Differential effects of clopidogrel and/or aspirin on the healing of tooth extraction wound bone tissue.

Introduction: A multitude of variables influence the healing of tooth extraction wounds, and delayed or non-healing extraction wounds might complicate later prosthodontic therapy. In this research, we analyzed the effects of systemic clopidogrel and aspirin alone or in combination on the healing of tooth extraction wounds in mice in order to provide experimental evidence for the healing of extraction wounds in patients who are clinically treated with the two medicines. Methods: 7-week-old ICR mice were randomly divided into four groups: control group (CON), clopidogrel group (CLOP), aspirin group (ASP), and clopidogrel combined with aspirin group (CLOP + ASP); left upper first molar was extracted, after which mice in 1 week of adaptive feeding, CLOP/ASP/CLOP + ASP groups were respectively administered with clopidogrel (10 mg/kg/d), aspirin (15 mg/kg/d), clopidogrel (10 mg/kg/d)+aspirin (15 mg/kg/d), and the control group was given an equal amount of 0.9% saline by gavage. Mice in each group were euthanized at 14 and 28 days postoperatively, and the maxilla was extracted. The tissues in the extraction sockets were examined using MicroCT and sectioned for HE staining, Masson staining, and TRAP staining, and immunohistochemistry staining (for TRAP, RANKL and osteoprotegerin). Results: MicroCT analysis showed that at day 14, BS/BV was significantly lower in CLOP and CLOP + ASP groups compared to control and ASP groups, while BV/TV, Tb.Th was significantly higher. At day 28, BV/TV was significantly higher in the CLOP + ASP group compared to the CLOP group, with p < 0.05 for all results. HE staining and Masson trichrome staining findings revealed that at day 28, the mesenchyme in the bone was further decreased compared to that at day 14, accompanied with tightly arranged and interconnected bone trabeculae. In the quantitative analysis of Masson, the fraction of newly formed collagen was significantly higher in the CLOP group in comparison with that in the CON group (p < 0.05). At day 14, the ASP group had substantially more TRAP-positive cells than the CLOP and CLOP + ASP groups (p < 0.05). In immunohistochemical staining, RANKL expression was found to be significantly higher in the ASP group than those in the other three groups at day 28 (p < 0.05); OPG expression was significantly higher in the CLOP group and the CLOP + ASP group compared with that at day 14, and was higher than that in the ASP group at day 14 and day 28. OPG/RANKL was significantly higher in the CLOP and the CLOP + ASP groups than in the ASP group (p < 0.05). Conclusion: Clopidogrel alone promotes osteogenesis in the extraction wound, whereas aspirin alone inhibits alveolar bone healing. When the two drugs were combined, the healing effect of the extraction wound was more similar to that of the clopidogrel alone group. These results indicated that clopidogrel could promote the healing of the tooth extraction wound, and neutralize the adverse effect of ASP on osteogenesis when the two drugs were used in combination.

Early detection of resistance to dual antiplatelet therapy in patients who have undergone percutaneous coronary intervention using the VerifyNow test and associated factors.

Resistance to dual antiplatelet therapy (DAPT), including aspirin and clopidogrel, in patients who have undergone percutaneous coronary intervention (PCI) leads to the inability to prevent thrombotic complications. The present study aimed to evaluate early resistance to aspirin and clopidogrel in patients following PCI using the VerifyNow test and associated factors. A total of 50 patients diagnosed with acute coronary syndromes (ACS) who underwent emergency PCI and received DAPT were recruited in the present study. The detection of resistance to aspirin and clopidogrel was performed using the VerifyNow system. Resistance to aspirin was determined with VerifyNow Aspirin >550 aspirin reaction units (ARU). Resistance to clopidogrel was determined with VerifyNow P2Y12 >208 P2Y12 reaction units (PRU). The resistance rate to aspirin was 14%, while the resistance rate to clopidogrel was higher, at 34%. There were 2 patients with resistance to aspirin and clopidogrel (4%). Univariable logistic regression analysis revealed that diabetes, the use of ß-blockers, and low levels of hemoglobin and hematocrit were associated with resistance to clopidogrel. Following multivariable logistic regression analysis, only the use of ß-blockers was truly associated with resistance to clopidogrel. On the whole, the results of the present study may also prove to be helpful in the selection of therapeutic drugs for patients undergoing PCI and who are diagnosed with ACS.

