The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics

Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization include CYP2C19 genotyping, pharmacokinetics, and platelets function testing. However, these methods lack precise prediction of clopidogrel outcome, often leading to insufficient prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics can give insight on unknown genetic and nongenetic factors associated with the response.This review aimed to review the literature on factors associated with the variable platelets reactivity response to clopidogrel, as well as appraising current methods for the personalization of clopidogrel therapy. We also aimed to review the literature on using pharmacometabolomics approach to predict drug response, as well as discussing the plausibility of using it to predict clopidogrel outcome

The role of genetic polymorphism and other factors on clopidogrel resistance (CR) in an Asian population with coronary heart disease (CHD)

Clopidogrel is a widely-used antiplatelet drug. It is important for the treatment and prevention of coronary heart disease. Clopidogrel can effectively reduce platelet activity and therefore reduce stent thrombosis. However, some patients still have ischemic events despite taking the clopidogrel due to the alteration in clopidogrel metabolism attributable to various genetic and non-genetic factors. This review aims to summarise the mechanisms and causes of clopidogrel resistance (CR) and potential strategies to overcome it. This review summarised the possible effects of genetic polymorphism on CR among the Asian population, especially CYP2C19 *2 / *3 / *17, where the prevalence rate among Asians was 23.00%, 4.61%, 15.18%, respectively. The review also studied the effects of other factors and appropriate strategies used to overcome CR. Generally, CR among the Asian population was estimated at 17.2–81.6%. Therefore, our overview provides valuable insight into the causes of RC. In conclusion, understanding the prevalence of drug metabolism-related genetic polymorphism, especially CYP2C19 alleles, will enhance clinical understanding of racial differences in drug reactions, contributing to the development of personalised medicine in Asia

Current insights on dyslipidaemia management for prevention of atherosclerotic cardiovascular disease: a malaysian perspective

Dyslipidaemia is highly prevalent in the Malaysian population and is one of the main risk factors for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) is recognised as the primary target of lipid-lowering therapy to reduce the disease burden of ASCVD. Framingham General CV Risk Score has been validated in the Malaysian population for CV risk assessment. The Clinical Practice Guidelines (CPG) on the management of dyslipidaemia were last updated in 2017. Since its publication, several newer randomised clinical trials have been conducted with their results published in research articles and compared in meta-analysis. This underscores a need to update the previous guidelines to ensure good quality care and treatment for the patients. This review summarises the benefits of achieving LDL-C levels lower than the currently recommended target of < 1.8mmol/L without any safety concerns. In most high and very high-risk individuals, statins are the first line of therapy for dyslipidaemia management. However, certain high-risk individuals are not able to achieve the LDL-C goal as recommended in the guideline even with high-intensity statin therapy. In such individuals, lower LDL-C levels can be achieved by combining the statins with non-statin agents such as ezetimibe and PCSK9 inhibitors. Emerging non-statin lipid-lowering therapies and challenges in dyslipidaemia management are discussed in this article. The review also summarises the recent updates on local and international guidelines for dyslipidaemia management

The management of myocardial injury related to SARS-CoV-2 pneumonia

The global evolution of the SARS-CoV-2 virus is known to all. The diagnosis of SARS-CoV-2 pneumonia is expected to worsen, and mortality will be higher when combined with myocardial injury (MI). The combination of novel coronavirus infections in patients with MI can cause confusion in diagnosis and assessment, with each condition exacerbating the other, and increasing the complexity and difficulty of treatment. It would be a formidable challenge for clinical practice to deal with this situation. Therefore, this review aims to gather literature on the progress in managing MI related to SARS-CoV-2 pneumonia. This article reviews the definition, pathogenesis, clinical evaluation, management, and treatment plan for MI related to SARS-CoV-2 pneumonia based on the most recent literature, diagnosis, and treatment trial reports. Many studies have shown that early diagnosis and implementation of targeted treatment measures according to the different stages of disease can reduce the mortality rate among patients with MI related to SARS-CoV-2 pneumonia. The reviewed studies show that multiple strategies have been adopted for the management of MI related to COVID-19. Clinicians should closely monitor SARS-CoV-2 pneumonia patients with MI, as their condition can rapidly deteriorate and progress to heart failure, acute myocardial infarction, and/or cardiogenic shock. In addition, appropriate measures need to be implemented in the diagnosis and treatment to provide reasonable care to the patient

2020 Asian Pacific Society of Cardiology Consensus Recommendations on the Use of P2Y12 Receptor Antagonists in the Asia-Pacific Region

