Prevalence of clopidogrel resistance in patients with atrial fibrillation undergoing percutaneous coronary intervention

Mikołaj Błaziak; Oscar Rakotoarison; Bartosz Balcer; Natalia Dolata; Weronika Wietrzyk; Wiktor Kuliczkowski

doi:10.5114/aic.2025.151854

Introduction

Atrial fibrillation (AF) is the most prevalent arrhythmia, with an estimated prevalence of 2–4% among adults, a figure that is expected to rise in the future [1]. The PREFER in AF registry indicates that among patients with AF, the prevalence of coronary artery disease (CAD), prior percutaneous coronary intervention (PCI), and previous acute coronary syndrome (ACS) is 23.4%, 10.2%, and 10.7%, respectively [2]. For patients with AF who have undergone PCI, current guidelines recommend a combination of oral anticoagulation therapy and a P2Y12 inhibitor [1]. Clopidogrel is considered the first-line P2Y12 inhibitor for this indication. However, an insufficient response to clopidogrel has been identified as a significant risk factor for adverse clinical outcomes, including myocardial ischemia and thromboembolic events [3]. Recent studies have demonstrated substantial variability in clopidogrel response, influenced by factors such as population characteristics, definitions, and methods of assessment. Cytochrome P450 2C19 (CYP2C19) plays a pivotal role in the bioactivation of clopidogrel, converting it from its prodrug form to its active metabolite. Variations in the CYP2C19 genotype have been implicated in the observed variability in clopidogrel efficacy. The prevalence of clopidogrel resistance (CR) among patients with CAD is reported to range between 5% and 31% [4, 5]. In patients with AF receiving anticoagulation therapy with clopidogrel, coexisting CR is associated with an elevated risk of ischemic complications and poor clinical outcomes. The prevalence of CR in patients with AF undergoing PCI has not been extensively studied.

Aim

The aim of this study was to determine the prevalence of CR in patients with AF after PCI and to evaluate the influence of CYP2C19 genetic polymorphisms on clopidogrel-mediated platelet inhibition in this group of patients.

Material and methods

Consecutive patients admitted to the Cardiology Department at Wroclaw University Hospital were screened for eligibility. The study was approved by the ethics committee at Wroclaw Medical University. The inclusion criteria were: (1) diagnosis of AF, (2) CAD managed with PCI, and (3) indication for clopidogrel therapy. Patients underwent PCI and received a loading dose of 600 mg of clopidogrel immediately afterward. Clopidogrel response was assessed 24 h after PCI using adenosine diphosphate (ADP)-induced platelet aggregation measured by impedance aggregometry (Multiplate Analyzer, Roche Diagnostics). Impedance changes were recorded for 6 min, with duplicate measurements performed for each patient. Results were expressed as the area under the aggregation curve (AUC), and these values were compared to established reference ranges for healthy individuals. AUC values exceeding 46 AU were classified as indicative of an insufficient response to clopidogrel. Patients identified as clopidogrel non-responders underwent genetic testing for CYP2C19 isoenzyme polymorphisms. The biological material for genetic testing was obtained from the oral mucosa, and the analysis was conducted using an in vitro diagnostic kit.

Statistical analysis

The data were rigorously analyzed, employing the median with interquartile range (IQR), frequency (percentage), or mean with standard deviation, depending on the distribution of variables. Categorical variables were assessed using Pearson’s χ² test for independence or Fisher’s exact test. Statistical significance was set at p < 0.05. All statistical analyses were performed using Statistica version 13.3. Informed consent was obtained from all participants.

