Pharmacogenomic Testing in a Bangladeshi Patient with Recurrent Cardiovascular Events Despite Clopidogrel Therapy: A Case Report

Abstract

Specifically, high-risk cardiovascular patients are concerned with clopidogrel resistance due to CYP2C19 polymorphism. The genetic variation, however, lowers clopidogrel’s effectiveness in preventing thrombotic events by influencing how the drug is metabolized in the body. CYP2C19 polymorphism is prevalent in different populations, and the frequency is higher in South Asian individuals. This report describes a case of a Bangladeshi patient who had recurrent cardiovascular events while on clopidogrel therapy and adhered to the treatment. A 55-year-old Bangladeshi male with a history of cardiovascular disease presenting with multiple episodes of acute coronary syndrome (ACS) included a myocardial infarction and percutaneous coronary intervention (PCI). He had the strictest adherence to the clopidogrel therapy but suffered from ischemic events. His metabolic status about clopidogrel activation was assessed using Pharmacogenomic testing. This result confirmed that he was a poor metabolizer of clopidogrel by carrying a CYP2C19 LOF variant. The patient’s antiplatelet regimen was adjusted based on the pharmacogenomic findings and clopidogrel was replaced with ticagrelor, a more potent P2Y12 inhibitor that, unlike clopidogrel, does not require CYP2C19 activation. After six months of follow up, improved platelet function test results and prevention of further cardiovascular events were noted after the change in therapy. Pharmacogenomic testing to optimize antiplatelet therapy is important in this case because of its high prevalence of CYP2C19 LOF variants, and because treatment response is influenced by the polymorphism status of genes, as evidenced in this case. Routinely performing genetic screening in Bangladesh could both improve patient outcomes and lead to a personalizing approach to cardiovascular disease management.

Keywords

Introduction

Within this role, clopidogrel is the most widely used antiplatelet agent; it is utilized in patients undergoing percutaneous coronary intervention (PCI) as well as in those presenting with acute coronary syndrome (ACS). It has an important role in the secondary prevention by reducing the thrombosis risk, inhibiting the platelet aggregation. However, while it has become very widely used, a significant number of patients fail to have adequate platelet inhibition (clopidogrel resistance) underlining an increased risk of ischemic events. Clopidogrel is a prodrug that requires liver CYP2C19 to metabolize it to its therapeutic active metabolite. Activation of diclofenac by the oxidation process involved is influenced by genetic polymorphisms in the CYP2C19 gene. There are studies showing that patients with CYP2C19 LOF alleles have higher rate of adverse cardiovascular events such as myocardial infarction and stent thrombosis than non-carriers 1,2,3. Even more prevalent in South Asians, particularly in Bangladesh, is the prevalence of CYP2C19 LOF alleles 4, 5, 6. Pharmacogenomic testing for personalized medicine has become promising and is now used to determine an individual’s genetic profile so that the antiplatelet therapy can be tailored to them. The aim of this case report is to present a Bangladeshi patient with recurrent cardiovascular events served by clopidogrel resistance, and to highlight the use of pharmacogenomic testing in optimizing treatment strategies.

2. Case Presentation

2.1 Patient Information

He was a 55-year-old hypertensive patient with DM, myocardial infarction and previous PCI. He had a smoking and obese and dyslipidemic cardiovascular risk factors. Because he had undergone PCI, he had been prescribed dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. This regimen was strictly adhered to, but during a one-year period, he had several episodes of acute coronary syndrome (ACS).

2.2 Clinical Investigations

Recurrent ischemic episodes were confirmed by patient’s cardiac biomarkers and ECG. Platelet function testing, including treatment platelet reactivity (HTPR), was elevated in a laboratory investigation suggesting an inadequate response to the clopidogrel. The recurrent cardiovascular events and suspected clopidogrel resistance serve as a reason to perform pharmacogenomic testing. Genetic analysis showed that the patient had CYP2C192 and CYP2C193 polymorphisms, hence is a poor metabolizer. This finding showed that clopidogrel was poorly activating, therefore not preventing adequate platelet inhibition. Coronary angiography is also demonstrated in stent restenosis, complicating his clinical picture further.

3. Treatment & Management

3.1 Initial Management

The patient was still receiving clopidogrel therapy before pharmacogenomic testing results came out. Nevertheless, given his HTPR and prior ACS episodes, alternatives in antiplatelet strategies were considered.

3.2 Post-Genetic Testing Adjustment

Refined treatment of antiplatelet therapy was given once the patient’s CYP2C19 LOF variant was confirmed. It was discontinued because there was no such metabolism and poor therapeutic response to Clopidogrel. Therefore, the patient received ticagrelor, a direct-acting P2Y12 inhibitor, which does not require metabolic activation as CYP2C19 substrate. Response to therapy was assessed in terms of close monitoring of platelet function and cardiovascular status.

3.3 Clinical Outcome

After switching to ticagrelor, platelet function test results significantly improved in the patient. He received no further cardiovascular events during a six-month followup suggesting effective antiplatelet management.

4. DISCUSSION

4.1 CYP2C19 Polymorphism and Clopidogrel Metabolism

Clopidogrel resistance is well known to be associated with CYP2C19 polymorphism. People with LOF alleles of the CYP2C19 (CYP2C192, CYP2C193) have lower conversion of clopidogrel to its active metabolite and therefore decreased platelet inhibition. Notably, these genetic variants are also prevalent for example in Bangladesh 7,8,9.

4.2 Pharmacogenomic Testing in Clinical Practice

Antiplatelet therapy is pharmacogenomic by providing genotype guided approach to treatment and thus clinicians can customize therapy to individual metabolic capacity. It has also been shown that patients who are poor metabolizers benefit greatly from switching to alternative P2Y12 inhibitors such as ticagrelor or prasugrel, which do not use CYP2C19 for activation 10,11,12.

4.3 Comparative Studies and Evidence

Genetic screening for patients at high risk carries with it the assumption that patients with clopidogrel resistance have an increased risk of ischemic events 13, 14, 15, which has been confirmed in comparative studies. Indeed, pharmacogenomic testing is associated with: Reduced incidence of cardiovascular events, Optimized healthcare resource utilization, Improved patient outcomes 16,17,18

4.4 Challenges in Bangladesh

However, due to its obvious benefits, pharmacogenomic testing is not yet broadly used in Bangladesh. Key challenges include: Limited access to genetic testing facilities, Lack of awareness among healthcare providers, Genetic screening has high costs associated with it. The integration of pharmacogenomic testing into routine cardiovascular care in Bangladesh will require both educational initiatives as well as policy reforms.

5. CONCLUSION

CYP2C19 polymorphism has a substantial effect on clopidogrel resistance and subsequent cardiovascular risks, and this case illustrates the importance of this. The key role in individualized antiplatelet therapy, reduction of the incidence of cardiovascular adverse events and the optimization of patient’s care is played by pharmacogenomic testing. Therefore, results from this case emphasized the necessity for genetic testing in clinical practice in Bangladesh to advance personalized medicine and improve the management of cardiovascular disease. Future research should be done with population-based studies to assess whether routine pharmacogenomic screening is possible in Bangladeshi healthcare settings.

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