The unique characteristics of patients with acute coronary syndrome in the Asia-Pacific region mean that international guidelines on the use of dual antiplatelet therapy (DAPT) cannot be routinely applied to these populations. Newer generation P2Y12 inhibitors (i.e. ticagrelor and prasugrel) have demonstrated improved clinical outcomes compared with clopidogrel. However, low numbers of Asian patients participated in pivotal studies and few regional studies comparing DAPTs have been conducted. This article aims to summarise current evidence on the use of newer generation P2Y12 inhibitors in Asian patients with acute coronary syndrome and provide recommendations to assist clinicians, especially cardiologists, in selecting a DAPT regimen. Guidance is provided on the management of ischaemic and bleeding risks, including duration of therapy, switching strategies and the management of patients with ST-elevation and non-ST-elevation MI or those requiring surgery. In particular, the need for an individualised DAPT regimen and considerations relating to switching, de-escalating, stopping or continuing DAPT beyond 12 months are discussed

The impact of CYP2C19 genotype on the platelet reactivity index (PRI) among chronic coronary syndromes (CCS) patients undergoing percutaneous coronary intervention (PCI): Affectability of rapid genetic testing

Background In the Asian population, the presence of the CYP2C19 loss-of-function (LOF) allele is a known genetic variation. This allele is associated with a reduced capacity to metabolize clopidogrel into its active forms through the CYP2C19 enzyme, resulting in diminished platelet inhibition and an elevated risk of recurrent cardiovascular events. Regulatory authorities have recommended an alternative P2Y12 inhibitor, ticagrelor, for individuals carrying the LOF allele. Consequently, this study seeks to assess the impact of the CYP2C19 genotype on the Platelet reactivity index (PRI) using a rapid genetic testing approach in Asian patients with chronic coronary syndromes (CCS) who undergo percutaneous coronary intervention (PCI). Methods This prospective study employed a parallel design, single-center design, and randomized approach. Genotyping for the CYP2C19*2 and *3 polymorphisms was conducted using the Nested Allele-Specific Multiplex PCR (NASM-PCR) technique. Patients meeting the inclusion criteria underwent genotyping for CYP2C19 polymorphisms. Following PCI, patients were randomly assigned to receive either ticagrelor or clopidogrel. PRI assessments were performed four hours after loading dose administration. The trial was registered with ClinicalTrials.gov under the identifier NCT05516784. Results Among the 94 patients recruited for the study, 40 (42.55%) were identified as carriers of the LOF allele for CYP2C19*2 and *3 (*1/*2, *2/*2, *1/*3). Out of the 84 patients evaluated for PRI (44 receiving clopidogrel and 40 receiving ticagrelor), 21 (47.7%) of the clopidogrel group and 39 (97.5%) of the ticagrelor group exhibited a favorable response to antiplatelet therapy (PRI < 50). Patients treated with ticagrelor demonstrated superior antiplatelet responses compared to those receiving clopidogrel, regardless of LOF carrier status (P = 0.005 and < 0.001 for non-LOF and LOF carriers, respectively). Conclusion NASM-PCR as a rapid genetic test holds promise for personalizing antiplatelet therapy in Asian CCS patients

Coronary Heart Disease (CHD) in Elderly Patients: Which Drug to Choose, Ticagrelor and Clopidogrel? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: A new generation P2Y12 receptor inhibitor (ticagrelor) is recommended in current therapeutic guidelines to treat patients with coronary heart disease (CHD). However, it is unknown if ticagrelor is more effective than clopidogrel in elderly patients. Therefore, a systematic review was done to assess the effectiveness and safety of ticagrelor and clopidogrel in older patients with CHD to determine the appropriate antiplatelet treatment plan. Methodology: We performed a systematic review of randomized controlled trials (RCTs) to compare the effectiveness and safety of ticagrelor vs. clopidogrel in elderly patients with CHD. We selected eligible RCTs based on specified study criteria following a systematic search of PubMed and Scopus databases from January 2007 to May 2021. Primary efficacy outcomes assessed were major adverse cardiovascular events (MACEs), myocardial infarction (MI), stent thrombosis (ST), and all-cause death. The secondary outcome assessed was major bleeding events. We used RevMan 5.3 software to conduct a random-effects meta-analysis and estimated the pooled incidence and risk ratios (RRs) with 95% confidence intervals (CIs) for ticagrelor and clopidogrel. Results: Data from 6 RCTs comprising 21,827 elderly patients were extracted according to the eligibility criteria. There was no significant difference in the MACE outcome (incidence: 9.23% vs. 10.57%; RR = 0.95, 95% CI = 0.70–1.28, p = 0.72), MI (incidence: 5.40% vs. 6.23%; RR = 0.94, 95% CI= 0.69–1.27, p = 0.67), ST (incidence: 2.33% vs. 3.17%; RR = 0.61, 95% CI= 0.32–1.17, p = 0.13), and all-cause death (4.29% vs. 5.33%; RR = 0.86, 95% CI = 0.65–1.12, p = 0.25) for ticagrelor vs. clopidogrel, respectively. In addition, ticagrelor was not associated with a significant increase in the rate of major bleeding (incidence: 9.98% vs. 9.33%: RR = 1.37, 95% CI = 0.97–1.94, p = 0.07) vs. clopidogrel. Conclusions: This study did not find evidence that ticagrelor is significantly more effective or safer than clopidogrel in elderly patients with CHD