Abstract
Continuation of single antiplatelet treatment (SAPT) is recommended for patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) after dual antiplatelet treatment (DAPT). However, the optimal long-term SAPT remains unclear for these patients. The retrospective study recruited ACS patients who underwent PCI and chosen clopidogrel to SAPT after DAPT between 01/2014 and 12/2016 at the Central Hospital of Wuhan, Wuhan, China. Patients were divided into 2 groups after standard DAPT: low dose group (clopidogrel, 50 mg/d) and control group (clopidogrel, 75 mg/d). Among 378 enrolled patients with ACS undergoing PCI, 49/378 (14.5%) were taking 50 mg clopidogrel after DAPT. At the mean follow-up of 34 months, the cumulative incidence of the primary outcomes (hazard ratio [HR] 1.345, 95% CI: 0.455–3.974; P = .592), secondary outcome (HR 1.483, 95% CI: 0.506–4.348; P = .473), and safety outcomes (HR 2.268, 95% CI: 0.835–6.160; P = .108) showed no significant differences between the 2 group. Propensity score-matched analysis confirmed these findings. A 50 mg maintenance dose of clopidogrel may be comparable to 75 mg clopidogrel for Chinese patients with ACS undergoing PCI after at least 12 months of DAPT in efficacy and safety.
Keywords: acute coronary syndromes, antiplatelet, clopidogrel, low dose, therapy
1. Introduction
At present, the American College of Cardiology, the American Heart Association, and the European Society of Cardiology (ESC) guidelines recommend dual antiplatelet treatment (DAPT) for at least 12 months for the management of patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI).[1,2] Following DAPT, a long-term single antiplatelet treatment (SAPT) of aspirin (81–162 mg daily) is recommended for continued treatment.[1,3] For patients who have contraindication or intolerance to aspirin, 75 mg clopidogrel is recommended.[1,3] However, most evidence which these recommendations based on come from the clinical studies of American and European populations.[4,5]
Increasing data suggest that East Asian populations have differing risk profiles for both thrombophilia and bleeding compared with Caucasian populations.[6] In Japan, studies have shown that a lower maintenance dose of ticlopidine (100 mg twice daily) is more common than in the United States and Europe (250 mg twice daily).[7,8] Therefore, investigation of the suitable “therapeutic window” of antithrombotic drugs in East Asian populations is warranted.[6,9]
In China, 1 alternative generic clopidogrel, which has a lower content of 25 mg per tablet and is much cheaper. And it is considered that lower dose usually is associated with more safety. As a result, the price advantage and lower dose encouraged both doctors and patients to switch to the alternative clopidogrel product with a lower dose (50 mg/d) from the innovator clopidogrel (75 mg/d) for patients with a history of digestive ulcers or intolerance to aspirin. However, there is little data on the efficacy and safety of long-term use of low dose clopidogrel (50 mg) in such patients in China.
In the present study, we aimed to investigate the clinical data to assess the efficacy and safety of long-term used low dose clopidogrel (50 mg/d) versus clopidogrel (75 mg/d) in Chinese ACS patients undergoing PCI after DAPT treatment.
2. Methods
2.1. Study design
This single-center retrospective cohort study enrolled patients with ACS undergoing PCI at the Central Hospital of Wuhan, Wuhan, China, between January 2014 and December 2016. The data cutoff was December 31, 2019. This study was approved by the Central Hospital of Wuhan Hospital Ethics Committee (No. 2021(9)). All methods all experiments were performed in accordance with relevant guidelines and regulations. Written informed consent was also waived by the Ethics Commission of the designated hospital.
2.2. Study population
The major inclusion criteria were chosen clopidogrel to SAPT after DAPT in the PCI patients. The major exclusion criteria were treated with anticoagulant or have malignancies. According to the type of SAPT after standard DAPT, PCI patients were divided into 2 groups: low dose clopidogrel (50 mg/d) group and standard dose clopidogrel (75 mg/d) group. Figure 1 presents the flowchart of confirmed patients enrolled in this study.
Figure 1.
Flowchart for the study. ACS = acute coronary syndromes, DAPT = dual antiplatelet treatment, PCI = percutaneous coronary intervention, SAPT = single antiplatelet treatment.
