Abstract
Objective
The effect of aspirin and clopidogrel is not uniform in all patients due to drug resistance. The study was designed to evaluate the prevalence of aspirin and clopidogrel resistance and its association with various risk factors in stable CAD patients.
Methods
Total 151 clinically stable CAD patients taking either aspirin and/or clopidogrel were recruited in this prospective cohort study. Platelet function testing was performed using light transmittance platelet aggregometry. All the patients were prospectively followed up to detect any MACE (death, non-fatal MI, stroke, revascularization), worsening angina and bleeding from any site.
Results
Total 11 (7.28%) patients showed complete resistance to aspirin, and an additional 35 (23.18%) patients showed semi-resistance. For clopidogrel, 44 (29.2%) and 11 (7.6%) patients had complete and semi-resistance, respectively. The prevalence of dual antiplatelet resistance was 7.6%. In univariate regression analysis, diabetes mellitus [OR 2.2 (95%CI 1.1-4.4); p=0.03] and clopidogrel resistance [OR 20.2 (8-50.7); p<0.01] showed significant association with aspirin resistance. The parameters significantly associated with clopidogrel resistance were – hemoglobin level [OR 0.8 (0.7-1); p=0.03], erythrocyte sedimentation rate [OR 1 (1-1.1); p=0.04], family history of CAD [OR 5.1 (1.5-17.1); p=0.01] and aspirin resistance [OR 20.2 (8.0-50.7); p<0.01]. In multivariable analysis, apart from the significant association between aspirin and clopidogrel resistance, family history of CAD was the only independent predictor of clopidogrel resistance. The study was underpowered to detect any meaningful effect on MACE due to low event rate.
Conclusion
In our study high prevalence of aspirin and clopidogrel resistance was detected. Although aspirin and clopidogrel resistance showed significant association with clinical risk factors, their association with MACE was inconclusive.
Keywords: Aspirin resistance, Clopidogrel resistance, Coronary artery disease, Light transmittance platelet aggregometry, Risk factors, Adverse outcomes
1. Introduction
Antiplatelet therapy with aspirin and clopidogrel is one of the essential pharmacological therapies administered to coronary artery disease (CAD) patients to block platelet reactivity and recurrent ischemic events. However, the therapeutic effect of aspirin and clopidogrel is not uniform in all patients because of drug resistance.1,2 The aspirin and clopidogrel resistance and their significance in cardiovascular disease (CVD) are one of the highly discussed topics in modern cardiology. Extensive research work has been conducted in the last decade to decode its mystery, especially in developed countries, but still, there are many disagreements in this subject. Moreover, the characteristics of cardiovascular diseases in the Indian population are different in many aspects from the rest of the world due to different lifestyle, socio-economic, environmental, and genetic factors. The cardiovascular disease risk is higher in the native and migrant Indians in comparison to other ethnic groups. The Indians, like the rest of the South-Asian population, have a higher risk of type 2 diabetes, dyslipidemia, body fat, and increased abdominal obesity, which partially explains the relatively high cardiovascular disease burden as well as cardiovascular morbidity and mortality.3 So, the antiplatelet resistance pattern and its effect on Indian patients with coronary artery disease may not be the same as the western populations. Though the major CVD guidelines have given recommendations against the routine use of antiplatelet resistance test in day-to-day practice, that statement needs an extensive evaluation in our population.4, 5, 6 Several research groups have conducted studies to assess the extent of aspirin and clopidogrel resistance in different parts of India7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, but still, the database is scarce in comparison to the western literature. This study has been designed to assess the prevalence of aspirin and clopidogrel resistance in stable CAD patients and to clarify their association with conventional clinical risk factors and adverse events.
2. Methods
2.1. Study design
The study was a prospective cohort study to assess the prevalence of aspirin and clopidogrel resistance in stable coronary artery disease patients. The other objectives were to identify various clinical and demographic factors as predictors of aspirin and clopidogrel resistance and evaluate the association of antiplatelet resistance with adverse outcomes. The patient recruitment was started in October 2016 and completed in July 2018. The study was approved by the institutional ethical committee.
2.2. Study population
The participants were screened from the patients attending the cardiology outpatient clinic and inpatient ward of the All India Institute of Medical Sciences, New Delhi. Stable patients with confirmed coronary artery disease taking a fixed dose of either aspirin (75-150 mg) or clopidogrel (75-150 mg) or a combination of both antiplatelets for at least seven days were included in the study. Written consent to participate in the trial was obtained from all the participants. The exclusion criteria were a history of significant bleeding, stroke, transient ischemic attack, platelet count <100x109/L or >450x109/L, non-coronary indication for aspirin, or clopidogrel (renal/carotid stenting), NSAIDS intake in last seven days and intolerance to aspirin or clopidogrel. Patients were also excluded if they were taking other antiplatelet medications (like prasugrel, ticagrelor) and were not willing to participate in the study.
