Platelet Reactivity Units Research Articles

Clopidogrel and Aspirin Resistance and Its Interaction with Peripheral Arterial Disease Outcomes in the Indian Population

Objectives: The objective of the study was to ascertain adverse events (major adverse cardiac and limb events) events in patients of established peripheral arterial disease (PAD), on clopidogrel and aspirin antiplatelet therapy. Patients and Methods: Patients aged 18 years or over, with PAD were screened for participation in the study. Patients were considered to have symptomatic PAD if they met either of two criteria: a history of intermittent claudication, rest pain, or tissue loss of presumed atherosclerotic origin, with either ankle–brachial index <0.85, previous leg amputation, peripheral vascular surgery, or percutaneous intervention; or angiographic or computed tomographic imaging of significant lower-extremity occlusive atherosclerotic disease. The patients took clopidogrel and aspirin at a dose ≥75 mg/day for at least 4 weeks before enrolment. Those with contraindications to antiplatelet usage were excluded from the study. Blood was used as genotyping material. Patient samples were genotyped for clopidogrel resistance (CR)-associated single-nucleotide polymorphism (SNPs) using Illumina Global Screening Array Ver 3 Bead Chip. Illumina Infinium Genotyping Assay protocol was implemented. Intensities of the beads’ fluorescence were detected using iScan Reader (Illumina Inc). Aspirin resistance (AR) was determined with the whole blood, point of care, turbidimetric cartridge-based method, platelet aggregation, and VerifyNow P2Y12 assay, and results were reported in platelet reactivity units (PRU), at a cutoff of 550 PRU. Results: The mean age was 58.4 (12.6) years with 90% males. The mean body mass index was 22.57 (3.54) kg/m2. The cohort comprised 58.9% smokers, 42% alcoholics, 33.5% diabetics, and 63% hypertensives. Limited efficacy of clopidogrel was observed in 52.38% of patients with loss of function (LOF) variations in the CYP2C19 gene. The mean duration of follow-up was 13.4 (4.7) months. Subjects with CYP2C19 LOF alleles showed more complications (39%) and the relationship between the LOF variation in the CYP2C19 gene and the adverse clinical outcomes (major adverse cardiac events [MACE] and major adverse limb events [MALE]) was found to be statistically significant (P = 0.11). CR and AR were found in 147 (50.3%) and 69 (23%) patients, respectively. Resistance to both the antiplatelets was found in 41 (14%) patients. Conclusion: In this largest observational study, the use of dual antiplatelet therapy in the Indian population with PAD on the MACE and MALE events was higher in the patients with CYP2C19 LOF alleles. The study found a statistically significant relationship between genetic testing results and clinical outcomes.

Safety of crushed/chewed P2Y12 inhibitors in acute coronary syndromes - a meta-analysis of randomized controlled trials.

The administration of crushed or chewed P2Y12 inhibitors (P2Y12i) allows faster platelet inhibition in patients presenting acute coronary syndrome (ACS). Whether this administration approach is safe needs further analysis. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing chewed/crushed to integral P2Y12i administration in patients with ACS. Major bleeding, minor bleeding, and major adverse cardiovascular events (MACE) were analyzed as binary outcomes. Platelet reactivity unit (PRU) was assessed as a continuous outcome to estimate the impact on platelet physiology. A subgroup analysis of P2Y12i administered was performed. Nine studies comprising 1091 patients with ACS were included, 77% were males. Overall, 87% presented with ST-segment elevation acute myocardial infarction. Six studies administered Ticagrelor, while 3 studies used Prasugrel. The absolute risk of bleeding, assessed by TIMI, was low in both intervention and control arms (0.36% vs. 0.95% for major bleedings and 3.3% vs. 4.4% for minor bleedings), and crushed/chewed administration did not increase the relative risk of bleeding events for TIMI major or minor bleedings (RR 0.51, 95% CI 0.09-2.77, p = 0.293; RR 0.76, 95% CI 0.24-2.43, p = 0.542) or MACE (RR 0.94, 95% CI 0.28-3.19, p = 0.902). PRU was significantly reduced within 1 h after administration in the crushed/chewed P2Y12i group (MD: -70.0%, 95% CI, -89.0 to -51.1%, p<0.01) while we did not observe a significant difference after 4 h (MD: -15.1%, 95% CI -34.2 to 4.0%, p = 0.12). The type of drug did not influence the relative risk of crushed/chewed P2Y12i on major or minor bleeding (pinteraction = 0.62 and pinteraction = 0.23, respectively). The crushed/chewed administration of P2Y12i in the setting of ACS was not associated with an increased risk of bleeding, suggesting the safety of this strategy.

Serial VerifyNow P2Y12 platelet reactivity units in cerebral aneurysm patients treated with ticagrelor surrounding stent-coiling or flow diversion.