2.3. Data collection and availability
Patient data – including epidemiological, demographic, clinical, laboratory, treatment, and outcome data – were extracted from electronic medical records using a standardized data collection form. Data collection was performed by experienced clinicians and independently reviewed by 2 researchers. Missing data were minimal (<5% for all variables). Key variables (e.g., outcomes, antiplatelet adherence) had no missing entries due to rigorous follow-up protocols.
2.4. Outcomes
All outcome assessments were verified through hospital records and telephonic interviews, ensuring reliability. The primary outcome was a composite measure comprising time to first occurrence of any confirmed death, myocardial infarction (MI), and stroke. MI was defined as 2017 ESC guideline,[2] including the elevation of cardiac biomarker values to a value above 99% of the upper reference limit and presence of one of the following: ischemic symptoms, electrocardiographic changes compatible with infarction, imaging evidence of new loss of viable myocardium or new regional wall motion abnormality, angiography, or autopsy identified intracoronary thrombus. Stroke was defined as focal loss of neurologic function lasting at least 24 hours, regardless of whether the symptom was caused by an ischemic or hemorrhagic event.[10] Time to event was defined as the number of days from the date of randomization to the confirmed date of the event. The secondary outcome was the occurrence of stent thrombosis, in-stent restenosis, or hospitalization due to heart failure or chest pain.
The safety outcome was complications associated with bleeding events during the follow-up period. Bleeding was defined based on the Bleeding Academic Research Consortium (BARC) criteria.[11] Total bleeding events includes all types of BARC-defined bleeding. All outcomes were confirmed by 3 experienced cardiovascular specialists (Xh.K., M.Z., and Q.H.).
2.5. Statistical analysis
Categorical variables are reported as numbers (%). Normally distributed continuous data are reported as the mean ± standard deviation and non-normally distributed continuous data are reported as the median (interquartile range [IQR]). Categorical data were compared using the χ2 test or Fisher’s exact test. Independent t-tests were used to compare normally distributed continuous data, while the Mann–Whitney U-test was used to compare non-normally distributed continuous data. We used the Cox proportional hazards model with adjusted age, sex, comorbidities, current smoke status, and low density lipoprotein cholesterol to estimate the hazard ratio (HR) with 95% confidence intervals (CI). Kaplan–Meier curves were used to estimate the time to the first event, which was compared between groups using the log-rank test.
To minimize selection bias compared to real-world populations, additional propensity score matching (PSM) analysis was performed. Patients with 50 mg clopidogrel were matched 1:1 with patients in the control group using nearest-neighbor matching with a caliper of 0.2. The propensity score was estimated using a logistic regression model with the variables age, sex, comorbidities, smoking, and low density lipoprotein cholesterol. A P value < .05 was considered to be statistically significant. Statistical analysis was performed using SPSS version 25.0 (IBM SPSS Inc., Chicago).
3. Results
3.1. Baseline characteristics of patients
A total of 378 patients with PCI met the inclusion criteria and completed the follow-up. Of these, 49 (12.96%) received clopidogrel (50 mg/d) after DAPT and 329 (87.04%) received clopidogrel (75 mg/d) after DAPT. The median duration for patients taking DAPT after PCI was 12 months (IQR 12–12 months) and the median duration of for patients taking SAPT was 34 months (IQR 28–40 months). No significant differences in basic characteristics, comorbidities, laboratory data, treatment, DAPT duration, and SAPT duration were found between the 2 groups (Table 1). After propensity score matching, there were 49 patients in each group and no significant differences in the baseline characteristics were present (Table 2).
Table 1.
Baseline characteristics in overall population.