Impact of proton pump inhibitor use on clinical outcomes in East Asian patients receiving clopidogrel following drug-eluting stent implantation.

BACKGROUND: Concomitant use of clopidogrel and proton pump inhibitor (PPI) is common, but PPI may reduce the antiplatelet effects of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We evaluated the impact of PPI use on clinical outcomes in post-PCI patients, by incorporating P2Y12 reaction unit (PRU) and CYP2C19 genotyping results. METHODS: From a multicenter registry of patients who underwent PCI with drug-eluting stent implantation and received clopidogrel-based dual antiplatelet therapy (DAPT), patients who were prescribed a PPI at the time of PCI (PPI users) were compared to those who were not (non-users). The primary outcome included all-cause death, myocardial infarction, stent thrombosis, or cerebrovascular accident at 12 months. Major bleeding (Bleeding Academic Research Consortium [BARC] types 3-5) and gastrointestinal (GI) bleeding (BARC types 3-5) were important secondary outcomes. The adjusted outcomes were compared using a 1:1 propensity-score (PS) matching and competing risk analysis. RESULTS: Of 13,160 patients, 2,235 (17.0%) were prescribed PPI, with an average age of 65.4 years. PPI users had higher on-treatment PRU levels than non-users. After PS matching, the primary outcome occurred in 51 patients who were PPI users (cumulative incidence, 4.7%) and 41 patients who were non-users (cumulative incidence, 3.7%; log-rank p = 0.27). In carriers of both CYP2C19 loss-of-function alleles, PPI use was linked to an increased risk of the primary outcome (hazard ratio, 3.22; 95% confidence interval, 1.18-8.78). The incidence of major bleeding and GI bleeding (BARC types 3-5) was comparable between PPI users and non-users in the PS-matched cohort. CONCLUSIONS: In post-PCI patients receiving clopidogrel-based DAPT, PPI use was not linked to an increased risk of adverse cardiac and cerebrovascular events, but there was a small but significant increase in on-treatment PRU. Future research using a more individualized approach would further elucidate these interactions and guide evidence-based clinical practices.

Can CYP2C19 genotyping improve antiplatelet therapy efficacy in real-life practice? Recent advances.

Clopidogrel remains the most widely used P2Y12 receptor inhibitor worldwide and is often used in combination with aspirin for secondary prevention in patients with arterial disease. The drug is associated with a wide response variability with one on three patients exhibiting little or no inhibition of adenosine diphosphate-induced platelet aggregation. It is a prodrug that is mainly metabolized by hepatic cytochrome P450 (CYP) 2C19. Patients who carry a CYP2C19 loss-of-function (LoF) allele have reduced metabolism of clopidogrel that is associated with reduced platelet inhibition compared to non-carriers that is associated with increased risk for thrombotic event occurrences, particularly, stent thrombosis. The United States Food and Drug Administration (US FDA) issued a black box warning in the clopidogrel label highlighting the importance of presence of CYP2C19 LOF allele during the insufficient metabolism of clopidogrel and availability of other potent P2Y12 inhibitor for the treatment in CYP2C19 poor metabolizers. Clinical trials have conclusively demonstrated greater anti-ischemic benefits of prasugrel/ticagrelor in the treatment of patients carrying the CYP2C19 LoF allele. However, uniform use of these more potent P2Y12 inhibitors has been associated with greater bleeding and cost, and lower adherence. The latter information provides a strong rationale for personalizing P2Y12 inhibitor therapy based on the laboratory determination of CYP2C19 genotype. However, cardiologists have been slow to take up pharmacogenetic testing possibly due to lack of provider and patient education, clear cardiology guidelines and, and lack of positive results from adequately sized randomized clinical trials. However, current evidence strongly supports genotyping of patients who are candidates for clopidogrel. Physicians should strongly consider performing genetic tests to identify LoF carriers and treat these patients with more pharmacodynamically predictable P2Y12 inhibitors than clopidogrel.

Updated Assessment of Practice Patterns of Perioperative Management of Antiplatelet and Anticoagulant Therapy in Interventional Pain Management.

