Year :
2021
| Month :
July
| Volume :
15
| Issue :
7
| Page :
FC06 - FC09
Full Version
Assessment of Clopidogrel Resistance
in Post Myocardial Infarction Patients
after 24 to 48 Hours of Initiation of
Treatment: A Cross-sectional Study
Published: July 1, 2021 | DOI: https://doi.org/10.7860/JCDR/2021/49310.15171
Mayukh Mukherjee, Suhrita Paul , Manasi Basu Banerjee , Sayanti Ghatak , Santanu Guha5 , Arnab Chattopadhyay
1. Assistant Professor, Department of Pharmacology, R. G. Kar Medical College, Kolkata, West Bengal, India.
2. Principal, Department of Pharmacology, Burdwan Medical College, Burdwan, West Bengal, India.
3. Professor, Department of Pharmacology, Medical College, Kolkata, West Bengal, India.
4. Junior Resident, Department of Physiology, Medical College, Kolkata, West Bengal, India.
5. Professor, Department of Cardiology, Medical College, Kolkata, West Bengal, India.
6. Associate Professor, Department of Haematology and Transfusion Medicine, Medical College, Kolkata, West Bengal, India.
Correspondence Address :
Dr. Mayukh Mukherjee,
28, Netaji Lane, Baidyabati, Hooghly, Kolkata-712222, West Bengal, India.
E-mail: mayukh.cnmc@gmail.com
Abstract
Introduction: Clopidogrel is an antiplatelet agent used to prevent platelet aggregation and further blockage of coronary arteries in Acute Coronary Syndrome (ACS) patients. Inadequate response to clopidogrel has been demonstrated in some patients that might lead to re-infarction even when receiving standard doses of clopidogrel.
Aim: To demonstrate the presence of resistance to standard oral doses of clopidogrel in a tertiary care hospital located in eastern India.
Materials and Methods: It was a descriptive cross-sectional study conducted from January 2015 to June 2016, in Medical College Kolkata, (previously known as Calcutta Medical College), India. Total 32 patients, previously not on any antiplatelet therapy, presenting with biomarker positive ACS were evaluated. The patients were given clopidogrel (300 mg) along with aspirin (325 mg) on presentation followed by clopidogrel (75 mg) and aspirin (75 mg) once daily. Blood samples were collected after 24-48 hours of administering the above mentioned doses orally. A 3.2% citrate was used as anti-coagulant. Platelet Rich Plasma (PRP) and Platelet Poor Plasma (PPP) were prepared from this blood samples by centrifugation. Platelet aggregation was studied by adding 10 μM Adenosine Diphosphate (ADP) in that PRP and it was compared with PPP in Light Transmittance Aggregometer (LTA). Platelet aggregation ≥50% in presence of 10 μM ADP was termed as Clopidogrel Resistance (CR). Differences between groups were assessed with Chi-square test and Fisher-exact test for categorical variables. The p-value of <0.05 was considered to be statistically significant.
Results: Mean age of the study participants was 60.7 years, and 23 (71.8%) out of 32 patients were male while 9 (28.2%) were female. Total 7 (21.8%) of the patients were found to be resistant to standard doses of clopidogrel. A 3 (60%) out of 5 patients with positive family history of Cardiovascular Diseases (CVD) showed CR (p-value=0.025). Incidences of CR was higher among women 3 (33.3%) and in patients receiving thrombolysis 4 (28.5%). Though these percentages were high but not statistically significant.
Conclusion: In this study, 21.8% ACS patients showed resistance to the antiplatelet effects of clopidogrel in the conventional dose. A long term prospective Randomised Controlled Trials (RCT) with larger sample size is required to give an insight into this problem.
Keywords
Antiplatelet, Re-infarction, Stent-thrombosis
Introduction
Clopidogrel is one of the most commonly used antiplatelet agents used in patients with ACS. Even after timely treatment with antiplatelet drugs many patients suffer from reinfarction (1). This has raised concern among the cardiologists throughout the world about a new phenomenon called antiplatelet resistance (2). The antiplatelet drugs, namely aspirin and clopidogrel, fail to prevent platelet aggregation despite administration of standard doses.
Clopidogrel is administered orally and only 50% of it is absorbed. It is a pro-drug and is partially converted into active metabolite by CYP2C19 enzyme in liver. It acts on P2Y12 receptor and irreversibly inhibits platelet function (3). But this antiplatelet action takes nearly four hours to start and develops over days. Moreover, due to genetic polymorphism, clopidogrel activation shows high inter individual variability (4). Sometimes, drugs like omeprazole which inhibit CYP2C19 may also be responsible for poor antiplatelet action of clopidogrel (5).
Some studies, done all over the world, showed varied presence of CR from 5-44% (6),(7). Studies done in India are few in number (6),(8). Ray S, found that CR is a problem here as well, but methods to identify it were not standardised and not freely available (6). Moreover, Kar R et al., showed that CR may be multifactorial but was not associated with single gene polymorphism (8). A large number of patients suffering from Acute Myocardial Infarction (AMI) are treated with clopidogrel and some of them develop adverse cardiovascular event like re-infarction or stent thrombosis within six months as a result of CR (7). The study was done to know the prevalence of CR among AMI patients and factors associated with it.