Results

Finally, 123 patients were screened, of whom 6 (4.8%) were identified as clopidogrel non-responders. In the non-CR group, the mean age was 73 ±9.4 years, with 72.6% of participants being male. PCI was performed due to CCS in 52.1% of cases and due to ACS in 47.8%. Diabetes mellitus was present in 42.7% of individuals, and 27.3% had kidney failure. The median hemoglobin level was 13 g/dl (IQR: 11–14), and the median platelet count was 195.5 × 10⁹/l (IQR 145.5–236). In the CR group, the mean age was 78.5 ±12.1 years, with 83.3% of participants being male. PCI was performed due to CCS in 33.3% of cases and due to ACS in 66.7%. Diabetes mellitus was present in 83.3% of individuals, and 16.7% had kidney failure. The median hemoglobin level was 15 g/dl (IQR: 13–16), and the median platelet count was 225.5 × 10⁹/l (IQR: 199–259). Clinical characteristics of the CR and non-CR patients are shown in Table I. Among CR patients, genetic profiles of the CYP2C19 isoenzyme showed two types of allele, CYP2C191/1 and CYP2C191/2. The statistical analysis was performed in Statistica 13.3.

Table I

Baseline characteristics

Parameter	Non-CR, n = 117	CR, n = 6	P-value
Age, mean ± SD	73 ±9.4	78.5 ±12.1	0.56
Sex, male, n (%)	85 (73)	5 (83)	0.49
Indication to PCI, n (%):			0.25
CCS	61 (52)	2 (33)
ACS	56 (48)	4 (67)
Hypertension, n (%)	107 (92)	6 (100)	0.55
Diabetes, n (%)	50 (43)	5 (83)	< 0.001
Heart failure, n (%)	68 (58)	4 (67)	0.71
LVEF, median (IQR)	50.5 (40–60)	49 (40–52)	0.47
Kidney failure, n (%)	32 (27)	1 (17)	0.49
PCI of vessel, n (%):			0.41
LM	3 (3)	0 (0)
LAD	58 (50)	2 (33)
CX	23 (20)	2 (33)
RCA	33 (28)	2 (33)
Hemoglobin, median (IQR)	13 (11–14)	15 (13–16)	0.62
Platelet, median (IQR)	195.5 (146–236)	225.5 (199–259)	0.61

[i] CR – clopidogrel resistance, PCI – percutaneous coronary intervention, LVEF – left ventricular ejection fraction, CCS – chronic coronary syndrome, ACS – acute coronary syndrome.

Discussion

The absence of standardized definitions and thresholds for CR presents significant challenges in its assessment and interpretation. Variability in criteria among studies can lead to inconsistent conclusions. Many studies define clopidogrel non-responders based on a less than 10% reduction in ADP-induced platelet aggregation compared to baseline following clopidogrel administration. Other definitions include maximal ADP-induced platelet aggregation exceeding 50% [6] platelet reaction units (PRU) greater than 208 [7] or inhibition of platelet aggregation below 30% [8]. Furthermore, the ADP concentration used to induce platelet aggregation varies across studies, typically ranging from 5 to 20 µmol/l. Clopidogrel loading doses also differ, spanning from 75 mg [7] to 600 mg [9]. In our study, we defined CR using 6.5 µmol/l ADP-induced platelet aggregation, with an AUC value greater than 46 considered indicative of resistance.

Several clinical factors have been identified as potential predictors of clopidogrel resistance, including obesity, diabetes, and hyperuricemia [10]. One plausible mechanism an underlying insufficient response to clopidogrel is genetic polymorphism in cytochrome P450 enzymes, which are crucial for the bioactivation of clopidogrel [11]. In our cohort, genotyping revealed that patients with CR carried the CYP2C191/1 and CYP2C191/2 alleles. The CYP2C191/1 allele represents the wild-type genotype associated with full enzymatic function and extensive metabolism. However, as noted by Correll et al., even patients with the wild-type genotype may exhibit poor metabolic activity [12]. The CYP2C191/2 allele, on the other hand, is a common loss-of-function variant linked to reduced clopidogrel bioactivation and diminished therapeutic response.