Platelet function testing using serial VerifyNow P2Y12 platelet reactivity units (PRUs) is established for guiding clopidogrel antiplatelet therapy in cerebral aneurysm stenting procedures. However, for ticagrelor, the impact of serial PRU testing and the identification of safe PRU ranges remains unexplored. Flow diversion stenting (n = 232) and stent-assisted coiling procedures (n = 83) performed 05/2017-12/2021 were reviewed. Out of these, 31 flow diversion and 18 stent-coiling procedures were performed on 44 patients using ticagrelor. Baseline demographics, ticagrelor PRUs, and clinical outcomes were assessed. Collectively, 257 ticagrelor P2Y12 PRUs were obtained. PRUs were <100 in 192/257 (74.7%) tests. Only 11/257 (4.3%) PRUs were >200. The overall median ticagrelor PRU was 38 (IQR 11-101). Among the 49 procedures, median PRUs before the procedure (25, IQR 10-67), on the day of the procedure (68, IQR 44-117), and on the day after the procedure (37, IQR 21-79) did not show the significant differences between the groups. A total of seven thromboembolic complications occurred. Median PRUs surrounding the thromboembolic complications (median 182, IQR 148-235) were significantly higher than preprocedural (p < .001), day of surgery (p < .01), and postprocedural PRUs (p < .01). All seven procedures harbored demographic, anatomic, or procedural features increasing the risk for thromboembolic complications. The majority of periprocedural ticagrelor PRUs were <100. PRUs at the time point of thromboembolic complications were >120. Despite procedure-complicating features in each thromboembolic case, it raises the question whether safe ticagrelor PRU levels might be lower than those commonly applied for clopidogrel.

Cangrelor use in ticagrelor-loaded ST-elevation myocardial infarction patients with high residual platelet reactivity: a randomized controlled trial

Abstract Background Despite the use of potent P2Y12 inhibitor, many patients still present with high platelet reactivity (HPR) at the time of primary percutaneous coronary intervention (PCI). HPR is associated with impaired myocardial reperfusion and the subsequent poor outcome. Purpose We sought to determine the impact of Cangrelor -a rapid and potent intravenous P2Y12 inhibitor- on myocardial reperfusion in patients with HPR admitted for primary PCI in a randomized trial. Methods Patients pre-treated with ticagrelor and aspirin with residual HPR (baseline platelet reactivity unit (PRU) &amp;gt; 208) were randomly assigned in a 1:1 ratio to receive cangrelor (experimental group) or not (control group) just before PCI. The primary endpoint was optimal myocardial reperfusion defined as a final myocardial blush grade (MBG) 3 assessed by an independent core laboratory. Results After screening of 128 patients, a total of 60 patients were with HPR were enrolled and randomized. The ticagrelor loading dose to PRU measurement times were 83 ± 32 and 90 ± 47 minutes in the experimental and control groups, respectively. Baseline PRU were 245 ± 30 and 252 ± 35 in the experimental and standard group, respectively. A final MBG 3 was observed in 21/30 (55%) and 17/30 (45%) the experimental and standard groups (p=0.29). A final TIMI flow grade 3 was observed in 30/30 (100%) and 27/30 (90%) the experimental and standard groups (p=0.24). Peak troponin levels after PCI were 51381 ± 50047 and 51078 ± 63960 ng/L (p=0.98) in the experimental and standard group, respectively. At the end of the PCI, control PRU were 36 ± 57 and 198 ± 107 (p&amp;lt;0.0001) in the experimental and standard group, respectively. One patient of the experimental group presented an in-hospital major bleeding (BARC 3). Conclusion In ticagrelor-loaded STEMI patients with residual HPR at the time of PCI, cangrelor use was associated with a more effective platelet inhibition but failed to significantly improve the rates of optimal final myocardial blush grades.

Reduction of thrombus burden by cangrelor in ticagrelor-loaded st-elevation myocardial infarction patients with high residual platelet reactivity: the imaging sub-study of the ERMIT randomized trial

Abstract Background Residual high platelet reactivity (HPR) at the time of primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with higher residual thrombus burden and the subsequent suboptimal reperfusion. Purpose We sought to determine the impact of intravenous Cangrelor on the residual post-PCI thrombus burden in patients with HPR admitted for primary PCI in a prespecified intracoronary optical coherence tomography (OCT) sub-study of the ERMIT randomized trial. Methods In the ERMIT trial patients pre-treated with ticagrelor and aspirin with residual HPR (baseline platelet reactivity unit &amp;gt;208) were randomly assigned in a 1:1 ratio to receive cangrelor on top of standard therapy or standard therapy alone prior to PCI. The primary endpoint of the sub-study was the relative thrombus volume quantified on OCT. Other OCT quantified parameters were predefined as secondary endpoints. Results After screening of 128 patients, a total of 60 patients with HPR were enrolled and randomized. The OCT sub-study included 53 patients, 29 in the cangrelor and 24 in the control group. As reported in the table, baseline characteristics were similar between the groups. The post-PCI PRU was dramatically lower in the cangrelor as compared to the standard group (p&amp;lt;0.001). The primary endpoint was 4.5% [3.4;7.2] versus 6.9% [5.2;8.5], (p=0.03) in the cangrelor and control groups respectively. All other imaging parameters confirmed the significantly lower thrombus burden in patients receiving cangrelor (Table). Conclusion The imaging sub-study of the randomized ERMIT trial shows that cangrelor use is associated with a more effective platelet inhibition and lower post-PCI residual thrombus burden in ticagrelor-loaded STEMI patients with residual HPR. The clinical implications of such finding warrant larger size trials.Table

Paraoxonase-1 as a Cardiovascular Biomarker in Caribbean Hispanic Patients Treated with Clopidogrel: Abundance and Functionality.

