Comparison of Fixed‐Dose Clopidogrel/Asetylsalicylic Acid Combination and Standard Loading Strategy During Percutaneous Coronary Intervention in Chronic Coronary Syndrome

ABSTRACT

Background

Dual antiplatelet therapy (DAPT), comprising acetylsalicylic acid and a P2Y12 receptor inhibitor such as clopidogrel, is the cornerstone of management in patients undergoing percutaneous coronary intervention (PCI). While conventional loading doses of acetylsalicylic acid and clopidogrel are well established, there is limited evidence supporting the use of fixed‐dose combinations (FDCs) for loading therapy in patients with chronic coronary syndrome (CCS).

Aims

This study aims to evaluate the efficacy and safety of an FDC of clopidogrel and acetylsalicylic acid (75/75 mg, four tablets) compared to the standard loading regimen in patients with CCS undergoing elective PCI.

Methods

In this prospective observational study, patients were divided into two groups based on the antiplatelet loading strategy: conventional loading (acetylsalicylic acid 300 mg and clopidogrel 300–600 mg) and FDC group (four tablets of 75/75 mg). Baseline demographic, clinical, laboratory, and procedural characteristics were compared. The primary outcomes were 1‐month rates of major adverse cardiovascular events (MACE), stent thrombosis, bleeding (BARC criteria), and mortality.

Results

A total of 410 patients were included (conventional: 326; FDC: 84). There were no statistically significant differences in baseline demographic or procedural characteristics between the groups. Laboratory findings and 1‐month clinical outcomes, including MACE, bleeding, and mortality, were similar (p > 0.05 for all outcomes).

Conclusion

Fixed‐dose clopidogrel/acetylsalicylic acid combination may be a feasible and clinically comparable option in carefully selected CCS patients to standard loading in CCS patients undergoing elective PCI. Its use may simplify treatment regimens.

Abbreviations

ACC

American College of Cardiology

AHA

American Heart Association

BARC

Bleeding Academic Research Consortium

CABG

coronary artery bypass grafting

CAD

coronary artery disease

CCS

chronic coronary syndrome

CKD

chronic kidney disease

COPD

chronic obstructive pulmonary disease

CRP

C‐reactive protein

CTA

computed tomography angiography

DAPT

dual antiplatelet therapy

ESC

European Society of Cardiology

FDC

fixed‐dose combination

HbA1c

hemoglobin A1c

HDL

high‐density lipoprotein

LDL

low‐density lipoprotein

LVEF

left ventricular ejection fraction

MACE

major adverse cardiovascular events

P2Y12

P2Y12 adenosine diphosphate receptor (platelet receptor target)

PCI

percutaneous coronary intervention

RCA

right coronary artery

SD

standard deviation

SPSS

Statistical Package for the Social Sciences

1. Introduction

Dual antiplatelet therapy (DAPT) combining acetylsalicylic acid and a P2Y12 inhibitor remains the foundational strategy for managing patients with coronary artery disease (CAD), particularly those undergoing percutaneous coronary intervention (PCI) [1, 2]. Current guidelines recommend loading doses of 300–600 mg clopidogrel and 300 mg acetylsalicylic acid to achieve optimal platelet inhibition before PCI in both acute and chronic coronary settings [3]. However, these guidelines do not clearly address whether fixed‐dose combinations (FDCs) can be utilized as a substitute for separate loading doses.

FDCs of clopidogrel and acetylsalicylic acid have previously demonstrated pharmacodynamic equivalence to individual formulations in the context of chronic secondary prevention [4, 5]. Furthermore, several studies have shown that FDCs improve medication adherence, reduce prescription complexity, and maintain antiplatelet efficacy [6, 7, 8]. Despite these advantages, evidence on the safety and efficacy of FDCs as a loading strategy in PCI remains scarce—particularly in patients with chronic coronary syndrome (CCS).

This study was designed to fill that gap by comparing a novel loading approach using a fixed‐dose clopidogrel/acetylsalicylic acid combination (75 mg/75 mg × 4 tablets) with the conventional loading strategy. We hypothesized that the FDC would demonstrate comparability with respect to 1‐month clinical outcomes, including major adverse cardiovascular events (MACE), bleeding, stent thrombosis, and mortality.

2. Materials and Methods

This prospective observational study was conducted between October 1, 2023, and August 31, 2024, at a tertiary cardiology center. The study enrolled adult patients with CCS undergoing elective PCI based on positive noninvasive tests, including coronary computed tomography angiography (CTA), exercise stress testing, or myocardial perfusion scintigraphy.

