Search Results (37)

Clopidogrel is widely used as an antiplatelet therapy for acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Genetic factors influence variability in clopidogrel response, with non-functional CYP2C19 alleles increasing the risk of major adverse cardiovascular events (MACEs). While CYP2C19 genotype-guided therapy after PCI improves outcomes, MACEs persist at variable rates. Pharmacogenomics (PGx) has primarily focused on genes related to drug metabolism, but therapeutic failure may stem from individual disease predisposition. This study aims to identify novel genetic variants underlying adverse events after PCI despite PGx-guided therapy. A custom sequencing panel was analyzed in 244 ACS-PCI-stent patients and 99 controls without cardiovascular (CV) disease. Association analysis was performed independent of treatment and by prescribed treatment (clopidogrel or prasugrel), complemented by random forest models to predict risk during antiplatelet therapy. No polymorphism reached genomic significance, but in clopidogrel-treated patients, rs2472434 in ABCA1, related to altered lipid metabolism, was strongly associated with secondary CV events (p = 1.7 × 10⁻³). Variants in the clopidogrel pathway, including CYP2C19, ABCB1, and UGT2B7, were also identified and may influence clopidogrel response. Predictive models incorporating these variants effectively discriminated patients with and without events (p = 0.02445). Our findings support combined genotyping of CYP2C19 loss-of-function and ABCB1 C3435T variants to guide antiplatelet therapy and suggest additional targets, such as rs2472434 (ABCA1) and rs7439366 (UGT2B7), to improve risk prediction of adverse CV events. Therefore, the unexplained variability in clopidogrel response may be due to disease pathogenesis itself, highlighting the need for a paradigm shift in PGx studies. Full article

Heart Failure (HF) remains a major cause of mortality despite the advances in pharmacological treatment. Anticoagulation therapies, including Clopidogrel, Aspirin, Warfarin, and novel oral anticoagulants (NOACs) such as Apixaban, Rivaroxaban, Edoxaban, and Dabigatran, are frequently administered to HF patients to prevent thromboembolism and adverse, life-threatening outcomes (e.g., stroke and myocardial infarction). In these settings, drug resistance and variability in responsivity to therapeutic approaches are challenging issues. Recent studies suggest that non-coding RNAs, particularly microRNAs (miRs) may play a modulatory role in HF therapy context, affecting drug efficacy. Specific miRs have been associated with resistance to Clopidogrel (e.g., miR-223 and miR-26a), Aspirin (e.g., miR-19b-1-5p and miR-92a) and Warfarin (e.g., miR-133 and miR-137). Moreover, Digoxin, a cardiac glycoside acting also over bleeding risk, upregulates miR-132, which is involved in HF-associated cardiac alteration and hypertrophy. Evidence linking miR expression to NOAC pharmacodynamics, cardiac remodeling and regulation of the coagulation is growing. These findings highlight the need of deeply harnessing the potential of miRs as predictive biomarkers or therapeutic targets in HF. Improving the knowledge on the relationship between miR and anticoagulant drugs in HF patients will contribute to personalization of the anticoagulant therapies, aimed at enhancing patient responsivity and minimizing adverse effects, ultimately improving patient life quality. Full article

In patients on oral anticoagulation (OAC), typically for atrial fibrillation (AF), undergoing percutaneous coronary intervention (PCI), the antiplatelet drugs to be added to direct oral anticoagulant (DOAC) are aspirin and clopidogrel during the initial, short (up to one week) period of triple antithrombotic therapy (TAT), and clopidogrel alone during the subsequent 6- to 12-month period of double antithrombotic therapy (DAT). Both direct and indirect data support the recommendation to avoid the more potent P2Y12 inhibitors—ticagrelor and prasugrel—as part of TAT, owing to the increased risk of bleeding. There is less and inconclusive data available regarding the safety and efficacy of DAT when ticagrelor or prasugrel are used instead of clopidogrel. Also, there is very limited evidence for the use of aspirin instead of clopidogrel in a DAT regimen. While acknowledging the safety and effectiveness of the recommended strategies above, it would, nonetheless, be valuable to have alternative options in the choice of antiplatelet agents. In case of very high thrombotic risk, especially when stents are positioned in potentially risky sites (such as the left main or last remaining vessel) a more potent P2Y12 inhibitor than clopidogrel may be warranted. Moreover, non-responsiveness to, or pharmacological interactions of, clopidogrel may hamper its efficacy. In this review, we aim at presenting and discussing the evidence supporting the current recommendations for the use of the various antiplatelet agents in AF patients on OAC undergoing PCI, as well as at giving a glimpse at future perspectives. Full article