2.3. Patient assessment and recruitment
All the potential candidates were questioned about coronary risk factors, medications they are taking, history of chronic stable angina, past history of unstable angina (UA), non-ST elevation myocardial ischemia (NSTEMI), ST-segment elevation myocardial ischemia (STEMI), and percutaneous coronary intervention (PCI) with stenting. Their left ventricular functional status and coronary angiography reports were recorded. All the demographic information, including residential addresses and phone numbers, was recorded in a structured proforma. Routine investigations like blood for complete blood count, liver function test, renal function test, fasting lipid profile, and fasting sugar level were sent for every patient. The standard definition of acute coronary syndromes (ACS), as defined by the latest ACC/AHA Guideline, was used in the study. The patients were managed according to the current guidelines.6,21,22
2.4. Definition and assessment of antiplatelet resistance
Platelet aggregation test was done on fasting venous blood samples collected in citrate anticoagulant and was done within 1-2 h of sample collection using Light Transmittance Platelet Aggregometer (LTA, Platelet Aggregation Profiler-8E, Biodata Corporation, USA). Complete aspirin resistance was characterized by platelet aggregation of 70% or greater in response to 10 μM adenosine diphosphate (ADP), as well as aggregation of at least 20% with 0.75 mM arachidonic acid. Meeting any of these criteria is indicative of aspirin semi-resistance. Complete clopidogrel resistance was defined as a <10% change in platelet aggregation from baseline after adding 10 μM ADP. Whereas a <30% (10–29%) change in platelet aggregation from baseline was regarded as clopidogrel semi-resistance.7, 13 To define the baseline range of platelet aggregation with ADP and to define the cut-off value for clopidogrel resistance and semi-resistance, ten healthy control subjects were recruited at the start of the study. Healthy control subjects with no history of hypertension, diabetes, dyslipidemia, alcoholism, smoking, renal failure, coronary artery disease, or family history of CAD were recruited in the trial. Patients diagnosed with coronary artery disease, including a considerable number who experienced a recent acute coronary syndrome, were enrolled in our study. In accordance with standard clinical protocols, many participants received parenteral heparin. Recognizing the substantial impact of parenteral heparin on platelet aggregation assays, an appropriate washout period was implemented before collecting blood samples to assess platelet function. Furthermore, the interval between clopidogrel administration and blood sampling may affect Light Transmittance Aggregometry (LTA) outcomes. To address this variable, all participants in our study underwent blood collection 2–4 h after antiplatelet medication intake. Additionally, each patient was on a maintenance dose of antiplatelet medications for secondary prevention of coronary artery disease (CAD).
2.5. Outcome measures
The primary outcome measure was major adverse cardiovascular event (MACE), i.e., composite of all-cause mortality, non-fatal acute coronary syndromes (STEMI/NSTEMI/UA), stroke, revascularization. The secondary outcome measures were all-cause mortality, non-fatal ACS, stroke, revascularization, and increasing angina. The safety outcome was bleeding from any site.
2.6. Follow-up
The patients were followed up prospectively to find out any adverse event. Follow up was done by telephonic contact during the 3rd and 9th month and by outpatient visit during the 6th and 12th month.
2.7. Statistical analysis
The statistical determination of the sample size was performed by anticipating clopidogrel resistance prevalence as 25% and a precision level of 5% with a 95% confidence level. This provided us with a sample size of 288 individuals. However, due to the operational reason, i.e., scarcity in terms of manpower and resource, we could recruit one hundred fifty patients with at least half patients having a history of ACS in the study.
The analysis was performed using the licensed SPSS statistical software (IBM Corp, Released 2012, Version 21.0. Armonk, NY). The quantitative variables were summarized through descriptive statistics, i.e., mean [standard deviation (SD)] and median (inter-quartile range). The association with the anti-platelet resistance was tested using student t-test. The categorical variables were summarized through frequency (%), and their association with the anti-platelet resistance was assessed through Chi-Square/Fisher Exact Test. The association of anti-platelet resistance with various significant risk parameters and adverse outcomes was tested through binary logistic regression analysis. The two-sided p ≤ 0.05 was considered statistically significant.
3. Results
3.1. Patient screening and recruitment
A total of 198 stable patients with CAD were screened for the study (Supplementary Material; Fig. S1). Among them total 47 patients were excluded as 44 patients were lost to follow up, and three patients had a platelet count of less than 100,000/dL in whom aggregation test could not be done.
3.2. Patient characteristics
The baseline characteristics of the study population are shown in Table 1. The mean age of the study population was 55.1 years, with a male-to-female ratio of 5:1. Among the CAD risk factors, dyslipidemia was most common. A Total of 40 (26.5%) patients had a history of chronic stable angina, and they were recruited during their OPD visit. Rest 111 (73.5%) patients presented with an acute coronary event. They were recruited in the study after hemodynamic stabilization with guideline-directed therapy. Most of these patients (87.4%) presented with STEMI, and among them, 84.7% of patients underwent PCI (primary PCI/early PCI for NSTEMI or UA).
Table 1.
