P2Y12 Reaction Units Values Research Articles

Periprocedural Variability of Platelet Functions in Carotid Artery Stenting: An Analysis Using VerifyNow.

The assessment of platelet functions is necessary to prevent both thromboembolic and hemorrhagic complications under dual antiplatelet therapy (DAPT). Using the VerifyNow (Accumetrics, Inc., San Diego, CA, USA) assay, this study aimed to reveal time-dependent changes in platelet functions after carotid artery stenting (CAS). We enrolled retrospectively 43 patients who underwent CAS under DAPT. Aspirin reaction unit (ARU) and P2Y12 reaction unit (PRU) values were determined on the day before and on days 1, 3, and 7 after the procedure. Multiple comparison tests (MCTs) were performed among ARU and PRU measurement points, and the proportions of hypo- and hyper-responses were compared. The median ARU values were 408 (interquartile range: 392-497) before CAS and 418 (405-470) on day 1, 405 (393.0-460.5) on day 3, and 402 (388.5-477.5) on day 7 (not significant in MCTs). The percentages of hypo-responses were 16.3%, 7.0%, 2.3%, and 7.0%, respectively (p = 0.11). The significantly different median PRU values were 173 (116.5-209.5), 233 (166.5-273.5), 139 (70.5-205.5), and 51 (9.0-79.5), respectively. The median PRU was before the procedure within the therapeutic range but exceeded the upper cutoff on day 1 and was below the lower cutoff on day 7. The percentages of hypo-responses were 14.0%, 51.2%, 18.6%, and 11.6%, respectively (p <0.001) and the percentages of hyper-responses were 9.3%, 2.3%, 23.3%, and 62.8%, respectively (p <0.001). In the periprocedural CAS period, ARU values were stable, but PRU values showed time-dependent changes. PRU values were above the therapeutic range the day after CAS but decreased below this range on day 7.

Post-procedural high platelet reactivity with prasugrel loading predicts in-hospital adverse events in ACS patients

Abstract Background/Introduction High platelet reactivity (HPR) is associated with adverse cardiovascular events, primarily intrastent thrombosis, after a percutaneous coronary intervention (PCI). However, the relationship between hyperacute postprocedural HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) remains unclear. Moreover, factors contributing to HPR in ACS with prasugrel loading are also unknown. Purpose To assess the effects of post-procedural HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, and to define the appropriate cut-off values and identify factors contributing to HPR. Methods A single-center, retrospective observational study that enrolled 154 patients who underwent emergent PCI for ACS with prasugrel loading was performed. The P2Y12 reaction unit (PRU) value was measured immediately after PCI using the VerifyNowR system. The primary end-point was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results The mean patient age (standard deviation) was 70.7 (±12.5) years, 76.6% were men, and the average time from the prasugrel intake to PRU calculation was 103.2 (±48.5) min. During the mean hospital stay of 15.6 (±8.5) days, 24 in-hospital MACE (15.5%) and 8 deaths (5.2%) occurred. Thrombosis events, including myocardial infarction recurrence, did not occur (only one case of spontaneous coronary artery dissection was considered as myocardial infarction recurrence). PRU was significantly higher in the MACE group than that in Non-MACE group (287±55 and 232±64, respectively, p&amp;lt;0.001). The ROC curve analysis of PRU for discriminating the significant in-hospital MACE showed the cut-off value of 293 (sensitivity: 62.5%, specificity: 83.1% [AUC=0.756, p&amp;lt;0.0001]). A total of 37 patients (24%) were thus categorized as HPR (PRU&amp;gt;293) immediately after the emergent PCI. Kaplan-Meier curve showing MACE events occurred in the HPR group than that in the non-HPR group (40.5% vs 7.6%, p&amp;lt;0.001). Multiple cox analysis demonstrated that HPR was independent predictors of MACE in patients with ACS who underwent PCI (OR 11.01, 95% CI 2.39–20.2, p&amp;lt;0.0001). Multiple logistic regression model showed old age, female sex, low systolic blood pressure, short prasugrel intake to measure time, and large acute gain were independent predictors of HPR. Conclusion PRU was significantly higher in the MACE group, with an appropriate cut-off value of HPR of 293 in this study. HPR was an independent predictor of MACE during hospitalization; however, thrombosis events were not significant. HPR predictors were old age, female sex, low systolic blood pressure, short prasugrel intake to measure time, and large acute gain. This study shows the post-procedural HPR with prasugrel loading in patients with ACS can be a useful predictive marker of adverse events during hospitalization. Funding Acknowledgement Type of funding source: None

