Defining predictive values using three different platelet function tests for CYP2C19 phenotype status on maintenance dual antiplatelet therapy after PCI

Abstract

Published data suggests that the presence of CYP2C19*2 or *3 loss of function (LOF) alleles is indicative of increased platelet aggregation and a higher risk of adverse cardiovascular events after clopidogrel administration. We sought to determine cut-off values using three different assays for prediction of the CYP2C19 phenotype in Korean percutaneous coronary intervention (PCI) patients. We enrolled 244 patients with drug-eluting stent implantation who were receiving clopidogrel and aspirin maintenance therapy for one month or more. Platelet reactivity was assessed with light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA) and the VerifyNow P2Y12 assay (VN). The CYP2C19 genotype was analyzed by polymerase chain reaction (PCR) and snapshot method. The frequency of CYP2C19 LOF allele carriers was 58.6%. The cut-off values from LTA, MEA and VerifyNow for the identification of LOF allele carriers were as follows: 10?µM ADP-induced LTA?≥?48 %, VN?>?242 PRU and MEA?≥?37?U. Between the three tests, correlation was higher between LTA vs. VN assays (r?=?0.69) and LTA vs. MEA (r?=?0.56), with moderate agreement (κ?=?0.46 and κ?=?0.46), but between VN assay and MEA, both devices using whole blood showed a lower correlation (r?=?0.42) and agreement (κ?=?0.3). Our results provide guidance regarding cut-off levels for LTA, VerifyNow and MEA assays to detect the CYP2C19 LOF allele in patients during dual antiplatelet maintenance therapy.     

Comparison of factors affecting platelet reactivity in various platelet function tests

Previous studies have reported that various factors affect ADP-induced platelet reactivity during clopidogrel therapy. The aim of this study was to determine whether clinical and laboratory variables for platelet reactivity during dual antiplatelet therapy (DAPT) are dependent on the assay used. We enrolled 904 patients receiving DAPT following coronary intervention. Platelet reactivity was measured using three methods: the VerifyNow P2Y12 assay, multiple electrode aggregometry (MEA) ADP assay, and the light transmittance aggregometry (LTA) ADP assay at 24–48 h following coronary intervention. The VerifyNow results demonstrated a significant inverse correlation with hematocrit value (r = –0.268, p < 0.0001); however, MEA results had no such correlation with hematocrit (r = 0.044, p = 0.188). There was a positive correlation between the MEA results and platelet count (r = 0.255, p < 0.0001). LTA was weakly influenced by hematocrit (r = –0.064, p = 0.057) and platelet count (r = 0.069, p = 0.040). Gender (odds ratio 1.53, 95% CI 1.10–2.14, p = 0.013) and hematocrit (odds ratio 0.91,95% CI 0.88–0.94, p < 0.0001) were the independent variables for HPR by VerifyNow. Smoking (odds ratio 0.38, 95% CI 0.16–0.94, p = 0.036) and platelet count (odds ratio 1.01, 95% CI 1.00–1.01, p < 0.0001) were independent factors for HPR when using the MEA assay, whereas platelet count (odds ratio 1.00, 95% CI 1.00–1.01, p = 0.006) was identified as the only independent variable for HPR when using LTA. The incidence of HPR and the influencing variables involved are dependent on the platelet function test used.     

Improved predictive value of GRACE risk score combined with platelet reactivity for 1-year cardiovascular risk in patients with acute coronary syndrome who underwent coronary stent implantation