Baseline characteristics of the study population.
| Baseline Characteristics | N (%) |
|---|---|
| Sex | |
| Male | 126 (83.4) |
| Female | 25 (16.6) |
| Mean Age (Years) | 55.1 |
| Male | 55.5 |
| Female | 58.5 |
| Diabetic | 56 (37.1) |
| Hypertensive | 62 (41.1) |
| Smoker | 82 (54.3) |
| Tobacco Chewer | 19 (12.6) |
| Dyslipidemia | 110 (72.8) |
| Positive Family History | 15 (9.9) |
| Chronic Stable Angina | 40 (26.5) |
| Past History of ACS Present | 21 (52.5) |
| Past History of PCI Present (Elective/Emergency) | 18 (45) |
| Acute Coronary Syndrome | 111 (73.5) |
| STEMI | 97 (87.4) |
| NSTEMI | 10 (9.0) |
| UA | 4 (3.6) |
| Post PCI [ Primary/Early (for NSTEMI or UA)] | 94 (84.7) |
| Medicine Pattern | |
| Antiplatelets | 151 (100) |
| Aspirin | 151 (100) |
| Clopidogrel | 144 (95.4) |
| DAPT (Aspirin + Clopidogrel) | 144 (95.4) |
| ACEI or ARB | 142 (94) |
| Beta-blockers | 128 (84.8) |
| Nitrates | 110 (72.8) |
| Statins | 151 (100) |
| Diuretics | 40 (26.5) |
| Spironolactone | 33 (21.8) |
ACS= Acute coronary syndrome, PCI= Percutaneous coronary intervention, Non-ST segment elevation myocardial ischemia, UA= Unstable angina, DAPT = Dual antiplatelet, ACEI = Angiotensin converting enzyme inhibitor, ARB = Angiotensin receptor blocker.
3.3. Antiplatelet resistance prevalence
The mean platelet aggregation of the healthy subjects with 10 μM ADP was 61.9%. According to the definition, the cut-off platelet aggregation value for complete clopidogrel resistance was calculated as >55.6%. The cut-off value for defining clopidogrel semi-resistance was calculated as 43.3-55.6%. Accordingly, the prevalence of aspirin and clopidogrel resistance was calculated (Fig. 1, Fig. 2).
Fig. 1.
Antiplatelet drug resistance prevalence in stable coronary artery disease patients. DAPT = dual antiplatelet.
Fig. 2.
Platelet aggregation patterns by Light Transmittance Platelet Aggregometry (LTE) in the study populations. AA = Arachidonic acid, ADP = Adenosine di-phosphate.
3.4. Risk factors with anti-platelet drug resistance
All the patients with complete aspirin resistance also had complete clopidogrel resistance (Fig. 2 and Table 2, Table 3), and clopidogrel resistance (semi and complete) was significantly [Odd Ratio (OR) 20.2 {95% Confidence Interval (CI) 8-50.7}; p=<0.01] associated with aspirin resistance (semi and complete). Among the well-known conventional risk factors, diabetes showed a significant association with aspirin resistance [OR 2.2 (95% CI 1.1-4.4); p = 0.03] in the univariate binary logistic analysis, but the association was insignificant under multivariable analysis (Table 2, Table 3). Other risk factors like age, gender, hypertension, dyslipidemia, smoking did not show any statistical significance. Among the investigational parameters, the HbA1C level was significantly higher in the aspirin resistance group (Table 2). However, it did not show statistical significance in the logistic regression analysis [OR 1.2 (95% CI 1-1.4); p = 0.06].
Table 2.
Various clinical and investigational parameters as predictor of clopidogrel resistance (Both total resistance and semi-resistance) and aspirin resistance in stable CAD patients.