Clopidogrel, a prescription drug to reduce ischemic events in cardiovascular patients, has been extensively studied in mostly European individuals but not among Caribbean Hispanics. This study evaluated the low abundance and reduced activity of paraoxonase-1 (PON1) in clopidogrel-resistant patients as a predictive risk biomarker of poor responders and disease severity in this population. Thirty-six patients on clopidogrel (cases divided into poor and normal responders) were enrolled, along with 11 cardiovascular patients with no clopidogrel indications (positive control) and 13 healthy volunteers (negative control). Residual on-treatment platelet reactivity unit (PRU), PON1 abundance by Western blotting, and PON1 activity by enzymatic assays were measured. PON1 genotyping and computational haplotype phasing were performed on 512 DNA specimens for two genetic loci (rs662 and rs854560). No statistical differences in mean relative PON1 abundance were found among the groups (p > 0.05). However, a significantly lower enzymatic activity was found in poor responders (10.57 ± 6.79 µU/mL) when compared to controls (22.66 ± 8.30 µU/mL and 22.21 ± 9.66 µU/mL; p = 0.004). PON1 activity among carriers of the most prevalent PON1 haplotype (AA|AA) was significantly lower than in wild types (7.90 µU/mL vs. 22.03 µU/mL; p = 0.005). Our findings suggested that PON1 is a potential biomarker of cardiovascular disease severity in Caribbean Hispanics.

Cost-effectiveness of platelet function testing in dual antiplatelet therapy decision-making after intracranial aneurysm treatment with flow diversion.

Dual antiplatelet therapy (DAPT) use is the standard of practice after flow diversion (FD) for intracranial aneurysms (IAs). Yet, no consensus exists in the literature regarding the optimal regimen. Certain institutions utilize various platelet function testing (PFT) to assess patient responsiveness to DAPT. Clopidogrel is the most commonly prescribed drug during DAPT; however, up to 52% of patients can be non-responders, justifying PFT use. Additionally, prices vary significantly among antiplatelet drugs, often further complicated by insurance restrictions. We aimed to determine the most cost-effective strategy for deciding DAPT regimens for patients after IA treatment. A decision tree with Monte Carlo simulations was performed to simulate patients undergoing various three-month postoperative DAPT regimens. Patients were either universally administered aspirin alongside clopidogrel, ticagrelor, or prasugrel without PFT, or administered one of the former thienopyridine medications based on platelet reactivity unit (PRU) results after clopidogrel. Input data for the model were extracted from the current literature, and the willingness-to-pay threshold (WTP) was defined as $100,000 per QALY as per standard practice in the US. The baseline comparison was with universal clopidogrel DAPT without any PFT. Probabilistic and deterministic sensitivity analyses were performed to evaluate the robustness of the model. Utilizing PFT and switching clopidogrel to prasugrel if resistance is documented was the most cost-effective regimen compared to universal clopidogrel, with a base-case incremental cost-effectiveness ratio (ICER) of $-35,255 (cost $2,336.67, effectiveness 0.85). Performing PFT and switching clopidogrel to ticagrelor (ICER $-4,671; cost $2,995.06, effectiveness 0.84), universal prasugrel (ICER $5,553; cost $3,097.30, effectiveness 0.84), or universal ticagrelor (ICER $75,969; cost $3,801.36, effectiveness 0.84) were all more cost-effective than treating patients with universal clopidogrel (cost $3,041.77, effectiveness 0.83). These conclusions remain robust in probabilistic and deterministic sensitivity analyses. The most cost-effective strategy guiding DAPT after FD for IAs is to perform PFTs and switch clopidogrel to prasugrel if resistance is documented, alongside aspirin. The cost of PFT is strongly justified and recommended when deciding patient-specific DAPT regimens.

The influence of P2Y12 gene polymorphisms on clopidogrel therapy in patients after percutaneous coronary intervention.

Aim: We aimed to define the influence of P2Y12 polymorphisms (rs6801273, rs2046934, and rs6809699), diabetes, hypertension, obesity, hypercholesterolemia, statins intake, and smoking habit on clopidogrel therapy in patients undergoing percutaneous coronary intervention.Materials & methods: We used PCR-RFLP and PCR-ASO for P2Y12 genotype analysis. The effectiveness of the therapy was measured with the VerifyNow method and defined in platelet reactivity units.Results: Studied polymorphisms had no statistically significant influence on PRU before (PRU0) and 6 months (PRU6) after the procedure. H1/H1 diabetic carriers had significantly higher PRU6 values than patients without diabetes. Obese H1/H2 subjects had significantly lower PRU6 values than H1/H2 non-obese carriers.Conclusion: We found that obesity and diabetes may influence the long-term outcome of antiplatelet therapy.

