2 kg/m2. Among the study population, 33.8% had diabetes mellitus, 12.4% had chronic kidney disease, and the clinical diagnosis at the time of PCI was ACS in 71.9%. The demographics, laboratory data, and angiographic data were well balanced between the 2 groups.
| Clopidogrel (n=2431) | Aspirin (n=2286) | |
|---|---|---|
| Demographics and comorbidities | ||
| Age, y | 63.3±10.8 | 63.3±10.7 |
| Body mass index, kg/m2 | 24.9±3.1 | 24.8±3.4 |
| Male, n (%) | 1807 (74.3) | 1723 (75.4) |
| Diabetes, n (%) | 818 (33.6) | 775 (33.9) |
| Insulin-dependent diabetes, n (%) | 48 (2.0) | 51 (2.2) |
| Hypertension, n (%) | 1493 (61.4) | 1402 (61.3) |
| Dyslipidemia, n (%) | 1690 (69.5) | 1613 (70.6) |
| Current smoker, n (%) | 479 (19.7) | 500 (21.9) |
| Chronic kidney disease, n (%) | 314 (12.9) | 273 (11.9) |
| Previous MI, n (%) | 406 (16.7) | 362 (15.8) |
| Previous CVA, n (%) | 103 (4.2) | 110 (4.8) |
| Clinical indication of PCI, n (%) | ||
| Silent ischemia | 52 (2.1) | 61 (2.7) |
| Stable angina | 620 (25.5) | 593 (26.0) |
| Unstable angina | 871 (35.8) | 773 (33.8) |
| NSTEMI | 471 (19.4) | 454 (19.9) |
| STEMI | 417 (17.2) | 404 (17.7) |
| Laboratory results | ||
| White blood cells, n/µL | 6740±1920 | 6810±1890 |
| Hemoglobin, g/dL | 13.7±1.7 | 13.8±1.6 |
| Creatinine, mg/dL | 1.00±0.67 | 0.99±0.64 |
| Total cholesterol, mg/dL | 137±30 | 138±30 |
| Triglycerides, mg/dL | 126±88 | 126±73 |
| HDL cholesterol, mg/dL | 46±12 | 46±12 |
| LDL cholesterol, mg/dL | 70±24 | 72±23 |
| Angiographic data per patient | ||
| Extent of CAD, n (%) | ||
| 1-Vessel disease | 1229 (50.6) | 1140 (49.9) |
| 2-Vessel disease | 763 (31.4) | 716 (31.3) |
| 3-Vessel disease | 439 (18.1) | 428 (18.7) |
| Left main disease, n (%) | 127 (5.2) | 112 (4.9) |
| PCI for bifurcation lesion, n (%) | 261 (10.7) | 232 (10.2) |
| 2-stenting for bifurcation PCI | 39 (1.6) | 33 (1.4) |
| PCI for CTO lesion, n (%) | 235 (9.3) | 223 (9.8) |
| Treated lesions, n | 1.32±0.59 | 1.30±0.57 |
| Mean diameter of implanted stents, mm | 3.08±0.43 | 3.08±0.43 |
| Minimum diameter of implanted stents, mm | 3.00±0.46 | 3.01±0.45 |
| Total length of implanted stents, mm | 36.3±24.3 | 35.3±23.2 |
| Total number of implanted stents, mm | 1.5±0.8 | 1.5±0.8 |
Among 721 patients who were excluded from the per-protocol analysis, 583 were excluded during the posttrial follow-up period because of a medication change. The baseline clinical characteristics for those who were excluded from the per-protocol analysis are shown in Table S2. The discontinuation rate was significantly higher in the aspirin group (8.0% [216 of 2648 patients] versus 13.5% [367 of 2710 patients] in the clopidogrel and aspirin groups, respectively; P<0.001), and the reasons for deviation from the originally allocated antiplatelet agent are provided in Table S3.
