High On-aspirin Platelet Reactivity Research Articles

High rates of high on-aspirin platelet reactivity in patients after transcatheter aortic valve implantation

Abstract Background Guidelines recommend aspirin monotherapy in patients after transcatheter aortic valve replacement (TAVR) without an indication for oral anticoagulation. The prevalence of high on-aspirin platelet reactivity (HAPR) varies from 1% to 34% and may be associated with long-term ischemic risk or subclinical valve thrombosis which occurs in 17-40% of the patients after TAVR. Purpose To determine the prevalence of HAPR and its association with subclinical valve thrombosis in patients undergoing TAVR using methods that directly indicate the degree of platelet cyclooxygenase inhibition. Methods Data were collected in a prospective, single-center, observational cohort study between October 2020 and June 2022. Patients were enrolled after TAVR, and platelet function was assessed during the hospital stay with light-transmittance platelet aggregation (LTA) and thrombelastography (TEG) platelet mapping. Platelet aggregation was induced with arachidonic acid (AA)-induced LTA (final concentration [fc] 1.64 mM) and TEG (fc 1.0mM). The maximum percent aggregation (%aggr) was recorded. According to the literature, HAPR was defined as >20% aggregation by LTA or >50% aggregation by TEG, respectively. All patients were under maintenance of 100 mg aspirin or received a loading dose of 300-600mg aspirin before measurement. 47 of 75 patients underwent computed tomography (CT) to detect valve thrombosis (VT) 6 months after TAVR. Results Data from 75 patients under maintenance of aspirin were analyzed. The median age was 82 years (interquartile range, IQR 79-85), and 52% were male. 12 patients (16%) had a history of stroke or TIA, and 7 (9%) had suffered a previous myocardial infarction. TEG and LTA were performed during the hospital stay between days 0 and 17 post-TAVR. Median AA-induced maximum aggregation by LTA was 17 % (interquartile range, IQR 13-38) and by TEG was 29 % (IQR 5-64). When determining platelet function using LTA, 33 patients (44%) had residual platelet function (i.e., %aggrLTA >20%) despite aspirin treatment. According to the TEG results, 27 patients (36 %) were identified as HAPR (i.e., %aggrTEG >50%). The agreement (Kappa=0.06) and correlation (r=0.32, Figure 1) between the two tests were low to moderate. 13 patients had HAPR in both methods. 19 of 47 patients (40%) had VT on CT 6 months after TAVI. 12 of these 19 patients (63%) with VT responded well to aspirin in the TEG and LTA, while 7 (37%) had HAPR in both tests. HAPR was not significantly associated with HALT when measured with TEG or LTA (OR 0.90 [95% CI 0.27.2.76], p=0.86 and 0.58 [95% CI 0.17-2.04], p=0.37, respectively; Table 1). Conclusion HAPR assessed by LTA and TEG is frequent in patients undergoing TAVR. In this exploratory study, HAPR was not significantly associated with the occurrence of HALT. Further studies are required to evaluate the long-term risk of leaflet thrombosis or thromboembolic events in patients with HAPR.

High-on-Aspirin Platelet Reactivity Differs Between Recurrent Ischemic Stroke Associated With Extracranial and Intracranial Atherosclerosis.

Background and PurposeIschemic stroke recurs despite the use of antiplatelet agents. Various mechanisms are involved in recurrence due to intracranial atherosclerosis (ICAS) and extracranial atherosclerosis (ECAS). High-on-aspirin platelet reactivity (HAPR) may differ between recurrent stroke due to ICAS and ECAS.MethodsPatients with recurrent ischemic stroke as a result of large-artery atherosclerosis despite taking aspirin were enrolled consecutively. Ischemic stroke was classified as stroke due to ICAS or ECAS according to the location of the culprit stenosis. An aspirin reaction units (ARU) value of >550 IU was defined as HAPR. HAPR and its associated factors were compared between the two groups and also considering the mechanism of stroke.ResultsAmong the 190 patients with recurrent stroke (111 with ICAS and 79 with ECAS), 36 (18.3%) showed HAPR. The ARU value was higher in the ECAS than the ICAS group (492±83 vs. 465±78, mean±standard deviation; p=0.028), as was the proportion of patients with HAPR (27.8% vs. 12.6%, p=0.008). Being male and having stroke due to ECAS (reference=stroke due to ICAS: odds ratio=5.760; 95% confidence interval=2.154–15.403; p<0.001) was independently associated with HAPR. The ARU value differed according to the stroke mechanism, and was highest in those with artery-to-artery embolism. Artery-to-artery embolism was independently associated with HAPR in both the ICAS and ECAS groups.ConclusionsRecurrent stroke due to ECAS was more strongly associated with HAPR and insufficient antiplatelet inhibition than was that due to ICAS. Artery-to-artery embolism was associated with HAPR in recurrent ischemic stroke as a result of ICAS or ECAS.