Cardiovascular disease (CVD) is the leading cause of death worldwide, with pathophysiological mechanisms often involving platelet activation and chronic inflammation. While antiplatelet agents targeting adenosine diphosphate (ADP)-mediated pathways are well established in CVD management, less is known about drug interactions with the platelet-activating factor (PAF) pathway, a key mediator of inflammation. This study aimed to evaluate the effects of several commonly used cardiovascular and anti-inflammatory drug classes—including clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin II receptor blockers (ARBs), β-blockers, and analgesics—on platelet function via both the ADP and PAF pathways. Using human platelet-rich plasma (hPRP) from healthy donors, we assessed platelet aggregation in response to these two agonists in the absence and presence of graded concentrations of each of these drugs or of their usually prescribed combinations. The study identified differential drug effects on platelet aggregation, with some agents showing pathway-specific activity. Clopidogrel and NSAIDs demonstrated expected antiplatelet effects, while some (not all) antihypertensives exhibited additional anti-inflammatory potential. These findings highlight the relevance of evaluating pharmacological activity beyond traditional targets, particularly in relation to PAF-mediated inflammation and thrombosis. This dual-pathway analysis may contribute to a broader understanding of drug mechanisms and inform the development of more comprehensive therapeutic strategies for the prevention and treatment of cardiovascular, hypertension, and inflammation-driven diseases. Full article

Background: Platelets are highly enriched in microRNAs (miRNAs), which are genomically encoded 19–25 nucleotide non-coding RNAs that target complementary mRNAs through total or near-total base pairing. MiR-223 is among the most abundant miRNAs in human and murine platelets, but despite ongoing investigations in recent years, miR-223 roles in platelet physiology and its putative roles in high on-treatment platelet reactivity (HTPR) remain controversial, as studies showed varying findings. Objectives: In the current hybrid review/report, we aim to compare studies that investigated miR-223 in platelet function and HTPR. Additionally, we briefly report our own findings on murine miR-223-deficient platelets. Methods: We have thoroughly searched the literature and found three studies that investigated the roles of miR-223 in platelet function by utilizing miR-223 global knockout mice, and three studies that explored the association between miR-223 and residual platelet reactivity by measuring miR-223 levels in platelets of patients treated with clopidogrel for cardiac artery disease. We assessed platelet function in response to different agonists and evaluated P2y12 levels in male and female miR-223-deficient platelets. Results: Integrin activation and α granule secretion were similar between WT and KO platelets in response to all agonists in platelets from both female and male mice, although both genotypes showed elevated thrombin response in females compared to males. Conclusions: In all studies, including ours, taken together, miR-233 appears to play a modest role in platelet function and development of HTPR. Full article

The intersection of COVID-19 and cardiovascular disease (CVD) has emerged as a significant area of research, particularly in understanding the impact of antiplatelet therapies like ticagrelor and clopidogrel. COVID-19 has been associated with acute cardiovascular complications, including myocardial infarction, thrombosis, and heart failure, exacerbated by the virus’s ability to trigger widespread inflammation and endothelial dysfunction. MicroRNAs (miRNAs) play a critical role in regulating these processes by modulating the gene expressions involved in platelet function, inflammation, and vascular homeostasis. This study explores the potential of miRNAs such as miR-223 and miR-126 as biomarkers for predicting resistance or responsiveness to antiplatelet therapies in COVID-19 patients with cardiovascular disease. Identifying miRNA signatures linked to drug efficacy could optimize treatment strategies for patients at high risk of thrombotic events during COVID-19 infection. Moreover, understanding miRNA-mediated pathways offers new insights into how SARS-CoV-2 exacerbates CVD, particularly through mechanisms like cytokine storms and endothelial damage. The findings of this research could lead to personalized therapeutic approaches, improving patient outcomes and reducing mortality in COVID-19-associated cardiovascular events. With global implications, this study addresses the urgent need for effective management of CVD in the context of COVID-19, focusing on the integration of molecular biomarkers to enhance the precision of antiplatelet therapy. Full article