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

AimThe 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. MethodsA 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. ResultsClopidogrel 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. ConclusionCYP2C19 loss of function variation is strongly associated with clopidogrel resistance and adverse clinical outcomes.

Association of Age- and Body Mass Index-Stratified High On-Treatment Platelet Reactivity With Coronary Intervention Outcomes in East Asian Patients.

Although age and body mass index (BMI) significantly affect platelet reactivity units and clinical outcomes after percutaneous coronary intervention, there are limited data on the relationship between high on-treatment platelet reactivity (HPR) and clinical outcomes on age and BMI differences. Thus, we investigated the association of HPR with clinical outcomes according to age and BMI. The study analyzed 11 714 patients who underwent platelet function tests after percutaneous coronary intervention. The primary end point was the occurrence of major adverse cardiac and cerebrovascular events (MACCEs), whereas the secondary end point was major bleeding. HPR was defined as platelet reactivity units ≥252. Patients were categorized by age (<67 years of age or ≥67 years of age) and BMI (≤22.6 kg/m2 or >22.6 kg/m2). Patients <67 years of age with HPR had increases in both MACCEs (adjusted hazard ratio [HR], 1.436 [95% CI, 1.106-1.867]; P=0.007) and major bleeding (adjusted HR, 1.584 [95% CI, 1.095-2.290]; P=0.015) compared with the those with non-HPR, respectively. In patients ≥67 years of age with HPR, there were no differences in MACCEs, but there was a decrease in major bleeding (adjusted HR, 0.721 [95% CI, 0.542-0.959]; P=0.024). Meanwhile, patients with HPR with BMI >22.6 kg/m2 had increases in MACCEs (adjusted HR, 1.387 [95% CI, 1.140-1.688]; P=0.001). No differences were shown in major bleeding. HPR was linked to an increase in MACCEs or a decrease in major bleeding in patients after percutaneous coronary intervention, depending on age and BMI. This study is the first to observe that clinical outcomes in patients with HPR after percutaneous coronary intervention may vary based on age and BMI. Because the study is observational, the results should be viewed as hypothesis generating and emphasize the need for randomized clinical trials.

Antithrombotic Stewardship: Evaluation of Platelet Reactivity-Guided Cangrelor Dosing Using the VerifyNow Assay.

Cangrelor may be used as a bridge when temporary interruption of dual antiplatelet therapy is necessary. However, the optimal dose and monitoring of cangrelor in patients remains unknown, especially in the setting of mechanical circulatory support (MCS). We conducted an observational, single-center, retrospective cohort study of patients who had percutaneous coronary intervention within 3 months and received cangrelor while admitted to any intensive care unit. The primary outcome was the incidence of any major adverse cardiovascular event. Secondary outcomes included VerifyNow platelet reactivity units (PRUs) measured while on cangrelor and any bleeding events while on cangrelor. A total of 92 patients were included. The most common reason for cangrelor use was in the periprocedural setting, with or without MCS (42%-45%), followed by NPO status (26%-28%) and MCS alone (22%-24%). The primary outcome of major adverse cardiovascular event occurred in 1 patient (1.1%). Of 92 patients, 77% had a P2Y12 level collected within 24 hours, and 89% of the cohort was able to achieve the goal P2Y12 PRU of <194. The median P2Y12 value within 24 hours of cangrelor initation was 115 PRU (40-168 PRU). We observed a bleed event rate of 23% (21/92). We found a standardized protocol of cangrelor dosing in critically ill patients who received a drug-eluting stent in the past 3 months to be successful in achieving a goal P2Y12 PRU. Although the optimal PRU remains unknown, cardiovascular clinicians may monitor these levels to help guide decisions regarding cangrelor management. Future randomized controlled trials should evaluate the optimal PRU threshold to balance risks of ischemia and bleeding.

Abstract WP150: Correlation Between CYP2C19 Genotype and Platelet Reactivity Units in Patients Receiving Clopidogrel After Acute Ischemic Stroke