| Descriptive Parameters | Aspirin |
Clopidogrel |
||||
|---|---|---|---|---|---|---|
| Responder [n = 105] (%) |
Resistance [n = 46] (%) |
p value (2-sided) |
Responder [n = 91] (%) | Resistance [n = 53] (%) |
p value (2 sided) |
|
| Male Sex | 90 (85.7) | 36 (78.3) | 0.34 | 79 (86.8) | 40 (75.5) | 0.07 |
| Female Sex | 15 (14.3) | 10 (21.7) | 12 (13.2) | 13 (24.5) | ||
| Diabetes | 33 (31.4) | 23 (50) | 0.04 | 29 (31.9) | 24 (45.3) | 0.08 |
| Hypertension | 40 (38.1) | 22 (47.8) | 0.29 | 34 (37.4) | 26 (49.1) | 0.12 |
| Dyslipidemia | 75 (71.4) | 35 (76.1) | 0.69 | 63 (69.2) | 41 (77.4) | 0.20 |
| Positive Family History | 9 (8.6) | 6 (13) | 0.39 | 4 (4.4) | 10 (18.9) | 0.01 |
| Smoking | 61 (58.1) | 21 (45.6) | 0.21 | 53 (58.2) | 28 (52.8) | 0.32 |
| Tobacco Chewer | 13 (12.4) | 6 (13) | 0.99 | 11 (12.1) | 7 (13.2) | 0.52 |
| Chronic Stable Angina | 26 (24.8) | 14 (30.4) | 0.55 | 20 (22) | 13 (24.5) | 0.44 |
| Acute Coronary Syndrome | 79 (75.2) | 32 (69.6) | 0.55 | 71 (78) | 40 (75.5) | 0.44 |
| Clopidogrel resistance | 18 (17.8) | 35 (81.4) | <0.01 | - | - | - |
| Aspirin resistance | - | - | - | 8 (8.8) | 35 (66) | <0.01 |
|
Continuous Parameters |
Aspirin | Clopidogrel | ||||
|
Responder (Mean [± SD]) |
Resistance (Mean [± SD]) |
p va (2 sided) |
Responder (Mean [± SD]) |
Resistance (Mean [± SD]) |
p (2 sided) |
|
| Age (Years) | 54.4 (10.5) | 56.8 (10) | 0.19 | 53.4 (10.2) | 56.8 (10.4) | 0.56 |
| Hb (g/dl) | 13.5 (2) | 13.3 (1.9) | 0.62 | 13.7 (1.9) | 12.9 (2.1) | 0.02 |
| TLC (/mm3) ∗ | 76.2 (8001.5) # |
75.5 (3474.5) # |
0.93 (2393.50) ^ |
75.3 (6851.5)# |
67.7 (3588.5)# |
0.29 (2157.50) ^ |
| Platelet (/mm3) ∗ | 78.6 (8257.5) # |
69.9 (3218.5) # |
0.26 (2137.50) ^ |
75.8 (6896) # |
66.9 (3544) # |
0.22 (2113.00) ^ |
| Urea (mg/dl) | 28.9 (12.2) | 31.1 (16.1) | 0.37 | 28.4 (12.7) | 31.9 (14.8) | 0.14 |
| Creatinine (mg/dl) | 0.8 (0.3) | 0.8 (0.4) | 0.64 | 0.8 (0.2) | 0.8 (0.4) | 0.58 |
| Total Bilirubin (mg/dl) | 0.9 (0.5) | 0.8 (0.4) | 0.11 | 0.9 (0.5) | 0.8 (0.5) | 0.15 |
| Direct Bilirubin (mg/dl) | 0.2 (0.2) | 0.2 (0.1) | 0.23 | 0.2 (0.2) | 0.2 (0.1) | 0.13 |
| SGOT (IU) | 83.2 (91) | 77.5 (76.5) | 0.71 | 84.9 (94.6) | 82.6 (75.7) | 0.87 |
| SGPT (IU) | 124.5 (169.6) | 87.4 (156.3) | 0.21 | 132.3 (175.9) | 90.30 (154.6) | 0.15 |
| Total Cholesterol (mg/dl) | 146.9 (36.3) | 139.8 (39.2) | 0.28 | 146.4 (36.7) | 143.7 (38.9) | 0.68 |
| LDL (mg/dl) | 95.8 (31.5) | 89.1 (30.1) | 0.22 | 96.7 (31.9) | 90.6 (29.6) | 0.25 |
| HDL (mg/dl) | 37.7 (9) | 35.1 (8.2) | 0.97 | 37.7 (9.4) | 35.8 (8.1) | 0.20 |
| VLDL (mg/dl) | 15.7 (6.3) | 15.6 (5.8) | 0.10 | 15.4 (6.3) | 15.7 (6.1) | 0.79 |
| Triglyceride (mg/dl) | 121.2 (59) | 141.3 (77.7) | 0.12 | 125.9 (68.8) | 132.1 (63.4) | 0.60 |
| ESR (mm/1st hr) | 20 (9.8) | 22.5 (8.7) | 0.15 | 19.3 (8.9) | 22.8 (10.1) | 0.03 |
| CRP (mg/l) | 25.1 (32.2) | 25.8 (22.4) | 0.90 | 26.6 (35.1) | 26.1 (17.2) | 0.89 |
| HbA1C (%) | 6.7 (2) | 7.3 (1.8) | 0.05 | 6.8 (2.1) | 7.2 (1.7) | 0.23 |
Bold values depict significant parameters (p ≤ 0.05); ∗ Non-parametric Analysis, # Mean Rank (Sum of Ranks), ^P value (Mann–Whitney U).
SD = standard deviation, LDL = Low density lipoproteins, HDL= High density lipoproteins, VLDL= Very low-density lipoproteins, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, Hb = Hemoglobin, TLC = Total leucocyte count.
Table 3.