In this research, the optimization of the electrochemical advanced oxidation treatment for the degradation of Clopidogrel was investigated. This study examined the influence of various experimental parameters including applied current, initial Clopidogrel concentration, and ferrous ion concentration by the use of the Doehlert design within a response surface methodology framework. The improved grey wolf optimizer was applied in order to define the optimum operating conditions. The monitoring of clopidogrel concentration during treatment revealed that complete disappearance of clopidogrel was achieved under an initial clopidogrel concentration of 0.02 mM, current intensity of 0.55 A, Fe²⁺concentration of 0.7 mM, and a reaction time of 20 min in a solution containing 50 mM Na₂SO₄ at pH 3. A quadratic polynomial model was developed, and its statistical significance was confirmed through the analysis of variance, demonstrating a high level of confidence in the model (R² = 0.98 and p-value < 0.05). Furthermore, following electrolysis treatment for 480 min, the synthetic clopidogrel solutions underwent mineralization, achieving a 70.4% removal rate of total organic carbon. Subsequently, the applicability of the optimized process was tested on real pharmaceutical wastewater, and mineralization was investigated under the identified optimal conditions, resulting in a total organic carbon removal rate of 87% after 480 min of electrolysis time. The energy consumption for this system was calculated to be 1.4 kWh·kg⁻¹ of the total organic carbon removed. These findings underscore the effectiveness and potential applicability of the electrochemical advanced oxidation for industrial wastewater treatment. Full article

Platelets play a significant role in hemostasis, forming plugs at sites of vascular injury to limit blood loss. However, if platelet activation is not controlled, it can lead to thrombotic events, such as myocardial infarction and stroke. To prevent this, antiplatelet agents are used in clinical settings to limit platelet activation in patients at risk of arterial thrombotic events. However, their use can be associated with a significant risk of bleeding. An enhanced comprehension of platelet signaling mechanisms should facilitate the identification of safer targets for antiplatelet therapy. Over the past decade, our comprehension of the breadth and intricacy of signaling pathways that orchestrate platelet activation has expanded exponentially. Several recent studies have provided further insight into the regulation of platelet signaling events and identified novel targets against which to develop novel antiplatelet agents. Antiplatelet drugs are essential in managing atherothrombotic vascular disease. The current antiplatelet therapy in clinical practice is limited in terms of safety and efficacy. Novel compounds have been developed in response to patient variability and resistance to aspirin and/or clopidogrel. Recent studies based on randomized controlled trials and systematic reviews have definitively demonstrated the role of antiplatelet therapy in reducing the risk of cardiovascular events. Antiplatelet therapy is the recommended course of action for patients with established atherosclerosis. These studies compared monotherapy with a P2Y12 inhibitor versus aspirin for secondary prevention. However, in patients undergoing percutaneous coronary intervention, it is still unclear whether the efficacy of P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy depends on the type of P2Y12 inhibitor. This paper focuses on the advanced-stage evaluation of several promising antiplatelet drugs. Full article

Introduction: Patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) require dual antiplatelet therapy (DAPT). However, the response to treatment can vary considerably. Certain platelet microRNAs (miRs) are suspected to predict DAPT response and influence platelet function. This study aimed to analyze selected miRs’ expressions and compare them among patients treated with different P2Y₁₂ inhibitors while assessing their association with platelet activity and turnover parameters. Materials and methods: We recruited 79 ACS patients post-PCI treated with clopidogrel, ticagrelor, or prasugrel, along with 18 healthy volunteers. Expression levels of miR-126-3p, miR223-3p, miR-21-5p, miR-197-3p, and miR-24-3p, as well as immature platelet fraction (IPF) and ADP-induced platelet reactivity, were measured and compared between groups. Results: Analyses revealed significantly lower expressions of miR-126-3p, miR-223-3p, miR-21-5p, and miR-197-3p in patients treated with ticagrelor, compared to clopidogrel (fold changes from −1.43 to −1.27, p-values from 0.028 to 0.048). Positive correlations were observed between platelet function and the expressions of miR-223-3p (r = 0.400, p = 0.019) and miR-21-5p (r = 0.423, p = 0.013) in patients treated with potent drugs. Additionally, miR-24-3p (r = 0.411, p = 0.012) and miR-197-3p (r = 0.333, p = 0.044) showed correlations with IPF. Conclusions: The identified platelet miRs hold potential as biomarkers for antiplatelet therapy. (ClinicalTrials.gov number, NCT06177587). Full article

Pharmacogenetics (PGx) can explain/predict drug therapy outcomes. There is, however, unclarity about the use and usefulness of PGx in primary care. In this study, we investigated PGx tests ordered by general practitioners (GPs) in 2021 at Dept. Clinical Chemistry, Erasmus MC, and analyzed the gene tests ordered, drugs/drug groups, reasons for testing and single-gene versus panel testing. Additionally, a survey was sent to 90 GPs asking about their experiences and barriers to implementing PGx. In total, 1206 patients and 6300 PGx tests were requested by GPs. CYP2C19 was requested most frequently (17%), and clopidogrel was the most commonly indicated drug (23%). Regarding drug groups, antidepressants (51%) were the main driver for requesting PGx, followed by antihypertensives (26%). Side effects (79%) and non-response (27%) were the main indicators. Panel testing was preferred over single-gene testing. The survey revealed knowledge on when and how to use PGx as one of the main barriers. In conclusion, PGx is currently used by GPs in clinical practice in the Netherlands. Side effects are the main reason for testing, which mostly involves antidepressants. Lack of knowledge is indicated as a major barrier, indicating the need for more education on PGx for GPs. Full article