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care for secondary prevention in non-cardioembolic minor acute ischemic stroke (AIS) and high-risk transient ischemic attack (TIA). However, clopidogrel is a prodrug metabolized to its active form by the CYP2C19 enzyme and therefore has decreased efficacy in patients with at least one loss-of-function (LOF) allele in the CYP2C19 gene that encodes the enzyme. The use of ticagrelor over clopidogrel for DAPT improves outcomes in CYP2C19 LOF carriers; however, CYP2C19 genotyping is not currently standard practice in the cerebrovascular population. P2Y12 assays that measure P2Y12 receptor-mediated platelet aggregation in platelet reactivity units (PRUs) are more widely accessible, but it is unclear if this assay correlates with CYP2C19 genotype in this population. Therefore, we aimed to investigate the correlation between CYP2C19 genotype and PRUs to evaluate PRUs as a potential surrogate biomarker for identifying suboptimal clopidogrel response. We hypothesized that PRUs would be increased in CYP2C19 LOF carriers compared to non-carriers due to the reduced bioactivation of clopidogrel in patients with decreased CYP2C19 enzymatic function. This prospective, observational study enrolled patients &gt; 18 years of age presenting with minor AIS or high-risk TIA and discharged from University of Virginia Health on DAPT for secondary stroke prevention. A whole blood sample for P2Y12 assay and CYP2C19 genotyping was obtained at least 12 hours after a 300 milligram clopidogrel loading dose. The primary outcome was the correlation between PRUs and CYP2C19 LOF allele carrier status. Of 35 patients genotyped, 27 (77%) subjects self-reported European ancestry, 7 (20%) African ancestry, and 1 (3%) Asian ancestry. Six participants (17%) were found to be LOF carriers. LOF carriers had significantly increased PRUs compared to non-carriers (mean difference +103.7; 95% CI +30.71 to +176.1; p&lt;0.01), indicating diminished pharmacodynamic response to clopidogrel. This suggests that measurement of PRUs via an accessible and established P2Y12 assay may be a viable surrogate biomarker for identifying suboptimal clopidogrel response in the cerebrovascular population.

Platelet reactivity and activated clotting time predict hemorrhagic site complications in patients with chronic coronary syndromes undergoing percutaneous coronary interventions.

Radial access is preferred in patients with chronic coronary syndromes (CCSs) treated with ad hoc percutaneous coronary intervention (PCI). Antithrombotic and antiplatelet treatment before PCI may affect outcomes at vascular access sites. QuikClot Radial is a kaolin-based band that may shorten hemostasis time. Using point-of-care testing, we investigated the effect of antithrombotic and antiplatelet treatment on access-site complications. This prospective observational study included consecutive patients with CCS on chronic aspirin therapy referred for ad hoc PCI. The activated clotting time (ACT), global thrombosis test and VerifyNow P2Y 12 test were done sequentially after unfractionated heparin (UFH) and clopidogrel administration. Patients were monitored for radial artery patency, bleeding and local hematoma until discharge. We enrolled 40 patients [mean age, 68.8 ± 8.8 years; men, 30 (75%)] who received UFH (median dose, 8000 IU; interquartile range, 7000-9000 IU) and clopidogrel (600 mg). All radial arteries remained patent during follow-up. Local bleeding and hematomas were noted in 11 patients (27.5%) each. Patients with bleeding had lower mean platelet activity at 2 h [122.5 ± 51 platelet reactivity units (PRU) vs. 158.7 ± 43 PRU, P = 0.04] and higher ACT (216.9 ± 40 s vs. 184.6 ± 28 s, P = 0.006) than patients without bleeding. An ACT >196 s at 2 h predicted bleeding or hematoma (AUC, 0.72; 95% CI, 0.56-0.85, P = 0.008). Lower platelet activity and higher ACT after PCI were associated with higher bleeding risk at a vascular access site. Point-of-care testing of ACT after the procedure may help identify patients with CCS undergoing PCI who are at higher risk of access-site bleeding.

Assessing the efficacy of VerifyNow platelet-function testing in predicting postoperative thromboembolic complications of neuroendovascular surgery: A systematic review and meta-analysis (part 1).

Despite the heavily debated use of routine platelet-function testing, the VerifyNow Platelet Reactivity Unit (PRU) assay has been increasingly adopted as standard of care for assessing risk of postoperative thromboembolic complications of neuroendovascular surgery. We conducted a systematic review and meta-analysis to examine the relationship between platelet response and risk of ischemic events from neuroendovascular surgery, assess the efficacy of point-of-care platelet-function testing in predicting thromboembolic outcomes, and assess whether a clinically useful threshold for platelet response can be defined in order to standardize guidelines. PubMed, Embase, and Scopus were searched. Following deduplication, articles were first screened for relevance by title and abstract, followed by full text. Of 735 resultant articles, 22 studies consisting of 3266 patients undergoing neuroendovascular intervention were included. Diagnoses included both intracranial and extracranial pathologies, of which 45.8% were treated with flow diversion, 16.4% with stent-assisted coil embolization, 15.8% with intracranial stenting, 12.0% with simple coil embolization, 3.4% with balloon-assisted coil embolization, 3.6% with extracranial stenting, and 3.0% with an alternate method. 54.5% (12/22) of studies determined platelet hyporesponse to be an independent predictor of postoperative thromboembolic complications, with 27.3% (6/22) of studies reporting a similar, but non-statistically significant trend. 18.2% (4/22) of studies found no relationship between platelet response and postoperative thromboembolic complications. The estimated clinical threshold for PRU to prevent thromboembolic complications varied greatly across studies (Range: > 144-295 PRU). Meta-analysis found platelet hyporesponse to have a 2.23-fold increased risk of thromboembolic complications compared to normoresponders (RR = 2.23, P = 0.03). While PRU demonstrates a significant predictive value for postoperative thromboembolic complications of neuroendovascular surgery, the target therapeutic threshold for minimizing ischemic events remains unclear. Further studies, such as large multicenter cohorts of the existing data, are needed to standardize guidelines.

