Duration of Clopidogrel-Based Dual Antiplatelet Therapy and Clinical Outcomes in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention　― A Real-World Observation in Taiwan From 2012 to 2015 ―

Abstract

Background: Little information is available in Asia about the real-world practice of dual antiplatelet therapy (DAPT) duration for acute coronary syndrome (ACS) and its influence on clinical outcomes.

Methods and Results: The Taiwan ACS STENT Registry was a prospective, multicenter study to observe ACS patients using clopidogrel-based DAPT after percutaneous coronary intervention (PCI). The primary outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Overall, 2,221 ACS patients (62 years, 83% men) were included. DAPT duration was ≤9 months in 935 (42.1%). The incidence of primary outcome was higher in patients receiving DAPT ≤9 months compared with those receiving DAPT >9 months at 1 year (3.5% vs. 1.6%, P=0.0026). The incidence of stent thrombosis (overall 0.5%) was similar between groups. Multivariable analysis showed that DAPT >9 months was associated with a significantly lower risk of primary outcome (odds ratio 0.725, 95% confidence interval 0.545–0.965).

Conclusions: Our data showed that short duration of DAPT (≤9 months) was common (42.1%) in Taiwan for ACS patients undergoing PCI. DAPT ≤9 months increased the risk of the primary outcome.

Dual antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitor is the standard treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Current American and European guidelines all recommend DAPT for at least 12 months for ACS patients regardless of the stent used in PCI.^1,2 In Asia, guidelines or consensus from Taiwan and Japan also suggest 12-month DAPT after acute myocardial infarction (MI).^3,4 The current suggestion of 12-month DAPT after ACS was arbitrarily determined based on the duration of follow-up in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) study and another 2 clinical trials of new-generation P2Y12 inhibitors.^5–7 The optimal duration of DAPT involves an assessment of the trade-off between ischemia and bleeding. Multiple lines of evidence suggest that East Asian patients have a higher bleeding risk than white patients when receiving antiplatelet treatment.^8,9 In Taiwan, bare metal stents (BMS) are still commonly used because the National Health Insurance only reimburses the price of BMS and patients have to pay at least US$1,500–2,000 for each drug-eluting stent (DES). The Taiwan National Health Insurance also reimburses only 9-month DAPT for ACS patients undergoing PCI. These considerations and insurance regulations may influence physicians’ determination of DAPT duration and potentially cause deviation from guideline recommendations. Most of the real-world data about DAPT duration come from Western countries, showing that 12-month DAPT is used in most patients with ACS and prolonged use of DAPT beyond 12 months is common.^10–12 Information is scarce in Asia about contemporary real-world practice patterns of DAPT duration and the effect on clinical outcomes following PCI for ACS.

In the present prospective cohort study, we used an ACS registry data in Taiwan to examine real-world practice patterns, patient characteristics, and clinical outcomes following PCI for ACS in relation to DAPT duration.

Methods

Study Participants

This study was a nationwide ACS registry performed from April 2012 to December 2015 in Taiwan by the Taiwan Society of Cardiology.¹³ Adult patients (age ≥20 years) admitted because of ACS, including ST-segment elevation MI (STEMI), non-STEMI (NSTEMI) and unstable angina, were enrolled consecutively from 24 major hospitals across Taiwan. The diagnosis was based on clinical symptoms, ECG and cardiac markers changes, and further confirmed by the in-charge cardiologists. In this registry, only patients undergoing PCI with stent placement during admission, treated with DAPT, and surviving to discharge were included. Because the 1st-generation DES were no longer used after 2012 in Taiwan, all patients received 2nd- or newer generation DES and/or BMS. Because clopidogrel was the most commonly used P2Y12 inhibitor and prasugrel was not available during the study period, only patients treated with aspirin and clopidogrel were included in this study. Patients were ineligible if they had ACS accompanying traffic accident, trauma, or severe bleeding. Patients with perioperative or periprocedural MI or had already participated in other clinical trials were also excluded from the study. The clinical data, including age, sex, vascular risk factors, previous disease history, clinical presentation, laboratory data, medications, and procedures used during the index admission, were collected prospectively according to a predetermined protocol.