Material and Methods
It was a descriptive cross-sectional study conducted from January 2015 to June 2016, in Medical College Kolkata, (previously known as Calcutta Medical College), India. After obtaining Institutional Ethics Committee clearance (memo no. MC/KOL/IEC/NON-SPON/421/11-2014) 32 consenting patients were recruited in the study.
Inclusion criteria: Patients admitted with history of AMI or biomarker positive ACS in the last 24-48 hours were included in the study.
Exclusion criteria: Patients who were on Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (other than Aspirin), receiving drugs like omeprazole which inhibit CYP2C19, had known personal or family history of bleeding diathesis or had platelet counts of <150×103/mL or >450×103/mL were excluded from the study.
On admission, patients were given 300 mg clopidogrel orally along with other medications. It was followed by oral dose of 75 mg clopidogrel/day. In this study, 32 patients, admitted in Intensive Coronary Care Unit (ICCU) following AMI, were recruited.
Collection of Blood Sample
After following proper aseptic technique, 21 gauge needles were used to draw blood from antecubital vein within 24-48 hours of initiation of treatment. Initial 3-4 mL of blood was used for other routine tests to avoid spontaneous activation of platelets. 3.2% citrate solution was used as anticoagulant while collecting blood.
Analysis of Platelet Function
Platelet-Rich Plasma (PRP) was prepared from this blood sample by centrifugation at 200 gm for 15 minutes. PPP, required for comparison in LTA, was prepared by centrifugation of blood at 1500 gm for 15 minutes. Platelet aggregation was studied by adding 10 μm ADP in that PRP and it was compared with PPP in LTA. Platelet aggregation ≥50% in presence of 10 μm ADP was termed as CR (9),(10).
Statistical Analysis
Windows Microsoft Excel 2010 was used for tabulation of data and statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software (version 22.0). Data were found to be normally distributed by using Kolmogorov-Smirnov test. Normally distributed continuous variables were presented as Mean±SD. Categorical variables were expressed as frequencies and percentages.
Results
All recruited patients were ≥45 years of age and mean age was 60.7 years. Out of 32 recruited patients, 23 (71.8%) were male and 9 (28.2%) were female. The study revealed that 7 (21.8%) patients were clopidogrel-resistant; most of them belonged to 51-60 years age group. The (Table/Fig 1) shows that more females were resistant to clopidogrel 3 (33.3%) than males 4 (17.3%) (p-value=0.327).
Thirty (93.75%) patients presented with STEMI and all seven CR cases belonged to this group (p-value 0.44). CR was more common in patients treated by thrombolysis though, it was not statistically significant (p-value 0.419). No statistically significant association was found between pathological Q wave and CR (p-value=0.732).
Among 10 diabetic patients, 2 (20%) were clopidogrel-resistant; whereas in non diabetic group, 5 (22.73%) patients were clopidogrel-resistant (p-value=0.863). Patients having positive family history of CVD showed statistically significant association with CR (p-value 0.025). Three patients (60%) with family history of CVD showed CR. Those having no such history showed clopidogrel-resistance in 4 (14.81%) cases. Seven patients (23.33%) with no history of AMI showed CR.
A 3 (17.6%) out of 17 patients having history of angina showed CR. Only two patients had known history of dyslipidaemia. All 7 (23.33%) clopidogrel-resistant patients had no known history of dyslipidaemia (p-value=0.44). One (6.67%) hypertensive patient showed CR and in the non hypertensive group it was 6 (35.29%) (p-value=0.051).
Discussion
All recruited patients were ≥45 years of age and mean age was 60.7 years. Out of 32 recruited patients, 23 (71.8%) were male and 9 (28.2%) were female. The study revealed that 7 (21.8%) patients were clopidogrel-resistant; most of them belonged to 51-60 years age group. The (Table/Fig 1) shows that more females were resistant to clopidogrel 3 (33.3%) than males 4 (17.3%) (p-value=0.327).
Thirty (93.75%) patients presented with STEMI and all seven CR cases belonged to this group (p-value 0.44). CR was more common in patients treated by thrombolysis though, it was not statistically significant (p-value 0.419). No statistically significant association was found between pathological Q wave and CR (p-value=0.732).
Among 10 diabetic patients, 2 (20%) were clopidogrel-resistant; whereas in non diabetic group, 5 (22.73%) patients were clopidogrel-resistant (p-value=0.863). Patients having positive family history of CVD showed statistically significant association with CR (p-value 0.025). Three patients (60%) with family history of CVD showed CR. Those having no such history showed clopidogrel-resistance in 4 (14.81%) cases. Seven patients (23.33%) with no history of AMI showed CR.
A 3 (17.6%) out of 17 patients having history of angina showed CR. Only two patients had known history of dyslipidaemia. All 7 (23.33%) clopidogrel-resistant patients had no known history of dyslipidaemia (p-value=0.44). One (6.67%) hypertensive patient showed CR and in the non hypertensive group it was 6 (35.29%) (p-value=0.051).
Conclusion
Clopidogrel resistance may be responsible for re-infarction in some patients presenting with ACS. The study found 21.86% patients to be Clopidogrel-resistant. Patients having positive family history for CVD were more likely to be clopidogrel-resistant. Further studies are required involving large number of patients in multiple centres to ascertain these findings.
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10.7860/JCDR/2021/49310.15171
Date of Submission: Mar 06, 2021
Date of Peer Review: Apr 27, 2021
Date of Acceptance: Jun 02, 2021
Date of Publishing: Jul 01, 2021
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA
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Etymology: Author Origin
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