| Overall population | Total (n = 378) | Clopidogrel (50 mg/d) (n = 49) |
Clopidogrel (75 mg/d) (n = 329) |
P value |
|---|---|---|---|---|
| Characteristics | ||||
| Age, yr | 61.00 (55.00, 68.00) | 62.00 (55.00, 68.50) | 61.00 (55.00, 68.00) | .719 |
| Gender | .530 | |||
| Male | 254 (67.19%) | 31 (63.26%) | 223 (67.78%) | |
| Female | 124 (32.81%) | 18 (36.74%) | 106 (32.22%) | |
| SBP, mm Hg | 125.00 (120.00, 132.00) | 126.00 (120.00, 132.75) | 125.00 (119.25, 131.50) | .362 |
| DBP, mm Hg | 70.00 (66.00, 79.50) | 71.50 (66.75, 79.25) | 70.00 (66.00, 79.75) | .825 |
| Current smoker | 148 (39.15%) | 17 (34.69%) | 131 (39.81%) | .483 |
| Comorbidities | ||||
| Diabetes | 123 (32.53%) | 16 (32.65%) | 107 (32.52%) | .986 |
| Hypertension | 232 (61.37%) | 35 (71.43%) | 197 (60.244%) | .121 |
| Laboratory data | ||||
| TC, μmol/L | 4.48 (3.74, 5.25) | 4.38 (3.76, 5.23) | 4.48 (3.73, 5.25) | .872 |
| LDL-C, μmol/L | 2.69 (2.10, 3.32) | 2.53 (2.08, 3.45) | 2.71 (2.10, 3.32) | .780 |
| HDL-C, μmol/L | 1.00 (0.86, 1.19) | 1.05 (0.95, 1.20) | 0.99 (0.86, 1.17) | .078 |
| HbA1c, % | 6.0 (5.0, 6.8) | 5.90 (5.60, 6.95) | 6.00 (5.60, 6.80) | .584 |
| Creatinine, μmol/L | 70.80 (57.85, 84.70) | 69.00 (63.00, 79.00) | 71.00 (56.40, 85.10) | .755 |
| Urea, mmol/L | 5.35 (4.33, 6.36) | 5.25 (4.43, 6.31) | 5.35 (4.31, 6.38) | .880 |
| Treatment | ||||
| ACEI/ARB | 239 (63.23%) | 31 (63.26%) | 208 (63.22%) | .995 |
| β-block | 277 (73.28%) | 41 (83.67%) | 236 (71.73%) | .078 |
| Statins | 377 (99.73%) | 49 (100.00%) | 328 (99.69%) | .699 |
| DAPT time, mo | 12.00 (12.00, 12.00) | 12.00 (12.00, 16.50) | 12.00 (12.00, 12.00) | .679 |
| SAPT time, mo | 34.00 (28.00, 40.00) | 31.00 (25.50, 37.00) | 32.00 (25.00,40.00) | .987 |
Data are n (%). Normal distributed data are mean ± SD and non-normal distributed data are median (IQR).
ACEI = angiotensin converting enzyme inhibitors, ARB = angiotensin receptor blocker, DBP = Diastolic blood pressure, DAPT = dual antiplatelet treatment, HbA1c = glycated hemoglobin/hemoglobin A1c, HDL-C = high density lipoprotein cholesterol, LDC-C = low density lipoprotein cholesterol, PSM = propensity score score-matched, SAPT = single antiplatelet treatment, SBP = systolic blood pressure, TC = total cholesterol.
Table 2.
Baseline characteristics in in the propensity score-matched population.
| PSM population | Total (n = 98) |
Clopidogrel (50 mg/d) (n = 49) |
Clopidogrel (75 mg/d) (n = 49) |
P value |
|---|---|---|---|---|
| Characteristics | ||||
| Age, yr | 63.00 (56.75, 68.00) | 62.00 (55.50, 68.50) | 63.00 (57.50, 67.00) | .917 |
| Gender | 1.000 | |||
| Male | 62 (63.26%) | 31 (63.26%) | 31 (63.26%) | |
| Female | 36 (36.74%) | 18 (36.74%) | 18 (36.74%) | |
| SBP, mm Hg | 125.00 (120.00, 130.00) | 126.00 (120.00, 132.75) | 124.00 (119.50, 130.00) | .626 |
| DBP, mm Hg | 70.00 (67.00, 79.00) | 71.50 (66.75, 79.25) | 70.00 (66.50, 78.00) | .707 |
| Current smoker | 148 (39.15%) | 17 (34.69%) | 131 (39.81%) | .839 |
| Comorbidities | ||||
| Diabetes | 30 (30.61%) | 16 (32.65%) | 14 (28.57%) | .665 |
| Hypertension | 65 (66.32%) | 35 (71.43%) | 32 (65.31%) | .520 |
| Laboratory data | ||||
| TC, μmol/L | 4.51 (3.73, 5.23) | 4.38 (3.76, 5.23) | 4.56 (3.68, 5.22) | .597 |