Plasma Fibrinogen Independently Predicts Hypofibrinolysis in Severe COVID-19

High rates of thrombosis are present in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Deeper insight into the prothrombotic state is essential to provide the best thromboprophylaxis care. Here, we aimed to explore associations among platelet indices, conventional hemostasis parameters, and viscoelastometry data. This pilot study included patients with severe COVID-19 (n = 21) and age-matched controls (n = 21). Each patient received 100 mg aspirin therapy at the time of blood sampling. Total platelet count, high immature platelet fraction (H-IPF), fibrinogen, D-dimer, Activated Partial Thromboplastin Time, von Willebrand factor antigen and von Willebrand factor ristocetin cofactor activity, plasminogen, and alpha2-antiplasmin were measured. To monitor the aspirin therapy, a platelet function test from hirudin anticoagulated whole blood was performed using the ASPI test by Multiplate analyser. High on-aspirin platelet reactivity (n = 8) was defined with an AUC > 40 cut-off value by ASPI tests. In addition, in vitro viscoelastometric tests were carried out using a ClotPro analyser in COVID-associated thromboembolic events (n = 8) (p = 0.071) nor the survival rate (p = 0.854) showed associations with high on-aspirin platelet reactivity status. The platelet count (p = 0.03), all subjects. COVID-19 patients presented with higher levels of inflammatory markers, compared with the controls, along with evidence of hypercoagulability by ClotPro. H-IPF (%) was significantly higher among non-survivors (n = 18) compared to survivors (p = 0.011), and a negative correlation (p = 0.002) was found between H-IPF and plasminogen level in the total population. The platelet count was significantly higher among patients with high on-aspirin platelet reactivity (p = 0.03). Neither the ECA-A10 (p = 0.008), and ECA-MCF (p = 0.016) were significantly higher, while the tPA-CFT (p < 0.001) was significantly lower among patients with high on-aspirin platelet reactivity. However, only fibrinogen proved to be an independent predictor of hypofibrinolysis in severe COVID-19 patients. In conclusion, a faster developing, more solid clot formation was observed in aspirin ‘non-responder’ COVID-19 patients. Therefore, an individually tailored thromboprophylaxis is needed to prevent thrombotic complications, particularly in the hypofibrinolytic cluster.

Impact of Calcium Channel Blockers on Aspirin Reactivity in Patients with Coronary Artery Disease.

Calcium channel blockers (CCBs) do not reduce the risk of initial or recurrent myocardial infarction (MI) in patients diagnosed with stable coronary artery disease (CAD). The aim of this current study was to evaluate the association between CCBs and aspirin resistance in patients with CAD. Patients with stable CAD who were regularly taking aspirin (75-100 mg qd) for at least 1 month prior to enrollment in the study were included. The VerifyNow system was used for platelet function testing with high on-aspirin platelet reactivity (HAPR) defined as aspirin reaction units (ARU) >550. We compared patients treated with CCBs versus control group. Five hundred three patients with CAD were included in this study, and 88 were treated with CCBs. Mean age (67.9±9.7 in the CCB group vs. 66.5±11.4 in the control group), gender (77.3 male vs. 82.9%), rates of diabetes mellitus (34.7 vs. 36.9%), rates of CKD (23.5 vs. 23.5%), dyslipidemia (85.1 vs. 85.3%), and statin therapy (89.5 vs. 90.7%) were similar. The mean ARU was 465.4±70.0 for patients treated with CCBs versus 445.2±60.0 in controls (p=0.006). Similarly, 15.9% of CCB patients demonstrated HAPR compared to 7.0% (p=0.006). The administration of CCBs was independently associated with HAPR in a multivariate analysis (OR 1.72, 95% CI: 1.04-8.91, p=0.047) as well as in propensity score matched analysis (OR 1.56; CI: 1.22-1.93; p<0.001). Usage of CCBs is positively correlated with aspirin resistance. These findings may suggest an adverse pharmacologic effect of CCBs among patients with stable CAD treated with aspirin.

The Association between Multi-Vessel Coronary Artery Disease and High On-Aspirin Platelet Reactivity.