Both high platelet reactivity (HPR) and Global Registry of Acute Coronary Events (GRACE) risk score have moderate predictive value for major adverse cardiovascular disease (CVD) events in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI), whereas the prognostic significance of GRACE risk score combined with platelet function testing remains unclear. A total of 596 patients with non-ST elevation ACS who underwent PCI were enrolled. The P2Y₁₂ reaction unit (PRU) value was measured by VerifyNow P2Y₁₂ assay and GRACE score was calculated by GRACE risk 2.0 calculator. Patients were stratified by a pre-specified cutoff value of PRU 230 and GRACE score 140 to assess 1-year risk of cardiovascular death, non-fatal myocardial infarction (MI), and stent thrombosis. Seventy-two (12.1%) patients developed CVD events during 1-year follow-up. Patients with CVD events had a higher PRU value (244.6 ± 50.9 vs. 203.7 ± 52.0, p < 0.001) and GRACE score (185.2 ± 45.6 vs. 149.7 ± 40.1, p < 0.001) than those without events. Multivariate logistic analysis showed that both platelet reactivity and GRACE score were associated with 1-year CVD risk independently. Compared to patients with normal platelet reactivity (NPR) and GRACE score < 140, those with HPR and GRACE score ≥ 140 were exposed to significantly elevated CVD risk (HR: 5.048; 95% CI: 2.268–11.237; p < 0.001). Adding platelet reactivity on the top of GRACE risk score yielded superior risk predictive capacity beyond GRACE score alone, which is shown by improved c-statistic value (0.871, p = 0.002) as well as net reclassification improvement (NRI 0.263, p < 0.001) and integrated discrimination improvement (IDI 0.018, p = 0.002). In patients with NSTE-ACS who underwent PCI, high on-treatment platelet reactivity and high GRACE score led to greater risk of adverse CVD events. The combination of platelet function testing and GRACE score predicted 1-year CVD risk better.     

Impact of platelet reactivity on long-term prognosis in Korean patients receiving percutaneous coronary intervention

Both high and low platelet responses to clopidogrel are highly associated with mortality. A therapeutic window for platelet reactivity was recently determined to be an important factor for improving clinical outcomes after percutaneous coronary intervention (PCI). We evaluated the impact of the antiplatelet activity of clopidogrel on long-term clinical outcomes in Korean patients receiving PCI. We analyzed the clinical outcomes of 814 Korean patients undergoing PCI for a median of 48 months. Platelet reactivity on clopidogrel was measured with the VerifyNow P2Y₁₂ assay. The primary endpoint was all-cause death at 4 years. Patients were classified into three groups according to the P2Y₁₂ reaction unit (PRU): low platelet reactivity (LPR; PRU < 85), normal platelet reactivity (NPR; 85 ≤ PRU < 208), and high platelet reactivity (HPR; PRU ≥ 208). The incidence of all-cause death was 7.0% in the LPR group, 1.5% in the NPR group, and 6.2% in the HPR group (log-rank p = 0.002). Based on multivariate analyses, all-cause death was significantly higher in both the LPR and HPR groups than in the NPR group (LPR, hazard ratio [HR]: 5.095; 95% confidence interval [95% CI]: 1.360–19.080, p = 0.016; HPR, HR: 3.315; 95% CI: 1.145–9.593, p = 0.027). Both LPR and HPR were significantly associated with long-term mortality in Korean patients receiving PCI, which suggests that the therapeutic concept of PRU may be an important prognostic factor.     

Usefulness of platelet response to clopidogrel by point-of-care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study)

Platelet reactivity predicts ischemic outcomes in patients who undergo percutaneous coronary intervention (PCI), but the correlation of heightened platelet response with bleeding has not been characterized. The aim of this study was to evaluate whether low platelet reactivity by point-of-care measurement after clopidogrel administration correlates with bleeding complications of PCI. A total of 310 patients receiving clopidogrel before PCI were prospectively enrolled. Platelet reactivity was measured with the VerifyNow P2Y12 assay. The primary end point was the 30-day incidence of major bleeding or entry-site complications according to quartile distribution of P2Y12 reaction units (PRU). The primary end point occurred more frequently in patients with preprocedural PRU levels in the lowest quartile compared to those in the highest quartile (10.1% vs 1.3%, p = 0.043), due mainly to entry-site hemorrhages. Absolute PRU levels were lower in patients with major bleeding (171 ± 49 vs 227 ± 68 in patients without, p = 0.002). On multivariate analysis, pre-PCI PRU levels in the first quartile were associated with a 4.5-fold increased risk for major bleeding (odds ratio 4.5, 95% confidence interval 1.9 to 25.9, p = 0.01). By receiver-operating characteristic curve analysis, the optimal cutoff for the primary end point was a pre-PCI PRU value ≤ 189 (area under the curve 0.76, 95% confidence interval 0.66 to 0.87, p = 0.001). In conclusion, this study suggests that an enhanced response to clopidogrel may be associated with higher risk for early major bleeding or entry-site complications in patients who undergo PCI. Point-of-care monitoring of platelet reactivity after clopidogrel administration may help identify patients in whom individualized strategies are indicated to limit bleeding complications after coronary intervention.     