Follow-up

The patients were followed up regularly and clinical data were collected at discharge and at 1, 3, 6, 9, and 12 months after discharge. The use of DAPT and the timing of discontinuation were recorded during each follow-up visit. The reasons for discontinuation were answered by the in-charge cardiologists and were related to adverse events, insurance regulations, doctor’s decision, preparation for invasive procedure or surgery, need for anticoagulation, or other unidentified cause. The patients were stratified according to DAPT duration (≤9 months vs. >9 months), and baseline characteristics, treatment variables, and primary outcome events were compared. The primary outcome was a composite endpoint of cardiovascular (CV) death, stroke, and MI at 12-month follow-up. The secondary outcome was the individual incidence of CV death, stroke, MI, stent thrombosis, and bleeding events. A bleeding event was defined as any spontaneous bleeding episode that was considered clinically significant by the in-charge physicians and reported as an adverse event during the follow-up.

Statistical Analysis

Continuous and categorical variables are presented as mean±standard deviation or number (percentage). Comparisons between DAPT groups were performed by unpaired t test for continuous variables and chi-square test for categorical variables. A multivariable logistic regression analysis was performed to identify independent predicting factors of DAPT duration ≤9 months. The odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated. Kaplan-Meier curves were used to evaluate the time to primary outcome events and the log-rank test was applied to compare the differences between groups of DAPT duration. To further assess the effect of DAPT duration on clinical outcome, propensity score adjustment was performed using logistic regression models with the following covariates: age, oral anticoagulant, cardiac arrest, prior MI, prior PCI, heart failure, transient ischemic attack/stroke, atrial fibrillation, prior coronary artery bypass grafting, hypertension, diabetes, hyperlipidemia and clinical presentation. Marginal mean weighting through stratification (MMWS) was adopted to perform the propensity score analysis. All propensity scores were estimated by multinomial logistic regression, with 4 propensity scores for each patient. The MMWS computed weights on the basis of stratified propensity scores and equated the pretreatment composition of different groups under the assumption that unmeasured covariates did not confound the treatment effects. We stratified propensity score into 5 quintiles per stratum in each DAPT duration group, followed by the MMWS calculation in each stratum and DAPT duration group. Data balance was adjusted by MMWS weights. Two adjusted estimates of the composite outcome were provided: using MMWS weights only or adjusted by additional covariate for constructing the propensity score for a “doubly robust model”. All statistical analyses were conducted using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA). A two-tailed P-value <0.05 was considered statistically significant.

Results

Baseline Characteristics

Of the initial 2,374 enrolled patients, 98 without a DAPT record, 53 not prescribed DAPT at discharge, and 2 ceasing DAPT before discharge were excluded, leaving 2,221 patients included in the analysis (Figure 1). Among these 2,221 patients, DAPT duration was >9 months in 1,286 (57.9%) and ≤9 months in 935 patients (42.1%). Overall, the mean duration of DAPT was 261.0±119.4 days (>9 vs. ≤9 months group, 345.5±44.5 days vs. 144.8±88.5 days, P<0.0001). Table 1 shows the baseline characteristics stratified by duration of DAPT. The group with shorter DAPT (≤9 months) were older, had more females, and lower body mass index. These subjects also had more heart failure, atrial fibrillation, peripheral arterial disease, coronary artery bypass graft, and diabetes. The proportion of STEMI was similar between groups. Table 2 outlines the procedural characteristics of the index PCI during admission. BMS was more commonly used in the group with shorter DAPT (≤9 months). The stent number, total length, and the distribution of target lesions were similar between groups. The use of DAPT decreased from 99.4% at discharge to 35.4% at 12-month follow-up (Figure 2). As for the use of other secondary preventive medications, patients with the shorter duration of DAPT (≤9 months) were less often prescribed with statins compared with the longer DAPT duration group at discharge and during follow-up (Supplementary Table 1). The use of β-blockers and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers were similar between groups at 12-month follow-up. In a multivariable logistic regression model for predicting shorter DAPT, atrial fibrillation (OR 1.500, 95% CI 1.040–2.162), use of BMS (OR 1.650, 95% CI 1.254–2.171) and any physician-reported bleeding event (OR 1.798, 95% CI 1.217–2.657) were the independent predictors of using DAPT ≤9 months (Supplementary Table 2). The most common identified reason for stopping clopidogrel was the regulation of Taiwan National Health Insurance (70.7%), followed by adverse events (3%), doctor’s decision (1.3%), patient’s decision (1.2%), and preparation for invasive procedure or surgery (0.4%).

