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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 1  |  Page : 36-41

Antiplatelet drug resistance in Indians


1 Department of Cardiology, Nizar Cardiac Center, Malapuram, Kerala, India
2 Department of Cardiology, Kerala Institute of Medical Sciences, Thiruvananthapuram, Kerala, India
3 Society for Continuing Medical Education and Research, Kerala Institute of Medical Sciences, Thiruvananthapuram, Kerala, India

Date of Submission13-Apr-2020
Date of Acceptance16-Apr-2020
Date of Web Publication16-Jun-2020

Correspondence Address:
Prof. G Vijayaraghavan
KIMS, Thiruvananthapuram, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ACCJ.ACCJ_6_20

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  Abstract 


Background and Objectives: Resistance to the antiplatelet drugs aspirin and clopidogrel is well recognized, and its prevalence has been reported from many countries. There is, however, a paucity of reports on the prevalence of resistance to these drugs in Indian patients. This information is important as resistance to one or both of these drugs may play a role in-stent thrombosis and post angioplasty complications while using drug-eluting stents. The present study was conducted in 200 consecutive patients with myocardial infarction (MI) who underwent elective percutaneous coronary intervention in a single center and who gave consent for the study. The objective of the study was to determine the prevalence of aspirin and clopidogrel resistance in Indian patients who were administrated either of the drugs after PCI, using the VerifyNow P2Y12 assay. Methods: All patients were evaluated on day 7 after the procedure, and blood was collected in the laboratory and immediately analyzed. Platelete resistance to aspirin and clopidogrel was determined by verifying now RPFT point of the care system. Asprin resistance was measured as Aspirin Reaction Unit (ARU); >550 ARU was considered as aspirin resistance. Clopidogrel resistance was considered when Platelet Reaction Unit (PRU) was >213. Results: Among the 200 patients with MI, 87% were males and 13% were female. Their age group varied from 35 to 83 years. Among the study participants, 22% were resistant to an aspirin dose of 150 mg orally and the remaining 78% had normal platelet aggregation. About 68% were sensitive to clopidogrel, and 32% were resistant. About 58% of females were resistant to aspirin as against 29% of male patients, and 38% of females were resistant to clopidogrel as against 18% of male patients. Further, aspirin and clopidogrel were not associated with age and diabetes mellitus (P ≥ 0.05). Conclusions: The prevalence of aspirin and clopidogrel resistance in India is similar to those reported from the United States of America and Europe. The resistance pattern was also found to be similar.

Keywords: Antiplatelet drugs, aspirin, clopidogrel, drug resistance, myocardial infarction


How to cite this article:
Pareed SA, Vijayaraghavan G, Kartha C C, Manoj M T. Antiplatelet drug resistance in Indians. Ann Clin Cardiol 2020;2:36-41

How to cite this URL:
Pareed SA, Vijayaraghavan G, Kartha C C, Manoj M T. Antiplatelet drug resistance in Indians. Ann Clin Cardiol [serial online] 2020 [cited 2020 Sep 27];2:36-41. Available from: http://www.onlineacc.org/text.asp?2020/2/1/36/286474




  Introduction Top


Aspirin and clopidogrel are standard therapeutic drugs for patients after acute myocardial infarction (MI) and after percutaneous coronary interventions (PCIs) followed by stenting.[1] Resistance to these antiplatelet drugs is associated with adverse clinical outcomes in patients postPCI. There is considerable heterogeneity in the response of individual patients to each of these drugs. Varying the incidence of aspirin and clopidogrel resistance could result in-stent thrombosis in patients after PCI.[2] Aspirin affects platelet function by irreversibly inhibiting cyclooxygenase-1 enzyme, which converts arachidonic acid to thromboxane A2, which activates the IIb/IIIa receptors involved in platelet aggregation. Clopidogrel irreversibly inhibits the P2Y12 subtype of Adenosine Diphosphate (ADP) receptors, which is important in the aggregation of platelets and cross-linking by fibrin.[3] The blockage of this receptor inhibits platelet aggregation through inactivation of the glycoprotein IIb/IIIa pathway, which is the final common pathway for platelet aggregation. Identifying drug resistance would aid in the choice of the right antiplatelet drug to prevent stent thrombosis after PCI.[4]

Lack of a standard definition for drug resistance and the absence of an established diagnostic test for its diagnosis have hampered both identification and treatment of resistance to antiplatelet drugs. Even though a few studies have been carried out in India, none of these studies have used “VerifyNow P2Y12 assay” which is considered as the most simple and reliable method for monitoring antiplatelet therapy.[5] In the study reported here, we sought to determine the prevalence of aspirin and clopidogrel resistance in Indian patients who were administrated either of the drugs after PCI, using the VerifyNow P2Y12 assay.