Comparison between a new platelet count drop method PL-11, light transmission aggregometry,VerifyNow aspirin system and thromboelastography for monitoring short-term aspirin effects in healthy individuals

Platelet function has been described by many laboratory assays, and PL-11 is a new point-of-care platelet function analyzer based on platelet count drop method, which counts platelet before and after the addition of agonists in the citrated whole blood samples. The present study sought to compare PL-11 with other three major more established assays, light transmission aggregometry (LTA), VerifyNow? aspirin system and thromboelastography (TEG), for monitoring the short-term aspirin responses in healthy individuals. Ten healthy young men took 100?mg/d aspirin for 3-day treatment. Platelet function was measured via PL-11, LTA, VerifyNow and TEG, respectively. The blood samples were collected at baseline, 2 hour, 1 day during the aspirin treatment and 1 day, 5?±?1 days, 8?±?1 days after the aspirin withdrawal. Moreover, 90 additional healthy subjects were recruited to establish a reference range for PL-11. Platelet function of healthy subjects decreased significantly 2 hours after 100?mg/d aspirin intake and began to recover during 4–6 days after the aspirin withdrawal. Correlations between methods were PL-11 vs. LTA (r?=?0.614, p?<?0.01); PL-11 vs. VerifyNow (r?=?0.829, p?<?0.01); PL-11 vs. TEG (r?=?0.697, p?<?0.001). There was no significant bias between PL-11 and LTA at baseline (bias?=?1.94%, p?=?0.804) using Bland-Altman analysis, while the data of PL-11 were significantly higher than LTA (bias?=?24.02%, p?<?0.001) during the aspirin therapy. The reference range for PL-11 in healthy young individuals was from 66.8 to 90.5% (95%CI). When aspirin low-responsiveness was defined as LTA?>?20%, the cut-off values for each method were, respectively: PL-11?>?50%, VerifyNow?>?533 ARU, TEG?>?60.2%. The results of different platelet function assays were uninterchangeable for monitoring aspirin response and correlations among them were also varied. Correlations among PL-11 and other three major assays suggested the ability of PL-11 to assess the treatment effects of aspirin. But a large cohort study is needed to confirm the cut-off value of aspirin response detected by PL-11.     

Impact of anemia on platelet response to clopidogrel in patients undergoing percutaneous coronary stenting

High residual platelet reactivity (HRPR) on clopidogrel is a predictor of recurrent ischemic events in patients undergoing percutaneous coronary interventions (PCI). Significant intraindividual variability in platelet aggregation on repeat testing has been reported. To understand factors contributing to the variability in platelet aggregation testing, we examined clinical and laboratory elements linked to HRPR in 255 consecutive patients tested ≥12 hours after PCI using light transmission aggregometry (LTA) in response to adenosine diphosphate 5 μmol/L and VerifyNow P2Y12 assay (VNP2Y12; Accumetrics). HRPR was defined as >46% residual aggregation for LTA and >236 P2Y12 response units (PRUs) for VNP2Y12. On multivariate analysis the only variable independently associated with HRPR with both LTA and VNP2Y12 was laboratory-defined anemia. Prevalences of HRPR by LTA were 34.3% in anemic patients, 15.6% in patients with normal hemoglobin levels, and 59.8% versus 25.9% by VNP2Y12 (p <0.005 for the 2 comparisons). In a subgroup of 50 patients, testing was done before and after the clopidogrel loading dose. At baseline there were no differences in platelet aggregation with either assay; however, absolute decrease in reactivity after the clopidogrel load was significantly less in anemic patients compared to patients with normal hemoglobin (change in residual aggregation by LTA 15.8 ± 5.8% vs 28.8 ± 3.2%, p <0.05; change in PRU by VNP2Y12 56.5 ± 35.5 vs 145.0 ± 14.2 PRUs, p <0.05, respectively). In conclusion, anemia is an important contributor to apparent HRPR on clopidogrel and may explain some of the intraindividual variability of platelet aggregation testing.     