Figure 1.

Study population flowchart. ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention.

Table 1. Baseline Characteristics

Clinical characteristics	DAPT ≤9 months (n=935)	DAPT >9 months (n=1,286)	P value
Age (years)	63.1±13.3	60.8±12.7	<0.0001
Male	754 (80.6%)	1,080 (84.0%)	0.0405
BMI (kg/m2)	25.4±3.8	25.9±3.7	0.0023
Medical history
PCI	152 (16.3%)	191 (14.9%)	0.3658
Myocardial infarction	85 (9.1%)	104 (8.1%)	0.4026
TIA/stroke	65 (7.0%)	67 (5.2%)	0.0865
Heart failure	62 (6.6%)	56 (4.4%)	0.0182
Atrial fibrillation	42 (4.5%)	22 (1.7%)	0.0001
PAD	28 (3.0%)	22 (1.7%)	0.0136
CABG	25 (2.7%)	18 (1.4%)	0.0314
Risk factors
Hypertension	591 (63.4%)	809 (63.0%)	0.8265
Diabetes	352 (37.8%)	404 (31.4%)	0.0019
Hyperlipidemia	416 (44.8%)	584 (45.5%)	0.7303
Current smoker	409 (43.7%)	601 (46.7%)	0.1623
Clinical presentation
STEMI	513 (54.9%)	697 (54.2%)	0.8295
NSTEMI	286 (30.6%)	409 (31.8%)
Unstable angina	135 (14.5%)	180 (14.0%)

BMI, body mass index; CABG, coronary artery bypass graft; DAPT, dual antiplatelet therapy (aspirin+clopidogrel); ECG, electrocardiography; NSTEMI, non-ST-elevation myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction; TIA, transient ischemic attack.

Table 2. Procedural Characteristics of PCI

PCI procedures	DAPT ≤9 months (n=935)	DAPT >9 months (n=1,286)	P value
Stent type
BMS	519 (55.5%)	497 (38.6%)	<0.0001
DES	393 (42.0%)	744 (57.9%)
Both	20 (2.1%)	39 (3.0%)
No. of lesions treated
1	545 (58.3%)	756 (58.8%)	0.5484
2	226 (24.2%)	328 (25.5%)
3	115 (12.3%)	134 (10.4%)
>3	49 (5.2%)	68 (5.3%)
No. of stents
1	622 (66.5%)	791 (61.5%)	0.1111
2	219 (23.4%)	343 (26.7%)
3	67 (7.2%)	111 (8.6%)
>3	27 (2.9%)	41 (3.2%)
Total length of stents (mm)	34.7±22.0	36.4±21.7	0.0707
PCI vessel
LAD	516 (55.2%)	746 (58.0%)	0.1849
RCA	376 (40.2%)	493 (38.3%)	0.3706
LCX	248 (26.5%)	351 (27.3%)	0.6865
Left main	43 (4.6%)	48 (3.7%)	0.3092
Saphenous vein graft	6 (0.6%)	5 (0.4%)	0.4019

BMS, bare metal stent; DAPT, dual antiplatelet therapy (aspirin+clopidogrel); DES, drug-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; PCI, percutaneous coronary intervention; RCA, right coronary artery.

Figure 2.

Percentage of patients under aspirin monotherapy, clopidogrel monotherapy or aspirin+clopidogrel dual therapy at discharge and during follow-up.

Clinical Outcomes

Table 3 illustrates the outcome events during the 12-month follow-up in the overall study population and after stratification by duration of DAPT. The incidence of the primary composite outcome was significantly lower in patients receiving DAPT >9 months (DAPT duration ≤ vs. >9 months: 3.5% vs. 1.6%, respectively; P=0.0026), which was mainly driven by the lower rate of CV death and stroke. The cumulative event curve of the primary outcome (Figure 3) showed a significantly increased risk in patients with a shorter duration of DAPT (log-rank test, P=0.0002). The risk of stent thrombosis was very low and did not vary significantly between groups despite a significant difference in the type of stent. A significantly higher incidence of physician-reported bleeding events was noted in the shorter DAPT duration group. In light of the significant differences noted in patients’ characteristics, propensity score analysis was applied for adjustments. The results after propensity score-matching analysis further consolidated the above observations. Longer DAPT duration >9 months was independently associated with a decreased risk of the primary composite outcome compared with duration ≤9 months (Figure 4).