Clinical End Points
During the follow-up duration, the primary end point occurred in 311 patients (12.8%) who received clopidogrel monotherapy and in 387 patients (16.9%) who received aspirin monotherapy (hazard ratio [HR], 0.74 [95% CI, 0.63–0.86]; P<0.001). The absolute risk reduction related to clopidogrel use was 4.1% (95% CI, 2.1%–6.2%), and the number needed to treat was 24 (Table 2 and Figure 2A). The secondary thrombotic end point of cardiac death, nonfatal MI, stroke, readmission attributable to ACS, or definite or probable stent thrombosis occurred in 196 patients (8.1%) in the clopidogrel group and 273 patients (11.9%) in the aspirin group (HR, 0.66 [95% CI, 0.55–0.79]; P<0.001; Figure 2B). Any bleeding (BARC type 2 or greater) occurred in 110 patients (4.5%) in the clopidogrel group and 140 patients (6.1%) in the aspirin group (HR, 0.74 [95% CI, 0.57–0.94]; P=0.016; Figure 2C). The incidence of all-cause death was similar (6.2% versus 6.0%; HR, 1.04 [95% CI, 0.82–1.31]); P=0.742) between the 2 groups (Figure 2D). The specific causes of mortality events are given in Table S4. Among other secondary end points, the risk of stroke, readmission attributable to ACS, major bleeding events, and any revascularization were lower in the clopidogrel group (Table 2). The frequency of gastrointestinal bleeding (2.2% versus 2.9%) and intracranial bleeding (0.5% versus 1.0%) was higher in the aspirin group. The specific site and individual type of bleeding, according to the BARC definition, are presented in Table S5.
| Clopidogrel (n=2431), n patients (%) | Aspirin (n=2286), n patients (%) | HR (95% CI) | P value | |
|---|---|---|---|---|
| Primary composite end point* | 311 (12.8) | 387 (16.9) | 0.74 (0.63–0.86) | <0.001 |
| Thrombotic composite end point† | 196 (8.1) | 273 (11.9) | 0.66 (0.55–0.79) | <0.001 |
| Any bleeding (BARC type 2 or greater)‡ | 110 (4.5) | 140 (6.1) | 0.74 (0.57–0.94) | 0.016 |
| All-cause death§ | 150 (6.2) | 136 (6.0) | 1.04 (0.82–1.31) | 0.742 |
| Cardiovascular death | 69 (2.8) | 71 (3.1) | 0.92 (0.66–1.28) | 0.602 |
| Noncardiovascular death | 81 (3.3) | 65 (2.8) | 1.18 (0.85–1.63) | 0.332 |
| Nonfatal MI | 40 (1.6) | 53 (2.3) | 0.71 (0.47–1.07) | 0.102 |
| Stroke | 37 (1.5) | 66 (2.9) | 0.53 (0.35–0.79) | 0.002 |
| Ischemic stroke | 27 (1.1) | 42 (1.8) | 0.61 (0.37–0.98) | 0.041 |
| Hemorrhagic stroke | 10 (0.4) | 24 (1.1) | 0.39 (0.19–0.82) | 0.013 |
| Readmission attributable to ACS∥ | 111 (4.6) | 176 (7.7) | 0.59 (0.47–0.75) | <0.001 |
| Major bleeding (BARC type 3 or greater) | 62 (2.6) | 90 (3.9) | 0.65 (0.47–0.90) | 0.008 |
| Any revascularization | 129 (5.3) | 157 (6.9) | 0.77 (0.61–0.98) | 0.030 |
| Target lesion revascularization | 53 (2.2) | 68 (3.0) | 0.73 (0.51–1.05) | 0.089 |
| Target vessel revascularization | 76 (3.1) | 98 (4.3) | 0.73 (0.54–0.98) | 0.039 |
| Definite or probable stent thrombosis | 12 (0.5) | 17 (0.7) | 0.67 (0.32–1.39) | 0.280 |
Figure 2. Cumulative incidence of the primary end point, secondary end points, and all-cause death. A, Cumulative incidence of the primary end point, consisting of all-cause death, nonfatal myocardial infarction, stroke, readmission attributable to acute coronary syndrome, and major bleeding (Bleeding Academic Research Consortium type ≥3 or greater bleeding) complications. B, Cumulative incidence of the secondary thrombotic end point, consisting of cardiac death, nonfatal myocardial infarction, ischemic stroke, readmission attributable to acute coronary syndrome, or definite or probable stent thrombosis. C, Cumulative incidence of any bleeding events. D, Cumulative incidence of all-cause death. Hazard ratio shown is for clopidogrel monotherapy vs aspirin monotherapy.