Association of significant risk factors with aspirin and clopidogrel resistance (Logistic regression analysis) in stable CAD patients.
| Predictors of aspirin resistance | ||||||
|---|---|---|---|---|---|---|
| Risk Factors | Univariate logistic regression analysis (n = 151) |
Multivariate logistic regression analysis (n = 144) |
||||
| Odd ratio (± SD) | p value | Odd ratio (± SD) | p value | |||
| Diabetes | 2.2 (1.1–4.4) | 0.03 | 1.4 (0.5-3.8) | 0.52 | ||
| HbA1c | 1.2 (1-1.4) | 0.06 | 1.2 (0.9-1.5) | 0.23 | ||
| VLDL | 1 (0.9-1.1) | 0.96 | 1 (0.9-1.1) | 0.60 | ||
| Clopidogrel resistance | 20.2 (8–50.7) | <0.01 | 20.2 (7.9–51.9) | <0.01 | ||
| Predictors of clopidogrel resistance | ||||||
| Risk Factors |
Univariate logistic regression analysis (n= 144) |
Multivariate logistic regression analysis (n=144) |
||||
|
Odd ratio (± SD) |
p value |
Odd ratio (± SD) |
p value |
|||
| Male sex | 2.1 (0.9-5.1) | 0.88 | 1.1 (0.3-4) | 0.88 | ||
| Family history of CAD | 5.1 (1.5–17.1) | 0.01 | 5.9 (1.4–25.8) | 0.02 | ||
| Diabetes | 1.8 (0.9-3.6) | 0.11 | 1 (0.4-2.8) | 0.93 | ||
| Hemoglobin | 0.8 (0.7–1) | 0.03 | 0.8 (0.6-1) | 0.09 | ||
| ESR | 1 (1–1.1) | 0.03 | 1 (1-1.1) | 0.52 | ||
| Aspirin resistance | 20.2 (8–50.7) | <0.01 | 26.8 (9.4–76.2) | <0.01 | ||
Bold values depict significant parameters (p ≤ 0.05).
CAD= Coronary artery disease, ESR= Erythrocyte sedimentation rate, CI= Confidence interval, VLDL= Very low-density lipoprotein.
For clopidogrel, positive family history of CAD [OR 5.9 (95% CI 1.4-25.8); p = 0.02] and aspirin resistance [OR 26.8 (95% CI 9.4-76.2); P=<0.01] showed significant association in the multivariate logistic regression analysis (Table 2, Table 3). Among the other parameters, the mean (±SD) hemoglobin level in the clopidogrel resistance vs. responder group was 12.9 (±2.1) g/dl and 13.7 (±1.9) g/dl, respectively. Higher hemoglobin level was significantly associated with decreased risk of clopidogrel resistance in the univariate logistic regression analysis [OR 0.8 (95% CI 0.7-1); p = 0.03]. Apart from the hemoglobin level, the erythrocyte sedimentation rate (ESR) was also significantly higher in the clopidogrel resistance arm in comparison to the clopidogrel responder arm [OR 1 (95% CI 1-1.1); p = 0.04]. However, both hemoglobin levels and ESR did not show statistical significance in multivariate regression analysis. Rest of the demographic and investigational parameters did not show any statistically significant association with clopidogrel resistance.
3.5. Adverse outcomes
All patients were followed up prospectively for a minimum of five months to a maximum of 20 months (mean = 13.4 months), depending on their date of recruitment in the study. MACE, the primary outcome measure, was achieved in total 14 (9.3%) patients and 11 (7.6%) patients receiving aspirin and clopidogrel respectively (Supplementary Materials; Table S1). The MACE rate was not significantly different between the aspirin (8.7% vs 9.5%, p = 0.57) and clopidogrel (5.7% vs 8.8%, p = 0.37) resistant and responder groups. However, because of the study's low event rate and brief follow-up period, it lacks sufficient power, so no meaningful conclusions can be made about the link between antiplatelet resistance and adverse events.
There was total of five deaths during the study period, and all of them did not have any anti-platelet resistance. One of them stopped most of his medications, including both anti-platelet drugs after four months of STEMI, which was managed initially with thrombolysis followed by angioplasty. Another patient had chronic stable angina with triple vessel disease. He got a late date for CABG before which he died due to STEMI and cardiogenic shock. Rest three patients were compliant with medication but succumb to chest pain followed by sudden cardiac death before getting treatment in the hospital. None of the patients had non-fatal STEMI and NSTEMI, but in the antiplatelet resistant group, one patient had unstable angina. A total of six patients underwent CABG due to triple vessel disease, and one patient underwent elective PCI for non-resolving angina despite optimum medical therapy. A total of six patients had an increase in angina severity during follow up, suggesting the progression of CAD despite guideline-directed medical therapy. Two of them underwent revascularization (one CABG and another PCI with stenting), and rest were managed with an escalation of antianginal drugs. Two patients had a history of minor bleeding from gum, which was managed conservatively without any change in antiplatelet doses. None of the patients in the DAPT resistance group suffered any adverse events in this study.