| LDL-C, μmol/L | 2.57 (2.07, 3.50) | 2.53 (2.08, 3.45) | 2.78 (2.05, 3.48) | .804 |
| HDL-C, μmol/L | 1.05 (0.91, 1.26) | 1.05 (0.95, 1.20) | 0.99 (0.88, 1.14) | .092 |
| HbA1c, % | 5.09 (5.50, 6.70) | 5.90 (5.60, 6.95) | 5.7 (5.50, 6.70) | .957 |
| Creatinine, μmol/L | 70.60 (63.00, 84.55) | 69.00 (63.00, 79.00) | 71.00 (61.8, 89.00) | .410 |
| Urea, mmol/L | 5.41 (4.54, 6.32) | 5.25 (4.43, 6.31) | 5.42 (4.48, 6.35) | .985 |
| Treatment | ||||
| ACEI/ARB | 66 (67.34%) | 31 (63.26%) | 35 (71.43%) | .394 |
| β-block | 74 (75.51%) | 41 (83.67%) | 33 (67.34%) | .061 |
| Statins | 98 (100.00%) | 49 (100.00%) | 49 (100.00%) | –* |
| DAPT time, mo | 12.00 (12.00, 18.00) | 12.00 (12.00, 16.50) | 12.00 (12.00, 21.00) | .822 |
| SAPT time, mo | 31.00 (26.00, 37.00) | 31.00 (25.50, 37.00) | 30.00 (26.00, 36.50) | .745 |
Data are n (%). Normal distributed data are mean ± SD and non-normal distributed data are median (IQR).
ACEI = angiotensin converting enzyme inhibitors, ARB = angiotensin receptor blocker, DAPT = dual antiplatelet treatment, DBP = diastolic blood pressure, HbA1c = glycated hemoglobin/hemoglobin A1c, HDL-C = high density lipoprotein cholesterol, LDC-C = low density lipoprotein cholesterol, PSM = propensity score score-matched, SAPT = single antiplatelet treatment, SBP = systolic blood pressure, TC = total cholesterol.
All patients were treated with statins.
3.2. Primary outcomes for the overall population
For the overall population, primary outcomes (any death, MI, or stroke) occurred in 4 of 49 patients (8.16%) in low dose clopidogrel (50 mg/d) group and 21 of 329 patients (6.38%) in standard dose clopidogrel (75 mg/d) group. And no difference in the rate of primary outcome was observed between the 2 groups (HR 1.345, 95% CI: 0.455–3.974; P = .592; Table 3, Figs. 2 and 3A). The cumulative incidence of all-cause death, MI and stroke were also no statistically significant difference between the 2 groups (P > .05, Table 3, Fig. 3B, D).
Table 3.
Clinical outcomes during follow-up in the overall population.
| Over population | Clopidogrel (50 mg/d) (n = 49) |
Clopidogrel (75 mg/d) (n = 329) |
Hazard ratio (95% CI) | P value |
|---|---|---|---|---|
| Primary outcomes | ||||
| Primary outcome events | 4 (8.16%) | 21 (6.38%) | 1.345 (0.455–3.974) | .592 |
| MI | 1 (2.04%) | 8 (2.43%) | 0.899 (0.109–7.440) | .921 |
| Stoke | 1 (2.04%) | 2 (0.61%) | 3.654 (0.235–56.845) | .355 |
| Any death | 2 (4.08%) | 11 (3.34%) | 1.463 (0.315–6.790) | .627 |
| Secondary outcomes | ||||
| Secondary outcome events | 4 (8.16%) | 22 (6.68%) | 1.483 (0.506–4.348) | .473 |
| Stent thrombosis | 1 (2.04%) | 1 (0.30%) | 6.112 (0.382–97.777) | .201 |
| In-stent restenosis | 1 (2.04%) | 11 (3.34%) | 0.698 (0.089–5.493) | .733 |
| Hospitalized for heart failure | 1 (2.04%) | 4 (1.21%) | 2.112 (0.219–20.393) | .518 |
| Hospitalized for chest pain | 1 (2.04%) | 6 (1.82%) | 1.320 (0.153–11.374) | .801 |
| Safety endpoints | ||||
| Bleeding events | 5 (10.20%) | 21 (6.38%) | 2.268 (0.835–6.160) | .108 |
| BARC type = 2 | 3 (6.12%) | 12 (3.65%) | 2.320 (0.632–8.515) | .205 |
| BARC type ≥ 3 | 2 (4.08%) | 9 (2.73%) | 2.063 (0.413–10.308) | .378 |
Data are n (%).