Assessing the efficacy of VerifyNow platelet-function testing in predicting postoperative hemorrhagic complications of neuroendovascular surgery: A systematic review and meta-analysis (part 2).

Dual antiplatelet therapy is used to reduce the risk of thromboembolic complications in neuroendovascular surgery. However, the predictive utility of preoperative platelet-sensitivity testing for decreasing bleed risk in patients undergoing endovascular neurointervention remains unclear. We conducted a systematic review and meta-analysis to illustrate the association between platelet response and risk of hemorrhagic complications from neuroendovascular surgery, examine the efficacy of the VerifyNow platelet reactivity unit (PRU) assay in predicting hemorrhagic outcomes, and assess whether a clinically useful threshold for platelet response can be defined to standardize guidelines. PubMed, Embase, and Scopus were searched. Articles were screened for relevance by title and abstract, followed by full text. Of 735 resultant articles, 17 studies of 2084 patients undergoing neuroendovascular intervention were included. Diagnoses included both intracranial and extracranial pathologies, of which 37.8% were treated with flow diversion, 22.4% with stent-assisted coil embolization, 14.3% with intracranial stenting, 12.8% with simple coil embolization, 5.8% with balloon-assisted coil embolization, 2.0% with extracranial stenting, and 4.8% with an alternate method. Precisely, 52.9% (9 out of 17) of studies determined platelet hyperresponse to be an independent predictor of postoperative hemorrhagic complications, with 11.8% (2 out of 17) of studies reporting a similar but non-statistically significant trend. 35.3% (6 out of 17) of studies found no relationship between platelet response and postoperative hemorrhagic complications. The estimated clinical threshold for PRU to prevent hemorrhagic complications varied considerably across studies (range: <46-118 PRU). Meta-analysis found platelet hyperresponse to have more than a 3-fold increased risk of hemorrhagic complications compared to normoresponders (relative risk = 3.2, p = 0.001). Although this meta-analysis shows the predictive utility of the P2Y12 assay for postoperative hemorrhagic complications in neuroendovascular surgery, the optimal therapeutic threshold for minimizing bleeding risk is still uncertain. To better understand the utility of the P2Y12 assay in the perioperative period, further prospective research is needed.

Platelet reactivity and activated clotting time predict haemorrhagic site complications in patients with chronic coronary syndromes undergoing percutaneous coronary intervention

Abstract Background/Introduction Same-day discharge has become a standard of care for patients with chronic coronary syndromes (CCS) treated with ad hoc percutaneous coronary interventions (PCI). QuickClot Radial kaolin-based haemostatic device may shorten haemostasis time and reduce the incidence of vascular site complications. Besides unfractionated heparin (UFH) and aspirin (ASA), an ad hoc procedure demands a loading dose of clopidogrel. Dynamic changes in platelets and thrombotic activity may influence the outcomes at vascular sites. Rapid "point-of-care" testing measures the effects of anticoagulation but the optimal threshold during and after PCI still requires further research. Purpose We investigated the effect of a standard dose of UFH and a loading dose of clopidogrel measured with point-of-care devices: Hemochron activated clotting time device (ACT), VerifyNow P2Y12 test on on-site outcomes. Methods We conducted a prospective, observational study of consecutive patients with CCS who qualified for ad hoc PCI. Patients were on chronic ASA therapy, received 100 IU/kg UFH, and a 600 mg loading dose of clopidogrel. ACT was measured before and 10 min, 2 h, and 6 h after the administration of UFH and clopidogrel, respectively, and the VerifyNow P2Y12 test measured after 2 and 6 h. A QuickClot haemostatic pad with gradually released compression for up to 2 h was used in all patients. Ultrasonographic assessment of artery diameter and patency was performed before and 6 h after the procedure. Bleeding (BARC criteria) or local haematoma (EASY scale) were observed regularly until hospital discharge. Results Forty patients were enrolled in the study. The mean±SD age was 68.8±8.8 years, 30 (75%) patients were men, 13 (35%) had diabetes, 38 (95%) hypertension, 16 (40%) previous myocardial infarction, and 15 (37,5%) were active smokers. Patients received a median [interquartile range (IQR)] 8000 [7000-9000] IU of UFH and 600 mg of clopidogrel. All of the radial arteries remained patent during observation; local bleeding (BARC 2) was observed in 11 (27,5%) and haematomas (EASY 1 and 2) in 11 (27,5%) patients. Patients with bleeding had lower platelet activity measured with platelet reactivity units (PRU) after 2 h (122.5± 51 vs 158.7± 43, p= 0.04) and higher ACT (s) (216.9 ±40 vs. 184.6±28 s, p=0.006). An ACT &amp;gt;196 s, measured 2 h after the procedure, predicted the occurrence of bleeding or haematoma (AUC 0.72; 95%CI 0.56-0.85, p=0.008). Conclusion Lower platelet activity and higher ACT after PCI were associated with higher risk of haemorrhagic site complications. "Point-of-care" measures post PCI in CCS patients may be clinically applicable.