Correlation of high post-treatment platelet reactivity assessed by light transmittance aggregometry and the VerifyNow P2Y12 assay

In vitro “high post-treatment platelet reactivity” (HPPR) measured with light transmittance aggregometry (LTA) and the VerifyNow P2Y₁₂ assay has been associated with an increased risk of ischemic events after percutaneous coronary intervention (PCI). However, there are many criteria for HPPR according to the methods used for assessment, and correlations among suggested criteria have not been evaluated. To this end, we enrolled 1,058 unselected patients undergoing PCI in real clinical practice, simultaneously assessed platelet measures with LTA (both 5 and 20 μmol/l ADP-induced) and the VerifyNow P2Y₁₂ assay, and based on previous studies, evaluated the following criteria for HPPR: 5 or 20 μmol/l ADP-induced maximal platelet reactivity (PR_max) ≥50%; 5 μmol/l ADP-induced late PR (PR_late) >14%; 20 μmol/l ADP-induced PR_max ≥62%; and P2Y₁₂ reaction unit (PRU) ≥240. Receiver-operating characteristics (ROC) curve analysis demonstrated that PRU (cut-off = 241) distinguished between patients with and without 5 μmol/l ADP-induced PR_max ≥50% (area under curve [AUC] 0.822, sensitivity 83.0%, specificity 66.0%, P < 0.001), and 20 μmol/l ADP-induced PR_max ≥62% (AUC 0.840, sensitivity 80.7%, specificity 71.4%, P < 0.001), respectively. PRU ≥240 showed a moderate agreement with 5 μmol/l ADP-induced PR_max ≥50% (κ = 0.438, concordant rate 71.6%, P < 0.001) and 20 μmol/l ADP-induced PR_max ≥62% (κ = 0.505, concordant rate 75.1%, P < 0.001). Cut-offs matched for 20 μmol/l ADP-induced PR_max ≥50% (PRU = 195) and 5 μmol/l ADP-induced PR_late >14 (PRU = 194) also were similar. The presence of significant correlations between the suggested criteria for HPPR has practical implications on the possible use of the VerifyNow P2Y₁₂ assay for risk stratification in PCI-treated patients.     

Correlation between light transmission aggregometry, VerifyNow P2Y12, and VASP-P platelet reactivity assays following percutaneous coronary intervention

BACKGROUND: High on-treatment platelet reactivity is an established risk factor for adverse cardiac events in patients taking clopidogrel following percutaneous coronary intervention (PCI). Methods: Two hundred patients underwent platelet reactivity testing with VerifyNow P2Y12, vasodilator-stimulated phosphoprotein phosphorylation (VASP), and light transmission aggregometry (LTA) with both 5 and 20 μM of adenosine diphosphate (ADP) following PCI. High on-treatment platelet reactivity was defined as a maximum platelet aggregation ≥46% for LTA ADP 5 μM or ≥60% for 20 μM; platelet reactivity index (PRI) ≥50% for VASP; and platelet reactivity units ≥235 for VerifyNow. Correlation between assays was tested using Spearman coefficients (ρ); agreement among tests in regards to high on-treatment platelet reactivity was evaluated with Kappa statistics (κ). Results: All Spearman correlations had P values <0.001, although ρ ranged from 0.60-0.86. The incidence of high on-treatment platelet reactivity was 39.3% with VASP, 27.3% with VerifyNow, 23.1% with LTA ADP 5 μM, and 16.2% with LTA ADP 20 μM. The strongest correlation was between LTA ADP 5 μM and LTA ADP 20 μM (κ= 0.53, 95% CI 0.37-0.68); the weakest was between VASP and LTA ADP 5 μM (κ= 0.33, 95% CI 0.19-0.47). Overall, the level of agreement between assays was in the moderate to poor range. CONCLUSION: Despite evidence that the most commonly used tests are correlated, agreement among tests is modest at best and demonstrates they are not interchangeable.     

