High On-treatment Platelet Reactivity Rates Research Articles

A novel machine learning model to predict high on-treatment platelet reactivity on clopidogrel in Asianpatients after percutaneous coronary intervention.

Various genetic and nongenetic variables influence the high on-treatment platelet reactivity (HTPR) in patients taking clopidogrel. This study aimed to develop a novel machine learning (ML) model to predict HTPR in Chinese patients after percutaneous coronary intervention (PCI). This cohort study collected information on 507 patients taking clopidogrel. Data were randomly divided into a training set (90%) and a testing set (10%). Nine candidate Machine learning (ML) models and multiple logistic regression (LR) analysis were developed on the training set. Their performance was assessed according to the area under the receiver operating characteristic curve, precision, recall, F1 score, and accuracy on the test set. Model interpretations were generated using importance scores by transforming model variables into scaled features and representing in radar plots. Finally, we established a prediction platform for the prediction of HTPR. A total of 461 patients (HTPR rate: 19.52%) were enrolled in building the prediction model for HTPR. The XGBoost model had an optimized performance, with an AUC of 0.82, a precision of 0.80, a recall of 0.44, an F1 score of 0.57, and an accuracy of 0.87, which was superior to those of LR. Furthermore, the XGBoost method identified 7 main predictive variables. To facilitate the application of the model, we established an XGBoost prediction platform consisting of 7 variables and all variables for the HTPR prediction. A ML-based approach, such as XGBoost, showed optimum performance and might help predict HTPR on clopidogrel after PCI and guide clinical decision-making. Further validated studies will strengthen this finding.

Randomized, Double-Blind, Active Comparator Pharmacodynamic Study of Platelet Inhibition with Crushed and Integral Formulations of Clopidogrel and Ticagrelor in Acute Coronary Syndrome.

Crushed formulations of specific antiplatelet agents produce earlier and stronger platelet inhibition. We studied the platelet inhibitory effect of crushed clopidogrel in patients with acute coronary syndrome (ACS) and its relative efficacy compared with integral clopidogrel, crushed and integral ticagrelor. We aimed to compare the platelet inhibitory effect of crushed and integral formulations of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS). Overall, 142 patients with suspected ACS were randomly assigned to receive crushed or integral formulations of clopidogrel or ticagrelor. Platelet inhibition at baseline and 1 and 8h was assessed using the VerifyNow assay. High on-treatment platelet reactivity (HTPR) ≥ 235 P2Y12reaction units (PRUs) 1h after the medication loading dose was also determined. The PRU and percentage inhibition median (interquartile range) at 1h for the different formulations were as follows: crushed clopidogrel: 196.50 (155.50, 246.50), 9.36 (- 1.79, 25.10); integral clopidogrel: 189.50 (159.00, 214.00), 2.32 (- 2.67, 19.89); crushed ticagrelor: 59.00 (10.00, 96.00), 75.53 (49.12, 95.18); and integral ticagrelor: 126.50 (50.00, 168.00), 40.56 (25.59, 78.69). There was no significant difference in PRU or percentage platelet inhibition between the crushed and integral formulations of clopidogrel (p=0.990, p=0.479); both formulations of ticagrelor were superior to the clopidogrel formulations (p<0.05). On paired comparison, crushed ticagrelor showed robust early inhibition of platelets compared with the integral formulation (p=0.03). Crushed clopidogrel exhibited the maximal HTPR of 34.3%, but was < 3% for both formulations of ticagrelor. The platelet inhibitory effect of crushed clopidogrel is not superior to integral preparation in patients with ACS. Crushed ticagrelor produced maximal platelet inhibition acutely. HTPR rates in ACS are similar and very low with both formulations of ticagrelor, and maximal with crushed clopidogrel. Clinical Trials Registry of India identifier number CTRI/2020/06/025647.

Clopidogrel versus ticagrelor in the treatment of Chinese patients undergoing percutaneous coronary intervention: effects on platelet function assessed by platelet function tests and mean platelet volume