Abstract 14703: Platelet Reactivity and Long-Term Outcomes Following Acute Myocardial Infarction

Introduction: A large volume of literature demonstrates a short term (1 year) association between high on treatment platelet reactivity in patients with acute myocardial infarction treated with clopidogrel and adverse cardiovascular outcomes. There is less literature examining whether this association extends beyond the duration of clopidogrel treatment. Hypothesis: That on-treatment platelet reactivity is associated wtih 5-year death and recurrent myocardial infarction in patients with acute myocardial infarction. Methods: We measured platelet reactivity in patients presenting with AMI to Wellington Hospital between 2012 and 2015 who had been treated with clopidogrel prior to angiography using Multiplate P2Y 12 assay (Roche Diagnostics). Platelet reactivity was measured in platelet reactive units (PRU). We examined the relationship between PRU and both death and myocardial infarction at 5 years follow-up. Results: In 921 patients with acute myocardial infarction (mean age 63.2, sd 10.8, 81% NSTEMI 19% STEMI) mean PRU was 39.3 (sd 23.6) PRU, with 74 patients (8%) having a PRU greater than 47, previously described as high on treatment platelet reactivity. 5-year mortality was observed in 10.4% (96 cases) and recurrent myocardial infarction in 12.2% (122 cases). Platelet reactivity was significantly associated with 5-year mortality in Receiver Operator Curve analysis, with AUC 0.58, p=0.009. Mean PRU was 45.8 (sd 27.5) in those who died versus 38.4 (sd 23.2) in those still alive at 5 years (p=0.004, unpaired t-test). Cox regression analysis demonstrated a hazard ratio of 1.01 (95% CI 1.003-1.017, p=0.01) for each increasing unit of PRU. Recurrent MI was not significantly associated with PRU, with an AUC of 0.55, p=0.09). Conclusions: Levels of platelet reactivity were associated with long-term mortality risk in AMI patients. This may suggest platelet reactivity in the acute phase following an AMI is a marker of poor cardiovascular repair, leading to an association with long-term mortality risk

Impact of transfusion strategy on platelet aggregation and biomarkers in myocardial infarction patients with anemia.

Higher rates of thrombotic events have been reported in myocardial infarction (MI) patients requiring blood transfusion. The impact of blood transfusion strategy on thrombosis and inflammation is still unknown. To compare the impact of a liberal vs. a restrictive transfusion strategy on P2Y12 platelet reactivity and biomarkers in the multicentric randomized REALITY trial. Patients randomized to a liberal (hemoglobin≤10g/dL) or a restrictive (hemoglobin≤8g/dL) transfusion strategy had VASP-PRI platelet reactivity measured centrally in a blinded fashion and platelet reactivity unit (PRU) measured locally using encrypted VerifyNow; at baseline and after randomization. Biomarkers of thrombosis (P-selectin, PAI-1, vWF) and inflammation (TNF-α) were also measured. The primary endpoint was the change in the VASP-PRI (difference from baseline and post randomization) between the randomized groups. A total of 100 patients randomized were included in this study (n=50 in each group). Transfused patients received on average 2.4±1.6 units of blood. We found no differences in change of the VASP PRI (difference 1.2% 95% CI (-10.3-12.7%)) or by the PRU (difference 13.0 95% CI (-21.8-47.8)) before and after randomization in both randomized groups. Similar results were found in transfused patients (n=71) regardless of the randomized group, VASP PRI (difference 1.7%; 95% CI (-9.5-1.7%)) or PRU (difference 27.0; 95% CI (-45.0-0.0)). We did not find an impact of transfusion strategy or transfusion itself in the levels of P-selectin, PAI-1, vWF, and TNF-α. In this study, we found no impact of a liberal vs. a restrictive transfusion strategy on platelet reactivity and biomarkers in MI patients with anemia. A conclusion that should be tempered due to missing patients with exploitable biological data that has affected our power to show a difference.

Platelet inhibition with orodispersible ticagrelor in acute coronary syndromes according to morphine use: the TASTER study final results.