Nuisance and alarming bleeding do not correlate with on-treatment platelet reactivity

AimsWe hypothesized that patients with a history of either alarming or nuisance bleeding events, compared to those with no history of bleeding, would have lower levels of on-treatment platelet reactivity (aspirin and a thienopyridine).Methods and ResultsIn total, 42 patients with no bleeding, 34 with nuisance bleeding, and 14 with alarming bleeding underwent platelet reactivity testing 1 month to 1 year after PCI with light transmission aggregometry (LTA 5 and 20 μM adenosine disphosphate [ADP]), vasodilator stimulated phosphoprotein phosphorylation (VASP) and VerifyNow P2Y12. Clinical and demographic characteristics of the 3 groups were generally similar, except that patients with alarming bleeding were less likely to be Caucasian; only 6 patients (6.7%) were taking prasugrel. There was considerable overlap between no bleeding, nuisance bleeding and alarming bleeding groups with respect to on-treatment platelet reactivity. Furthermore, there was no difference in the median platelet reactivity values for all assays. Prevalence of high on-treatment platelet reactivity did not differ among the 3 groups; 32.6% of patients had high on-treatment platelet reactivity as measured by LTA with 5 μM ADP (P= .91); 40.0% as measured by VASP (P= .35); and 35.6% as measured by VerifyNow P2Y12 (P= .61).ConclusionThe use of platelet reactivity assays to identify patients on thienopyridine therapy at higher risk of bleeding is an unfounded strategy.     

Intensified P2Y12 inhibition for high-on treatment platelet reactivity

High on treatment platelet reactivity (HPR) during treatment with clopidogrel has been consistently found to be strong risk factor for recurrent ischemic events after percutaneous coronary intervention (PCI). Insufficient P2Y12 receptor inhibition contributes to HPR measured by the VerifyNow (VN) assay. Prasugrel and ticagrelor are more potent P2Y12 inhibitors than clopidogrel and commonly substituted for clopidogrel when HPR is documented, however benefit of VN guided intensified antiplatelet therapy is uncertain. We identified patients who had undergone platelet reactivity testing after PCI with VN after pretreatment with clopidogrel (n?=?252) in a single center observational analysis. Patients who had HPR defined as PRU?>?208 were switched to alternate P2Y12 inhibitors. Primary clinical endpoint was 1-year post PCI combined cardiovascular death, myocardial infarction (MI), and stent thrombosis. One hundred and eight (43%) subjects had HPR and were switched to prasugrel (n?=?60) and ticagrelor (n?=?48). Risk of recurrent 1-year primary endpoint remained higher for HPR patients switched to either ticagrelor or prasugrel as compared to subjects who had low on treatment platelet reactivity (n?=?144) (LPR) on clopidogrel [Hazard Ratio: 3.5 (95% CI 1.1–11.1); p?=?0.036)]. Propensity score matched analysis demonstrated higher event rates in patients with HPR on alternate P2Y12 inhibitor as compared to patients with LPR (log-rank: p?=?0.044). The increased risk of recurrent events associated with HPR measured by VN is not completely attenuated by switching to more potent P2Y12 inhibitors. Non-P2Y12 mediated pathways likely contribute to increased incidence of thrombotic events after PCI in subjects with HPR.

     

Cangrelor in combination with ticagrelor provides consistent and potent P2Y12-inhibition during and after primary percutaneous coronary intervention in real-world patients with ST-segment-elevation myocardial infarction