Cangrelor with Heparin for Patients with Heparin-Induced Thrombocytopenia Undergoing Pulmonary Thromboendarterectomy

Optimal intraoperative anticoagulation strategy for patients with heparin-induced thrombocytopenia (HIT) undergoing pulmonary thromboendarterectomy (PTE) that necessitates deep hypothermic circulatory arrest (DHCA) remains controversial. Cangrelor is an intravenous direct-acting P2Y12 platelet receptor antagonist that achieves therapeutic effect and eliminates rapidly. Its antiplatelet activity is unaffected by stagnation of blood, nor is it influenced by patient's age, renal status or hepatic function. We report our novel strategy and experience in utilizing cangrelor in combination with heparin for anticoagulation during cardiopulmonary bypass (CPB) and DHCA in HIT patients undergoing PTE. Retrospective chart review of 297 patients who underwent PTE from January 2018 through June 2019 was performed. Patients with suspected, acute, subacute A/B, and remote HIT at the time of procedure were identified (n=7). All 7 patients received cangrelor with heparin intraoperatively for anticoagulation during CPB and DHCA. Our institutional intraoperative anticoagulation strategy for HIT patients is to administer a loading dose of cangrelor (30 μg/kg) prior to giving full-dose heparin for CPB. Cangrelor infusion is initiated at 4 μg/kg/min and is adjusted throughout CPB depending on the intraoperative VerifyNow P2Y12 reaction unit values. Cangrelor infusion is stopped 10 minutes before heparin reversal with protamine. Postoperatively, bivalirudin and warfarin were used for anticoagulation. Of these 7 patients, HIT was suspected in 3 patients (43%) at the time of procedure, whilst 1 patient had subacute B HIT and 1 patient had remote HIT. Acute HIT was confirmed by serotonin release assay in 2 patients (29%) who underwent emergent PTE. All patients survived the procedure. Intraoperative platelet transfusion was required by 4 patients (57%). There were no serious postoperative thrombotic events nor major bleeding complications that required re-operation. One in-hospital death was associated with advanced intracardiac malignancy. The mean postoperative hospital stay was 10.6±5.5 days. In patients with various phases of HIT who require PTE, the use of cangrelor in combination with heparin may be a promising alternative intraoperative anticoagulation strategy providing acceptable outcomes.

Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes.

AimsTo study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS).Methods and resultsIn this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4–11%).ConclusionsSelatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

In vitro analysis of the effect of contrast agents on the antiaggregant effects of P2Y12 inhibitors

ObjectivesThe contrast agents have different molarities and ionic structures. The high osmolar contrast agents could increase platelet aggregation but the ionic contrast agents decrease platelet aggregation. However there is insufficient data on whether the antiaggregan effect of P2Y12 inhibitors used during coronary interventions are affected by the contrast agents. This study aimed to evaluate the in vitro effects of different contrast agents on the antiaggregant activity of P2Y12 inhibitors (clopidogrel, ticagrelor and prasugrel). Materials and methodsThirty patients (who underwent percutaneous coronary interventions and were treated with a P2Y12 inhibitor for a minimum of 10 days) and five healthy volunteers were divided into four groups: the clopidogrel (10 patients), ticagrelor (10 patients), prasugrel (10 patients) and control (five volunteers) groups. Antiaggregant activity was measured by using the Verify-Now method and was represented as P2Y12 reaction unit (PRU) values. Three tubes of blood were collected from the participants in the three patient groups and in the control group; as the contrast material, 10% iohexol was added to a second tube, and 10% iodixanol was added to a third tube. PRU values of the control and the contrast tubes were measured at 5 min and at 30 min after the contrast material was added. ResultsIohexol and iodixanol led to a significant decrease in the PRU values in the control group (iohexol: 188.4 ± 39.2 vs 142.4 ± 17.0, p = .04; iodixanol: 188.4 ± 39.2 vs 159.2 ± 33.7, p = .04) and in the clopidogrel group (iohexol: 140.8 ± 50.8 vs 106.3 ± 44.4, p = .04; iodixanol: 140.8 ± 50.8 vs 109.4 ± 47.6, p = .009) but not in the ticagrelor and prasugrel groups. The PRU values were significantly lower in the ticagrelor (23.1 ± 26.2) and prasugrel (23.4 ± 27.5) groups than in the clopidogrel (140.8 ± 50.8) and control (188.4 ± 39.2) groups (p < .01), and the PRU values for the ticagrelor and prasugrel groups were similar for both the 5-min and 30-min time periods (p > .05). The antiaggregant activities of iohexol and iodixanol were observed to be similar at the 5- and 30-minute time points for all of the groups (p > .05). ConclusionIohexol and iodixanol had in vitro antiaggregant effects, and their antiaggregant effects were similar. Iohexol and iodixanol increased the clopidogrel antiaggregant activity in vitro, but they did not significantly alter the antiaggregant activities of prasugrel and ticagrelor.