BARC = Bleeding Academic Research Consortium, CI = confidence intervals, MI = myocardial infarction.
Figure 2.
Hazard ratios of benefit with low dose group (clopidogrel, 50 mg/d) versus control group (clopidogrel, 75 mg/d) for clinical outcomes in overall population and propensity score-matched population. CI = confidence intervals, HR = hazard ratio, PSM = propensity score-matched.
Figure 3.
The cumulative final rate of event and the number at risk in overall population between the low dose group (clopidogrel, 50 mg/d) and control group (clopidogrel, 75 mg/d).
3.3. Secondary outcomes for the overall population
For the overall population, any secondary endpoint occurred in 4 of 49 patients (8.16%) in 50 mg/d clopidogrel group and 22 of 329 patients (6.68%) in 75 mg/d clopidogrel group. The rate of secondary outcomes was not significantly difference between the 2 groups (HR 1.483, 95% CI: 0.506–4.348; P = .473; Table 3, Fig. 2). And there was no significant difference in the cumulative incidence of stent thrombosis, in-stent restenosis, hospitalization for heart failure, and hospitalization for chest pain between the 2 groups (P > .05, Table 3).
3.4. Safety outcomes for the overall population
For the overall population, the rate of safety outcomes (total bleeding events) was similar in the 2 groups (HR 2.268, 95% CI: 0.835–6.160; P = .108; Table 3, Fig. 2). Briefly, 5/49 (10.20%) in 50 mg/d clopidogrel group and 21/329 (6.38%) in 75 mg/d clopidogrel group. BARC type 2 bleeding events occurred in 3 patients (6.12%) in the low dose group compared with 12 patients (3.65%) in the control group (HR 2.320, 95% CI: 0.632–8.515; P = .205; Table 3). BARC type ≥ 3 bleeding events occurred in 2 patients (4.08%) in the low dose group and in 9 patients (2.73%) in the control group (HR 2.063, 95% CI: 0.412–10.308; P = .378; Table 3).
3.5. Clinical outcomes for the PSM population
For the PSM sample, the primary outcomes occurred in 4 of 49 patients (8.16%) in 50 mg/d clopidogrel group and 2 of 49 patients (4.08%) in 75 mg/d clopidogrel group, while secondary outcomes occurred in 4 of 49 patients (8.16%) in 50 mg/d clopidogrel group and 4 of 49 patients (8.16%) 75 mg/d clopidogrel group. No significantly difference in primary outcomes (HR 0.897, 95% CI: 0.095–8.441; P = .925; Table 4, Figs. 2 and 4) and secondary outcomes (HR 1.217, 95% CI: 0.272–5.444; P = .798; Table 4, Fig 2) were found in the 2 groups, respectively. The cumulative incidence of safety outcome was no different in low dose clopidogrel (50 mg/d) group (5, 10.20%) compared to the standard dose clopidogrel (75 mg/d) group (6, 12.24%; HR 0.296, 95% CI: 0.051–1.709; P = .174, Table 4).
Table 4.
Clinical outcomes during follow-up in the propensity score-matched population.
| PSM population | Clopidogrel (50 mg/d) (n = 49) |
Clopidogrel (75 mg/d) (n = 49) |
Hazard ratio (95% CI) | P value |
|---|---|---|---|---|
| Primary outcomes | ||||
| Primary outcome events | 4 (8.16%) | 2 (4.08%) | 0.897 (0.095–8.441) | .925 |
| MI | 1 (2.04%) | 2 (4.08%) | – | .084 |
| Stoke | 1 (2.04%) | 0 | – | .891 |
| Any death | 2 (4.08%) | 0 | – | .974 |
| Secondary Outcomes | ||||
| Secondary outcome events | 4 (8.16%) | 4 (8.16%) | 1.217 (0.272–5.444) | .798 |
| Stent thrombosis | 1 (2.04%) | 0 | – | .981 |
| In-stent restenosis | 1 (2.04%) | 3 (6.12%) | 3.723 (0.344–40.236) | .279 |
| Hospitalized for heart failure | 1 (2.04%) | 1 (2.04%) | 1.882 (0.045–78.866) | .740 |
| Hospitalized for chest pain | 1 (2.04%) | 0 | – | .321 |
| Safety outcomes | ||||
| Bleeding events | 5 (10.20%) | 6 (12.24%) | 0.296 (0.051–1.709) | .174 |
| BARC type = 2 | 3 (6.12%) | 5 (10.20%)) | 0.396 (0.048–3.294) | .391 |
| BARC type ≥ 3 | 2 (4.08%) | 1 (2.04%) | 0.356 (0.076–2.898) | .970 |
Data are n (%).