To date, it is still unknown whether orodispersible tablet (ODT) ticagrelor might represent a suitable way to reach a proper antiaggregation in acute coronary syndrome (ACS) patients receiving morphine. Aim of the present study was to evaluate platelet inhibition with 180 mg ticagrelor loading dose (LD) administered as ODT compared with standard coated tablet ticagrelor formulation in ACS patients undergoing percutaneous coronary intervention (PCI) according to morphine use. One-hundred and 30 patients presenting with STEMI or very high-risk NSTE-ACS were randomly assigned to receive ODT or standard ticagrelor LD. Potential morphine-ticagrelor interaction was assessed by stratified randomization according to morphine use. Platelet reactivity was evaluated by Platelet Reactivity Units (PRU) VerifyNow™ฏ 1, 2, 4 and 6 hours after ticagrelor LD. The primary endpoint was residual platelet reactivity 1 hour after LD across the two ticagrelor formulation and according to morphine use. Safety endpoints were major bleedings and other in-hospital ticagrelor administration-related adverse events. One hour after LD, PRU median value was higher in morphine-treated patients (N=32) as compared with patients not receiving morphine (N=98; PRU= 187 [70-217]) vs 73 [7-187]; p=0.012). In patients with morphine, 1-hour PRU values were similar between study groups (192 [114-236] vs 173 [16-215] in ODT and standard tablet ticagrelor, respectively). Similarly, in patients without morphine, 1-hour PRU values were not significantly different between study groups (69 [8-152] vs 110 [6 - 193] in ODT and standard tablet ticagrelor, respectively). Platelet reactivity appeared similar in the 2 study arms at 2, 4 and 6 hours after LD. No significant difference was observed among patients with or without morphine regarding in-hospital adverse events or drug side-effects, even if a reinfarction due to acute stent thrombosis was observed in a patient treated with morphine. There was no difference between ODT and standard ticagrelor tablets in terms of post-LD residual platelet reactivity, percentage of platelet inhibition or safety regardless to morphine use.

Evaluation of Clopidogrel Resistance and Its Role in Predicting Stent Thrombosis in Transcarotid Artery Revascularization

While up to 70% of patients have resistance to clopidogrel (Plavix) in the coronary literature, resistance testing is not routinely performed despite its common use as an antiplatelet for prevention of stent thrombosis in transcarotid arterial revascularization (TCAR) procedures. The extent to which resistance exists in patients undergoing TCAR has not been well-described. We sought to compare the modalities for clopidogrel resistance testing and determine the prevalence of resistance and its effect on stent outcomes. Patients undergoing TCAR at our institution between 2018 and 2022 were retrospectively identified. Clopidogrel-resisting test results were recorded. Patient characteristics, perioperative details, and outcomes are described. A total of 85 patients underwent TCAR, 52 (61%) for symptomatic disease. Sixty-five patients (77%) were on dual antiplatelet therapy (DAPT) for at least 7 days prior to TCAR. 7 (8%) patients not on DAPT were on anticoagulation prior to surgery and most (6) received a loading dose of a second antiplatelet the day of their procedure. Nine patients (10.6%) developed stent thrombosis during the follow-up period. Patients not taking DAPT for at least 7 days prior to surgery were more likely to develop stent thrombosis (30% vs 4.6%; P < .001). Clopidogrel resistance testing was performed in 35 (41%) patients, with 25 patients undergoing thromboelastogram with platelet mapping, 5 undergoing VerifyNow P2Y12 inhibitor testing, and 5 undergoing testing with both modalities. Clopidogrel resistance was noted in 24 patients (69%) using all testing results. In patients that underwent both testing modalities, agreement was poor (Cohen's Kappa −0.05) (Table I). Among patients with clopidogrel resistance, 17 (72%) did not thrombose and 5 (20%) patients did thrombose. Comparatively, 1 (9.1%) patient without resistance thrombosed (P = .161). Of the five patients with thrombosed stents that underwent testing, four were clopidogrel resistant (80%) (Table II). VerifyNow correctly predicted resistance and nonresistance more accurately than thromboelastogram (7 of 9 correct, 78% vs 11 of 29 correct, 38%; P = .001). VerifyNow had a sensitivity of 60% and specificity of 100% for stent thrombosis. Our experience demonstrates that clopidogrel resistance rates are high in the TCAR patient population, with higher thrombosis rates in those that test positive for resistance. VerifyNow more reliably predicts clopidogrel resistance than thromboelastography. In addition to determining clopidogrel susceptibility, patients may also obtain benefit by initiating DAPT at least 7 days prior to surgery.Table IComparison of platelet mapping methodsThromboelastogram value (% ADP inhibition)VerifyNow value (P2y12 reaction units)Clopidogrel resistance present?Congruence in testing results?Patient 125.6182YesNoPatient 235.6172YesNoPatient 350.6187YesNoPatient 474.5163NoNoPatient 545.39YesYesAdenosine diphosphate (ADP) inhibition ≤ 50% confers platelet resistance by thromboelastography. Platelet reactivity unit (PRU) >194 confers platelet resistance by VerifyNow testing. Open table in a new tab Table IIDescription of testing among nine patients with thrombosed stentsTEG value (% ADP inhibition)Verify Now value (P2y12 reaction units)Clopidogrel resistance present?Testing result correctly predicts thrombosis?Stent 1N/AN/AN/AN/AStent 2N/AN/AN/AN/AStent 3-213YesYesStent 4-253YesYesStent 5-413YesYesStent 622.4-YesYesStent 774.5163NoNoStent 845.39Yes- TEGNo- VerifyNowYes- TEGNo- VerifyNowStent 9N/AN/AN/AN/AAdenosine diphosphate (ADP) inhibition ≤50% confers platelet resistance by thromboelastography. PRU >194 confers platelet resistance by VerifyNow testing. Open table in a new tab