BackgroundKnowledge on the pharmacodynamic effects of antiplatelet drugs including clopidogrel and ticagrelor on Asian patients is scarce. We aim to evaluate the effects of the two drugs on platelet reactivity in the treatment of Chinese patients who underwent percutaneous coronary intervention (PCI), using two platelet function tests (PFT). Meanwhile, the relationship between mean platelet volume (MPV), a routine index of platelet size, and high on-treatment platelet reactivity (HPR) is also investigated.MethodsPatients receiving dual antiplatelet therapy (DAPT) were scheduled for the assessment of platelet reactivity at 2–3 days after PCI. Two PFTs, light transmission aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP)-FCM assay, were applied in the evaluation of platelet reactivity. The MPV was measured simultaneously with EDTA plasma using a Sysmex XN 2000 automated hematology analyzer.ResultsThe final study population included the aspirin + clopidogrel group (n = 46) and the aspirin + ticagrelor group (n = 66). In the aspirin + ticagrelor group, the maximal light transmittance (LT) changes in response to 5 μM ADP assessed by LTA was obviously lower than that in the aspirin + clopidogrel group (P < 0.001). The platelet reactivity index (PRI) level in the VASP test was also markedly lower in the group given aspirin and ticagrelor (P < 0.001). There was a significant difference in HPR between the two groups. MPV showed a potent ability to predict the presence of HPR at VASP assay (AUC = 0.788, 95% CI: 0.701–0.875, P < 0.001) in receiver-operating characteristic curve analysis.ConclusionsCompared with clopidogrel, ticagrelor has dramatically greater antiplatelet effect, with a superiority in suppressing platelet function and a lower HPR rate. In addition, there existed a significant independent association between MPV and high prevalence of HPR in the VASP assay.

Platelet reactivity among patients with acute coronary syndromes and multivessel coronary artery disease

Abstract Background Patients with multivessel or complex coronary artery disease (CAD) are at increased risk of atherothrombotic events. It has been suggested that these patients may derive an incremental benefit with more intense antiplatelet strategies, according to prior subgroup analyses from randomized clinical trials. However, whether there is any association between the presence and extension of multivessel CAD and platelet aggregability (PA) in patients with acute coronary syndromes (ACS) is unknown. Purpose To analyze the independent association between PA and presence of multivessel CAD in patients with ACS. Methods Patients with ACS on dual antiplatelet therapy (aspirin plus clopidogrel) were included in this study. Multivessel CAD was defined as the presence of significant ≥50% stenosis at two or more major epicardic vessels. Platelet aggregability was assessed by VerifyNow P2Y12 assay expressed in P2Y12 Reactivity Units (PRU) on the day of discharge from the coronary care unit. High On-treatment platelet reactivity (HPR) was defined as PRU ≥208. Stepwise linear and logistic regression models were applied to adjust for confounders. Models were adjusted for: age, sex, race, diabetes, hypertension, smoking, dyslipidemia, prior MI, prior PCI, prior CABG, prior HF, prior stroke and ACS phenotype (STEMI vs. Non-ST-segment elevation ACS). Results A total of 237 patients were included, among whom 143 (60.3%) had multivessel CAD at the coronary angiogram and 175 (73.8%) were submitted to PCI during index hospitalization. Patients with multivessel disease were older (mean age 64.8±12.1 vs. 58.9±11.2 years; p&amp;lt;0.001) and more likely to have a history of diabetes (47.6% vs. 29.8%; p=0.006) and non-ST-segment elevation ACS as the index event (55.2% vs. 28.7%; p&amp;lt;0.001), compared to patients without multivessel CAD. After adjustments, presence of multivessel CAD was associated with higher PA (mean 161.4±74 PRU in patients with versus 140.3±70.9 PRU in patients without multivessel CAD; adjusted mean difference 23.7 PRU; 95% CI 4.8 to 42.5; p=0.014). Additionally, there was an incremental of 12.5 PRU (95% CI 2.8 to 22.3; adj p=0.012) for each diseased vessel and of 4.67 PRU (95% CI 0.11 to 9.22; adj p=0.045) for each diseased coronary segment. Compared to patients with single-vessel disease, patients with three-vessel disease had higher rates of HPR. (Figure). Conclusion In patients with ACS, the presence and extension of multivessel CAD were associated with higher levels of platelet aggregability and higher rates of high on-treatment platelet reactivity with clopidogrel. This finding may explain the incremental benefit with more intense antiplatelet therapies seen in this particular subgroup in prior clinical trials. Prevalence of HPR and extension of CAD Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Sao Paulo Research Foundation (FAPESP)

Association of CYP2C19*2 polymorphisms and high on-treatment platelet reactivity in acute myocardial infarction or coronary artery in-stent restenosis patients during dual antiplatelet therapy