Multi-vessel coronary artery disease (MV-CAD) is correlated with worse clinical outcomes compared with single-vessel CAD (SV-CAD). The aim of this study was to evaluate the association between MV-CAD and high on-aspirin platelet reactivity (HAPR) in patients with stable CAD treated with aspirin. The current study is an analysis of prospectively enrolled randomly selected patients with known stable CAD, who were taking aspirin (75-100mg qd) regularly for at least one month, and had undergone coronary angiography at least 3months prior to the enrollment to the study. acute coronary syndrome at the time of platelet function testing, active malignancy, acute infection, active inflammatory/rheumatic disease, major surgery in the past 6months, chronic liver failure, treatment with oral anticoagulation, non-adherence with Aspirin and thrombocytopenia (<100K/micl). Blood was drawn from the participants and sent for platelet function testing (VerifyNow, Instrumentation Laboratory Company, Bedford, Massachusetts, United States). MV-CAD was defined as >50% stenosis in ≥2 separate major coronary territories per coronary angiography. HAPR was defined as aspirin reaction units (ARU) >550. Overall, 507 patients were analyzed; age 66.7 ± 11.2, 17.9% women, 223 (44%) had MV-CAD. The rate of HAPR was significantly higher among patients with MV-CAD vs. SV-CAD (14.8% vs. 3.5%, p < 0.001, respectively). Furthermore, a "dose response"-like association was found between the number of stenotic coronary arteries and the rate of HAPR (3.5%, 13.5 and 17.3% for SV-CAD, 2-vessel and 3-vessel disease, respectively). In a multivariate analysis adjusted for potential confounders, MV-CAD was found to be a strong independent predictor of HAPR [OR = 1.8 (95%CI: 1.05-4.7), p = 0.014]. A significant association between MV-CAD and HAPR was found. Additional studies designed to investigate the mechanisms of HAPR and different therapeutic options for this subset of patients are warranted.

Relation of multi-vessel coronary artery disease to response to aspirin

Abstract Background Multi-vessel coronary artery disease (MV-CAD) is correlated with worse outcomes compared with single-vessel CAD (SV-CAD), potentially attributed to more advanced atherosclerotic disease in other vascular beds, greater endothelial dysfunction, thrombin activation and possibly greater platelet reactivity. Objectives The aim of the current study was to evaluate the association between MV-CAD and high on-aspirin platelet reactivity (HAPR) in patients with stable CAD treated with aspirin. Methods Patients with known stable CAD, who were taking aspirin (75–100 mg qd) regularly for at least one month, and had undergone coronary angiography at least 3 months prior to the test, were enrolled. Blood was drawn from the participants and sent for platelet function testing. MV-CAD was defined as &amp;gt;50% stenosis in ≥2 separate major coronary territories per coronary angiography. HAPR was defined as aspirin reaction units (ARU) &amp;gt;550. Results Overall 507 patients were analyzed; age 66.7±11.2, 17.9% women, 223 (44%) had MV-CAD. Mean ARU was significantly higher among patients with MV-CAD vs. SV-CAD (460±68 vs. 440±55, p&amp;lt;0.001, respectively). Furthermore, the rate of HAPR was significantly higher among patients with MV-CAD (figure 1). In a multivariate analysis adjusted for potential confounders, MV-CAD was found to be a strong independent predictor of HAPR [OR=1.8 (95% CI1.05–4.7), p=0.014]. In a reverse analysis, HAPR was associated with a higher number of coronary vessels involved (1.95±0.65 vs. 1.45±0.57, p&amp;lt;0.01) and a strong independent predictor of MVD (OR-2.44, CI 1.83–25.6, p=0.015). Conclusions MV-CAD is significantly associated with HAPR. This could potentially explain, in part, the increased risk and/or worse outcomes in patients with MV-CAD and implies considering intensive anti-thrombotic therapy among these patients. Funding Acknowledgement Type of funding source: None

Association of CMTM5 gene expression with the risk of in-stent restenosis in patients with coronary artery disease after drug-eluting stent implantation and the effects and mechanisms of CMTM5 on human vascular endothelial cells