In a landmark analysis 2 years after randomization, the beneficial effect was consistent in the in-trial period (HR, 0.69 [95% CI, 0.56–0.86]; P=0.001) and in the posttrial period (HR, 0.78 [95% CI, 0.63–0.97]; P=0.022) in terms of the primary end point (Figure S2). This trend was also consistent for the secondary composite end points and all-cause death (Figures S3–S5 and Table S6).
Subgroup Analyses and Intention-to-Treat Analysis
In terms of the primary end point, the beneficial effect of clopidogrel monotherapy compared with aspirin monotherapy was generally consistent across all subgroups (Figure 3). This was also consistent for the secondary thrombotic end point (Figure S6) and bleeding end point (Figure S7). The intention-to-treat analyses based on patients who were randomized in the HOST-EXAM trial yielded results similar to those of the per-protocol analyses for the primary study end point (HR, 0.79 [95% CI, 0.69–0.91]; P=0.001) and the secondary end points (Figures S8–S10). Detailed individual end points for the intention-to-treat analyses at both 2 years and the final follow-up are provided in Table S7.
Figure 3. Subgroup analysis. The hazard ratio for the primary end point (a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission attributable to acute coronary syndrome, and major bleeding complications) in the 2 groups is shown according to various subgroups. †Complex percutaneous coronary intervention (PCI) was defined as having at least 1 of the following features: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion.7 ‡High bleeding risk was defined according to the Academic Research Consortium for High Bleeding Risk definition.8
Discussion
In this HOST-EXAM Extended study, we compared the long-term effects of clopidogrel and aspirin monotherapy during the long-term maintenance period in patients who received stenting with drug-eluting stents. During a median follow-up of 5.8 years after randomization, the incidence of the primary end point of all-cause death, nonfatal MI, stroke, readmission attributable to ACS, and major bleeding was lower in the clopidogrel group. Furthermore, the secondary thrombotic end point and bleeding end point were also lower in the clopidogrel group, suggesting continuous benefit of clopidogrel beyond the initial trial study period. The incidence of all-cause death was similar between the 2 groups, indicating no difference in mortality risk. In a landmark analysis 2 years after randomization, the beneficial effect was sustained in both the trial period and the posttrial extended follow-up period with continued divergence of the curves. Subgroup analyses showed consistent treatment effects of clopidogrel in various subgroups with no significant interaction. Collectively, the extended follow-up of the HOST-EXAM trial shows the persistent benefit of clopidogrel monotherapy over aspirin monotherapy in patients with coronary artery disease treated with drug-eluting stents.
The HOST-EXAM trial was the first randomized trial to compare clopidogrel and aspirin monotherapy head-to-head during the long-term maintenance phase in patients who received stenting with drug-eluting stents and had successfully completed 6 to 18 months of dual antiplatelet therapy without events. In that trial, clopidogrel was superior to aspirin in the prevention of the net composite outcome of all-cause death, nonfatal MI, stroke, readmission attributable to ACS, and major bleeding during 24 months of follow-up. Furthermore, clopidogrel was associated with a lower risk of both ischemic and bleeding events.2 Previously, the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events) trial also compared aspirin and clopidogrel monotherapy in 19 185 patients with atherosclerotic vascular disease for a mean follow-up of 1.91 years. Clopidogrel was associated with an 8.7% relative risk reduction in the primary end point of ischemic stroke, MI, or vascular death compared with aspirin. Aspirin was also related to a higher rate of gastrointestinal discomfort and bleeding events.9 However, the study participants were not a PCI population, and this trial was performed in the early 1990s, before the era of high-intensity statins. Therefore, the results cannot be purely extrapolated to patients in the current era. In addition, a recent meta-analysis of >24 000 patients (PANTHER study [P2Y12 Inhibitor or Aspirin Monotherapy as Secondary Prevention in Patients With Coronary Artery Disease: An Individual Patient Data Meta-Analysis of Randomized Trials]; PROSPERO registration number: CRD42021290774) confirmed that P2Y12 inhibitor monotherapy was associated with a lower risk of adverse clinical outcomes in patients with coronary artery disease.