4. Discussion
There is significant heterogeneity in the reported prevalence of aspirin resistance in the literature ranging from 1% to over 60% depending upon the population studied.23 Different cut-offs for defining aspirin resistance, use of different tools for platelet function testing, heterogeneous genetic architectures of different ethnic populations are responsible for such a wide range in the reported prevalence. The aspirin resistance prevalence in our study was 30.5%. Among them, 7.3% of patients had complete aspirin resistance, and 23.2% of patients had partial aspirin resistance. A previous study conducted by Arya V et al,13 used similar criteria for defining aspirin resistance, but their reported prevalence of aspirin resistance was much lower than our study. The majority of the high-risk population in our study, as evidenced by a higher proportion of patients with a history of recent ACS, as well as higher frequencies of conventional risk factors like diabetes, smoking, family history, may have resulted in such a difference in the two studies. A study conducted by Sadiq PA et al,19 reported 2.1% complete aspirin resistance prevalence and 39.6% aspirin semi responder prevalence using the same criteria for defining aspirin resistance. Another previous study conducted in Maharashtra, India, which recruited stable CAD patients and used the same definition for aspirin resistance, reported a prevalence of 2% and 34% for complete aspirin resistance and semi resistance, respectively.17 Rest of the Indian studies have reported a wide range of prevalence rates ranging from 3.1% to 38.1% due to the usage of different tests and criteria for the diagnosis of aspirin resistance (Table 4).
Table 4.
Studies on antiplatelet resistance in Indian population with coronary artery disease.
| Reference [Year] |
Patient studied | Place | Dose (mg) | Assay (cut-off for resistance) |
Clinical outcome |
|---|---|---|---|---|---|
|
Sadiq PA et al. (19) 2005 |
Stable CAD (n = 50) |
Lucknow, Uttar Pradesh | Aspirin = 150 mg OD | LTA (Aspirin resistance = mean platelet aggregation of ≥70% with 10 μM ADP and a mean aggregation of ≥20% with 0.5 mg/mL A A Aspirin semi-resistance = Any of above criteria) |
Aspirin resistance = 2.08 % Aspirin semi-responders = 39.58 % Females tended to be more aspirin semi-responsive (p = 0.08) Other risk parameters were not associated with Aspirin resistance |
|
Kumar S et al. (7) 2007 |
ACS (n = 39) |
Lucknow, Uttar Pradesh | Clopidogrel: 300 mg bolus f/b 75 mg OD Aspirin: 325 mg OD |
LTA (Clopidogrel Resistance = <10% decrease from baseline in platelet aggregation with 10 μM ADP Clopidogrel semi-responder= <30% decrease from baseline) |
Clopidogrel resistant = 2.54% Clopidogrel semi-responder = 12.7% Females gender and high triglyceride level were significantly associated |
|
Mandikar H et al. (12) 2007 |
CAD or Stoke/TIA or PAD or multiple atherosclerotic risk factors (n = 130) |
Nagpur, Maharashtra | Aspirin = 150 mg OD | LTA (Aspirin hyporesponder = platelet aggregation value >2SD of mean with 0.5 mM AA) |
Aspirin resistance = 3.1% |
|
Guha S et al. (8) 2009 |
ACS (n = 144) |
Kolkata, West Bengal | Loading: Aspirin-325 mg Clopidogrel-300 mg Maintenance: Aspirin-150 mg Clopidogrel-75 mg |
LTA (NA) |
Aspirin resistance = 15.27% Clopidogrel resistance = 19.44% Dual = 12.5% |
|
Guha S et al. (10) 2009 |
ACS (n = 210) |
Kolkata, West Bengal | Loading: Aspirin-325 mg Clopidogrel-300 mg Maintenance: Aspirin-150 mg Clopidogrel-75 mg |
LTA (Aspirin and Clopidogrel resistance = ≥50% platelet aggregation with collagen and ADP respectively) |
Aspirin resistance = 35% Clopidogrel resistance = 72.5% Dual = 32.5% |
|
Thomson VS et al. (16) 2009 |
Stable CAD (n = 63) |
Vellore, Tamilnadu | Aspirin 75 mg | Urinary 11-Dehydro Thromboxane B2 Aspirin resistance = normalized urinary DTB2 level >67.9 ng/mmol of creatinine |
Aspirin resistance: 38.1% Elevated metabolite level (>320 pg/ml): high risk of vascular events at mean36 months of follow up |
|
Kar R et al. (18) 2012 |
Stable CAD (n = 100) |
Delhi, Delhi | Clopidogrel 75 mg ± aspirin | LTA (Clopidogrel Resistance = <10% decrease from baseline in platelet aggregation with 5 μM ADP Clopidogrel semi-responder= <30% decrease from baseline) |
Clopidogrel non responder: 13% Clopidogrel semi responder: 19% No association with P2Y12 polymorphism |
|
Paul R et al. (9) 2013 |
ACS (n = 94) |
Kolkata, West Bengal | Aspirin = 150 mg OD Clopidogrel = 75 mg OD |