To elucidate the correlation between CKLF-like marvel transmembrane domain containing member (CMTM5) gene and the risk of in-stent restenosis (ISR) with coronary artery disease (CAD) patients and to detect the effects and mechanisms of CMTM5-stimulated genes on human vascular endothelial cells (ECs) proliferation and migration. A total of 124 hospitalized patients in Shijitan Hospital were enrolled in this study. All the CAD patients were detected with platelet reactivity and grouped into two groups according to platelet reactivity; ISR was conformed by coronary angiography; RT-PCR method was used to detect CMTM5 gene expression; The CMTM5 over expression, reduction and control EC lines were established; Cell count, MTT, Brdu and flow cytometry methods were used to detect the proliferation of ECs, scratch and transwell experiments to test the migration of ECs, Western blot was used to detect signal path expressions. CMTM5 gene expression in HAPR (High on aspirin platelet reactivity) group was 1.72 times compared with No-HAPR group, which was significantly higher than No-HAPR group. HAPR group ISR rate was 25.8% (8 cases), the incidence of No-HAPR ISR group was 9.7% (9 cases), and the results showed that in HAPR group, the incidence of ISR was significantly higher than that in No-HAPR group (P=0.04, OR=0.04, 95%CI=1.16－7.52), which showed that CMTM5 gene was significantly correlated with the risk of ISR. In HAPR group ISR rate was 25.8% (8 cases), the incidence of ISR in No-HAPR group was 9.7% (9 cases), and the results showed that the risk of ISR in HAPR group was significantly higher than that in No-HAPR group. All the results showed that CMTM5 was significantly correlated with the risk of ISR in CAD patients (P < 0.05). CMTM5 overexpression inhibited the proliferation and migration ability of ECs (P < 0.05), PI3K/Akt signaling pathways were involved in the role of regulation on ECs. Our results revealed that CMTM5 gene was closely related with ISR, CMTM5 overexpression may repress ECs proliferation and migration through regulating PI3K-Akt signaling.

Association between High On-Aspirin Platelet Reactivity and Reduced Superoxide Dismutase Activity in Patients Affected by Type 2 Diabetes Mellitus or Primary Hypercholesterolemia.

Platelet hyperactivation is involved in the established prothrombotic condition of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM) and familial hypercholesterolemia (HC), justifying the therapy with aspirin, a suppressor of thromboxane synthesis through the irreversible inhibition of cyclooxygenase-1 (COX-1), to prevent cardiovascular diseases. However, some patients on aspirin show a higher than expected platelet reactivity due, at least in part, to a pro-oxidant milieu. The aim of this study was to investigate platelet reactivity in T2DM (n = 103) or HC (n = 61) patients (aspirin, 100 mg/day) and its correlation with biomarkers of redox function including the superoxide anion scavenger superoxide dismutase (SOD) and the in vivo marker of oxidative stress urinary 8-iso-prostaglandin F2α. As results, in T2DM and HC subjects the prevalence of high on-aspirin platelet reactivity was comparable when both non-COX-1-dependent and COX-1-dependent assays were performed, and platelet reactivity is associated with a lower SOD activity that in a stepwise linear regression appears as the only predictor of platelet reactivity. To conclude, in T2DM and HC, similarly, the impairment of redox equilibrium associated with a decrease of SOD activity could contribute to a suboptimal response to aspirin.

Relation of Hypoalbuminemia to Response to Aspirin in Patients With Stable Coronary Artery Disease

Serum albumin (SA) level is a powerful cardiovascular prognostic marker, suggested to be involved in regulation of platelet function. High on-aspirin platelet reactivity (HAPR) is associated with increased risk for deleterious cardiovascular events. The aim of the present study was to evaluate the association between HAPR and albumin levels in patients with stable coronary artery disease (CAD) treated with aspirin. Patients with known stable CAD, who were taking aspirin (75 to 100 mg qd) regularly for at least 1 month, were screened for the present study. Exclusion criteria: cancer, sepsis or acute infection, active inflammatory/rheumatic disease, recent major surgery, chronic liver failure, the administration of other antiplatelet drugs, nonadherence with aspirin and thrombocytopenia. Blood was drawn from the participants and sent for SA level and platelet function test (VerifyNow). HAPR was defined as aspirin reaction units (ARU) >550. Overall 116 patients were analyzed; age 69 ± 10, 28% women. Twenty (17%) were hypoalbuminemic (≤3.5 g/dl). Hypoalbuminemic patients had similar characteristics to the normal albumin group except mildly higher creatinine in the former. SA levels were significantly lower in the hypoalbuminemic group (3.2 ± 0.2 g/dl vs 4.2 ± 0.4 g/dl, respectively, p <0.001) whereas mean ARU was significantly higher compared with the normal albumin group (548 ± 45 vs 444 ± 66 ARU, respectively, p <0.001). A significant inverse association was observed between SA and ARU with (R2 = 0.67, p <0.001). Multivariate analysis adjusted for potential confounders found that albumin ≤3.5 is the strongest predictor of HAPR in patients with stable CAD (hazards ratio 4.9, 95% confidence interval 2.2 to 32, p = 0.002). In conclusion, hypoalbuminemia is strongly associated with HAPR in patients with stable CAD.