BACKGROUND: The role of antiplatelet/anticoagulant therapy is well known for its primary and secondary prevention of sequela from cardiovascular disease by decreasing the incidence of acute cerebral, cardiovascular, peripheral vascular, and other thrombo-embolicevents. The overwhelming data show that the risk of thrombotic events is significantly higher than that of bleeding during surgery after antiplatelet drug discontinuation. It has been assumed that discontinuing antiplatelet therapy prior to performing interventional pain management techniques is a common practice, even though doing so may potentially increase the risk of acute cerebral and cardiovascular events. A survey of practice patterns was conducted in 2012, since then the risks associated with thromboembolic events and bleeding, has not been systematically evaluated. OBJECTIVE: To conduct an updated assessment of the perioperative antiplatelet and anticoagulant practice patterns of U.S. interventional pain management physicians and compare this with data collected in 2012 with 2021 data regarding practice patterns of continuing or discontinuing anticoagulant therapy. STUDY DESIGNn: Postal survey of interventional pain management physicians. STUDY SETTING: Interventional pain management practices in the United States. METHODS: The survey was conducted based on online responses of the members of the American Society of Interventional Pain Physicians (ASIPP) in 2021. The survey was designed similar to the 2012 survey to assess updated practice patterns. RESULTS: The questionnaire was sent out to 1,700 members in October 2021. Out of these, 185 members completed the survey, while 105 were returned due to invalid addresses. The results showed that 23% changed their practice patterns during the previous year. The results also showed that all physicians discontinued warfarin therapy with the majority of physicians accepting an INR of 1.5 as a safe level. Low dose aspirin (81 mg) was discontinued for 3 to 7 days for low-risk procedures by 8% of the physicians, 34% of the physicians for moderate or intermediate risk procedures, whereas they were discontinued by 76% of the physicians for high-risk procedures. High dose aspirin (325 mg) was discontinued at a higher rate. Antiplatelet agents, including dipyridamole, cilostazol, and Aggrenox (aspirin, extended-release dipyridamole) were discontinued from 3 to 5 days by 18%-23% of the physicians for low-risk procedures, approximately 60% of the physicians for moderate or intermediate-risk procedures, and over 90% of the physicians for high-risk procedures. Platelet aggregation inhibitors clopidogrel, prasugrel, ticlopidine, and ticagrelor were discontinued for 3 to 5 days by approximately 26% to 41% for low-risk procedures, almost 90% for moderate or intermediate-risk procedures, and over 97% for high-risk procedures. Thrombin inhibitor dabigatran was discontinued by 33% of the physicians for low-risk procedures, 92% for moderate or intermediate-risk procedures, and 99% for high-risk procedures. Anti-Xa agents, apixaban, rivaroxaban, and Edoxaban were discontinued in over 25% of the physicians for low-risk procedures, approximately 90% for moderate or intermediate-risk procedures, and 99% for high-risk procedures. LIMITATIONS: This study was limited by its being an online survey of the membership of one organization in one country, that there was only a 11.6% response rate, and the sample size is relatively small. Underreporting in surveys is common. Further, the incidence of thromboembolic events or epidural hematomas was not assessed. CONCLUSION: The results in the 2021 survey illustrate a continued pattern of discontinuing antiplatelet and anticoagulant therapy in the perioperative period. The majority of discontinuation patterns appear to fall within guidelines.

A network meta-analysis: evaluating the efficacy and safety of concurrent proton pump inhibitors and clopidogrel therapy in post-PCI patients.