Patients pretreated with ticagrelor with less than 1 hour from percutaneous coronary intervention (PCI) or receiving ticagrelor in cath lab were prospectively included and received cangrelor. Cangrelor was infused for 2 hours and platelet function was assessed as P2Y12 reactivity units (PRU) with the VerifyNow P2Y12 function assay before start of infusion, 15 min after the start of infusion, and 30 min after the end of infusion. A total of n = 32 patients with an average age of 68 (±13) years with n = 22 (69%) males were included. The level of P2Y12 inhibition before cangrelor infusion was started was 249 PRU (IQR 221–271). After 15 min of cangrelor infusion the P2Y12 reactivity was markedly decreased to 71 PRU (IQR 52–104, p < 0.001). At 30 min after end of infusion PRU remained within the therapeutic range, 89 PRU (IQR 50–178; p < 0.001 for comparison with preinfusion) with only n = 4 (12.5%) patients with PRU >225. Results were consistent between patients receiving ticagrelor prehospital or in the cath lab and no statistical differences in PRU were noted between the two groups in any of the three measurements. In conclusion, cangrelor in combination with ticagrelor results in consistent and strong P2Y12 inhibition during and after infusion and cangrelor may bridge the gap until oral P2Y12 inhibitors achieve effect in real-world STEMI patients undergoing primary PCI.     

Pharmacodynamic effects of a new fixed-dose clopidogrel–aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial

Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG^®). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, ?5 PRU; 90% confidence interval of difference, ?23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). “BASE” and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG^® measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel–aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.     

St. John’s Wort in Patients Non-responders to Clopidogrel Undergoing Percutaneous Coronary Intervention: a Single-Center Randomized Open-Label Trial (St. John’s Trial)

We assessed if St. John’s Wort (SJW) improves platelet response in patients (pts) resistant to clopidogrel after percutaneous coronary intervention (PCI). Stable angina pts non-responders to 600 mg clopidogrel (P2Y12 reaction units (PRU) >240) were randomized (2:1) to SJW (n?=?15) or placebo (n?=?8). SJW (300 mg × 3/day) was administrated for 2 weeks after PCI. Platelet reactivity was assessed by VerifyNowTM before (BL), 2 (T1), and 4 weeks (T2) after PCI. PRU significantly changed during protocol in SJW (BL (316?±?60) vs. T1 (170?±?87) vs. T2 (220?±?96), p?<?0.0001) and placebo group (BL (288?±?36) vs. T1 (236?±?31) vs. T2 (236?±?62), p?=?0.046). Yet, PRU changes from BL were higher at T1 in SJW than in placebo group (Δ%, ?47?±?24 vs. ?16?±?15, p?=?0.0033), with no differences at T2 between the groups (Δ%, ?30?±?29 vs. ?17?±?24, p?=?0.30). Residual platelet reactivity improved with SJW during the first month post-PCI.     

Dipstick proteinuria is an independent predictor of high on treatment platelet reactivity in patients on clopidogrel,but not aspirin,admitted for major adverse cardiovascular events

The effectiveness of aspirin and clopidogrel in patients with chronic kidney disease (CKD) suffering from acute cardiovascular events is unclear. High on treatment platelet reactivity (HTPR) has been associated with worse outcomes. Here, we assessed the association of dipstick proteinuria (DP) and renal function on HTPR and clinical outcomes. Retrospective cohort analysis of 261 consecutive, non-dialysis patients admitted for Major Adverse Cardiovascular Events (MACE) that had VerifyNow P2Y12 and VerifyNow Aspirin assays performed. HTPR was defined as P2Y12 reactivity unit (PRU)?>?208 for clopidogrel and aspirin reaction units (ARU)?>?550 for aspirin. Renal function was classified based on the estimated glomerular filtration rate (eGFR), and dipstick proteinuria was defined as ≥30?mg/dl of albumin detected on a spot analysis. All cause mortality, readmissions, and cardiac catheterizations were reviewed over 520 days. In patients on clopidogrel (n?=?106), DP was associated with HTPR, independent of eGFR, diabetes mellitus, smoking or use of proton pump inhibitor (AOR?=?4.76, p?=?0.03). In patients with acute coronary syndromes, HTPR was associated with more cardiac catheterizations (p?=?0.009) and readmissions (p?=?0.032), but no differences in in-stent thrombosis or re-stenosis were noted in this cohort. In patients on aspirin (n?=?155), no associations were seen between DP and HTPR. However, all cause mortality was significantly higher with HTPR in this group (p?=?0.038). In this cohort, DP is an independent predictor of HTPR in patients on clopidogrel, but not aspirin, admitted to the hospital for MACE.     