Patients were excluded if they had:

• A history of prior coronary angiography,

• Left main CAD,

• Complex bifurcation lesions requiring two‐stent techniques,

• Acute coronary syndromes,

• A history of coronary artery bypass grafting (CABG).

The study was approved by the local ethics committee, and written informed consent was obtained from all participants.

Antiplatelet loading strategies were determined by the operating physician based on standard clinical practice. Patients were assigned into two groups:

• Conventional loading group: Received separate loading doses of acetylsalicylic acid (300 mg) and clopidogrel (300–600 mg).

• FDC Group: Received a FDC of acetylsalicylic acid and clopidogrel (75 mg/75 mg), administered as four tablets (total 300 mg of each).

All patients underwent PCI using current‐generation drug‐eluting stents and were followed for 30 days postprocedure.

Baseline characteristics included demographic data (age, sex), cardiovascular risk factors (hypertension [HT], diabetes mellitus [DM], hyperlipidemia, chronic kidney disease [CKD], smoking status, family history of CAD, chronic obstructive pulmonary disease [COPD], and atrial fibrillation), and preprocedural laboratory values (lipid profile, CRP, HbA1c, creatinine). Procedural details such as target vessel, number of stents, stent diameter, and total stent length were also recorded.

The primary endpoints were:

• MACE: defined as the composite of cardiac death, target lesion revascularization, or nonfatal myocardial infarction,

• Stent thrombosis,

• Bleeding events: classified by the Bleeding Academic Research Consortium (BARC) criteria,

• All‐cause mortality.

All clinical outcomes were assessed during a 1‐month follow‐up period.

2.1. Statistical Analysis

Continuous variables were expressed as mean ± standard deviation and compared using Student's t‐test or the Mann–Whitney U test, depending on the distribution. Categorical variables were presented as counts and percentages and compared using the chi‐square test or Fisher's exact test as appropriate. A p‐value of < 0.05 was considered statistically significant.

We performed multivariable logistic regression for 30‐day binary outcomes, entering treatment group (FDC vs. conventional) and available clinical covariates (e.g., age, sex, diabetes, HT, smoking, left ventricular ejection fraction (LVEF), renal function, prior coronary history, and lesion complexity variables). Adjusted odds ratios (aORs) with 95% confidence intervals are reported. All statistical analyses were performed using SPSS 22 (Central Figure 1).

Central Figure Illustration.

Comparison of 1‐month clinical outcomes between conventional loading and fixed‐dose combination strategies in patients with chronic coronary syndrome undergoing elective percutaneous coronary intervention. [Color figure can be viewed at wileyonlinelibrary.com]

3. Results

A total of 410 patients with CCS who underwent elective PCI were included in the study. Of these, 326 patients received the conventional loading strategy, and 84 received the FDC of acetylsalicylic acid and clopidogrel.

As shown in Table 1, no statistically significant differences detected between the two groups in terms of demographic variables. Cardiovascular risk factors such as HT, DM, hyperlipidemia, CKD, smoking status, family history of CAD, COPD, and atrial fibrillation were also comparable between the groups (p > 0.05 for all). The rate of complete revascularization was not significantly different between groups.

Table 1.

Baseline demographic characteristics of the patients.

Variable	Conventional (n = 326)	Fixed‐dose (n = 84)	p value
Age (years) (mean ± SD)	64.2 ± 11.5	63.7 ± 10.9	0.620
Female (%)	94 (28.8%)	27 (32.1%)	0.480
Hypertension (%)	110 (33.7%)	30 (35.7%)	0.118
Diabetes mellitus (%)	87 (26.7%)	26 (30.6%)	0.561
Chronic kidney disease (%)	15 (4.6%)	1 (1.2%)	0.255
Smoking (%)	26 (8.0%)	5 (5.9%)	0.532
Family history (%)	9 (2.8%)	5 (5.9%)	0.281
Atrial fibrillation (%)	30 (9.2%)	7 (8.2%)	0.948
COPD (%)	17 (5.2%)	0 (0.0%)	0.065

Abbreviations: COPD = chronic obstructive pulmonary disease, SD = standard deviation.

Baseline laboratory results, summarized in Table 2, revealed no statistically significant differences detected in inflammatory, lipid, or metabolic parameters. CRP, LDL, total cholesterol, HDL, triglycerides, HbA1c, and creatinine levels were statistically similar between the groups (p > 0.05).

Table 2.

Laboratory findings at baseline.