ObjectiveCytochrome CYP2C19 mutant allele is associated with high on-treatment platelet reactivity (HTPR) after standard clopidogrel treatment, which is accompanied by an increased risk of ischemic events. This study assesses the association of CYP2C19 mutant allele with HTRR and its response to antiplatelet therapy in acute myocardial infarction (AMI) or coronary artery in-stent restenosis (ISR). MethodsCYP2C19 (*2, *3, *17) and ABCB1 genotyping were performed in a series of 98 AMI or ISR patients treated with standard-dose clopidogrel (75 mg, term daily). Platelet activity was measured by VerifyNow assay, with HTPR defined as P2Y12 reaction units (PRUs) >208. The patients with HTPR (n = 48) were randomly assigned to receive either high-dose clopidogrel (150 mg, term daily; n = 24) or ticagrelor (90 mg, bid; n = 24). ResultsNo association was observed between CYP2C19*3, ABCB1 genotype and platelet reactivity (PR) (P > .05 for all). A significantly higher frequency of HTPR were observed in the patients carrying CYP2C19*2 homozygotes (n = 9; 9/11, 81.8%) than the CYP2C19*2 allele carriers (n = 26; 26/48, 54.2%, P < .05) and the non-carriers (n = 13; 13/39, 33.3%, P < .001). No patient exhibited HTPR after treatment with ticagrelor irrespective of CYP2C19 genotype, whereas 5 (100%) patients with CYP2C19*2 homozygotes, 7 (50%) CYP2C19*2 allele carriers and 3 (60%) non-carriers after high-dose clopidogrel remained HTPR (P < .05 for all). ConclusionA higher rate of HTPR was observed in AMI or ISR patients with CYP2C19*2 homozygotes than those with one or none allele. In patients carrying CYP2C19*2 homozygotes, ticagrelor is significantly more effective in reducing platelet reactivity than high-dose clopidogrel.

P6406Platelet reactivity in Hepatitis C virus infected patients on dual antiplatelet therapy for acute coronary syndrome

Abstract Background Coronary artery disease (CAD) has been recognized as a serious and potentially life-threatening complication of Hepatitis C Virus (HCV) infection. High on treatment platelet reactivity has been associated with high risk of ischemic events in patients with CAD, but data regarding the association with HCV infection are still lacking. Purpose We sought to assess platelet reactivity on dual anti-platelet therapy and long-term outcome of acute coronary syndrome (ACS) patients infected with HCV. Methods ACS patients infected with HCV were matched to ACS patients without HCV for age, sex, diabetes, hypertension and renal function. Primary and secondary study endpoints were the proportion of patients with high on treatment platelet reactivity (HTPR) and long-term outcomes, respectively. Results HCV-infected ACS patients had higher levels of platelet reactivity (ADP10-LTA: 56% ± 18% vs. 44% ± 22%; p=0.002; Arachidonic Acid-LTA: 25% ± 21% vs. 16% ± 15%; p=0.011) and higher rate of HTPR on clopidogrel and aspirin compared with non-HCV patients. Multivariable analysis demonstrated HCV-infection to be an independent predictor of HTPR. At follow-up, estimated major adverse clinical events (MACE: cardiac death, non fatal myocardial infarction and any revascularization) were 57% vs. 37%, p=0.006 in HCV-infected ACS and non-HCV, respectively. Also, TIMI major bleeding rates were higher in HCV-infected subjects (11% vs. 3%; p=0.043) as compared with non-infected patients. Platelet function according to HCV status Conclusions ACS patients with HCV infection have increased on treatment platelet reactivity, higher rate of HTPR, MACE and bleedings as compared with non-HCV patients.

Measuring high on-treatment platelet reactivity in clinical practice; should we use a panel of platelet function tests?

: High on-treatment platelet reactivity (HPR) on P2Y12-inhibitors in patients treated with dual antiplatelet therapy is strongly associated with adverse ischaemic events. Studies have shown conflicting results with regard to the correlation and agreement between the different tests. Several assays are available to establish HPR. A composite advice based on more than one test might be a better way to identify HPR patients. To compare HPR rates and agreement between individual platelet function tests and a panel of three tests In our large percutaneous coronary intervention centre, all patients who suffered a stent thrombosis were invited back to a dedicated clinic. Platelet function testing was performed in all patients and matched control patients. HPR rates were compared between individual tests and with a composite comprised of three tests. A total of 242 patients were included, of whom in 193 patients all tests were available. HPR rates ranged from 14.6% [VerifyNow cut-off >235 platelet reactivity units (PRU)] to 49.7% (Vasodilator-Stimulated Phosphoprotein Assay). HPR according to the composite advice (≥2 out of 3 tests indicating HPR) was present in 29.8% of patients. The best correlation with the composite advice was observed with light transmittance aggregometry (kappa = 0.78) and VerifyNow (lower cut-off >208 PRU; kappa = 0.68). VerifyNow with cut-off more than 235 PRU identified the smallest proportion of patients with HPR, whereas Vasodilator-Stimulated Phosphoprotein Assay seemed to 'over-identify' HPR. In this real life patient cohort, a large variability was observed between four different platelet function tests. The use of a composite advice based on three tests is a promising alternative.