P4634Acute-phase high platelet reactivity with prasugrel loading is correlated with clinical outcomes during hospitalization in acute coronary syndrome

Abstract Background/Introduction Although high platelet reactivity (HPR) seems to be associated with adverse cardiovascular events after percutaneous coronary intervention (PCI), the relationship between post-procedure HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) is still unclear. Moreover, factors contributing to HPR in ACS with prasugrel loading are also unknown. Purpose This study aimed to assess the impact of post-procedure HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, as well as to define appropriate cut-off values and identify factors contributing to HPR. Methods We performed a single-centre, retrospective observational study that enrolled 132 patients who underwent emergent PCI for ACS with prasugrel loading. The P2Y12 reaction unit (PRU) value was measured immediately after PCI with the VerifyNowR System. The primary endpoint was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results Mean patient age (standard deviation) was 70.7 (±12.5) years, 76% were male, and average time from prasugrel intake to PRU calculation was 101 (±48.8) min. During a mean hospital stay of 15.4 (±8.0) days, there were 22 (16%) MACE events and 6 (4%) deaths. The post-procedure PRU value was 241±66. HPR was significantly higher in MACE group than non-MACE group [287 (±55) vs 232 (±64), p&lt;0.001]. The ROC curve analysis of PRU for discriminating significant in-hospital MACE showed a cut off value of 293 (sensitivity: 64%, specificity: 84% [AUC=0.764, p&lt;0.0001]). Thus, 33 patients (25%) were found to have HPR (PRU&gt;293) immediately after emergent PCI. Kaplan-Meier curve analysis showed MACE events occurred more frequently in the HPR group than in the non-HPR group (42% vs 8%, log rank p&lt;0.001). Multiple Cox regression analysis showed that peak creatine phosphokinase &gt;3,000 U/L and HPR were independent predictors of MACE in patients with ACS who underwent PCI (OR 4.96, 95% CI 1.86–13.26, p=0.001, and OR 7.52, 95% CI 2.73–20.7, p&lt;0.0001, respectively). HPR was significantly correlated with age, female sex, and reference lumen short diameter (pre-dilation) used in PCI. Conclusion HPR was significantly associated with adverse event during hospitalization in ACS patients. Female patients with large culprit lesion diameter were more likely to have HPR. Appropriate cut-off value of HPR in this study was 293. HPR in early-phase of ACS with prasugrel loading is a useful predictor of adverse events during hospitalization.

2349Selatogrel, a novel P2Y12 inhibitor for emergency use, achieves rapid, consistent and sustained platelet inhibition following single-dose subcutaneous administration in stable CAD patients

Abstract Background In the setting of AMI, rapid platelet inhibition is desirable but the onset of pharmacodynamic (PD) effect of oral platelet P2Y12 inhibitors is delayed, sometimes for hours. Subcutaneous (s.c) administration of a rapidly-acting P2Y12 inhibitor would overcome many of the limitations of available therapies. Patients with stable CAD were investigated initially. Purpose To characterise the inhibition of platelet aggregation and pharmacokinetics (PK) of a single dose of selatogrel, a novel s.c P2Y12 inhibitor, in patients with stable CAD. Methods Patients with stable CAD receiving oral antiplatelet therapy (aspirin and/or oral P2Y12 inhibitor) were randomized to 1 of 8 groups based on treatment (selatogrel or matching placebo), dose (8 mg or 16 mg) and s.c injection site (thigh or abdomen). Venous blood samples were collected into PPACK anticoagulant tubes. Platelet reactivity was assessed by VerifyNow PRU (P2Y12 reaction units) test before and 15 min, 30 min and 1, 2, 4, 8 and 24 h after injection. Light-transmittance aggregometry (LTA; ADP 20 uM) was also performed. PK samples were collected up to 24 h post-dose. Adverse events occurring within 30 days were recorded. Responders were defined as having PRU &lt;100 at 30 min after injection and lasting ≥3 h. Results 345 patients (mean age 65 y; 20% female; 31% diabetes) received selatogrel 8 mg (n=114), selatogrel 16 mg (n=115) or placebo (n=116). 97% were on background therapy with aspirin (or its derivative carbasalate) and 35% with oral P2Y12 inhibitor (clopidogrel 23%, prasugrel 4%, ticagrelor 8%). 89% of subjects were responders to selatogrel 8 mg, 90% to selatogrel 16 mg and 16% to placebo (P&lt;0.0001). At 15 min post-dose, PRU values (mean±SD) were 10±25 with selatogrel 8 mg, 5±10 with selatogrel 16 mg and 163±73 with placebo (Figure). PRU levels were maintained at 2 and 4 h for both doses and gradually returned to pre-dose levels by 24 h post-dose (Figure). LTA results were consistent with the VerifyNow results. PD responses were similar for thigh and abdomen injection sites. Selatogrel was well tolerated: mild dyspnoea (or moderate dyspnoea, n=1, with 16 mg) occurred in 5% and 9% with selatogrel 8 mg and 16 mg, respectively, vs 0% with placebo; dizziness occurred in 4% and 4% vs 1%, respectively, without significant haemodynamic or ECG changes. Bleeding events occurred in 9.6% and 4.3% with selatogrel 8 mg and 16 mg, respectively, vs 6.9% with placebo. Pharmacokinetic data will be presented. Conclusions Selatogrel has a rapid PD effect following s.c injection in patients with stable CAD, within 15 min in most patients. The consistent and high levels of P2Y12 inhibition with a single 8 mg or 16 mg dose are sustained for over 4 hours, following which platelet reactivity progressively recovers over 24 h. Selatogrel was well tolerated, with mostly mild, transient dyspnoea observed in &lt;10% patients. These data support further studies of selatogrel for emergency treatment of AMI patients. Acknowledgement/Funding Fully funded by Idorsia Pharmaceuticals Ltd