Introduction: The objective of this research was to evaluate the risk of major adverse cardiovascular events (MACEs) associated with the use of various proton pump inhibitors (PPIs) in combination with clopidogrel in patients who underwent percutaneous coronary intervention (PCI). Methods: To accomplish this, we analyzed data from randomized controlled trials and retrospective cohort studies sourced from key electronic databases. These studies specifically examined the effects of different PPIs, such as lansoprazole, esomeprazole, omeprazole, rabeprazole, and pantoprazole, when used in conjunction with clopidogrel on MACEs. The primary focus was on the differential impact of these PPIs, while the secondary focus was on the comparison of gastrointestinal (GI) bleeding events in groups receiving different PPIs with clopidogrel vs. a placebo group. This study's protocol was officially registered with INPLASY (INPLASY2024-2-0009). Results: We conducted a network meta-analysis involving 16 studies with a total of 145,999 patients. Our findings indicated that rabeprazole when combined with clopidogrel, had the lowest increase in MACE risk (effect size, 1.05, 95% CI: 0.66-1.66), while lansoprazole was associated with the highest risk increase (effect size, 1.48, 95% CI: 1.22-1.80). Esomeprazole (effect size, 1.28, 95% CI: 1.09-1.51), omeprazole (effect size, 1.23, 95% CI: 1.07-1.43), and pantoprazole (effect size, 1.38, 95% CI: 1.18-1.60) also significantly increased MACE risk. For the secondary outcome, esomeprazole (effect size, 0.30, 95% CI: 0.09-0.94), omeprazole (effect size, 0.34, 95% CI: 0.14-0.81), and pantoprazole (effect size, 0.33, 95% CI: 0.13-0.84) demonstrated an increased potential for GI bleeding prevention. Conclusions: In conclusion, the combination of lansoprazole and clopidogrel was found to significantly elevate the risk of MACEs without offering GI protection in post-PCI patients. This study is the first network meta-analysis to identify the most effective regimen for the concurrent use of clopidogrel with individual PPIs. Systematic Review Registration: https://inplasy.com/inplasy-2024-2-0009/, identifier (INPLASY2024-2-0009).

Non-invasive recanalization of first-generation sirolimus-eluting stent thrombosis due to stent fracture and coronary artery aneurysm after clopidogrel treatment 15 years after implantation.

In 2020, a 48-year-old male patient was admitted to our hospital due to unstable angina. In 2005, three first-generation sirolimus-eluting stents (1st-SESs) had been deployed to his right coronary artery (RCA). Over the past 10 years or so, the patient has been treated with single antiplatelet therapy using aspirin. Coronary angiography (CAG) revealed severe stenosis in the left circumflex artery (LCx) and total occlusion at the proximal portion of the stented RCA. Furthermore, fluoroscopy showed multiple 1st-SES fractures. After ad hoc percutaneous coronary intervention of the LCx, dual antiplatelet therapy (DAPT) was resumed by adding the P2Y12 inhibitor clopidogrel to aspirin. Two months later, CAG revealed complete recanalization and multiple peri-stent coronary artery aneurysms (CAAs) in the RCA. Intravascular ultrasound revealed late-acquired stent malapposition (LSM) and formation of true aneurysms. Coronary angioscopy showed the uncovered struts of the 1st-SES and mural red thrombus. DAPT was continued thereafter, and 8 months later, follow-up CAG showed no significant RCA restenosis. To date, the patient remains free from cardiovascular events. This report documents a rare case of thrombotic occlusion of a 1st-SES with LSM, CAA, and stent fractures followed by non-invasive recanalization after clopidogrel treatment 15 years after 1st-SES implantation. Learning objective: Stent thrombosis due to stent fracture and coronary aneurysm can occur even years after first-generation sirolimus-eluting stent (1st-SES) implantation. Risk assessment using coronary imaging should be made and long-term dual antiplatelet therapy (DAPT) should be recommended in patients with a high risk of stent thrombosis after 1st-SES implantation. In cases of stent thrombosis of the 1st-SES, resuming DAPT, including P2Y12 receptor inhibitors, may be a useful non-invasive treatment option.

Clopidogrel Hyperresponsiveness and Hemorrhagic Complications Using On-Label Clopidogrel Dosing after Pipeline Embolization.

Introduction: Clopidogrel hyperresponsiveness is a timely topic, with wide ranging reports of hemorrhagic complications, using various clopidogrel dosing strategies following neuroendovascular procedures. This study serves to investigate hemorrhagic complications using standard clopidogrel doses and timing of these complications in relation to the procedure. Materials and Methods: Retrospective cohort of consecutive adult patients undergoing flow diversion with Pipeline Embolization Device (PED) at an academic medical center, receiving on-label clopidogrel doses. Patients with clopidogrel hyperresponsiveness (VerifyNowTM P2Y12 reaction unit (PRU) ≤ 70) were compared to those who were normoresponsive. The primary outcome is the rate of hemorrhagic complications between groups. Results: Of 148 included patients, 54 (36.5%) were identified as clopidogrel hyperresponsive (PRU ≤ 70) and 94 (63.5%) as clopidogrel normoresponsive (PRU 71 - 194). There were no hemorrhagic complications observed in patients who were clopidogrel hyperresponsive, with 5 occurring in patients who were normoresponsive (P = 0.09). Three (60%) of the hemorrhages were intracranial with most occurring intra-procedure or within the first week of the procedure. Age > 60 years was the only candidate predictor for hemorrhagic complications (P = 0.004). Conclusion: Our findings are contradictory, with lower hemorrhagic complications in clopidogrel hyperresponders than prior literature, and most occurring intra-op or in the immediate acute post-op phase.