Despite the positive results of the HOST-EXAM trial, we still need a longer-term follow-up for us to consider lifelong clopidogrel monotherapy instead of aspirin for a few reasons. First, because antiplatelet therapy for secondary prevention needs to be continued for the duration of the life expectancy of the patients we treat, confirming the long-term beneficial effect of clopidogrel monotherapy is essential. However, even for aspirin, the benefit for lifelong secondary prevention in the contemporary era of high-intensity statins is controversial and sometimes not supported by previous trials.10,11 Moreover, long-term data can be used to calculate the impact of clopidogrel on not only clinical outcomes but also the cost-effectiveness of switching from aspirin to clopidogrel monotherapy. Second, although clopidogrel monotherapy showed benefit in reducing the incidence of the primary end point in the HOST-EXAM trial, there was a statistically insignificant but mild trend of higher mortality in the clopidogrel arm. This raised substantial concerns of the impact of antiplatelet monotherapy on mortality and caused confusion in translating the results of the HOST-EXAM trial. Longer-term data could clarify whether the statistically insignificant trend was a chance finding or whether aspirin indeed had non–platelet-related benefits on mortality. Third, despite the current guideline recommendations to continue aspirin lifelong for secondary prevention,3 many patients do not adhere to aspirin for various reasons, including but not limited to bruising, minor bleeding events, or gastrointestinal discomfort, especially in the elderly population.12,13 Therefore, longer-term follow-up can confirm whether adherence issues can be improved with the use of clopidogrel.
During the extended follow-up period, clopidogrel monotherapy was associated with a 26% risk reduction of the primary end point, which was similar to the results during the in-trial period (HR, 0.73 [95% CI, 0.59–0.90] in the HOST-EXAM trial). The consistent divergence of the cumulative incidence curve suggests continuous benefit of clopidogrel throughout the extended follow-up period. An interesting finding that should be noted is that clopidogrel monotherapy was associated with a reduction in both thrombotic and bleeding end points. The reduction in bleeding events without an elevation of ischemic events, which, at a glance, seems counterintuitive, has been seen in recent trials. This can be explained by various mechanisms. First, both outcomes are closely related to medication adherence. An even minor bleeding complication may affect adherence to the antiplatelet medication, leading to a higher risk of ischemic events. Therefore, an antiplatelet agent with a lower bleeding risk has the potential to lower even the ischemic risk of the patient. Second, although the ischemic and bleeding events may have an opposite phenotype, patients at higher risk for these events share risk factors. Clinical risk factors such as older age, chronic kidney disease, and diabetes are risk factors for ischemic and bleeding events, leaving these patients at higher risk for any adverse events, regardless of the antiplatelet regimen.14
In terms of all-cause death, when follow-up was extended to beyond 5 years, there was no difference between aspirin and clopidogrel. In particular, a landmark analysis from 2 years showed very similar curves, with no differences (in-trial period: HR, 1.27 [95% CI, 0.85–1.92]; posttrial follow-up period: HR, 1.04 [95% CI, 0.71–1.25]). In addition, as shown in the Supplemental Appendix, the risk of cardiovascular death was numerically lower in the clopidogrel group during the posttrial follow-up period (4.0% versus 4.3%; P=0.688). Even with longer-term follow-up, the trial was not powered to detect mortality differences; therefore, we cannot confirm whether there is a difference in mortality. However, the extended follow-up suggests that the statistically insignificant trend toward higher mortality of the clopidogrel arm in the original trial was probably a play-of-chance finding.