Low-Dose Prasugrel vs Clopidogrel-Based Tailored Premedication for Endovascular Treatment of Cerebral Aneurysms.

Antiplatelet premedication is widely accepted for interventional treatment of cerebral aneurysms to prevent thromboembolism. However, antiplatelet resistance sometimes limits the effectiveness of premedication. To compare 2 groups administered low-dose prasugrel (PSG group) or clopidogrel-based tailored antiplatelet (CPG group) in terms of platelet function and procedure-related complications. A total of 411 patients with 505 unruptured aneurysms who underwent endovascular treatment within the past 17 mo were retrospectively enrolled in this study. The PSG (225 patients with 277 aneurysms) and CPG groups (186 patients with 228 aneurysms) were administered the respective medication prior to endovascular treatment. We measure the response to the antiplatelet medication with a laboratory test. Episodes of periprocedural bleeding and thromboembolism were compared between the 2 groups. There were significant differences between the 2 groups in terms of the mean P2Y12 reaction unit values (125.7 in the PSG group vs 251.0 in the CPG group; P<.001) and percentage inhibition (57.8% vs 18.7%, respectively; P<.001). Drug resistance was 29.6% per patient in the CPG group and 2.7% per patient in the PSG group. The PSG group reported 1 thromboembolism and bleeding each; meanwhile, the CPG group reported 7 thromboembolism and 3 bleeding. Compared to clopidogrel administration, prasugrel administration significantly decreased the risk of thromboembolism (weighted hazard ratio, 0.17; 95% confidence interval, 0.03-0.99). However, the risk of bleeding was not significant. Prasugrel was found to be more effective in reducing periprocedural thromboembolism compared to clopidogrel.

Influence of statin treatment on pharmacokinetics and pharmacodynamics of clopidogrel and its metabolites in patients after coronary angiography/angioplasty

Possible interaction between clopidogrel and CYP3A4-metabolised atorvastatin or non-CYP3A4-metabolised rosuvastatin was investigated based on pharmacokinetic parameters of clopidogrel and its metabolites as well as the platelet reactivity test in patients undergoing coronary angiography/angioplasty.The study involved 50 patients (62.7 ± 7.8 years old) who underwent coronary angiography/angioplasty and were treated with clopidogrel and atorvastatin or rosuvastatin during the six months after the procedure. The P2Y12 reaction units (PRU) and pharmacokinetic parameters of clopidogrel, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive carboxylic metabolite were measured 12–18 h and six months after the coronary angiography/angioplasty.There were no significant differences in concentrations of clopidogrel and its metabolites including the H4 active metabolite in plasma of patients co-treated with clopidogrel and atorvastatin or rosuvastatin. The use of statins did not affect the pharmacokinetic parameters of the studied compounds. A significant correlation was found between the Cmax and AUC0-t of the active H4 isomer and platelet aggregation in a group of patients treated with rosuvastatin but not in the atorvastatin group. No significant differences in PRU values were observed between the atorvastatin and rosuvastatin groups at the beginning of the study (171.4 ± 54.3 vs 146.3 ± 48.1 PRU, p = 0.192) as well as at six months (173.7 ± 45.8 vs 157.3 ± 54.9 PRU, p = 0.562). However, in a small group of patients, who were discharged from atorvastatin to rosuvastatin, an increase in the PRU values accompanied by a decreased AUC of the H4 active isomer was observed.The study confirmed that the systemic exposure to clopidogrel and its active H4 isomer of thiol metabolite, as well as the antiplatelet effect of the drug, were not negatively affected by co-administration of atorvastatin as compared with rosuvastatin.