  Methods Top


Study design and setting

We conducted a prospective descriptive study between September 01, 2011 and August 30, 2013, at Kerala Institute of Medical Science, a 650-bedded tertiary Care Centre located in Trivandrum of Kerala State, India. The study was approved by the Institutional Human ethics Committee.

Selection of participants

Two-hundred patients with MI who underwent PCI were selected for the study. All patients were given aspirin 150 mg once daily and clopidogrel 75 mg twice daily after PCI for one month and later once daily for one year as per the hospital protocol. Patients with hemoglobin <10 g/dl, platelet count <75000/cumm, or creatinine clearance <90 ml/min were excluded from the study. Platelet function was assessed using verify now point of care platelet function test, 5 days after PCI. Detailed clinical history was recorded and physical examination, electrocardiography, echocardiography, complete blood count, renal function tests, estimation of serum levels of troponin I and creatinine kinase-MB and coagulation profile were done in all patients.

Verify Now RPFT system uses whole blood and involves a light transmission-based optical detection assay. Platelet aggregation is measured in a cartridge containing fibrinogen coated beads. The assay was performed within 15 min of venepuncture. Platelet activity was assessed by measuringin vitro platelet aggregation in blood samples after the addition of a specific agonist. Aspirin assay is a qualitative test to aid in the detection of platelet dysfunction after aspirin ingestion.[6] In this assay, arachidonic acid is used as an agonist to activate platelets, and platelet function is assessed on the ability of activated platelets to bind to fibrinogen.[6] Fibrinogen coated microparticles aggregate in whole blood in proportion to the number of activated platelet GP IIb/IIIa receptors. If aspirin has produced the expected antiplatelet effect, such aggregation will be reduced. The extent of platelet aggregation was reported as an aspirin reaction unit (ARU); values <550 was considered consistent with aspirin-induced inhibition of platelet function. Values greater than or equal to 550 ARU were regarded to indicate aspirin resistance [Figure 1].[7]
Figure 1: Distribution aspirin resistance level

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The Verify Now P2Y12 assay (Accumetrics Inc, San Diego, California, USA) was used to measure clopidogrel sensitivity. The assay incorporates the agonist ADP to activate platelets. The Verify Now P2Y12 assay also uses PGE1 to increase intra platelet c-AMP and reduce the contribution of the P2Y1 receptor on activation.[8] This makes the assay more specific for the effects of ADP on the P2Y12 receptor. It measures platelet function based upon the ability of activated platelets to bind to fibrinogen. Fibrinogen-coated micro particles aggregate in whole blood in proportion to the number of activated platelet GP IIb/IIIa receptors, and if the P2Y12 inhibitor has produced the expected antiplatelet effect, such aggregation will be reduced.[9] The result is reported in P2Y12 reaction units (PRU). PRU indicates the amount of ADP mediated aggregation specific to the platelet P2Y12 receptor. PRU <213 is consistent with clopidogrel induced inhibition of platelet function, whereas values >213 indicate clopidogrel resistance [Figure 2].[5]
Figure 2: Distribution of Clopidogrel resistance level

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Statistical analysis

Statistical analysis was performed using the Statistical Package for the Social Science, Version 11.0 (Chicago, SPSS Inc). Descriptive statistics (frequencies and percentages for categorical variables) were conducted to describe the distribution of the demographic variable of the study sample. Chi-square test was used to find the association between the sensitivity of aspirin and clopidogrel with selected variables. A value of P < 0.05 was considered as statistically significant.


  Results Top


Among the 200 participants, 87% were male and 13% were female. The age of the patients ranged from 35 years to 83 years. The mean age of the patients was 59 years, with a standard deviation of 10 years. About 16% of patients were of less than 50 years of age; 63 patients (32.0%) were 50–59-years-old, 74 patients (37%) belonged to the age group of 60–69 years and 30 patients (15.0%) were above the age group of 70 and above years. Diabetes mellitus was present in 105 (52.5%) patients [Table 1].
Table 1: Clinical characteristics of study subjects and prevalence of aspirin and clopidogrel resistancea

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Among the study participants, 22% were resistant to aspirin [Figure 3]. The distribution of aspirin resistance with respect to males and females is shown in [Table 2]. About 71% of males and 42% of females were aspirin-sensitive as against 29% of the males and 58% females who were resistant to aspirin. Aspirin resistance was not associated with age of the participants (P = 0.45) or diabetes (P = 0.973) [Table 2].
Figure 3: Distribution of Aspirin resistance

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Table 2: Clinical characteristics of patients with and without aspirin resistance