Cardiovascular disease (CVD) is one of the leading causes of death in Puerto Rico, where clopidogrel is commonly prescribed to prevent ischemic events. Genetic contributors to both a poor clopidogrel response and the severity of CVD have been identified mainly in Europeans. However, the non-random enrichment of single-nucleotide polymorphisms (SNPs) associated with clopidogrel resistance within risk loci linked to underlying CVDs, and the role of admixture, have yet to be tested. This study aimed to assess the possible interaction between genetic biomarkers linked to CVDs and those associated with clopidogrel resistance among admixed Caribbean Hispanics. We identified 50 SNPs significantly associated with CVDs in previous genome-wide association studies (GWASs). These SNPs were combined with another ten SNPs related to clopidogrel resistance in Caribbean Hispanics. We developed Python scripts to determine whether SNPs related to CVDs are in close proximity to those associated with the clopidogrel response. The average and individual local ancestry (LAI) within each locus were inferred, and 60 random SNPs with their corresponding LAIs were generated for enrichment estimation purposes. Our results showed no CVD-linked SNPs in close proximity to those associated with the clopidogrel response among Caribbean Hispanics. Consequently, no genetic loci with a dual predictive role for the risk of CVD severity and clopidogrel resistance were found in this population. Native American ancestry was the most enriched within the risk loci linked to CVDs in this population. The non-random enrichment of disease susceptibility loci with drug-response SNPs is a new frontier in Precision Medicine that needs further attention. Full article

In clinical practice, drug–drug interactions (DDIs) pose significant risks to a large number of patients. Consequently, healthcare providers are required to diligently identify, monitor, and effectively handle these interactions in order to enhance patient outcomes. In Egypt, DDIs are poorly addressed, with no reports for DDIs in primary care. In our cross-sectional, retrospective, observational study, we collected a total of five thousand, eight hundred and twenty prescriptions across eight major governorates in Egypt. Prescriptions were collected over a span of 15 months between 1 June 2021 and 30 September 2022. These prescriptions were analyzed for potential DDIs using the Lexicomp^® drug interactions tool. The prevalence of DDIs was found to be 18%, with 22% of the prescriptions having two or more potential DDIs. Moreover, we found 1447 DDIs of categories C (monitoring therapy recommended), D (therapy modification suggested), and X (avoid combination). The most commonly interacting drugs in our study were diclofenac, aspirin, and clopidogrel, while non-steroidal anti-inflammatory drugs (NSAIDs) were the most reported therapeutic class implicated in pharmacologic DDIs. Pharmacodynamic agonistic activity was the most common mechanism of interaction. Therefore, it is crucial to conduct screenings, detect early signs, and closely monitor drug–drug interactions (DDIs) to enhance patients’ overall health outcomes, medication responses, and safety. In this regard, the clinical pharmacist assumes a vital role in implementing these preventive measures. Full article

Background and Objectives: Dual antiplatelet therapy (DAPT) is essential in the treatment of patients with acute coronary syndrome (ACS). The objective of this study was to evaluate the effectiveness of antiplatelet medication in our practice and to investigate the factors that influence it. Materials and Methods: A prospective cohort observational study was conducted, in which 193 patients with ACS were enrolled. The patients were stented in the catheterization laboratory between May 2019 and October 2020, before and during the COVID-19 pandemic, and were receiving DAPT. Their platelet functions were tested using a Multiplate Analyzer. In addition to this, clinical data, demographics, laboratory tests, and cardiovascular risk factors were also analyzed. Results: 43.46% of the patients treated with aspirin were found to be resistant to it. This phenomenon was more common in men (48.17% vs. 31.48%, p = 0.036), and it was associated with being under the age of 50 (OR: 2.08; 95% CI: 1.11–3.90) and weighing over 70 kg (OR: 3.00; 95% CI: 1.21–7.40). Most of the patients treated with clopidogrel were in the optimal treatment window, while about half of the patients treated with ticagrelor had an exaggerated pharmacological response. Among the laboratory parameters, leukocytosis and platelet count were found to be determinants of platelet reactivity for both the aspirin and ticagrelor treatments. Conclusions: Many patients treated with antiplatelet agents are outside of the treatment window. The results obtained showed that low doses of gastro-resistant aspirin tablets are ineffective, and their efficacy can be influenced by various clinical and laboratory factors. Patients receiving ticagrelor have significantly reduced platelet reactivity, influenced only by certain laboratory indicators. The pandemic significantly influenced the results of the platelet aggregation tests only in patients treated with clopidogrel. Full article