The effect of smoking on residual platelet reactivity to clopidogrel: a systematic review and meta-analysis

Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its influence on platelet ADP-P2Y12 receptor inhibitors lack consistency. Thus, we conducted a systematic review and meta-analysis of already existing data/studies to further explore this issue. PubMed, Web of science, EMBASE, Clinical Trials, and the Cochrane Library were searched from inception to March 2018. Studies investigating the residual platelet reactivity categorized by smoking status and patients treated with platelet ADP-P2Y12 receptor inhibitors qualified the inclusion criteria. The primary outcome was P2Y12 reaction unit (PRU) value measured by VerifyNow P2Y12 assay, compared with different smoking status in ADP-P2Y12 receptor inhibitors treatment groups. Secondary outcome was post-treatment with 5 μmol/L ADP-inhibition of platelet aggregation (ADP-IPA) measured by light transmittance aggregometry (LTA). Of the 4954 citations retrieved, 12 studies involving 16 296 patients with acute coronary syndrome and/or stent deployment using platelet ADP-P2Y12 receptor inhibitors were included for meta-analysis. Pooled analysis revealed that PRU values of current smokers were 25.70 lower than nonsmokers (95% CI −38.81 to −12.60, p = 0.0001), getting better effects of antiplatelet treatment. In the smoking extent subgroup analysis, patients smoking >10 cigarettes/day shown about 46.49 lower of PRU values than patients smoking <10 cigarettes/day (p < 0.00001). Racial subgroup analyses found that smokers had increased platelet inhibition in the Caucasian population. Further, pooled analysis of ADP-IPA values for 1658 patients from five studies showed a significantly lower residual platelet reactivity in current smokers compared to that in nonsmokers (MD = −4.19; 95% CI −6.55 to −1.83; p = 0.0005). This systematic review and meta-analysis suggested that smokers have increased platelet inhibition and lower aggregation in response to clopidogrel than nonsmokers. These residual platelet reactivity observations may help to explain differential clinical outcomes in smokers vs. nonsmokers in large scale clinical trials.

Candidate gene and pathway analyses identifying genetic variations associated with prasugrel pharmacokinetics and pharmacodynamics

AimWe aimed to investigate the genetic polymorphisms and pharmacogenetic variability associated with the pharmacodynamics (PD) and pharmacokinetics (PK) of prasugrel, in healthy Han Chinese subjects. Patients & methodsHealthy, native, Han Chinese subjects (n = 36) aged 18 to 45 years with unknown genotypes were included. All subjects received a loading dose (LD) on day 1 and a maintenance dose (MD) from day 2 until day 11. Candidate gene association and gene-set analysis of biological pathways related to prasugrel and platelet activity were analyzed. Results28 SNPs of 17 candidate genes previously associated with prasugrel or platelet activity were selected after a literature search. In the 30 mg LD groups (n = 24), ITGA2-rs28095 was found to be significantly associated with the P2Y12 reaction unit (PRU) value at 24 h after the LD (p = 0.015). 165 study genes related to platelet activation-related processes and prasugrel activity were selected from the MSigDB database, including curated gene sets from KEGG, Bio Carta, and Gene Cards. 14 SNPs of 9 genes were found to be significantly correlated both at 24 h and 12 days after LD: ADAMTSL1, PRKCA, ITPR2, P2RY12, P2RY14, PLCB4, PRKG1, ADCY1, and LYN. Seven SNPs of 6 protein-coding genes associated with area under the concentration-time curve (AUC0-tlast) were significantly identified among the 47 selected genes, including ADAMTSL1, CD36, P2RY1, PCSK9, PON1, and SCD. ConclusionThese results show that genetic variation affects the PK and PD of prasugrel in normal individuals. Further studies with larger sample sizes are required to explore whether the SNPs are associated only with prasugrel activity or also with cardiovascular events and all-cause mortality.

Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population.