Table 3. Clinical Outcomes in 12-Month Follow-up

Outcome events	Overall (n=2,221)	DAPT ≤9 months (n=935)	DAPT >9 months (n=1,286)	P value
Primary outcome*	53 (2.4%)	33 (3.5%)	20 (1.6%)	0.0026
Cardiovascular death	17 (0.8%)	16 (1.7%)	1 (0.1%)	<0.0001
Myocardial infarction	29 (1.3%)	12 (1.3%)	17 (1.3%)	0.9371
Stroke	10 (0.5%)	8 (0.9%)	2 (0.2%)	0.0347
Stent thrombosis	12 (0.5%)	4 (0.4%)	8 (0.6%)	0.5375
Bleeding event	46 (2.1%)	32 (3.4%)	14 (1.1%)	0.0001

*Composite outcome of cardiovascular death, myocardial infarction, and stroke. DAPT, dual antiplatelet therapy (aspirin+clopidogrel).

Figure 3.

Kaplan-Meier curves of the primary composite outcome (cardiovascular death, myocardial infarction, or stroke) in patients with different DAPT duration: DAPT ≤9 months (blue) and DAPT >9 months (red). DAPT, dual antiplatelet therapy.

Figure 4.

Adjusted primary composite outcome in relation to DAPT duration in the propensity score MMWS model and doubly robust model. CI, confidence interval; DAPT, dual antiplatelet therapy; MMWS, marginal mean weighting through stratification.

Discussion

The major findings of our study were: (1) short-duration DAPT was common (42.1% had DAPT ≤9 months) in Taiwan despite the guideline recommendation of ≥12-month duration for patients; (2) atrial fibrillation, use of BMS in PCI and any bleeding event were the major independent predicting factors of DAPT ≤9 months; (3) the clinical outcomes in patients receiving DAPT >9 months were superior to those with DAPT ≤9 months at 1-year follow-up.

In recent years, real-world studies from Western countries showed that prolonged DAPT is a common practice for ACS treatment. In the FAST-MI (French Registry of Acute ST-elevation or non ST-elevation Myocardial Infarction) study, 75% and 43% of patients were receiving DAPT at 1- and 2-year follow-up¹⁰ and the results were similar to the PARIS (Patterns of Non-Adherence to Antiplatelet Regimens in Stented Patients) registry that recruited patients undergoing PCI with stent implantation in the USA and Europe.¹¹ The EPICOR (long-tErm follow-uPof antithrombotic management patterns In acute CORonary syndrome patients) study recruited 8,593 ACS patients using DAPT in Europe and Latin America; among them, 76% and 57% remained on uninterrupted DAPT at 1- and 2-year follow-up.¹² In Asia, several randomized clinical trials with new-generation DES were performed in Japan, Korea, and China, demonstrating non-inferiority of short (6 months) to standard (12 months) or longer (18 months) DAPT.^14–16 However, both stable coronary artery disease (CAD) and ACS patients were included in those studies. The SMART-DATE trial from Korea was a pure DAPT duration study for ACS in Asia.¹⁷ The trial randomized 2,712 ACS patients undergoing PCI to receive either 6-month or 12-month DAPT. There was no significant difference in the primary composite endpoint of all-cause death, MI, or stroke between the groups. But the post-hoc landmark analysis found a significant increased risk of recurrent MI in the 6-month DAPT group compared with those who had longer DAPT. The results from the SMART-DATE trial and our real-world observation study reconfirm that DAPT duration of at least 9–12 months after ACS is necessary for Asian patients.