Clopidogrel-Mediated P2Y12 Inhibition According to Renal Function in Patients With Diabetes Mellitus and CAD.

This prospective ex vivo and in vitro pharmacodynamic (PD)/pharmacokinetic investigation was conducted in patients with diabetes mellitus with (n = 31) and without chronic kidney disease (n = 30). PD assessments included platelet reactivity index, maximum platelet aggregation, and P2Y12 reaction units. Ex vivo pharmacokinetic assessments included plasma levels of clopidogrel and its active metabolite. In vitro PD assessments were conducted on baseline samples incubated with escalating concentrations of clopidogrel and its active metabolite. Among patients with diabetes mellitus treated with clopidogrel, impaired renal function was associated with increased maximum platelet aggregation. This finding could be attributed partially to upregulation of the P2Y12 activity without differences in drug absorption or metabolism. (Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus; NCT03774394).

Efficacy and safety of aspirin plus clopidogrel versus aspirin alone in ischemic stroke or high-risk transient ischemic attack: A meta-analysis of randomized controlled trials.

Background: Antiplatelet therapy plays an important role in reducing the risk of stroke recurrence in patients with mild ischemic stroke or high-risk transient ischemic attack (TIA). However, data regarding the effectiveness and safety of using aspirin plus clopidogrel in dual antiplatelet therapy (DAPT) compared to aspirin alone in mild ischemic stroke is limited. Methods: PubMed/MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) that compared DAPT to aspirin alone started within 72 hours in mild ischemic stroke or high-risk TIA. We used a random effects model to pool risk ratios (RRs) along with 95% CIs for clinical outcomes. Results: Four RCTs with 16,547 patients were included in this study. DAPT significantly reduced the risk of recurrent stroke by 26% (RR: 0.74; 95% CI: 0.67-0.83; p < 0.00001), ischemic stroke by 28% (RR: 0.72; 95% CI: 0.65-0.80; p < 0.00001), and major adverse cardiovascular events (MACE) by 24% (RR: 0.76; 95% CI: 0.68-0.84; p < 0.00001) compared to aspirin monotherapy. However, DAPT was associated with a significantly increased risk of moderate or severe bleeding (RR: 1.88; 95% CI: 1.10-3.23; p = 0.02) compared to aspirin alone. No significant differences were observed for hemorrhagic stroke (RR: 1.77; 95% CI: 0.96-3.29; p = 0.07), all-cause mortality (RR: 1.25; 95% CI: 0.87-1.80; p = 0.23), cardiovascular mortality (RR: 1.38; 95% CI: 0.81-2.33; p = 0.23), and myocardial infarction (RR: 1.63; 95% CI: 0.77-3.46; p = 0.20). Conclusion: DAPT involving aspirin plus clopidogrel reduces stroke recurrence and MACE but can lead to an increased risk of moderate or severe bleeding compared to aspirin monotherapy. (PROSPERO ID: CRD42024499310).

Effect of loss-of-function CYP2C19 variants on clinical outcomes in coronary artery disease patients treated with clopidogrel: A systematic meta-analysis approach.

For many years, clopidogrel has been a commonly utilised antiplatelet drug in the management of coronary artery disease (CAD). It's thought that the CYP2C19 loss of function (LoF) polymorphism causes clopidogrel's poor metabolism, which eventually leads to resistance. Previous research produced extremely divergent and inconsistent results, making it impossible to draw definitive conclusions. Therefore, current, investigation was carried out to obtain definitive evidence from an updated meta-analysis on the connection between CYP2C19 LoF polymorphism and coronary artery event in patients treated with clopidogrel. 52,542 individuals with coronary artery disease who were receiving clopidogrel treatment were included in 87 carefully chosen trials from reliable databases that we used for our meta-analysis. According to our data, those who carry one or more CYP2C19 LoF alleles worldwide are much more likely to experience composite events and coronary artery events than people who do not carry these alleles, especially in Asian populations. Our meta-analysis observed that the global population, particularly Asians receiving clopidogrel treatment, is at risk of recurrent coronary artery events and composite events if they carry the CYP2C19 LoF alleles. Additional research is essential on alternative antiplatelet therapies for individuals who exhibit poor or intermediate metabolic activity. OBJECTIVES: 1.To systematically analyze the current evidence regarding the association of CYP2C19 variants with coronary artery disease (CAD). 2.To conduct a meta-analysis to investigate the association between loss of function (LoF) CYP2C19 modifications and CAD.