P329Residual platelet reactivity after pre-treatment with ticagrelor prior to primary percutaneous coronary intervention is associated with suboptimal myocardial reperfusion

Abstract Background The evidence of a clinical benefit of P2Y12 inhibitor pre-treatment in primary percutaneous coronary intervention (PCI) and the relation between the level of platelet inhibition and myocardial reperfusion with newer potent P2Y12 inhibitors remain unclear. Objectives We aimed to assess the relationship between platelet reactivity at the time of primary PCI after pre-treatment with aspirin and ticagrelor and the post-PCI myocardial blush grade (MBG). Methods We prospectively included 61 patients. Platelet reaction units for ticagrelor (PRU) and aspirin reaction units (ARU) were measured using the point-of-care test VerifyNow before PCI. The high on-ticagrelor (PRU &gt;208) and on-aspirin (ARU ≥550) platelet reactivity (HPR and HaPR) were assessed. Patients were divided into two groups according to MBG 3 or &lt;3. Results MBG 3 was identified in 28 (46%) patients. Mean PRU was lower in such patients as compared to those with MBG &lt;3 (155.82±90.91 vs 227.42±65.18; p=0.001) while mean ARU was similar between groups. HPR and HaPR were observed in 30 (49.2%) and 11 patients (18%), respectively. HPR but not HaPR was more frequent in the group with impaired MBG (66.7 vs 28.6%; p=0.003 and 21.2 vs 14.3%; p=0.48 respectively). Table 1. Platelet reactivity results Verify Now at admission All Final Blush &lt;3 Final Blush 3 p n=61 (100%) n=33 (54%) n=28 (46%) PRU P2Y12 194.56±85.32 227.42±65.18 155.82±90.91 0.001 Base 193.54±49.01 194.79±45.68 192.07±53.48 0.83 Inhibition of platelet aggregation (%) 15.61±29.85 5.7±17.55 27.29±36.79 0.007 ARU 463.97±76.45 472.58±72.5 453.82±81 0.34 PRU &gt;208 30 (49.1%) 22 (66.7%) 8 (28.6%) 0.003 ARU ≥550 11 (18%) 7 (21.2%) 4 (14.3%) 0.48 Verify Now at day 1 n=57 n=30 n=27 p PRU P2Y12 40.86±41.43 47.27±45.87 33.74±35.35 0.21 Base 196.98±36.19 193.67±30.67 200.81±41.97 0.47 Inhibition of platelet aggregation (%) 79.8±17.96 76.37±20.54 83.77±13.78 0.11 ARU = Aspirin reaction units; PRU = P2Y12 reaction units. Conclusion In conclusion, our study shows that higher PRU and the subsequent HPR at the time of primary PCI, after pretreatment with ticagrelor, are the only correlates of post PCI MBG. These findings support the earliest possible loading with ticagrelor prior to primary PCI. Acknowledgement/Funding The study was supported by grants from Terumo. The funder has no role in any step of the study.

Residual platelet reactivity after pre-treatment with ticagrelor prior to primary percutaneous coronary intervention is associated with suboptimal myocardial reperfusion.

The evidence of a clinical benefit of P2Y12 inhibitor pre-treatment in primary percutaneous coronary intervention (PCI) and the relation between the level of platelet inhibition and myocardial reperfusion with newer potent P2Y12 inhibitors remain unclear. We aimed to assess the relationship between platelet reactivity at the time of primary PCI after pre-treatment with aspirin and ticagrelor and the post-PCI myocardial blush grade (MBG). We prospectively included 61 patients. Platelet reaction units for ticagrelor (PRU) and aspirin reaction units (ARU) were measured using the point-of-care test VerifyNow before PCI. The high on-ticagrelor (PRU >208) and on-aspirin (ARU ⩾ 550) platelet reactivity (HPR and HaPR) were assessed. Patients were divided into two groups according to MBG 3 or <3. MBG 3 was identified in 28 (46%) patients. Mean PRU was lower in such patients as compared with those with MBG <3 (155.82 ± 90.91 vs. 227.42 ± 65.18; p=0.001) while mean ARU was similar between groups. HPR and HaPR were observed in 30 (49.2%) and 11 patients (18%), respectively. HPR but not HaPR was more frequent in the group with impaired MBG (66.7 vs. 28.6%; p=0.003 and 21.2 vs. 14.3%; p=0.48 respectively). Our study shows that higher PRU and the subsequent HPR at the time of primary PCI, after pretreatment with ticagrelor, are the only correlates of post PCI MBG. These findings support the earliest possible loading with ticagrelor prior to primary PCI.