IntroductionHigh on-treatment platelet reactivity (HTPR) to clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease.MethodsWe performed a retrospective study of 111 patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay and HTPR was defined as P2Y12 reaction units (PRU) ≥230. Genotyping testing was performed using Taqman® Genotyping Assays.ResultsThe mean PRU across the cohort was 203±61 PRU (range 8–324), and 42 (38%) patients had HTPR. Multiple logistic regression showed that 27% of the total variation in PRU was explained by a history of diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R. Body mass index (odds ratio [OR]=1.15; 95% CI: 1.03–1.27), diabetes mellitus (OR=3.46; 95% CI: 1.05–11.43), hematocrit (OR=0.75; 95% CI: 0.65–0.87), and CYP2C19*2 (OR=4.44; 95% CI: 1.21–16.20) were the only independent predictors of HTPR.ConclusionMoreover, we propose a predictive model to determine PRU values as measured by VerifyNow P2Y12 assay for the Puerto Rican Hispanic population. This model has the potential to identify Hispanic patients at higher risk for adverse events on clopidogrel.

Patterns, Predictors, and Outcomes of Postprocedure Delayed Hemorrhage Following Flow Diversion for Intracranial Aneurysm Treatment

To evaluate patterns, predictors, and outcomes of postprocedure delayed hemorrhage (PPDH) following flow diversion therapy for intracranial aneurysm treatment. From 2012 to 2016, 50 patients with 52 aneurysms were treated with the Pipeline embolization device. Device placement was performed as a standalone therapy or with adjunctive coil embolization. Patients underwent dual antiplatelet therapy for 6 months after treatment. Medical comorbidities; aneurysm traits; and treatment factors, including platelet function testing, were studied. Statistical analysis was performed using cross-tabulation. Six PPDHs (12%) occurred 2-16 days (mean 6.8 days) after Pipeline placement, manifesting as 1 of 2 distinct patterns: convexity subarachnoid hemorrhage (cSAH) (n= 4) or lobar intraparenchymal hemorrhage (IPH) (n= 2). All PPDHs occurred ipsilateral to the device; 1 IPH occurred ipsilateral but in a different arterial territory. PPDH occurred in both treated anterior communicating artery aneurysms. Cases of PPDH demonstrated on average lower P2Y12 reaction unit values at the time of treatment. Platelet function testing at the time of hemorrhage was consistently hypertherapeutic. Patients with cSAH had only minimal worsening of modified Rankin Scale score at the time of discharge, whereas the 2 patients with IPH experienced significant deterioration. PPDH is a poorly understood complication following flow diversion therapy that can result in significant morbidity. In our experience, nonaneurysmal cSAH does not result in poor clinical outcomes, whereas IPH leads to long-term deficits or death. As previously suggested, there appears to be a correlation between low P2Y12 reaction unit values and PPDH.

Time course of the antiplatelet effect after switching to clopidogrel from initial prasugrel therapy in patients with acute coronary syndrome

Prasugrel is often replaced with clopidogrel after a certain period of time following coronary stenting. However, the time course of platelet aggregation during this replacement is unknown. We performed a prospective, single-arm study to monitor platelet reactivity before and after the replacement. Forty-five patients (mean age 62.6±13years, 40 male) who received coronary stenting for acute coronary syndrome were initially treated with the loading dose (20mg) of prasugrel followed by the maintenance dose (3.75mg/day) for 7days, then switched to 75mg/day of clopidogrel. The P2Y12 reaction unit (PRU) level was measured at baseline and selected time points. Prasugrel effectively suppressed PRU from 248±59 at baseline to 145±65 on day 1 (P<0.001). The PRU value on the final day of prasugrel treatment (day 7) was 156±68 (P<0.001 vs. baseline). After switching to clopidogrel, PRU was consistently suppressed [146±60, 139±54, and 135±60 on days 9, 11, and 13, respectively (P<0.001, each point vs. baseline)]. Switching from the initial prasugrel therapy to clopidogrel using the maintenance dose does not cause a drug efficacy gap and stays effective for preventing stent thrombosis.