Data on the prevalence of C among patients with AF undergoing PCI are limited. Zhang et al. reported that in a cohort of 80 patients, 50% were classified as poor clopidogrel metabolizers based on their CYP2C19 genotype [13]. In contrast, our findings differ from many prior studies that suggest a higher prevalence of CR in patients with CAD. Notably, Müller et al. reported a CR prevalence of 5% in CAD patients, assessed using ADP-induced platelet aggregation (5 µmol/l) 4 h after a 600 mg loading dose of clopidogrel [4]. Similarly, Snoep et al. demonstrated that a 600 mg loading dose of clopidogrel can overcome resistance more effectively than lower doses [14]. This might explain the relatively low rate of CR observed in our study. Furthermore, many studies reporting higher CR prevalence were conducted in Asian populations. A recent meta-analysis highlighted significant ethnic variability in response to clopidogrel, indicating that genetic and demographic factors strongly influence the prevalence of CR [15].

The available evidence on CR prevalence in this cohort remains sparse and inconsistent. Our findings suggest that the incidence of insufficient antiplatelet effects in the AF population within the Polish setting may be lower than previously reported in earlier studies, and a higher clopidogrel loading dose could probably mitigate CR. Routine platelet function testing is not currently recommended by clinical guidelines; however, it may be considered in patients experiencing recurrent ischemic events following PCI during clopidogrel therapy. However, further well-designed studies are required to accurately determine the true prevalence of CR among patients with AF and CAD. To achieve reliable and comparable results, the development of a unified definition of CR and standardized testing protocols is needed.

This study has several limitations. First, the sample size of individuals exhibiting clopidogrel resistance was relatively small. Second, we did not conduct follow-up assessments of clopidogrel non-responders, which may have restricted our ability to evaluate the long-term clinical implications of resistance.

Ethical approval

Approval number: KB 53/2021.

Conflict of interest

The authors declare no conflict of interest.

References

Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021; 42: 373–498.

Kirchhof P, Ammentorp B, Darius H, et al. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention of thromboemolic events-European Registry in Atrial Fibrillation (PREFER in AF). Europace 2014; 16: 6–14.

Wang L, Wang X, Chen F. Clopidogrel resistance is associated with long-term thrombotic events in patients implanted with drug-eluting stents. Drugs R D 2010; 10: 219–24.

Müller I, Besta F, Schulz C, et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783–87.

Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908–13.

Zhang L, Chen Y, Jin Y, et al. Genetic determinants of high on-treatment platelet reactivity in clopidogrel treated Chinese patients. Thromb Res 2013; 132: 81–7.

Saydam F, Değirmenci İ, Birdane A, et al. The CYP2C19*2 and CYP2C19*17 polymorphisms play a vital role in clopidogrel responsiveness after percutaneous coronary intervention: a pharmacogenomics study. Basic Clin Pharmacol Toxicol 2017; 121: 29–36.

Zhuo ZL, Xian HP, Long Y, et al. Association between cyp2c19 and abcb1 polymorphisms and clopidogrel resistance in clopidogrel-treated Chinese patients. Anatol J Cardiol 2018; 19: 123–9.

Amin AM, Sheau Chin L, Mohamed Noor DA, et al. The effect of CYP2C19 genetic polymorphism and non-genetic factors on clopidogrel platelets inhibition in East Asian coronary artery disease patients. Thromb Res 2017; 158: 22–4.

Wu ZK, Wang JJ, Wang T, et al. Clopidogrel resistance response in patients with coronary artery disease and metabolic syndrome: the role of hyperglycemia and obesity. J Geriatr Cardiol 2015; 12: 378–82.

Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. Curr Atheroscler Rep 2009; 11: 157–60.

Correll M, Johnson CK, Ferrari G, et al. Mutational analysis clopidogrel resistance and platelet function in patients scheduled for coronary artery bypass grafting. Genomics 2013; 101: 313–7.

Zhang Q, Zhong Z, Li B, et al. Effects of different CYP2C19 genotypes on prognosis of patients complicated with atrial fibrillation taking clopidogrel after PCI. Exp Ther Med 2018; 16: 3492–6.

Snoep JD, Hovens MM, Eikenboom JC, et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J 2007; 154: 221–31.

Jafrin S, Naznin NE, Reza MS, et al. Risk of stroke in CYP2C19 LoF polymorphism carrier coronary artery disease patients undergoing clopidogrel therapy: an ethnicity-based updated meta-analysis. Eur J Intern Med 2021; 90: 49–65.