Impact of Mild Hypothermia on Platelet Responsiveness to Aspirin and Clopidogrel: an In Vitro Pharmacodynamic Investigation

The combination of percutaneous coronary intervention (PCI) and therapeutic hypothermia in comatose patients after cardiac arrest due to an acute coronary syndrome has been reported to be safe and effective. However, recent investigations suggest that hypothermia may be associated with impaired response to clopidogrel and greater risk of thrombotic complications after PCI. This investigation aimed to evaluate the effect of hypothermia on the pharmacodynamic response of aspirin and clopidogrel in patients (n?=?20) with ST elevation myocardial infarction undergoing primary PCI. Higher platelet reactivity (ADP stimulus) was observed in samples incubated at 33 °C compared with those at 37 °C (multiple electrode aggregometry, 235.2?±?31.4 AU×min vs. 181.9?±?30.2 AU×min, p?<?0.001; VerifyNow P2Y12, 172.9?±?20.3 PRU vs. 151.0?±?19.3 PRU, p?=?0.004). Numerically greater rates of clopidogrel poor responsiveness were also observed at 33 °C. No differences were seen in aspirin responsiveness. In conclusion, mild hypothermia was associated with reduced clopidogrel-mediated platelet inhibition with no impact on aspirin effects. Clinical relevance: Mild therapeutic hypothermia is associated with impaired response to clopidogrel therapy, which might contribute to increase the risk of thrombotic events in ACS comatose patients undergoing PCI.     

Angiographic and platelet reactivity outcomes with prasugrel 60?mg pretreatment and clopidogrel 600?mg pretreatment in primary percutaneous coronary intervention

Pretreatment with 60?mg of prasugrel is more effective than 300?mg of clopidogrel in reducing thrombotic complications with primary percutaneous coronary intervention (PCI). We compared angiographic outcomes and platelet reactivity between treatment with 60?mg of prasugrel and 600?mg of clopidogrel administered before primary PCI. In this single centre non-randomized study, 65 consecutive Asian patients with ST-elevation myocardial infarction (STEMI) received 60?mg of prasugrel before primary PCI. The pre- and post-PCI corrected thrombolysis in myocardial infarction frame count (CTFC) and the 8-h post-treatment platelet vasodilator-stimulated phosphoprotein (VASP) index was compared with a matched historical Asian STEMI cohort (n?=?65) receiving 600?mg of clopidogrel pretreatment. Comparing the prasugrel and clopidogrel groups, the mean age was 54.1?±?10.2 versus 55.5?±?11.8?years, P?=?0.238, and the mean body mass index was 24.6?±?2.0 versus 24.7?±?2.8?kg?m^?2, P?=?0.393. The mean pre-PCI CTFC was 82.1?±?30.2 versus 86.1?±?27.6, P?=?0.045, and the mean post-PCI CTFC was 21.1?±?13.9 versus 20.1?±?9.2, P?=?0.309. Pre-PCI coronary thrombi were visualised in 6.3 versus 18.1?%, P?=?0.038. The median VASP index was 22.2?±?24.5 versus 70.5?±?17.5?%, P?<?0.001, and high on-treatment platelet reactivity (VASP index?>?50?%) was observed in 13.8 versus 84.3?%, P?=?0.001. Rescue intracoronary glycoprotein inhibitors were administered to 29.7 versus 51.0?%, P?=?0.018, respectively. Treatment with 60?mg of prasugrel before primary PCI was associated with lower platelet reactivity, a modest trend towards better pre-PCI angiographic outcomes, less pre-PCI coronary thrombi and less rescue glycoprotein inhibitor use compared with 600?mg of clopidogrel. The very high frequency of high on-clopidogrel platelet reactivity with 600?mg of clopidogrel in this Asian STEMI cohort deserves further study.     