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The prevalence of clopidogrel resistance was 32.0% in our patients [Figure 4]. The distribution of clopidogrel resistance with respect to males and females is shown in [Table 3]. 82% of the males and 62% of the females were sensitive to clopidogrel as against 18% of males and 38% of females who were resistant to clopidogrel [Table 3]. There was no significant association of clopidogrel resistance with age (P = 0.07) [Table 3]. Clopidogrel resistance was not associated with diabetes mellitus (P = 0.141) [Table 3].
Figure 4: Distribution of Clopidogrel resistance

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Table 3: Clinical characteristics of patients with and without clopidogrel resistance

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  Discussion Top


Given the paucity of information on the prevalence of resistance to the antiplatelet drugs aspirin and clopidogrel in Indians, we studied their prevalence in patients with MI who underwent PCI in our Center. We used “Verify Now P2Y12 assay” which is considered as the most simple and reliable method for monitoring antiplatelet therapy. In our prospective study of patients who underwent PCI, the prevalence of aspirin resistance was found to be 22%. The prevalence of clopidogrel resistance was 32%. Aspirin resistance was not associated with gender, age, or diabetes.

There have been only a few previous Indian studies on resistance to antiplatelet drugs. In a nonrandomized single-center prospective study on 63 patients with stable documented coronary artery disease (CAD) and 21 healthy volunteers, Thomson et al.[10] observed a 38.1% prevalence of aspirin resistance. They used urinary 11-Dehydrothromboxane B2 levels as a surrogate marker for checking the efficacy of the antiplatelet drug. In another study using optical aggregometer (chrono-log), Guha et al.[11] noted that among 144 patients suffering from acute coronary syndrome (ACS), 12.5% were resistant to both aspirin and clopidogrel used in conventional doses. Patel et al.[12] carried out a case-control study on 65 patients with ischemic stroke who were stable on dual antiplatelet therapy (clopidogrel 75 mg OD and aspirin 75 mg OD) and 65 age-matched controls. The platelet function was tested using light transmission aggregometry. They found that 64.6% (42/65) of patients had an inadequate response to clopidogrel; 15.4% were resistant and 49.2% were semi-responders. 4.6% (3/65) of patients had an inadequate response to aspirin; 3.1% were resistant and 1.5% were semi-responders. Dhanvijay et al.[13] conducted a cross-sectional observational study in 102 patients with ACS to find out the prevalence of resistance to aspirin and or clopidogrel using platelet works kit (with agonist added in the test tube along with sodium citrate as anticoagulant and buffers). They found that 45.09% of patients were aspirin resistant, and 76.13% were clopidogrel resistant.

Clopidogrel, in combination with aspirin, is currently the choice for antiplatelet treatment in the care of patients who undergo coronary intervention. Clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major adverse cardiac events (MACE).[9],[14],[15],[16] Despite the use of such therapy, a considerable number of patients continue to have recurrent thrombotic events.[17],[18],[19],[20] Previous studies have shown significant inter-individual variability in platelet response to clopidogrel therapy as measured by platelet function assay in patients with CAD, with up to 25% of patients found to be nonresponders. Chen et al. investigated the effect of aspirin resistance on myonecrosis after PCI among 151 patients pre-treated with 300 mg of clopidogrel >12 h before PCI and 75 mg of clopidogrel on the day of the PCI.[20] The point-of-care verify now RPFA test was utilized to determine therapeutic responsiveness. Twenty-nine patients (19.2%), despite pre-treatment with clopidogrel, were found to be aspirin-resistant with an increased risk of myonecrosis (51.7% vs. 24.6%) as assessed by troponin elevation following nonurgent PCI.

There is a growing body of evidence that links the recurrence of adverse cardiac events to a poor response to clopidogrel.[21],[22],[23] Many clinical studies have demonstrated that clopidogrel nonresponsiveness is associated with a higher risk of cardiovascular events, including cardiac death and stent thrombosis.[24],[25],[26] In addition, clopidogrel nonresponsiveness is also associated with a higher incidence of periprocedural myocardial damage, thrombotic complications, and long-term ischaemic events in patients undergoing PCI.[27] Snoep et al., in a meta-analysis, investigated the association between clopidogrel nonresponsiveness and clinical outcome and found evidence for an increased risk of clinical recurrences in those on clopidogrel treatment and with residual platelet reactivity.[28] They opine that laboratory evidence of clopidogrel nonresponsiveness is a marker of increased risk for adverse cardiovascular outcomes in patients undergoing PCI with stenting. Gum et al. performed a randomized prospective trial in 326 patients, treated with aspirin and no other antiplatelet agents.[29] Aspirin sensitivity was tested by optical platelet aggregation. Among their patients, 17% of patients were found to be aspirin-resistant, and during follow-up, they had a nearly three-fold increased risk of death, MI, or cerebrovascular accident.