BARC = Bleeding Academic Research Consortium, CI = confidence intervals, MI = myocardial infarction, PSM = propensity score score-matched.
Figure 4.
The cumulative final rate of event and the number at risk in propensity score-matched population between the low dose group (clopidogrel, 50 mg/d) and control group (clopidogrel, 75 mg/d). PSM = propensity score-matched.
4. Discussion
In this retrospective study, we sought to evaluate the efficacy and safety of using a low dose (50 mg/d) of clopidogrel in Chinese patients with ACS who underwent PCI after at least 12 months of DAPT, in comparison to the standard dose of clopidogrel (75 mg/d). Our study, spanning approximately 3 years of follow-up, revealed no significant differences in the risk of MI, stroke, all-cause mortality, or bleeding events between the 2 treatment groups following the initial 12 months of DAPT.
Recent research has highlighted the potential benefits of long-term use of lower dose antithrombotic medications, particularly in cases where there is a lower risk of bleeding. The PEGASUS-TIMI 54 trial, for instance, demonstrated that both 90 mg twice daily and 60 mg twice daily doses of ticagrelor were associated with similar efficacy in reducing the risk of cardiovascular death, MI, or stroke.[12] Similarly, in a retrospective study involving 525 East Asian patients with coronary chronic total occlusion undergoing PCI, 60 mg of ticagrelor exhibited comparable effectiveness to 90 mg while also significantly reducing the risk of bleeding.[13–15]
Despite their substantial population size, East Asian individuals are often underrepresented in major clinical trials assessing the use of P2Y12 inhibitors. As a result, the recommended dosage of P2Y12 inhibitors in Chinese guidelines aligns with those of American and European guidelines. However, emerging data suggest that East Asian populations possess distinct risk profiles for both thrombophilia and bleeding when compared to their Caucasian counterparts.[6,16] Consequently, the dosages recommended in European and American guidelines may not be entirely suitable for East Asian patients.
Many cardiovascular medications, particularly P2Y12 inhibitors like clopidogrel, exhibit notable interethnic variations in pharmacokinetic and pharmacodynamic profiles. Specifically, clopidogrel demonstrates marked interethnic differences linked to the presence of the CYP2C19 loss-of-function allele.[17,18] East Asian individuals have a higher prevalence of this allele than Caucasians,[19,20] resulting in elevated platelet reactivity during clopidogrel treatment in East Asian patients compared to Caucasians.[6,21] This discrepancy could explain why low dose clopidogrel exhibits similar clinical efficacy to the standard dose in East Asian populations.