Bivalirudin for left ventricular assist device thrombosis

We investigated the impact of suboptimal platelet reactivity on clinical outcomes after percutaneous coronary intervention (PCI). We enrolled 500 patients with stable coronary artery disease undergoing elective PCI. Platelet reactivity was measured before PCI using the VerifyNow P2Y12 assay. Primary endpoint was the incidence of ischemic or bleeding events at 1 month and 5 years. Patients with high platelet reactivity (HPR) showed significantly higher rates of ischemic events both during the 1st month after PCI (HR 2.06, 95% CI 1.02–4.06), and beyond 1 month compared with patients without HPR (HR 1.73, 95% CI 1.02–2.95). Conversely, compared with patients without low platelet reactivity (LPR), patients with LPR presented significantly higher rates of bleeding only during the 1st month (HR 3.67, 95% CI 1.68–8.02). In conclusion, pre-procedural HPR is associated with ischemic events even beyond the 1st month after PCI. The association of LPR with bleeding events seems to be confined to the periprocedural period.     

Ticagrelor vs clopidogrel followed by ticagrelor re-loading in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: A randomized,pharmacodynamic comparison

Among patients allocated to ticagrelor in the primary percutaneous coronary intervention (PCI) cohort of Platelet Inhibition and Patient Outcomes (PLATO) trial, 40.7% had received pre-randomization 600 mg of clopidogrel. This scenario is frequently employed in real-world practice. In a prospective, three-center, single-blind, parallel design study, 74 P2Y₁₂ inhibitor-naive patients undergoing primary PCI were randomized (Hour 0) to ticagrelor 180 mg loading dose (LD) vs clopidogrel 600 mg LD followed after 2 h by ticagrelor 180 mg re-LD. Platelet reactivity (VerifyNow, in PRU) was assessed at Hour 0, 2, 4, 6, and 24. The primary comparison was non-inferiority of ticagrelor to clopidogrel followed by ticagrelor re-LD regarding platelet reactivity at 24 h using a prespecified margin of <35 PRU for the upper bound of the one-sided 97.5% confidence interval (CI). Ticagrelor was proven non-inferior to clopidogrel followed by ticagrelor re-LD with a difference between arms of 13.5 PRU (28.8 upper 97.5% CI), p = 0.001. At Hour 2, platelet reactivity was lower in ticagrelor only vs clopidogrel followed by ticagrelor re-LD groups with least square estimate mean difference (95% CI) ?105.7 (?140.6 to ?70.8), p < 0.001, without significant difference thereafter. In conclusion, in patients undergoing primary PCI, a strategy of ticagrelor LD only was proven non-inferior to clopidogrel LD followed by ticagrelor re-LD, in terms of antiplatelet efficacy at 24 h post-randomization and provided an earlier onset of platelet inhibition.     

High platelet reactivity is associated with vascular function in patients after percutaneous coronary intervention receiving clopidogrel

Background

In the present study, we evaluated the association of platelet reactivity with vascular function in patients after percutaneous coronary intervention receiving clopidogrel treatment.

Methods

We enrolled 150 patients with stable CAD receiving clopidogrel regimen (75 mg/d), 1 month after percutaneous coronary intervention. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as an index of arterial wave reflections. High on treatment platelet reactivity (HPR) was evaluated using VerifyNow Assay. VerifyNow reports its results in P2Y12 reaction units (PRU), and the diagnostic cutoff value is 230 PRU. Patients were evaluated prospectively up to 24 months. The primary end point was a composite of death from cardiovascular causes, nonfatal major cardiovascular events and hospitalization for cardiovascular causes.

Results

There was no difference in the basic clinical and demographic characteristics between subjects with HPR and non-HPR. Subjects with high on treatment platelet reactivity and PRU > 230 had significantly increased PWV (8.81 ± 2.25 m/s vs. 7.69 ± 1.95 m/s, p = 0.001) and AIx (25.27 ± 8.67% vs. 20.87 ± 10.57%, p = 0.04) compared to subjects with PRU ≤ 230. PWV was also associated with PRU (r = 0.23, p = 0.02). HPR was associated with significantly increased risk of primary end point [HR = 5.38, 95%CI:(1.15, 26.04), p = 0.03].

Conclusions

Increased platelet reactivity is associated with impaired arterial stiffness in patients after percutaneous coronary intervention receiving clopidogrel treatment, highlighting another clinical factor implicated in individual platelet response to antiplatelet therapy. Moreover, increased platelet reactivity is associated with adverse outcome in these patients.