Vitamin D levels and platelet reactivity in diabetic patients receiving dual antiplatelet therapy

BackgroundHypovitaminosis D represents an emerging cardiovascular risk factor, and especially among higher-risk subsets of patients, such as in those with diabetes mellitus. The anti-inflammatory and anti-thrombotic properties of vitamin D, in fact, could be even more beneficial among diabetics, where platelet hyperreactivity and suboptimal response to antiplatelet drugs has been associated with poorer outcomes. However, no study has so far evaluated the impact of vitamin D levels on platelet reactivity and high-on treatment platelet reactivity (HRPR) among diabetic patients receiving dial antiplatelet therapy (DAPT). MethodsOur population is represented by a consecutive cohort ofdiabetic patients treated with DAPT (ASA + clopidogrel or ticagrelor or dose-adjusted prasugrel) for an acute coronary syndrome or elective PCI, undergoing platelet reactivity assessment at 30–90 days post-discharge. Aggregation was assessed by multiple-electrode aggregometry. HRPR was defined for values above the lower limit of normality (in non-treated patients). ResultsWe included 440 patients, that were divided according to quartiles values of vitamin D (< 9.4; 9.4–15.59; 15.6–21.64; ≥ 21.65 ng/ml). Among them, 31 were excluded as chronically treated with vitamin D supplementation. Lower vitamin D quartiles were associated with more advanced age (p = 0.01), female gender (p = 0.04), renal failure (p = 0.005), history of previous MI (p = 0.01), CABG and use of diuretics (p = 0.003), severe coronary disease (p = 0.002), but lower ejection fraction (p = 0.001), treatment with statins (p = 0.04) and new ADP-antagonists (p = 0.002). Vitamin D levels related with higher HbA1c (p = 0.001), cholesterol (p = 0.02) and creatinine (p = 0.004) and lower hemoglobin (p = 0.004).The prevalence of HRPR with ASA was low and not related to vitamin D quartiles (3.4% vs 2.7% vs 1.8% vs 2.1%, p = 0.44; adjusted OR[95%CI] = 1.16[0.60–2.26], p = 0.67).The prevalence of HRPR for ADP antagonists was associated to hypovitaminosis D (40.2% vs 29.1% vs 29.4% vs 25.5%, p = 0.03; (adjusted OR[95%CI] = 1.76[1.04–2.98], p = 0.036for I vs II-IV quartile). The impact of vitamin D quartiles, was significant only in patients on new ADP antagonists (n = 225, of whom 81 on prasugrel 5 mg; p = 0.03; adjusted OR[95%CI] = 3.12[1.34–7.49], p = 0.009) but not with clopidogrel (p = 0.85, adjusted OR[95%CI] = 1.05[0.49–2.24], p = 0.89). ConclusionsAmong diabetic patients receiving dual antiplatelet therapy for an acute coronary syndrome or elective percutaneous coronary intervention, severe vitamin D deficiency is associated with a higher ADP-mediated platelet reactivity and rate of HRPR, and especially for new ADP-antagonists over clopidogrel.

Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study).

High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90mg LD, then 45mg twice daily) or high-dose clopidogrel (150mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30days. The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%-91.70%] vs. 44.25% [34.67%-79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).

Clinical outcomes and predictive model of platelet reactivity to clopidogrel after acute ischemic vascular events.