Sepsis favors high-on-clopidogrel platelet reactivity

High-on-treatment platelet reactivity (HPR) is associated with ischemic events in patients on antiplatelet therapy with a history of cardiovascular disease. On the other hand, recent data have associated sepsis with adverse cardiovascular events in patients admitted with bacteremia or respiratory infection. We aimed to assess P2Y12-mediated platelet reactivity (PR) during sepsis and recovery in patients under clopidogrel. This was a prospective observational study. Incoming patients presenting with signs/symptoms of sepsis already on a maintenance dose of clopidogrel of 75 mg qd for cardiovascular events were included in this study. Patients were assessed for their PR on presentation and following septic syndrome, using the VerifyNow point-of-care P2Y12 assay. Patients were excluded in the presence of evidence of noncompliance to antiplatelet regimen or in need of discontinuation during this study. Twenty-two septic patients on clopidogrel were included in this study (Supplemental Figure S1). Clopidogrel was administered for previous stroke, coronary, and peripheral artery disease in 27.3, 40.9, and 31.8% of patients, respectively. The main site of infection was respiratory tract followed by urinary tract, while the same amounts of gram-negative and -positive pathogens were isolated. HPR was noted in 77% and 29% of patients during sepsis and recovery, respectively, presenting a significant decrease in P2Y12 reaction units values during follow-up [240.7 ± 58.3 versus 179.5 ± 58.4, 95% CI (–102.7, –39.76), p = 0.0002]. Five patients died of infection, while no adverse cardiovascular events were noted in our study. Our study shows that sepsis may favor HPR, which is reversed when recovery occurs. This finding may underlie the adverse cardiovascular events in patients admitted with sepsis, possibly requiring alteration of antiplatelet regimen during the inflammation period.

Morphological and pharmacological determinants of peri-procedural myocardial infarction following elective stent implantation: Optical coherence tomography sub-analysis of the PRASFIT-Elective study

BackgroundPrevious studies have suggested that peri-procedural myocardial infarction (PMI) following percutaneous coronary intervention (PCI) is associated with adverse short- and long-term outcomes, and several morphological predictors of PMI have been studied. However, the determinants of PMI under novel anti-platelet therapy are not fully elucidated. Methods and resultsPRASFIT-Elective is a multicenter, parallel-group study of PCI patients in non-acute settings receiving either prasugrel or clopidogrel in addition to aspirin. Among 742 study patients, 94 (116 lesions) underwent optical coherence tomography (OCT) to evaluate the area of intra-stent tissue (IST, which comprises tissue protrusion and thrombus) after stenting in addition to standard parameters. We investigated the relationship between the peak creatine kinase (CK)-MB fraction levels after PCI and post-stent OCT findings, as well as on-treatment platelet reactivity determined by the P2Y12 reaction units (PRU) at PCI, in a post hoc manner. The multivariate linear analysis revealed that a larger total IST area (standardized coefficient: 0.370, p<0.001) and smaller minimal stent diameter (standardized coefficient: −0.242, p<0.014), but not the PRU value (p=0.988), were independently associated with CK-MB leakage. The IST area after stenting was mainly determined by the target lesion lipid index (averaged lipid arc×lipid length) (r=0.583, p<0.001). ConclusionFollowing elective PCI, a large IST area originating from a lipid-rich plaque and a smaller minimal stent diameter were associated with PMI.

Comparison of the Antiplatelet Effects of Once and Twice Daily Low-Dose Ticagrelor and Clopidogrel After Percutaneous Coronary Intervention

Although Asian people are believed to be more susceptible to bleeding on currently recommended dose of ticagrelor, there is limited evidence supporting low-dose ticagrelor. We prospectively randomized patients receiving dual antiplatelet therapy with aspirin and clopidogrel into 3 groups; aspirin plus clopidogrel 75mg versus aspirin plus ticagrelor 90mg once daily versus aspirin plus ticagrelor 45mg twice daily. Platelet function assessments were conducted using VerifyNow P2Y12 assay at baseline and 28days after randomization. No differences in baseline P2Y12 reaction unit (PRU) values were observed among the 3 groups. PRU values at the end of the treatment periods were significantly lower in low-dose ticagrelor (90mg QD group, 98.6 ± 73.4 and 45mg BID group, 65.5 ± 58.8) compared with clopidogrel (221.2 ± 50.1, both p <0.001). There was no significant difference in PRU values between 2 groups of low-dose ticagrelor (p= 0.208). The rates of high on-treatment platelet reactivity were significantly lower in low-dose ticagrelor compared with clopidogrel, whereas clopidogrel showed higher rate of optimal on-treatment platelet reactivity than ticagrelor 45mg BID. However, similar rate of optimal on-treatment platelet reactivity was observed in clopidogrel and ticagrelor 90mg QD. In conclusion, low-dose ticagrelor treatment, either with 90mg QD or 45mg BID, was associated with a more potent antiplatelet effect compared with clopidogrel treatment and once daily dose provided similar antiplatelet effect but favorable effect on optimal plateletinhibition compared with twice daily dose.