Previous studies have also reported differences in maintenance doses of certain drugs between Asian and Caucasian patients.[8,22] For instance, research by Fukushima et al found a similar antiplatelet effect between 200 mg of ticlopidine and 50 mg of clopidogrel in Japanese patients, despite the latter being significantly lower than the “standard” dose of 75 mg for Caucasian patients.[23] In a randomized pilot trial involving Japanese patients who underwent drug-eluting stent implantation, the efficacy and safety of 50 mg clopidogrel versus 75 mg clopidogrel were evaluated. All patients received 100 mg of aspirin daily before the procedure, a regimen maintained indefinitely. The results demonstrated no occurrences of cardiac death, MI, or stent thrombosis in either group, with similar side effects during the 21.8 ± 5.7 months of follow-up.[24] As a result, it is common practice to reduce the dose of clopidogrel in Japanese patients from 75 mg daily during the first 3 months of treatment to 50 mg daily from 3 months to 1 year, typically in patients with stable coronary artery disease who have undergone PCI. After 1 year of clopidogrel treatment, the dose is often further reduced to 25 mg.[25]
However, the generalizability of our findings to non-East Asian populations remains uncertain. In Caucasian cohorts, where CYP2C19 LOF prevalence is lower, standard dose clopidogrel (75 mg) is often insufficient for rapid platelet inhibition, necessitating alternative strategies such as prasugrel or ticagrelor in high-risk patients.[6,16] This contrast underscores the importance of population-specific dosing strategies. For instance, the POPULAR Genetics trial demonstrated that genotype-guided escalation to potent P2Y12 inhibitors improved outcomes in CYP2C19 LOF carriers among Europeans,[26] whereas East Asian studies favor dose reduction or adjunctive therapies (e.g., cilostazol) to balance efficacy and bleeding.[9,27]
Our study offers valuable insights into the efficacy and safety of low dose clopidogrel in Chinese patients with ACS; however, several limitations must be acknowledged. Firstly, the retrospective design and single-center setting inherently restrict the ability to draw causal inferences and limit the generalizability of the findings. Although our institution, a provincial key specialty in cardiology located in Hubei Province, China, strictly adheres to international guidelines, such as those from the ESC and the American College of Cardiology for PCI management and follow-up protocols: including standardized DAPT duration, uniform bleeding risk assessments, and systematic outcome adjudication: these rigorous practices may not fully capture the variability present in real-world settings across different regions or healthcare systems. For example, variations in patient demographics, such as the higher proportion of rural populations in our cohort, access to advanced therapies, or local prescribing habits, could potentially influence outcomes. Secondly, the small sample size in the low dose clopidogrel group (n = 49) may have resulted in insufficient statistical power, particularly concerning rare endpoints like stent thrombosis. Thirdly, the median follow-up duration of 34 months limits our ability to draw conclusions regarding the long-term cardiovascular risks or benefits of low dose therapy beyond a 3-year period. In conclusion, the absence of pharmacogenetic and body mass index data, such as CYP2C19 polymorphisms, which are essential for optimizing clopidogrel dosing in East Asian populations, represents a limitation of this retrospective cohort study. Future research should focus on prospective, multicenter studies with larger sample sizes, longer follow-up periods, and comprehensive genotype-phenotype correlation analyses to validate these findings and enhance dose optimization strategies across diverse populations.
5. Conclusion
In conclusion, while this retrospective study suggests the potential suitability of low dose clopidogrel (50 mg/d) for monotherapy in Chinese patients after at least 12 months of DAPT, it is important to acknowledge the limitations imposed by the relatively small sample size. Further large-scale randomized studies are warranted to confirm these findings and provide more robust conclusions.
Author contributions
Conceptualization: Qin He.
Data curation: Xianghai Kong, Mi Zhou.
Formal analysis: Biao Cheng, Xianghai Kong, Jian Chen.
Investigation: Qin He, Mi Zhou.
Methodology: Jian Chen.
Supervision: Aiping Deng.
Writing – original draft: Biao Cheng.
Writing – review & editing: Aiping Deng.
Abbreviations:
- ACS
- acute coronary syndromes
- BRAC
- Bleeding Academic Research Consortium
- CI
- confidence intervals
- DAPT
- dual antiplatelet treatment
- ESC
- European Society of Cardiology
- HR
- hazard ration
- IQR
- interquartile range
- MI
- myocardial infarction
- PCI
- percutaneous coronary intervention
- PSM
- propensity score matching
- SAPT
- single antiplatelet treatment.
The ethics committee of the Central Hospital of Wuhan has approved this study (No. 2021(9)). All methods all experiments were performed in accordance with relevant guidelines and regulations of the 1975 Declaration of Helsinki. Written informed consent was also waived by the ethics committee of the Central Hospital of Wuhan.
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
How to cite this article: Cheng B, Kong X, Chen J, He Q, Zhou M, Deng A. Assessing the efficacy and safety of low dose clopidogrel in Chinese ACS patients undergoing PCI: A retrospective study. Medicine 2025;104:22(e42551).
BC, XK, JC, and QH contributed to this article equally.
Contributor Information
Xianghai Kong, Email: 1078009175@qq.com.
Jian Chen, Email: chenjian361016508@163.com.
Qin He, Email: ph610528@hotmail.com.
Mi Zhou, Email: olivejay@126.com.
References
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