Background:High on-treatment platelet reactivity (HTPR) has been suggested as a risk factor for patients with ischemic vascular disease. We explored a predictive model of platelet reactivity to clopidogrel and the relationship with clinical outcomes.Methods:A total of 441 patients were included. Platelet reactivity was measured by light transmittance aggregometry after receiving dual antiplatelet therapy. HTPR was defined by the consensus cutoff of maximal platelet aggregation >46% by light transmittance aggregometry. CYP2C19 loss-of-function polymorphisms were identified by DNA microarray analysis. The data were compared by binary logistic regression to find the risk factors. The primary endpoint was major adverse clinical events (MACEs), and patients were followed for a median time of 29 months. Survival curves were constructed with Kaplan-Meier estimates and compared by log-rank tests between the patients with HTPR and non-HTPR.Results:The rate of HTPR was 17.2%. Logistic regression identified the following predictors of HTPR: age, therapy regimen, body mass index, diabetes history, CYP2C19∗2, or CYP2C19∗3 variant. The area under the curve of receiver operating characteristic for the HTPR predictive model was 0.793 (95% confidence interval: 0.738–0.848). Kaplan-Meier analysis showed that patients with HTPR had a higher incidence of MACE than those with non-HTPR (21.1% vs. 9.9%; χ2 = 7.572, P = 0.010).Conclusions:Our results suggest that advanced age, higher body mass index, treatment with regular dual antiplatelet therapy, diabetes, and CYP2C19∗2 or CYP2C19∗3 carriers are significantly associated with HTPR to clopidogrel. The predictive model of HTPR has useful discrimination and good calibration and may predict long-term MACE.

Platelet Inhibition With Cangrelor and Crushed Ticagrelor in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

The platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention (P-PCI). In turn, this leads to a gap in platelet inhibition, exposing patients to an increased risk of early thrombotic complications and underscoring the need to define strategies associated with more effective platelet inhibition in the peri-primary percutaneous coronary intervention period. Cangrelor is an intravenous P2Y12 inhibitor with prompt and potent antiplatelet effects. However, to date, there are limited data on the effects of cangrelor used in combination with ticagrelor in patients undergoing primary percutaneous coronary intervention. Moreover, questions have emerged on the potential for drug-drug interactions during the transition from cangrelor to oral P2Y12 inhibitors. This was a prospective, randomized, double-blind, placebo-controlled pharmacodynamic study conducted in patients undergoing primary percutaneous coronary intervention (n=50) who were randomized to treatment with either cangrelor or matching placebo (bolus followed by 2-hour infusion). All patients received ticagrelor 180-mg loading dose administered as crushed tablets at the time of cangrelor/placebo bolus administration. Pharmacodynamic analyses were performed at 8 time points. Pharmacodynamic effects were measured as P2Y12 reaction units by VerifyNow and platelet reactivity index by vasodilator-stimulated phosphoprotein. Compared with placebo, cangrelor was associated with reduced P2Y12 reaction units as early as 5 minutes after bolus, which persisted during the entire duration of drug infusion, including at 30 minutes (63 [32-93] versus 214 [183-245]; mean difference, 152 [95% CI, 108-195]; P<0·001; primary end point). Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with cangrelor. After discontinuation of cangrelor/placebo infusion, there were no differences in levels of platelet reactivity between groups, ruling out a drug-drug interaction when cangrelor and ticagrelor are concomitantly administered. In patients undergoing primary percutaneous coronary intervention, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y12 inhibition induced by ticagrelor. Ticagrelor can be administered as a crushed formulation concomitantly with cangrelor without any apparent drug-drug interaction. The clinical implications of these pharmacodynamic findings warrant investigation in an adequately powered clinical trial. URL: https://www.clinicaltrials.gov . Unique identifier: NCT03247738.

High and low on-treatment platelet reactivity to P2Y12 inhibitors in a contemporary cohort of acute coronary syndrome patients undergoing percutaneous coronary intervention

IntroductionThere is compelling evidence supporting the association between high on-treatment platelet reactivity (HPR) and low on-treatment platelet reactivity (LPR) to clopidogrel with atherothrombotic and bleeding events, respectively. However, it is uncertain if current cutoff values should be used in prasugrel- or ticagrelor-treated subjects. The objective of this analysis was to evaluate the pharmacodynamic (PD) efficacy of P2Y12 antagonists in a contemporary real-world population. Materials and methodsThis PD study included 988 patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) and receiving dual therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor). Platelet function was assessed at day 1 and day 30 post-PCI by VerifyNow P2Y12 assay, multiple electrode aggregometry and vasodilator-stimulated phosphoprotein (VASP) assay. ResultsClopidogrel-treated patients (n = 324) had greater platelet reactivity than those receiving ticagrelor (n = 469) or prasugrel (n = 195) at both time points (p < 0.001 for all comparisons). No difference between ticagrelor and prasugrel was observed at day 1 with the VerifyNow P2Y12 assay (51.5 ± 2.8 vs. 42.7 ± 3.5 PRUs; p = 0.298), whereas ticagrelor achieved greater platelet inhibition at day 30 (48.1 ± 2.5 vs. 89.2 ± 4.2 PRUs; p < 0.001). Similar results were obtained with the VASP assay. Both prasugrel and ticagrelor had markedly lower HPR rates than clopidogrel and very high rates of LPR at both time points. ConclusionsPrasugrel and ticagrelor displayed more potent and consistent PD effects than clopidogrel in ACS patients undergoing PCI, with a trend towards greater platelet inhibition with ticagrelor during the maintenance phase of therapy compared to prasugrel.