Reaktywność płytek krwi we wczesnym okresie po pomostowaniu tętnic wieńcowych bez użycia krążenia pozaustrojowego u pacjentów stosujących małą dawkę kwasu acetylosalicylowego

Introduction. Acetylsalicylic acid (ASA) is the antiplatelet drug most used in the perioperative period in patients undergoing coronary artery bypass grafting (CABG). Off-pump coronary artery bypass grafting (OPCAB) is likely to alter platelet (PLT) function to a lesser extent than CABG with the use of cardiopulmonary bypass and may potentially result in high on-aspirin platelet reactivity (HAPR) in the postoperative period. Materials and methods. The aim of this prospective study was to characterise serum thromboxane B2 (TXB 2 ) variability and ASA-dependent platelet reactivity in patients with stable coronary artery disease undergoing OPCAB treated with a single daily dose of 75 mg of ASA. Blood sampling was performed 2 hours and 24 hours after ASA intake on the day before surgery, and on the 2 nd and 7 th days after the operation. Results. A PLT counts reduction and a mean platelet volume increase were observed on the 2 nd day after OPCAB. A PLT counts increase was found on the 7 th postoperative day. A significant increase (p = 0.03) in the percentage of patients with insufficient laboratory ASA efficacy (defined by serum TXB 2 ≥ 7.2 ng/mL) was observed on the 7 th postoperative day compared to preoperative values (52% vs 20% respectively, p = 0.02). A significant increase in median platelet reactivity and in the percentage of patients with HAPR (defined by VerifyNow ® Aspirin test result ≥ 550 ARU) was observed on the 7 th postoperative day in comparison with the values before OPCAB (48% vs 12%, p = 0.007). Conclusions. In the group of patients taking a standard daily dose of 75 mg of ASA, a substantial number of patients failed to attain optimal inhibition of serum TXB 2 or had HAPR before surgery and on the 7 th day after OPCAB. A significant decrease in serum TXB 2 levels on the 2nd day after OPCAB did not correlate with PLT reactivity. The optimal dose of ASA is of interest for further studies of efficacy and clinical outcomes after OPCAB.

Impact of high on-aspirin platelet reactivity on outcomes following successful percutaneous coronary intervention with drug-eluting stents

Whether high on-aspirin platelet reactivity (HAPR) confers an increased risk of adverse outcomes after percutaneous coronary intervention (PCI) remains unclear. We sought to examine the specific relationship between HAPR and clinical outcomes in ADAPT-DES. A total of 8,526 "all-comer" patients in the ADAPT-DES registry who underwent placement of drug-eluting stents (DES) and were treated with aspirin and clopidogrel were assessed to measure platelet reactivity. HAPR was characterized as ≥550 aspirin reaction units and high on-clopidogrel platelet reactivity as >208 P2Y12 reaction units. Univariable and propensity-adjusted multivariable analyses were used to assess the relationship between HAPR and clinical outcomes. HAPR was present in 478 (5.6%) patients. Patients with HAPR were older and had more comorbid illnesses and more complex coronary anatomy. During 2-year follow-up, HAPR was not associated with increased rates of major adverse cardiac events (MACE), stent thrombosis, myocardial infarction, or all-cause mortality. In propensity-adjusted multivariable analyses, HAPR was not an independent predictor of MACE after successful PCI (multivariable adjusted hazard ratio: 1.04; 95% CI 0.64-1.69, P = .87). Nor was HAPR associated with reduced bleeding. Even among patients with concomitant high on-clopidogrel platelet reactivity, HAPR was not associated with worse ischemic outcomes (adjusted hazard ratio for 2-year MACE: 1.06; 95% CI 0.55-2.00, P = .87). HAPR was infrequently present in a large registry of patients undergoing PCI. There was no clear relationship between HAPR and 2-year clinical outcomes. Investigations of antiplatelet regimens without aspirin after DES implantation are ongoing and should inform future management of patients undergoing PCI.

Clinical Significance of Acute and Serial Platelet Function Testing in Acute Ischemic Stroke.

BackgroundWe sought to investigate the clinical implications of platelet reactivity to aspirin and the variability in the platelet reactivity to aspirin during acute periods for the risk of vascular events in patients with acute ischemic stroke.Methods and ResultsThis was a single‐center, prospective, observational study. The aspirin reaction unit was blindly measured at the following two times: after 3 hours of aspirin loading and on the fifth day of aspirin administration. High on‐aspirin platelet reactivity (HAPR) was defined as an aspirin reaction unit ≥550 IU. The primary outcome measure was the 1‐year composite of stroke, myocardial infarction, and vascular death. A total of 805 patients (aged 66±12 years, 61% male) were analyzed in this study. Ninety‐nine of 805 (12.3%) patients and 78 of 558 (14.0%) patients had HAPR at the time of the fifth day of aspirin administration and after 3 hours of aspirin loading measurements, respectively. Patients with HAPR than normal on‐aspirin platelet reactivity at the fifth day of aspirin administration measurement were more likely to have experienced 1‐year vascular event. HAPR at the fifth day of aspirin administration measurement was independently associated with a greater risk of experiencing 1‐year vascular event (hazard ratio, 1.84; 95% confidence interval, 1.07–3.19). Moreover, persistently HAPR substantially increased the risk of 1‐year vascular events (hazard ratio, 3.11; 95% confidence interval, 1.23–7.86).ConclusionsThese results suggest that HAPR during the acute stage of ischemic stroke increases the risk of subsequent vascular events and that serial aspirin reaction unit measurements may identify patients with acute ischemic stroke who are at a higher risk for vascular events. Additional studies are warranted to determine the appropriate treatments for patients with acute ischemic stroke with HAPR.