Real-world data of DAPT duration for ACS are scarce in Asia. The current study found 42.1% patients with ACS who underwent PCI had DAPT ≤9 months and only 35.4% patients were being treated with DAPT at 12-month follow-up in Taiwan. In Korea, a study using the database of the Korean National Health Insurance Service since 2009 to 2011 found 31% of the 2,369 patients undergoing PCI with DES had early discontinuation of DAPT before 1 year.¹⁸ Unfortunately, the percentage of ACS patients in that study cohort was unknown. In Japan, the PACIFIC (Prevention of AtherothrombotiC Incidents Following Ischemic Coronary attack) registry showed that 62.9% of the 3,597 Japanese ACS patients were being treated with DAPT at 12-month follow-up.¹⁹ A more recent study using a medical information database of 7,473 patients who underwent PCI in Japan demonstrated that DAPT was used in only 42% patients at 12 months, in both stable CAD and ACS patients.²⁰ It seems that the DAPT duration for ACS is shorter in Asian countries than is reported from Western studies, which may more accurately reflect the real-world situation in Asia. Cardiologists in this region consider that East Asian patients have a different response to antiplatelet agents compared with Caucasians.²¹ East Asian patients also have a higher risk of bleeding but lower risk of ischemic events after PCI than Caucasians.^9,22 Our study found that atrial fibrillation, use of BMS, and bleeding events were the major predictors of short DAPT. Therefore, despite the risk being higher in the short-duration DAPT group in our study cohort, more cases of atrial fibrillation that need anticoagulation and more bleeding events prevent these patients receiving longer DAPT after PCI. After multivariable adjustment, we still found the clinical outcomes of DAPT duration >9 months were better than with the short duration. Together with the SMART-DATE trial from Korea, sticking to the standard of care for DAPT duration for ACS patients is necessary for Asian patients. The most common reason reported by cardiologists in Taiwan for early discontinuation of clopidogrel was the regulation of National Health Insurance, which only reimburses up to 9 months of DAPT for ACS. It reveals the need for updating the regulations in line with guideline recommendations to improve the quality of care for ACS patients in Taiwan.²³

Our study has both strengths and limitations. The strength is the coverage of a wide range of ACS patients which reflected the problems in real-world clinical practice in Taiwan. For example, many ACS patients were still treated with BMS despite the recommendation of new-generation DES in the guidelines. Use of BMS was an independent predictor of shorter DAPT duration. Currently, the financial barrier is the main reason that prevents the use of DES in Taiwan. Our study demonstrated the urgent need to revise the national reimbursement policy. The major limitation of our study is that there were many differences in the baseline characteristics of the study groups, which could influence the clinical outcomes we observed. To deal with this, we used propensity score-matching to reduce heterogeneity, but some unadjusted potential confounders may still exist. Second, the BARC or TIMI bleeding classification was not used to define bleeding events, so the severity of bleeding was unknown and its potential effect on clinical outcomes could not be evaluated. Third, only patients treated with clopidogrel were included in the study. We do not know if the results of this study can be extrapolated to other P2Y12 inhibitors. Ticagrelor was not reimbursed by the Taiwan National Health Insurance when the study started, and prasugrel was not available in Taiwan during the study period. Therefore, the clinical efficacy and safety between clopidogrel and ticagrelor or prasugrel was not compared in this study. Finally, our follow-up was not long enough. The long-term benefit and risk of DAPT longer than 12 months were unknown.

Conclusions

The current study found DAPT duration ≤9 months for ACS patients undergoing PCI was a common practice in Taiwan. Extending clopidogrel-based DAPT to more than 9 months improved the clinical outcomes of the patients.

Acknowledgments

This study was supported by the Taiwan Society of Cardiology and sponsored by Sanofi Taiwan Co. Ltd. We express our gratitude and appreciation to the physicians participating in the registry.

Principal Investigators (by alphabetical order): Chien-Cheng Chen, Show Chwan Memorial Hospital; Zhih-Cherng Chen, Chi-Mei Hospital; Shu-Meng Cheng, Tri-Service General Hospital; Ching-Chang Fang, Tainan Municipal Hospital; Chih-Neng Hsu, National Taiwan University Hospital, Yun-Lin Branch; Kwan-Lih Hsu, E-Da Hospital; Eng-Thiam Ong, Cathay General Hospital; Chun-Ming Shih, Taipei Medical University Hospital; Ji-Hung Wang, Hualien Tzu Chi General Hospital; Chiung-Jen Wu, Kaohsiung Chang Gung Memorial Hospital; Wei-Hsian Yin, Cheng-Hsin General Hospital.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-18-1283

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