Impact of immature platelet fraction on platelet reactivity during prasugrel maintenance treatment

Residual high on-treatment platelet reactivity (HTPR) despite dual antiplatelet therapy (DAPT) has emerged as a predictor of major ischemic events in patients undergoing percutaneous coronary interventions (PCIs), especially after an acute cardiovascular event. However, its determinants are still poorly defined. Therefore, the aim of the present study was to evaluate the role of the percentage of reticulated platelets on HTPR in patients on DAPT with ASA (100–160 mg) and prasugrel (10 mg).Platelet reactivity and the reticulated platelets fraction (immature platelets fraction [IPF]) were assessed at 30–90 days after an acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HTPR was defined as ADP test > 417 AU × min.Our population is represented by 180 ACS patients undergoing stent implantation, divided according to median values of IPF (< or ≥ 2.8%). Higher IPF values were associated to lower platelet count (p < 0.001) and a higher rate of active smokers (p = 0.02). No difference was observed in terms of mean platelet reactivity, with different activating stimuli. The prevalence of HTPR on prasugrel did not significantly differ in patients with IPF < or ≥ 2.8% (8%vs. 11.8%, p = 0.46; adjusted OR [95% CI] = 1.89 [0.66–5.4], p = 0.24).Our study showed that in patients treated with prasugrel after PCI for ACS, the immature platelet fraction influences neither platelet reactivity nor the rate of HTPR.

Effect of Tailored Antiplatelet Therapy to Reduce Recurrent Stent Thrombosis and Cardiac Death After a First Episode of Stent Thrombosis

The recurrence rate of coronary stent thrombosis (ST) is high. Patients with ST often demonstrate high on-treatment platelet reactivity (HPR). It is suggested that patients at high risk of atherothrombotic events, that is patients with ST, could benefit from tailored antiplatelet therapy (APT). This study evaluated whether tailored APT, based on platelet function testing, reduced the rate of cardiac death and/or recurrent ST at 1 year after ST, compared with a historical cohort of patients with ST without tailored APT. Patients with definite ST visited our ST outpatient clinic for platelet function testing and tailored APT. These patients were evenly matched to a historical cohort of patients with ST treated with aspirin and clopidogrel, which was the standard of care at that time. The primary end point was a composite of cardiac death and/or recurrent definite ST after 1year. In total, 113 patients who visited the outpatient clinic were included. HPR was observed in 46%, 6.7%, and 0% of the patients on clopidogrel, prasugrel, and ticagrelor, respectively. After tailored APT, 93% of the patients with HPR demonstrated normal platelet reactivity. The primary end point was observed in 4 patients who had visited the outpatient clinic and in 23 patients of the historical cohort. The odds ratio of tailored APT on the primary end point was 0.26 (95% confidence interval 0.11 to 0.64, p= 0.003), independent from the possible confounders prior myocardial infarction and stent type. In conclusion, the outpatient ST clinic was associated with lower HPR rates in patients with ST after tailored APT. Patients who visited the ST outpatient clinic had a lower risk for cardiac death and/or recurrent ST compared with a historical cohort of patients with ST without tailored APT. Regarding the high HPR rate in patients with ST on clopidogrel, these patients might benefit in particular from the strategy of tailored APT.

Administration of Ticagrelor and Double-Dose Clopidogrel Based on Platelet Reactivity Determined by VerifyNow-P2Y12 for Chinese Subjects After Elective PCI.

Previous studies have identified high on treatment platelet reactivity (HTPR) as a potent factor predicting ischemic events for patients with coronary heart disease. We assessed the efficacy and safety of ticagrelor (90 mg twice-daily) and double-dose of clopidogrel (150 mg once-daily) among Chinese patients for elective percutaneous coronary intervention. We enrolled 40 patients with HTPR from among 317 patients with non-ST-segment elevation acute coronary syndromes after a successful elective percutaneous coronary intervention (PCI). Platelet reactivity was measured by VerifyNow P2Y12 assay. Platelet reactivity was significantly lower for both groups when compared with baseline platelet reactivity after medication adjustment (all P < 0.001). The mean platelet reactivity units (PRU) was significantly lower for the ticagrelor group compared with that of the clopidogrel group over time (all P < 0.001). The differences in the rate of sustained HTPR at different time points between the two groups were significant (2 hours: 0% versus 60%; 8 hours: 5.6% versus 50%; 24 hours: 5.9% versus 43.8%, all P < 0.05). Genetic variation of CYP2C19*2 had no impact on PRU means or rate of HTPR in the ticagrelor group (P > 0.05). During the 30-day follow-up, no MACE occurred in any patient, and the overall risk of bleeding showed no difference between the two groups (35% versus 21%, P = 0.48). Our results suggest that ticagrelor may achieve a more rapid and greater platelet inhibition than double-dose clopidogrel. Further studies are still needed to assess the differences in efficacy and safety between ticagrelor and double-dose clopidogrel administration for Chinese patients post elective PCI.