Variable	Conventional (n = 326)	Fixed‐dose (n = 84)	p value
Total cholesterol (mg/dL)	174.57 ± 45.19	182.00 ± 45.49	0.242
LDL (mg/dL)	101.02 ± 40.74	107.71 ± 39.71	0.233
HDL (mg/dL)	42.23 ± 11.51	43.61 ± 16.19	0.517
Triglycerides (mg/dL)	159.40 ± 85.61	170.91 ± 123.40	0.478
Creatinine (mg/dL)	1.07 ± 0.79	1.00 ± 0.97	0.581
CRP (mg/L)	22.61 ± 43.13	23.04 ± 46.09	0.956
HbA1c	7.11 ± 1.94	7.04 ± 1.80	0.817
PLT	256.47 ± 129.77	259.56 ± 97.89	0.742

Abbreviations: CRP = C‐reactive protein, HbA1c = hemoglobin A1c, LDL = low‐density lipoprotein, PLT = platelet count.

As outlined in Table 3, there were no statistically significant differences in procedural aspects of PCI. The mean number of stents used, stent diameter, and total stent length were similar between groups.

Table 3.

Procedural characteristics of patients.

Variable	Conventional (n = 326)	Fixed‐dose (n = 84)	p value
Number of stents	1.41 ± 0.72	1.33 ± 0.66	0.314
Stent diameter (mm)	2.95 ± 0.09	2.94 ± 0.10	0.511
Stent length (mm)	29.24 ± 15.15	31.77 ± 17.65	0.237
LVEF (%)	55.28 ± 0.10	55.26 ± 0.10	0.373

Abbreviation: LVEF = left ventricular ejection fraction.

Target vessels included the left anterior descending artery (LAD), right coronary artery (RCA), and circumflex artery (Cx), and their distributions did not significantly differ between groups. Additionally, LVEF was similar.

Clinical outcomes at 1‐month follow‐up are presented in Table 4. There were no statistically significant differences detected between the two groups in terms of stent thrombosis, bleeding events, MACE, all‐cause mortality, stent thrombosis.

Table 4.

One‐month clinical outcomes.

Outcome	Conventional (n = 326), n (%)	FDC (n = 84), n (%)	Risk ratio (FDC vs. Conv) [95% CI]	p value
MACE	5 (1.53%)	1 (1.19%)	0.78 [0.09–6.56]	0.89
Stent thrombosis	2 (0.61%)	0 (0.00%)	0.77 [0.04–15.88]	0.41
Bleeding (BARC ≥ 1)	4 (1.23%)	1 (1.19%)	0.97 [0.11–8.57]	1.00
All‐cause mortality	1 (0.31%)	0 (0.00%)	1.28 [0.05–31.20]	0.67

Abbreviations: BARC = Bleeding Academic Research Consortium, MACE = major adverse cardiac events.

In multivariable models, no statistically significant differences were detected for the 30‐day endpoints (Table 5).

Table 5.

Multivariable logistic regression for the 30‐day endpoints.

Variables	OR	95% CI (L−U)	p
Stent number	1.671	0.815−3.426	0.161
Stent size	0.504	0.215−1.178	0.114
hypertension	1.273	0.371−4.372	0.701
DM	1.548	0.478−5.019	0.466
Hyperlipidemia	0.126	0.014−1.104	0.061
CRF	0.78	0.067−9.033	0.843
Smoking status	1.284	0.141−11.712	0.825
Atrial fibrillation	3.436	0.779−15.153	0.103
FDC	0.384	0.110−1.345	0.135
LVEF%	0.613	0.009−42.270	0.821

4. Discussion

This prospective observational study demonstrates that the use of a FDC of acetylsalicylic acid and clopidogrel as a loading strategy in patients with CCS undergoing elective PCI is safe and effective, showing no statistically significant differences detected relative to the conventional loading strategy in terms of short‐term clinical outcomes.

Although our primary objective was to assess short‐term clinical outcomes rather than mechanistic endpoints, we acknowledge that platelet function assays and pharmacokinetic profiling could have further substantiated mechanistic equivalence. Prior studies, Oh et al. reported that platelet aggregation was similarly suppressed by both regimens in stable CAD patients undergoing PCI, supporting the clinical interchangeability of these strategies [6]. Moreover, Lim et al. highlighted better adherence rates with FDC regimens compared to conventional two‐pill regimens, which may translate into improved real‐world outcomes over time [7]. Nevertheless, future randomized trials incorporating such mechanistic assessments are warranted.

Significantly, our study goes one step further by evaluating the use of FDCs as a loading dose, an area not clearly addressed in current European Society of Cardiology (ESC) or American College of Cardiology (ACC) guidelines. This is a novel contribution, as most prior studies have focused on maintenance therapy. Early platelet inhibition is crucial in preventing periprocedural complications such as stent thrombosis and ischemic events, so the safety of FDCs in this context is particularly relevant.