An interesting point is that the medication discontinuation rate was significantly higher in the aspirin group, with a higher risk of gastrointestinal discomfort or bleeding events. Various previous trials have reported such side effects in aspirin users,15,16 which have raised concerns and resulted in a recent paradigm shift in the role of aspirin. The paradigm shift away from aspirin is attributed to not only the side effects but also the better antithrombotic efficacy of P2Y12 inhibitors compared with aspirin.1,17 As explained, poor adherence to medication itself is a risk of adverse events. A previous study reported that discontinuation of medication was independently associated with a 3- to 4-fold higher mortality rate for patients with coronary artery disease.18,19 The higher adherence to clopidogrel monotherapy also supports the benefit of clopidogrel as the lifelong antiplatelet agent in the long-term maintenance period after PCI.
Several limitations of the current trial should be considered. First, this was an extended follow-up of a randomized clinical trial. Therefore, the antiplatelet regimen was open labeled, and a specific antiplatelet regimen was not obligatory. The physicians’ discretion on antiplatelet selection could have been influenced by multiple factors, including the results of the original study. However, we performed a per-protocol analysis to reflect the actual antiplatelet agent, with all end points specifically adjudicated by an independent committee made up of members who were unaware of the treatment group. Second, this trial was not powered to evaluate the impact of antiplatelet therapy on mortality. Nevertheless, we cross-checked data for mortality for 99.9% of the patients and found no mortality difference between the 2 groups. Along with the present study results, we are continuing follow-up of these patients for up to 10 years. Third, phenotypic and genetic testing for clopidogrel was not performed, and the study population was an East Asian population; therefore, the generalizability of the study to other ethnicities may be limited. However, routine platelet function or genetic testing is not recommended in clinical practice.20,21
Conclusions
In the extended follow-up of patients who were event-free for 6 to 18 months after PCI and successfully received the intended duration of dual antiplatelet therapy, clopidogrel monotherapy compared with aspirin monotherapy significantly reduced the risk of the composite of all-cause death, nonfatal MI, stroke, readmission attributable to ACS, and BARC type 3 or greater bleeding.
Article Information
Sources of Funding
This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center (HI19C0481 and HC19C0305) and Korea Health Technology R&D Project (HI17C2085), funded by the Ministry of Health & Welfare, Korea. This research was partially supported by a grant from Seoul National University Hospital (research identifiers: 06-2011-2830, 06-2015-2150, and 06-2015-2860). The study funder had no role in trial design, data collection, analysis, and interpretation, or writing of the manuscript.
Supplemental Material
Investigators and collaborators
Data-sharing statement
Inclusion and exclusion criteria of the HOST-EXAM trial
Definition of subgroups and clinical outcomes
Study design and execution
Tables S1–S7
Figures S1–S10
| ACS | acute coronary syndrome |
| BARC | Bleeding Academic Research Consortium |
| CAPRIE | Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events |
| HOST-EXAM | Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy |
| HR | hazard ratio |
| MI | myocardial infarction |
| PANTHER | P2Y12 Inhibitor or Aspirin Monotherapy as Secondary Prevention in Patients With Coronary Artery Disease: An Individual Patient Data Meta-Analysis of Randomized Trials |
| PCI | percutaneous coronary intervention |
Disclosures Dr Kim has received research grants or speakers’ fees from Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Dio, Medtronic, Abbott Vascular, Edwards Life Science, AmGen, and Behringer Ingelheim. Dr Park reports speakers’ fees from Daiichi Sankyo, InnoN Pharmaceutical, DaeWoong Pharmaceutical, and JW Pharmaceutical outside of the submitted work. The other authors report no conflicts.
Footnotes
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