Serotonin (5-hydroxytriptamine or 5-HT) is known to be a weak platelet agonist, and is involved in thrombus formation. While 5-HT cannot induce platelet aggregation on its own, when secreted from the alpha granules, it binds to its G-protein Coupled Receptor (GPCR; i.e., 5HT_2AR), thereby acting to amplify platelet functional responses (e.g., aggregation). Thus, 5HT_2AR-mediated responses are more involved in the secondary amplification of platelet aggregation in the growing thrombus. Therefore, even though 5-HT can be seen as a weak inducer of platelet activation, it is an important amplifier of aggregation triggered by agonists such as ADP, collagen, and epinephrine, thereby enhancing thrombogenesis. The 5HT_2AR/5HT_2A signaling pathway is of clinical interest to the scientific and medical communities as it has been implicated in the genesis of several forms of cardiovascular disorders. However, efforts to develop antagonists for 5HT_2AR as therapeutic agents in cardiovascular diseases have thus far failed due to these reagents having deleterious side-effects, and/or to lack of selectivity, amongst other reasons. In light of research efforts that identified that the 5HT_2AR ligand binding domain resides in the second extracellular loop (EL2; amino acids P²⁰⁹-N²³³), we developed an antibody, i.e., referred to as 5HT_2ARAb, against the EL2 region, and characterized its pharmacological activity in the context of platelets. Thus, we utilized platelets from healthy human donors, as well as C57BL/6J mice (10–12 weeks old) to analyze the inhibitory effects of the 5HT_2ARAb on platelet activation in vitro, ex vivo, and on thrombogenesis in vivo as well as on 5HT_2AR ligand binding. Our results indicate that the 5HT_2ARAb inhibits 5-HT-enhanced platelet activation in vitro and ex vivo, but has no apparent effects on that which is agonist-induced. The 5HT_2ARAb was also found to prolong the thrombus occlusion time, and it did so without modulating the tail bleeding time, in mice unlike the P2Y12 antagonist clopidogrel and the 5HT_2AR antagonist ketanserin. Moreover, it was found that the 5HT_2ARAb does so by directly antagonizing the platelet 5HT_2AR. Our findings document that the custom-made 5HT_2ARAb exhibits platelet function blocking activity and protects against thrombogenesis without impairing normal hemostasis. Full article

Background: East Asian patients receiving treatment with the potent P₂Y₁₂ inhibitors prasugrel or ticagrelor experience more potent platelet inhibition than with clopidogrel. Methods: This study investigated differences in OPR rates with reduced doses of prasugrel (n = 38) or ticagrelor (n = 40) for maintenance therapy in 118 Korean ACS patients who had undergone PCI, in comparison to conventional-dose clopidogrel (n = 40). We assessed drug responses at one- and three-months post-PCI with VerifyNow and multiple electrode aggregometry assays. Results: At the one-month period, patients receiving standard-dose prasugrel or ticagrelor had lower platelet reactivity as determined by the three assays than those receiving the conventional dose of clopidogrel (VN: p = 0.000; MEA: p = 0.000; LTA: p = 0.000). At the 3-month point, platelet reactivity was lower in those receiving reduced-dose prasugrel or ticagrelor than the clopidogrel-treated patients (VN: p = 0.000; MEA: p = 0.012; LTA: p = 0.002). Prasugrel resulted in significantly lower platelet inhibition than ticagrelor as determined by VN and LTA (VN: p = 0.000; LTA: p = 0.003). At three months, there was a significant overall difference in OPR among the three groups when measured by VN (p < 0.001), but not when measured by MEA (p = 0.596). OPR in the reduced-dose prasugrel group was not significantly different to the clopidogrel group at three months (VN: p = 0.180; MEA: p = 0.711). OPR in the reduced-dose ticagrelor group was similar to clopidogrel as determined by MEA at three months, but was different when assessed by VN (VN: p = 0.000; MEA: p = 0.540). Compared to standard-dose, the reduced-dose prasugrel OPR rate was significantly increased (VN: p = 0.008; MEA: p = 0.020). Conclusions: OPR values for reduced-dose prasugrel and conventional-dose clopidogrel at three months were similar but higher than for reduced-dose ticagrelor as determined by VN, but no differences were noted by MEA. The MEA assay might have less sensitivity and consistency than the VN assay. Further studies are needed to explore this discrepancy. Full article