P2Y12 Inhibitor Monotherapy After Short DAPT in Acute Coronary Syndrome: A Systematic Review and Meta-analysis.

BACKGROUND: P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) may balance ischemic and bleeding risks in patients with acute coronary syndrome (ACS). However, it remains uncertain how different P2Y12 inhibitors used as monotherapy affect outcomes. METHODS: Randomized controlled trials comparing P2Y12 inhibitor monotherapy after a short course of DAPT (≤3 months) versus 12-month DAPT in ACS were included. The primary endpoint was major adverse cardiovascular events (MACE). All analyses included an interaction term for the P2Y12 inhibitor used as monotherapy. Trial sequential analysis were run to explore whether the effect estimate of each outcomes may be affected by further studies. RESULTS: Seven trials encompassing 27,284 ACS patients were included. Compared with 12-month DAPT, P2Y12 inhibitor monotherapy after a short course of DAPT was associated with no difference in MACE (OR 0.92, 95% CI 0.76-1.12) and a significant reduction in net adverse clinical events (NACE) (OR 0.75; 95% CI 0.60-0.94), any bleeding (OR 0.54, 95% CI 0.43-0.66) and major bleeding (OR 0.47, 95% CI 0.37-0.60). Significant interactions for subgroup difference between ticagrelor and clopidogrel monotherapy were found for MACE (pint=0.016), all-cause death (pint=0.042), NACE (pint=0.018), and myocardial infarction (pint=0.028). Trial sequential analysis showed conclusive evidence of improved NACE with ticagrelor, but not with clopidogrel monotherapy, compared with standard DAPT. CONCLUSIONS: In patients with ACS, P2Y12 inhibitor monotherapy after short DAPT halves bleeding without increasing ischemic events compared with standard DAPT. Ticagrelor, but not clopidogrel monotherapy, reduced MACE, NACE and mortality compared with standard DAPT, supporting its use after aspirin discontinuation. Protocol registration: This study is registered in PROSPERO (CRD42023494797).

Pharmacogenomic Polygenic Model of Clopidogrel Predicts Recurrent Ischemic Events in Chinese Patients With Coronary Artery Disease.

PURPOSE: Patients with coronary artery disease (CAD) need to take antiplatelet drugs regularly in order to prevent thrombosis; however, there is existing inter-individual variability in drug response. Pharmacogenomic studies indicate that drug response may also be influenced by genetic variants, and multiple genetic variants may work together. We assumed that patients carrying more risk alleles might have a worse clopidogrel drug response and that a polygenic model integrated different single variants might have the potential to explain clopidogrel drug response variability better. We aimed to investigate whether the polygenic model could be used to predict clopidogrel drug response. METHODS: A total of 935 CAD patients were enrolled in the study. We investigated the association between 19 clopidogrel-related single-nucleotide polymorphisms (SNPs) and the incidence of recurrent ischemic events. Additionally, a polygenic model was constructed to assess the risk of ischemic events. FINDINGS: There were only 2 SNPs of CYP2C8 gene (rs1934980 and rs17110453) that were nominally associated with incidence of recurrent ischemic events. We constructed a polygenic model integrated with 6 clopidogrel-related SNPs. When compared with patients carrying 6 or fewer risk alleles, patients with 7 or more risk alleles had a higher risk of ischemic events (hazard ratio = 1.87; P = 0.04). IMPLICATIONS: The polygenetic model may be useful for clopidogrel drug response prediction in patients with CAD.

Evaluation of clopidogrel response in healthy cats using a novel viscoelastic test and thromboelastography.