Efficacy of prasugrel administration immediately after percutaneous coronary intervention in ST-elevation myocardial infarction.

Prasugrel, a potent thienopyridine, achieves stronger inhibition of platelet activation than clopidogrel. However, onset of inhibition is significantly delayed in patients with acute ST-elevation myocardial infarction (STEMI), as haemodynamic instability and morphine application seem to exhibit significant influence. Since rapid onset of effect was demonstrated in non-STEMI patients when prasugrel was administered only after percutaneous coronary intervention (PCI) without increasing cardiovascular event rates we assessed the efficacy of prasugrel loading immediately after PCI for STEMI instead of pre-loading before revascularisation. We investigated 50 consecutive patients with acute STEMI (mean age 56 ± 10 years) admitted for primary PCI. Prasugrel efficacy was assessed by platelet reactivity index (PRI; VASP assay) before, 1, 2, 4, 6, 12, and 24 hours following an oral loading dose of 60 mg immediately after PCI. High on-treatment platelet reactivity (HTPR) was defined as PRI>50 %. Prasugrel significantly and rapidly reduced platelet reactivity in acute STEMI patients (p<0.0001 at each time point vs control). Morphine application resulted in a significantly higher HTPR rate among patients having received morphine less than 1 hour before prasugrel loading (p<0.001) while concomitant metoclopramide (MCP) treatment did not significantly affect prasugrel efficacy. In conclusion, in contrast to previous reports describing a significant delay in onset of prasugrel-mediated P2Y12 inhibition in acute STEMI, we observed a rapid onset with low HTPR rates comparable to those observed in stable non-STEMI patients. Prasugrel administered directly after primary PCI might therefore be a useful therapeutic strategy in patients with STEMI to provide strong and effective P2Y12 inhibition.

Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study

BackgroundPlatelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), which may be attributed to impaired absorption affecting drug pharmacokinetics (PK) and pharmacodynamics (PD). Crushing tablets has been suggested to lead to more favorable PK/PD profiles. To date, no studies have investigated the PK/PD effects of crushing prasugrel. ObjectivesThis study sought to determine whether crushing prasugrel is associated with more favorable drug bioavailability and platelet inhibitory effects compared with whole tablets in STEMI patients undergoing PPCI. MethodsOur prospective, randomized, open-label study assessed STEMI patients undergoing PPCI (n = 52) who were treated with a prasugrel 60-mg loading dose (LD) either as whole or crushed tablets. PK/PD analyses were performed at 7 time points. PD effects were measured as P2Y12 reaction units and platelet reactivity index, and PK by plasma levels of prasugrel’s active metabolite. ResultsCompared with whole tablets, crushed prasugrel led to reduced P2Y12 reaction units by 30 min post-LD, which persisted at 1, 2 (164 vs. 95; least square mean difference = 68; 95% confidence interval: 10 to 126; primary endpoint), and 4 h post-LD. Significant differences were no longer present at 6 h post-LD. Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with crushed prasugrel. PK analyses showed a >3-fold faster absorption with crushed compared with whole prasugrel. ConclusionsIn STEMI patients undergoing PPCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. (Pharmacological Effects of Crushing Prasugrel in STEMI Patients; NCT02212028)

Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Patients With Low-Risk ACS Undergoing Ad Hoc PCI