The effect of correcting VerifyNow P2Y12 assay results for hematocrit in patients undergoing percutaneous coronary interventions

Background High on-treatment platelet reactivity is predictive for the occurrence of atherothrombotic events following percutaneous coronary interventions (PCIs). A low hematocrit (HCT) value is associated with higher platelet reactivity values, expressed in P2Y12 reaction units (PRU), as measured with the VerifyNow P2Y12 assay. However, it is suggested that this is only an in vitro phenomenon. Objective To determine whether adjusting PRU for HCT improves the predictive value for thrombotic events following PCI. Material and methods The VerifyNow P2Y12 assay was performed in clopidogrel-treated patients undergoing non-urgent PCI included in a prospective cohort study. PRU values were corrected for HCT with a formula proposed in recent literature. Receiver operating characteristic (ROC) curves were made to determine the optimal cut-off values to predict the occurrence of the primary endpoint, a composite of all-cause death and non-fatal myocardial infarction, stent thrombosis and ischemic stroke, during 1 year of follow-up. The chi-squared test was performed to determine whether correcting PRU for HCT improved the prediction of the primary endpoint. Results A total of 978 patients were analyzed. A negative correlation between PRU and HCT was observed (R2 = 0.104). The optimal cut-off value for the corrected PRU was 215. ROC analyses showed that prediction of the primary endpoint did not differ for the corrected PRU (area under the curve, 0.61; sensitivity, 0.57; specificity, 0.64) and the uncorrected PRU (area under the curve, 0.61; sensitivity, 0.69; specificity, 0.53). Conclusion Correcting PRU for HCT does not improve the prediction of thrombotic events following PCI.

Effects of autologous platelet transfusion on platelet inhibition in ticagrelor‐treated and clopidogrel‐treated subjects

Background Antiplatelet agents increase bleeding risk. Few data on hemostatic benefits of platelet transfusion exist. Objective To assess the effect of autologous platelet transfusion on ticagrelor-mediated and clopidogrel-mediated platelet inhibition in a single-center, open-label, randomized, cross-over study (NCT01744288). Methods Forty-four healthy subjects received ticagrelor (180 mg) or clopidogrel (600 mg; two functional CYP2C19 alleles [*1 or *17] required) with or without platelet transfusion (14-day washout). Subjects received one autologous platelet apheresis unit (approximately six pooled donor platelet units) 24 h (n = 15) or 48 h (n = 13) after ticagrelor or 48 h after clopidogrel (n = 16). Platelet apheresis was conducted 72 h before transfusion. Aspirin (81 mg per day) was taken from after apheresis until 24 h before transfusion. P2Y12 reaction units (PRUs) and inhibition of platelet aggregation (IPA) induced by ADP were measured. Results Mean age and body mass index were 30 years (standard deviation [SD] 6 years) and 26.9 kg m-2 (SD 4.0 kg m-2 ), respectively; 98% of subjects were men, and 39 of 44 completed treatment. Platelet transfusion 24 h after ticagrelor had minimal effects on IPA or PRU values within 48 h after transfusion. Platelet transfusion 48 h after ticagrelor also had minimal effects on IPA or PRU values at most post-transfusion times. Platelet transfusion 48 h after clopidogrel, versus no transfusion, had a small reversing effect on IPA (24 h, 36 h, and 48 h) and PRU values (12 h, 24 h, and 36 h) after transfusion. Conclusions Autologous platelet transfusion is unlikely to be of clinical benefit in reversing the antiplatelet effects of ticagrelor. The clinical relevance of the small effects seen with clopidogrel is unknown.

Chewed ticagrelor tablets provide faster platelet inhibition compared to integral tablets: The inhibition of platelet aggregation after administration of three different ticagrelor formulations (IPAAD-Tica) study, a randomised controlled trial

AimsTo provide pharmacodynamic data of crushed and chewed ticagrelor tablets, in comparison with standard integral tablets. MethodsNinety nine patients with stable angina were randomly assigned, in a 3:1:1 fashion, to one of the following 180mg ticagrelor loading dose (LD) formulations: A) Integral B) Crushed or C) Chewed tablets. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60min after LD. High residual platelet reactivity (HRPR) was defined as >208 P2Y12 reaction units (PRU). ResultsThere was no significant difference in PRU values at baseline. PRU 20min after LD were 237 (182–295), 112 (53–238) and 84 (29–129) and 60min after LD, 56 (15–150), 51 (18–85) and 9 (7–34) in integral, crushed and chewed ticagrelor LD, respectively (p<0.01 for both). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60min. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20min whereas no difference was observed at 60min.At 20min, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01). ConclusionWith crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared to standard integral tablets. We also show that administration of chewed tablets is feasible and provides faster inhibition than either crushed or integral tablets.CLINICAL TRIAL REGISTRATION: European Clinical Trial Database (EudraCT number 2014-002227-96).