Prognostic Implications of Dual Platelet Reactivity Testing in Acute Coronary Syndrome.

Studies on platelet reactivity (PR) testing commonly test PR only after percutaneous coronary intervention (PCI) has been performed. There are few data on pre- and post-PCI testing. Data on simultaneous testing of aspirin and adenosine diphosphate antagonist response are conflicting. We investigated the prognostic value of combined serial assessments of high on-aspirin PR (HASPR) and high on-adenosine diphosphate receptor antagonist PR (HADPR) in patients with acute coronary syndrome (ACS). HASPR and HADPR were assessed in 928 ACS patients before (initial test) and 24 hours after (final test) coronary angiography, with or without revascularization. Patients with HASPR on the initial test, compared with those without, had significantly higher intraprocedural thrombotic events (IPTE) (8.6 vs. 1.2%, p ≤ 0.001) and higher 30-day major adverse cardiovascular and cerebrovascular events (MACCE; 5.2 vs. 2.3%, p = 0.05), but not 12-month MACCE (13.0 vs. 15.1%, p = 0.50). Patients with initial HADPR, compared with those without, had significantly higher IPTE (4.4 vs. 0.9%, p = 0.004), but not 30-day (3.5 vs. 2.3%, p = 0.32) or 12-month MACCE (14.0 vs. 12.5%, p = 0.54). The c-statistic of the Global Registry of Acute Coronary Events (GRACE) score alone, GRACE score + ASPR test and GRACE score + ADPR test for discriminating 30-day MACCE was 0.649, 0.803 and 0.757, respectively. Final ADPR was associated with 30-day MACCE among patients with intermediate-to-high GRACE score (adjusted odds ratio [OR]: 4.50, 95% confidence interval [CI]: 1.14-17.66), but not low GRACE score (adjusted OR: 1.19, 95% CI: 0.13-10.79). In conclusion, both HASPR and HADPR predict ischaemic events in ACS. This predictive utility is time-dependent and risk-dependent.

Obesity and Altered Aspirin Pharmacology.

Obesity is an independent risk factor for cardiovascular morbidity and mortality due to atherothrombotic events and represents a group of patients who are in need of optimized antithrombotic therapy. Central to the obesity-related risk of atherothrombosis is a pro-thrombotic state characterized by increased levels of coagulation factors, impaired fibrinolysis, and platelet hyper-reactivity, which results from the interaction among the features clustering in obesity: insulin resistance, inflammation, oxidative stress, and endothelial dysfunction. Aspirin is a cornerstone antiplatelet drug that has substantial interpatient variability in pharmacodynamic response and a number of reports have demonstrated that obesity is a risk factor for a reduced aspirin pharmacodynamic response. The inflammatory state associated with obesity, particularly a metabolic endotoxemia, may set in motion a number of mechanisms that increase platelet reactivity and platelet turnover and decrease aspirin bioavailability, all contributing to a poor aspirin response. A greater understanding of the mechanisms underlying obesity-related high on-aspirin platelet reactivity will help in optimization of antithrombotic therapy in this patient population.

Predictors of high on-aspirin platelet reactivity in elderly patients with coronary artery disease.