Introduction: Cats with cardiomyopathy face an increased risk of arterial thromboembolism (ATE). Although clopidogrel is frequently utilized to mitigate this risk, feline responses to this therapy exhibit variability. This study evaluated 2 viscoelastic devices, thromboelastography (TEG) and Viscoelastic Coagulation Monitor (VCM), for monitoring clopidogrel in cats in comparison to light transmission aggregometry (LTA). Methods: Twenty-eight healthy cats received clopidogrel for 7 days. Blood was collected at baseline and after treatment for analysis by TEG, VCM, and LTA. Results: On LTA, maximum amplitude, slope, and area under the curve (AUC) significantly decreased after treatment (p < 0.0001). On VCM, maximum clot firmness (MCF) significantly increased after treatment (p = 0.002). On TEG, R-time significantly prolonged (p = 0.024), while K and alpha angle significantly changed (p = 0.0002 and p = 0.0014, respectively). There was a moderate negative correlation between TEG R-time and LTA AUC (r = -0.39, p = 0.042). Eight cats were identified as non-responders to clopidogrel. Of the 8 non-responders, 6 (75%) had shortened R time after treatment. VCM appeared to be less discriminatory in identifying non-responders. Discussion: LTA remained the gold standard of monitoring clopidogrel treatment in cats. Unexpected changes on VCM and TEG were likely related to high interindividual and assay variability and increased sensitivity of feline platelets. R-time on TEG may have potential utility for point-of-care monitoring of clopidogrel response in cats.

Clopidogrel resistance and its effect on clinical outcomes in acute coronary syndrome.

AIM: The genetic polymorphism of CYP2C19 influences clopidogrel metabolism and resistance. Aim was to assess the association between CYP2C19 loss of function variation, clopidogrel resistance based on platelet reactivity units and clinical outcomes. METHODS: A total of 668 patients of Acute Coronary Sundrome (ACS) who underwent Percutaneous Coronary Intervention (PCI) were subjected to genetic screening and 143 patients undrewent platelet function test to study the association between drug metabolization and its effects based on platelet reactivity unit values. RESULTS: Clopidogrel resistance with CYP2C 19 loss of function variation was noted in 54.64% of patients. Clinical outcomes, such as target vessel revascularization, target lesion revascularization, in-stent restenosis, and stent thrombosis, were also studied. CONCLUSION: CYP2C19 loss of function variation is strongly associated with clopidogrel resistance and adverse clinical outcomes.

Duration of triple antithrombotic therapy and clinical outcomes after percutaneous coronary intervention in atrial fibrillation.

BACKGROUND: Triple antithrombotic therapy (TAT) with aspirin, a P2Y12 inhibitor, and oral anticoagulation in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) raises concerns about increased bleeding. Regimens incorporating more potent P2Y12 inhibitors over clopidogrel have not been investigated adequately. RESEARCH DESIGN AND METHODS: A retrospective observational study was performed on 387 patients with AF receiving TAT for 1 month (n = 236) or ≤1 week (n = 151) after PCI. Major and clinically relevant non-major bleeding and major adverse cardiac and cerebrovascular events (MACCE) were assessed up to 30 days post-procedure. RESULTS: Bleeding was less frequent with ≤1 week versus 1 month of TAT (3.3 vs 9.3%; p = 0.025) while MACCE were similar (4.6 vs 4.7%; p = 0.998). No differences in bleeding or MACCE were observed between ticagrelor/prasugrel and clopidogrel regimens. For patients receiving ≤1 week of TAT, no excess of MACCE was seen in the subgroup given no further aspirin post-PCI compared with those given aspirin for up to 1 week (3.6 vs 5.2%). CONCLUSIONS: TAT post-PCI for ≤1 week was associated with less bleeding despite greater use of ticagrelor/prasugrel but similar MACCE versus 1-month TAT. These findings support further studies on safety and efficacy of dual therapy with ticagrelor/prasugrel immediately after PCI.

Clinical Outcomes of Aspirin and Clopidogrel among Patients with Chronic Obstructive Lung Disease: Insights from a Meta-Analysis.