Recent literature supports broader adoption of FDCs in cardiovascular care. For instance, several studies suggest that FDCs improve long‐term medication adherence, particularly in populations with polypharmacy concerns [9, 10]. Improved adherence has been shown to significantly reduce the risk of cardiovascular events over time [11]. The simplicity and clarity of single‐pill regimens are increasingly emphasized in international guidelines, with emerging data highlighting their potential to enhance secondary prevention outcomes and reduce healthcare utilization [12, 13].

In addition to adherence, pharmacoeconomic evaluations indicate that FDCs may reduce total healthcare costs, particularly in systems with high medication burden and limited patient engagement [9, 10, 14]. These advantages are amplified in chronic settings like CCS, where long‐term preventive strategies are vital.

Our data showed no statistically significant differences detected in the incidence of MACE, stent thrombosis, bleeding, or mortality at 1 month between the conventional and FDC groups. This reinforces the clinical equivalence of the two strategies. Moreover, the use of FDC tablets may offer several practical advantages:

• −Simplified drug administration for both patients and providers,
• −Reduced risk of dosing errors in emergency or high‐volume settings,
• −Potential improvement in patient adherence due to reduced pill burden and more intuitive regimens.

A growing body of evidence also supports the safety profile of FDCs in cardiovascular interventions. A recent systematic review and meta‐analysis by Mohamed et al. emphasized the comparable safety of FDCs in antiplatelet therapy, with no increased risk of major bleeding [15, 16].

Another relevant consideration is the pharmacokinetic stability and bioequivalence of FDC tablets. Studies in both Asian and Western populations have shown consistent absorption profiles, reinforcing their reliability for clinical use [17, 18].

Our study specifically evaluates the loading phase and 30‐day outcomes. Longer‐term outcomes of fixed‐dose ASA/clopidogrel combinations have been explored elsewhere [19]. While our results are encouraging, future studies should consider broader inclusion criteria. Most existing research—including our own—is limited to relatively stable CCS populations. There is a need for data on high‐risk groups, such as elderly patients, those with diabetes, or individuals undergoing complex interventions. Furthermore, the role of FDCs in acute coronary syndromes and their interaction with newer P2Y12 inhibitors warrant exploration [20, 21].

Our findings contribute to the growing body of evidence supporting fixed‐dose antiplatelet strategies. While traditionally reserved for maintenance therapy, our results suggest that FDCs may also be feasible as a loading strategy, offering logistical and clinical advantages without compromising safety or efficacy.

5. Limitation

Despite these promising findings, certain limitations must be acknowledged. First, the study design was observational and not randomized, introducing potential selection bias. Second, the relatively small number of patients in the FDC group may limit the power to detect rare adverse events. Third, the follow‐up period was limited to 1 month. Platelet function testing was not performed, which could have provided mechanistic insights into the equivalence of the two strategies.

Lastly, it should be noted that the cost‐effectiveness and adherence benefits discussed here are extrapolated from prior literature and were not directly measured in the present study [9, 10]. These points should not be considered as primary findings from our data set.

6. Conclusion

This study provides preliminary evidence that a FDC of clopidogrel and acetylsalicylic acid (75 mg/75 mg × 4 tablets) is a safe and effective alternative to conventional loading doses in patients with CCS undergoing elective PCI. One‐month clinical outcomes—including stent thrombosis, MACE, bleeding, and mortality—were similar between groups, suggesting comparability of the FDC approach.

Given its potential advantages in terms of ease of administration, patient adherence, and simplification of treatment protocols, the use of fixed‐dose loading regimens may be considered as a practical and clinically equivalent strategy in routine care.

However, further large‐scale, randomized controlled trials with extended follow‐up and platelet function testing are warranted to confirm these findings and to determine the role of FDCs in broader patient populations, including those with acute coronary syndromes.

Ethics Statement

Local Non‐Invasive Clinical Ethics Committee (Decision No. 2023/1165, date: 13.09.2023) approved the study that was designed in conformity with the Helsinki Declaration. Written and verbal informed consent was obtained from all patients in this study.

Consent

All authors gave their consent for the publication of this manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Başkurt A. A., Şenöz O., Demir Y., et al., “Comparison of Fixed‐Dose Clopidogrel/Asetylsalicylic Acid Combination and Standard Loading Strategy During Percutaneous Coronary Intervention in Chronic Coronary Syndrome,” Catheterization and Cardiovascular Interventions 106 (2025): 2825‐2830, 10.1002/ccd.70136.

Data Availability Statement

The data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.