LTA (Aspirin resistance= >50% platelet aggregation with 2 μM/mL collagen Clopidogrel resistance= >50% platelet aggregation with 10 μM ADP |
Aspirin resistance = 22% Clopidogrel resistance = 20.2% Significant association of Metabolic syndrome and serum fibrinogen level with antiplatelet resistance. CRP showed a strong correlation with Aspirin resistance |
|
Koshy SK et al. (20) 2014 |
Stable CAD (n = 100) |
Calicut, Kerala | Aspirin = 75-150 mg Clopidogrel = 75 mg |
Impact R device (Aspirin Resistance = With 0.32 mM AA <2.5% SC (Surface Covered) value. Clopidogrel Resistance = With 1.38 μM ADP <2.8% SC (Surface Covered) value. |
Aspirin resistance: 12% Clopidogrel resistance: 19% Dual: 10% |
|
Priyadarshini R et al. (15) 2014 |
CSA (n = 147) |
Puducherry | Clopidogrel = 75 mg | Impedance aggregometer (Clopidogrel resistance = platelet aggregation < 5Ω with 10 μM ADP by impedance aggregometry) |
Clopidogrel resistance = 33% Significant association with CYP 3A5∗3 polymorphism |
|
Chadha DS et al. (17) 2014 |
Stable CAD (n = 126) |
Pune, Maharashtra | Aspirin = 150 mg | LTA (Aspirin resistance = mean platelet aggregation of ≥70% with 10 μM ADP and a mean aggregation of ≥20% with 0.5 mg/mL AA Aspirin semi-resistance = Any of above criteria) |
Aspirin resistance = 2% Aspirin semi-responders = 34% |
|
Dalal JJ et al. (11) 2015 |
Post PCI (n = 539) |
Mumbai, Maharashtra | Aspirin, Clopidogrel, Ticagrelor, Prasugrel (doses NA) | Thromboelastography (Antiplatelet Resistance = mean platelet inhibition <50%) |
Clopidogrel resistance = 27.85% (Prasugrel resistance = 5.77% Ticagrelor resistance = 0.85%) |
|
Arya V et al. (13) 2015 |
Stable CAD (n = 72) |
Delhi, Delhi | Aspirin 75-150 mg Clopidogrel 75 mg |
LTA (Aspirin resistance = mean platelet aggregation of ≥70% with 10 μM ADP and a mean aggregation of ≥20% with 0.75 mg/mL AA Clopidogrel Resistance = <10% decrease from baseline in platelet aggregation with 10 μM ADP Clopidogrel semi-responder= <30% decrease from baseline) |
Clopidogrel non responder: 1.4% Clopidogrel semi responder: 50% Aspirin semi responder: 5.5% Aspirin resistance = nil Significant association with CYP2C19∗2 polymorphism |
Our study was also designed to evaluate the association of various conventional risk factors and investigational parameters with the anti-platelet resistance. Among the risk markers, clopidogrel resistance was the only independent predictor of aspirin resistance in our study. Whether this association was because of the similarity of the platelet aggregation criteria with ADP for defining aspirin and clopidogrel resistance or due to true biological interaction, need to be evaluated by further trials. History of diabetes was significant, although not an independent risk factor for aspirin resistance in this study. Poor efficiency of aspirin in diabetic patients is a well-known entity in the previous literature.24, 25, 26 One of the proposed hypothesis behind this association is that hyperglycemia may decrease the effectiveness of aspirin by increasing reactive oxidant species in the blood.27 Extensive protein glycation may also attenuate aspirin's ability to acetylate target platelet proteins in diabetic patients.28 Though other factors like hypertension, hypercholesterolemia, acute coronary syndrome have been shown to be associated with aspirin resistance in western population, they did not show statistical significance in our study.27,29 Regarding Indian data, most of the studies did not report any significant association of conventional clinical risk markers with aspirin resistance (Table 4).
The reported prevalence of clopidogrel resistance is heterogeneous in different studies conducted in the western population. In a systematic review, the clopidogrel resistance prevalence was reported to range from 5% to as high as 44%.30 In India, the cumulative prevalence of clopidogrel resistance, i.e., the combination of complete resistance and semi responder ranged from 15.2% to as high as 72.5% (Table 4). The difference in the study protocol, inclusion criteria, method for resistance testing, and definition for clopidogrel resistance are responsible for such a high variation in clopidogrel resistance prevalence rates in Indian as well as western population data. In our study, the prevalence of clopidogrel resistance in stable CAD patients was 36.8%, among which 29.2% of patients had complete resistance, and 7.6% of patients had semi resistance.