(1) Background: Aspirin and clopidogrel have been found helpful in improving clinical outcomes among patients with chronic obstructive lung disease (COPD). However, the evidence on the efficacy of aspirin and/or clopidogrel on clinical outcomes has not been synthesized and summarized in the prior reviews. Hence, we undertook a meta-analysis of the research studies examining the effect of aspirin and/or clopidogrel on varying clinical outcomes among COPD patients; (2) Methods: Using key search terms, we searched databases, including MEDLINE, CINAHL, Google Scholar, and EMBASE to find observational studies and RCTs. Our search was limited to research written in English. We used a random effect model to calculate the 95% confidence intervals and pooled hazard ratio; (3) Results: We included 12 eligible research studies (33,8008 patients) in the current meta-analysis. Among COPD patients, the hazard of all-cause mortality among users of aspirin or clopidogrel was 17% lower (HR: 0.83; 95% CIs (0.70, 0.97; I2 = 73%, X2: 33.34) compared to non-users of anticoagulants (aspirin or clopidogrel). The hazard of dyspnea among users of aspirin or clopidogrel was 3% lower (HR: 0.97; 95% CIs (0.27, 3.49; I2 = 93%, X2: 42.15) compared to non-users of anticoagulants (aspirin or clopidogrel). There was no statistically significant effect of aspirin on other clinical outcomes such as myocardial infarction (HR: 2.04; 95% CIs (0.02, 257.33) and major bleeding (HR: 1.93; 95% CIs (0.07, 1002.33). The funnel plot and Egger's regression test did not show any evidence of publication bias; (4) Conclusions: Overall, we found a positive and beneficial effect of aspirin and/or clopidogrel in reducing all-cause mortality among COPD patients. However, there is uncertainty of evidence for other clinical outcomes such as exacerbation of dyspnea, myocardial infarction, and major bleeding. A limited number of studies examining other clinical outcomes warrant conducting more robust epidemiological studies to assess the efficacy and safety of aspirin and clopidogrel on other clinical outcomes among COPD patients.

An update on oral antiplatelet drug interactions with proton pump inhibitors: what are the risks?

INTRODUCTION: Aspirin and anti-P2Y12 are widely prescribed in cardiovascular patients, often in combination with proton pump inhibitors (PPIs) to limit the risk of upper gastrointestinal bleedings. The potential interaction between PPIs and antiplatelet agents has been widely discussed, but doubts remain as to whether PPIs may reduce the cardiovascular protection provided by aspirin, prasugrel, ticagrelor, and clopidogrel. AREAS COVERED: Many pharmacokinetic (PK) and pharmacodynamic (PD) studies have confirmed the interaction, especially between PPIs and clopidogrel, but with uncertain consequences on clinical outcomes. Therefore, we aimed to summarize the evidence for the widespread combined use of oral antiplatelet drugs and PPIs, to outline the current evidence supporting or opposing drug-drug interaction, and to discuss the clinical implications of such interactions. EXPERT OPINION: A large body of evidence describes the PK/PD interaction of antiplatelet drugs with PPIs and its potential role in increasing clinical cardiovascular adverse events, but no solid clinical data have confirmed these effects. In the light of the published studies, there seems to be no restriction on the choice of PPI with aspirin, prasugrel, and/or ticagrelor. The choice of a PPI with no (or minimal) interference with the hepatic cytochrome P450 2C19 is preferred in patients receiving clopidogrel.

The pharmacology of antiplatelet agents for primary, secondary, and tertiary prevention of ischemic stroke.

INTRODUCTION: Ischemic etiology accounts for two thirds of all strokes in which platelet activation and aggregation play a major role. A variety of antiplatelet therapies have been tested for primary, secondary, and tertiary prevention, with certain patient subtypes benefiting more than others from a specific regimen. AREAS COVERED: This review aims at synthetizing current evidence on pharmacology of antiplatelet agents approved for primary, secondary, and tertiary stroke prevention and their application among possible patient subtypes that may benefit more from their administration. EXPERT OPINION: Management of ischemic stroke has largely evolved over the past decades. A better understanding of stroke pathophysiology has allowed to identify patients who can benefit most from antiplatelet therapies, with varying degrees of benefit depending on whether these agents are being used for primary, secondary, or tertiary prevention. Importantly, the antiplatelet treatment regimens currently available have expanded and no longer limited to aspirin but include other drugs such as P2Y12 and phosphodiesterase inhibitors, also used in combination, as well as precision medicine approaches using genetic testing aiming at optimizing the safety and efficacy in this population.