Kim et al. in their study on the prevalence and risk factors for aspirin and clopidogrel resistance in patients with CAD, observed a 14% prevalence of aspirin resistance and clopidogrel resistance in 38.8%.[30] They also used Verify Now analyzer to detect drug resistance.

Aspirin or clopidogrel resistance was more common in our female patients compared to males. Ivandic et al.[31] reported that female patients are predisposed to clopidogrel resistance. The exact reason for women being more resistant to clopidogrel is unknown. There was no significant association of clopidogrel resistance with age or diabetes in our patients. Even though several studies revealed a high incidence of clopidogrel resistance in patients with diabetes, our study did not find a significant difference in clopidogrel resistance in patients with diabetes. Angiolillo et al. in their study of platelet function profile in patients with type 2 diabetes and CAD who were on combined aspirin and clopidogrel treatment, discovered that clopidogrel non-responsiveness is more prevalent in patients with diabetes than in nondiabetic patients; clopidogrel non responsiveness was the highest among patients requiring insulin therapy.[32]

The mechanisms leading to a poor response to clopidogrel have not been fully elucidated. They are considered to involve both acquired and genetic factors. Clopidogrel is transformed into its active metabolite by cytochrome P-450 (CYP) enzymes. Genetic polymorphism exists for CYP2C19 expression. CYP2C19 alleles are *1, *2, *3, *4, and *7. Allele *1 is associated with normal, *2, *3, *4 were reduced, and *7 with increased enzymatic activity. Depending on ethnicity, 30% to 55% of persons harbor a loss of function of the CYP2C19 allele (CYP2C19*2). Compared with non-carriers, CYP2C19*2 carriers treated with clopidogrel had lower levels of active clopidogrel metabolite, high rate of platelet reactivity as assessed by Verify Now and VASP and a higher rate of MACE[33] and stent thrombosis.[34] In the GIFT study, the genetic substudy of GRAVITAS, blood samples were tested for 40 polymorphisms, and these were correlated with the results of Verify Now P2Y12 assay during treatment.[35] The rate of platelet reactivity was increased 11-fold in homozygotes and increased 62% in heterozygotes for the CYP2C19*2 gene, compared with noncarriers. The study did not find any association of the CYP2C19*17 gain-of-function gene with reduced platelet reactivity during treatment. Recently, Shetkar et al. in a study of 110 consecutive patients with angiographically proven coronary artery study with various genetic polymorphism in CYP 450 2C19 gene and taking clopidogrel, found that CYP 450 2C19 polymorphisms are common in the Indian population and that a loss of function mutation do not affect clinical outcome.[36] Clinical factors such as obesity, insulin resistance, and the nature of the coronary event have also been found to contribute to the variability in response to clopidogrel.[19]

Even as the mechanisms of aspirin and clopidogrel resistance are becoming clearer, defining the clinical correlates continue to be a challenge. In its broadest sense, resistance refers to the continued occurrence of ischemic events despite adequate antiplatelet therapy and compliance. The lack of a standard definition for resistance as well as the lack of a standard diagnostic modality has hampered identification and management of the clinical entity. Attempts have been made to develop a more meaningful definition with the goal of correlating laboratory tests with clinical outcomes. There is, however, no definition which unifies the biochemical and clinical expression of failed treatment. Rather than attempt to characterize patients as simply resistant or sensitive to medication, therapeutic resistance could be considered as a continuous variable similar to blood pressure.[37] Our study indicates that patients with a platelet reaction unit (PRU) <213 can be considered as responding to clopidogrel. PRU in those with resistance varies from 213 to 418, and the variation could probably reflect the variable response to clopidogrel. At a higher level of resistance, patients may be prone to develop complications of PCI. Such variability was not found in patients with aspirin resistance. By shifting the criterion for the diagnosis of drug resistance from the use of a specific value to the idea that resistance is a continuous variable, treatment failure may be better managed.

Genetic predilection for clopidogrel resistance is considered to be low in Caucasians while it is >3 times among the Asian population.[38] However, we find that the findings in point-of-care testing for clopidogrel resistance are similar in both Caucasians and Indians.

The limitations of our study are that we have not followed up with our patients to find the relationship between antiplatelet drug resistance and adverse outcomes. We have also not investigated whether, in our patients, there was any genetic basis for the drug resistance.


  Conclusions Top


Our prospective study reveals a 22% prevalence of aspirin resistance and 32% clopidogrel resistance in south Indian patients who underwent PCI for MI. Prevalence of clopidogrel resistance (32%) is similar to that reported in other ethnic populations elsewhere in the world. A high prevalence of aspirin and clopidogrel resistance is seen among women as reported from other countries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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