ObjectivesPrevious studies have illustrated the link between high on-aspirin platelet reactivity (HAPR) with increasing thrombotic risks. The aim of our study was to investigate relative risk factors of HAPR in elderly patients with coronary artery disease.MethodsElderly, hospitalized coronary artery disease patients on regular aspirin treatment were enrolled from January 2014 to September 2016. Medical records of each patient were collected, including demographic information, cardiovascular risk factors, concomitant drugs and routine biological parameters. Arachidonic acid (AA, 0.5 mg/mL) and adenosine diphosphate (ADP, 5 µmol/L) induced platelet aggregation were measured via light transmission assay (LTA) to evaluate antiplatelet responses, referred as LTA–AA and LTA–ADP.ResultsA total of 275 elderly patients were included, with mean age of 77.2±8.1 years, and males accounted for 81.8%. HAPR was defined as LTA–AA in the upper quartile of the enrolled population. HAPR patients tended to have lower renal function (P=0.052). Higher serum uric acid (SUA) level, as well as lower platelet count, hemoglobin and hematocrit were observed in HAPR patients, with a higher proportion of diuretics use (P<0.05). Multivariate analysis revealed that SUA (OR: 1.004, 95% CI: 1.000–1.007, P=0.048), platelet count (OR: 0.994, 95% CI: 0.989–1.000, P=0.045), hematocrit (OR: 0.921, 95% CI: 0.864–0.981, P=0.011) and concomitant P2Y12 receptor inhibitors use (OR: 1.965, 95% CI: 1.075–3.592, P=0.028) were correlated with HAPR. Spearman’s correlation analysis demonstrated an inverse association of LTA–AA with hematocrit (r=−0.234, P<0.001), hemoglobin (r=−0.209, P<0.001) and estimated glomerular filtration rate (r=−0.132, P=0.031).ConclusionSUA, platelet count, hematocrit and P2Y12 receptor inhibitors use were independently correlated with HAPR. These parameters might provide novel therapeutic targets for optimizing antiplatelet therapy.

Validation of aspirin response-related transcripts in patients with coronary artery disease and preliminary investigation on CMTM5 function

Aspirin is widely used in the prevention of cardiovascular diseases, but the antiplatelet responses vary from one patient to another. To validate aspirin response related transcripts and illustrate their roles in predicting cardiovascular events, we have quantified the relative expression of 14 transcripts previously identified as related to high on-aspirin platelet reactivity (HAPR) in 223 patients with coronary artery disease (CAD) on regular aspirin treatment. All patients were followed up regularly for cardiovascular events (CVE). The mean age of our enrolled population was 75.80±8.57years. HAPR patients showed no significant differences in terms of co-morbidities and combined drugs. Besides, the relative expression of HLA-DQA1 was significantly lower in low on-aspirin platelet reactivity (LAPR) patients, when compared with HAPR and high normal (HN) group (p=0.028). What's more, the number of arteries involved, HAPR status and the relative expression of CLU, CMTM5 and SPARC were independent risk factors for CVE during follow up (p<0.05). In addition, overexpression of CMTM5 attenuated endothelial cells (ECs) migration and proliferation, with significantly decreased phosphorylated-Akt levels, while its inhibition promoted these processes in vitro (p<0.05).Our study provides evidence that circulating transcripts might be potential biomarkers in predicting cardiovascular events. CMTM5 might exert anti-atherosclerotic effects via suppressing migration and proliferation in the vessel wall. Nevertheless, larger-scale and long-term studies are still needed.

Salicylic acid retention impairs aspirin reactivity in type 2 diabetes

High on-aspirin platelet reactivity (HAPR) has been associated with compromised aspirin efficacy in patients with diabetes suffering from acute cardiovascular events, but the key mechanisms remain elusive. The objective of this study was to uncover the potential link between pathogenic accumulation of salicylic acid (SA), the major metabolite of aspirin, and HAPR in diabetic state. Aspirin failed to inhibit platelet CD62P expression and thromboxane (TX) B2/6-keto-prostaglandin（PG）F1α ratio in a type 2 diabetes mellitus (T2DM) mice model, particularly in the female, which were unanimously accompanied by significantly higher plasma SA concentrations. Pre-administration with SA increased both platelet CD62P expression and TXB2/6-keto-PGF1α ratio in female T2DM mice, while pretreatment with NaHCO3 caused the opposite effect. On the in vitro human umbilical vein endothelial cells (HUVECs)-platelet interaction assay, SA suppressed inflammation-induced cyclooxygenase-2 upregulation on HUVECs and attenuated their inhibitory effect on platelet aggregation in a dose-dependent manner. The prolonged retention of SA in diabetes may be partially explained by the downregulation of various SA efflux transporters in the kidney and the decreased urine pH. Importantly, in female aspirin non-responsive patients, the trough plasma concentration of SA are markedly increased with T2DM treated with long-term aspirin, and TXB2/6-keto-PGF1α ratio and uric acid level in plasma are positively correlated with SA concentration. Our findings support that the accumulation of SA represents an important factor in causing HAPR in diabetes, and that targeting impaired SA excretion may become a novel intervention strategy to diabetes-associated HAPR.

DUAL PLATELET REACTIVITY TESTING IN ACUTE CORONARY SYNDROME

Platelet reactivity (PR) testing has prognostic value in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). There are conflicting data on the optimal type and timing of PR testing. We investigated the prognostic value of high on-aspirin PR (ASPR) and