BackgroundMany low-risk acute coronary syndrome (ACS) patients are not pre-treated with a P2Y12 receptor inhibitor, and percutaneous coronary interventions (PCIs) are often performed on an ad hoc basis in this population. Pharmacodynamic (PD) studies comparing ticagrelor versus clopidogrel in patients undergoing ad hoc PCI are lacking. ObjectivesThis study sought to assess PD effects of ticagrelor versus clopidogrel loading dose (LD) in the peri-procedural period among troponin-negative ACS patients undergoing ad hoc PCI. MethodsThis was a prospective, open-label, randomized, multicenter, parallel-group, phase IV PD study. One hundred P2Y12 inhibitor-naïve patients presenting with biomarker-negative ACS and undergoing ad hoc PCI, on a background of aspirin therapy, were randomized to receive either ticagrelor 180 mg LD or clopidogrel 600 mg LD. Platelet reactivity (P2Y12 reaction units [PRU]; VerifyNow assay) was measured at 5 time points: pre-LD, at 0.5, 2, and 8 h post-LD, and at end of PCI. The primary endpoint was PRU levels 2 h post-LD; secondary endpoints included PRU levels at all other time points and inhibition of platelet aggregation; an exploratory analysis evaluated rates of high on-treatment platelet reactivity (HPR) (PRU >208). ResultsAt 2 h, PRU levels were significantly lower with ticagrelor versus clopidogrel (98.4 ± 95.4 vs. 257.5 ± 74.5; p < 0.001; primary endpoint). PRU levels diverged as early as 0.5 h post-LD, with significant differences observed by the end of PCI (mean 0.6 h post-LD) and maintained up to 8 h post-LD. HPR rates were also significantly reduced with ticagrelor compared with clopidogrel at the end of PCI (p = 0.030), and at 2 h (p < 0.001) and 8 h (p < 0.001) after LD. ConclusionsIn low-risk ACS patients undergoing ad hoc PCI, ticagrelor LD provides more prompt and potent platelet inhibition, and lower HPR rates, compared with clopidogrel LD. (Ad Hoc Percutaneous Coronary Intervention Study in Acute Coronary Syndrome Patients: NCT01603082)

High on-treatment platelet reactivity with ticagrelor versus prasugrel: a systematic review and meta-analysis

Ticagrelor and prasugrel have shown superiority over clopidogrel. However, it remains unclear if one is superior to another regarding on-treatment platelet reactivity. To compare the impact of ticagrelor and prasugrel on high on-treatment platelet reactivity (HTPR). The PubMed and Cochrane databases were searched for eligible studies in December 2014. Studies were eligible if they compared ticagrelor and prasugrel regarding high on-treatment platelet reactivity (HTPR). Pooled estimates were calculated by using a random-effects model with 95% confidence intervals. We included 14 studies and 1822 patients: 805 and 1017 in the ticagrelor and prasugrel groups, respectively. The rate of HTPR was significantly lower in the ticagrelor group: 1.5% vs. 9.8% (RR = 0.27 [0.14-0.50]). The pre-specified analysis focusing on randomized trials (n = 10) showed consistent results (RR = 0.27 [0.12-0.60]). Our results suggest that ticagrelor allows a higher platelet reactivity inhibition as compared with prasugrel and leads to a further decrease in the rate of HTPR.

Optimal- vs. standard-antiplatelet therapy on platelet function and long-term clinical outcomes in patients with high on-treatment platelet reactivity: 2-year outcomes of the multicentre, randomized Optimal-antiPlatelet Therapy (OPT) trial

Optimal strategy for the management of high on-treatment platelet reactivity (HPR), an independent predictor of ischaemic events, is not yet clear. The aim of this study was to explore the safety and efficacy of personalized antiplatelet therapy based on platelet function testing in patients with HPR. A total of 840 patients with HPR who underwent coronary stenting for acute coronary syndrome (ACS) were randomly assigned in a 1:2 ratio to receive standard dual-antiplatelet therapy ( n = 280) or platelet function-guided optimal-antiplatelet therapy ( n = 560). In the optimal group, patients initially received clopidogrel 150 mg/day on top of aspirin and switched to triple antiplatelet therapy with additional cilostazol if repeat platelet function assay after 3 days indicated a sustained HPR. The primary endpoint was the composite of all-cause death, myocardial infarction, clinically driven target vessel revascularization (TVR), or stroke. Optimal therapy resulted in significantly lower 30-day HPR rate (30.1 vs. 44.3%, P < 0.001). At 1-year follow up, optimal therapy was associated with significantly lower incidence of primary endpoint events (2.7 vs. 6.8%, P = 0.006) compared with standard therapy, mainly due to the reduction of TVR. These beneficial effects were sustained at 2 years (4.5 vs. 9.2%, P = 0.006), with similar bleeding event rates between groups (7.3 vs. 6.5%, P = 0.565). Optimal-antiplatelet therapy based on platelet function testing is effective in attenuating HPR and improving long-term outcomes for ACS patients with no increase in bleeding events.