Among the risk factors, positive family history of CAD and aspirin resistance were significant and independent predictors of clopidogrel resistance in this study. None of the previous studies have described such a significant association between a positive family history of CAD and clopidogrel resistance. A common genetic mutation leading to both clopidogrel resistance and familial atherosclerosis may be responsible for such a significant association. Polymorphisms in various genes have been identified to modulate clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) leading to variation in clopidogrel action. Among them, polymorphism of the ABCB1 gene (C3435T polymorphism) has also been described as a contributory factor for the risk of CAD, especially for MI and ACS, among the Caucasian populations.31 Whether a novel mutation of the ABCB1 gene or any other unknown gene has resulted in such a significant association between clopidogrel resistance and family history of CAD, is a matter of further investigation. Hemoglobin level has shown a significant inverse relationship with the clopidogrel resistance in the univariate logistic regression analysis of our study, an effect that has been noted by others.32,33 The exact mechanism behind this relationship is not known. It was thought that this observed association might be because of an artefactual effect of low hematocrit value on platelet function tests employed. Moreover, change in hemoglobin level can affect calcium concentration in citrated blood used for LTA assay, resulting in decreased ADP induced platelet aggregation with a higher hemoglobin level. In a study conducted by Toma C et al,34 anemia was the only variable that was independently associated with clopidogrel resistance by both LTA and Verify Now assay. However, this significant association was absent before the administration of clopidogrel, indicating a possible true biological interaction between anemia and response to clopidogrel. The proposed mechanisms for this interaction were – elevated erythropoietin-induced platelet activation and an increase in immature reticulated platelet counts leading to diminished inhibition by clopidogrel. Furthermore, the conversion of clopidogrel to its active metabolite may be different in anemic patients.34 Apart from the hemoglobin level, elevated ESR showed a significant correlation with clopidogrel resistance in the univariate analysis. Though there is evidence linking inflammatory markers (IL-6, CRP) with increased platelet-associated atherosclerotic thrombotic events like stent thrombosis, the relationship between inflammatory markers and clopidogrel resistance is still unclear.35 To the best of our knowledge, this is the first study that has shown a significant correlation of elevated ESR with clopidogrel resistance. Whether there is a true biological relationship, or the association is secondary to a significantly low hemoglobin level in the clopidogrel resistance group, needs further evaluation. Although, the absence of a significant association between ESR level and clopidogrel resistance in the multivariate logistic regression analysis is leading more towards the second possibility.
Several large trials in the western population have shown significant adverse outcomes of both aspirin and clopidogrel resistance in terms of non-fatal myocardial infarction, stroke, stent thrombosis, urgent revascularization and cardiovascular death.36, 37, 38, 39, 40 A similar outcome study in the Indian population is scarce. Only one Indian study prospectively followed up patients with aspirin resistance for an average of 36 months.16 In that study, patients with aspirin resistance had a higher risk of vascular adverse events. Though our study followed up the study population for a mean of 13.4 months, it did not show any significantly higher adverse events in the antiplatelet resistance groups than in the responder groups. A relatively smaller sample size and a shorter follow-up may have resulted in such a disparity in the outcome measures.
To our best knowledge, this is the first study designed to assess the prognostic significance of both aspirin and clopidogrel resistance in Indian stable CAD patients. Gold standard equipment and standard definitions were used to diagnose anti-platelet resistance. However, there were several limitations. First, the trial design was an observational cohort study with its inherent biases and shortcomings. Secondly, the small sample size, brief follow-up period and low event (MACE) rate led to low statistical power to evaluate the connection between antiplatelet resistance, clinical risk factors and major clinical outcomes or MACE. Third, cut-off values for clopidogrel resistance were based on only 10 healthy control subjects due to logistical issues. Establishing a reference range for a test using such a limited number of subjects may lead to imprecise results. Fourth, we were unable to investigate the association between clopidogrel resistance and a family history of CAD through mechanistic or genetic analysis due to limitations in funding, resources, and logistics. Additionally, this was not within the scope of our original hypothesis. We consider our findings to be hypothesis-generating and look forward to future studies that may confirm and elucidate this observation. Furthermore, the trial was not designed to evaluate the cause-and-effect relationship of various risk factors with antiplatelet resistance.
5. Conclusions
Aspirin and clopidogrel resistance are common phenomena in stable coronary artery disease patients. For clopidogrel resistance - hemoglobin level, ESR and for aspirin resistance - diabetes were significant risk factors only in the univariate regression analysis. In multivariable analysis, a family history of CAD and aspirin resistance were the independent predictors of clopidogrel resistance. For aspirin resistance, clopidogrel resistance was the only independent risk factor. Due to the study's low event rate and short follow-up duration, its statistical power is limited; therefore, no definitive conclusions can be drawn regarding the relationship between antiplatelet resistance and adverse events. Larger multicenter trials with sufficient follow-up period will be required in the future to assess the prognostic significance of antiplatelet resistance in Indian coronary artery disease patients.
Ethical review board
This study protocol was reviewed and approved by Institutional Ethical Committee (AIIMS, New Delhi), approval number IECPG/478/2016.
Statement of ethics
Written informed consent was obtained from participants to participate in the study.
Data availability statement
The data that support the findings of this study are not publicly available [as that could compromise the privacy of research participants] but are available from the corresponding author [RN; r_narang@yahoo.com] upon reasonable request.
Funding sources
This research did not receive any grant from funding agencies in the government, public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nirmal Ghati and Aseem Basha are Editorial Board Member for Indian Heart Journal and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.
Acknowledgement
The information reported in the article has been presented as a poster in the 3rd European Congress on Thrombosis and Haemostasis, held at the Scottish Event Campus (SEC) in Glasgow, United Kingdom, from 2 to 4 October 2019.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ihj.2026.03.001.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are not publicly available [as that could compromise the privacy of research participants] but are available from the corresponding author [RN; r_narang@yahoo.com] upon reasonable request.